bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of individualized positive end-expiratory pressure on intraoperative oxygenation and postoperative pulmonary complications in patients requiring pneumoperitoneum with Trendelenburg position: a systematic review and meta-analysis
Authors: Gao Lingqi , Zhang Bingyan , Qi Jiazheng , Zhao Xu , Yan Xiaojie , Li Bing , Shen Jingjing , Gu Tingting , Yu Qiong , Luo Mengqiang , Wang Yingwei
Published: August 2024

Background:

Whether individualized positive end-expiratory pressure (PEEP) improves intraoperative oxygenation and reduces postoperative pulmonary complications (PPCs) remains unclear. This systematic review and meta-analysis examined whether individualized PEEP is associated with improved intraoperative oxygenation and reduced PPCs for patients needing pneumoperitoneum with the Trendelenburg position during surgery.

Methods:

Medline, Embase, the Cochrane Library, and www.clinicaltrials.gov were searched for randomized controlled trials evaluating the effects of individualized PEEP on intraoperative oxygenation and PPCs in patients who required Trendelenburg positioning with pneumoperitoneum. The primary outcome was the oxygenation (PaO2/FiO2) during the procedure. Secondary outcomes included PPCs, intraoperative respiratory mechanics (driving pressure, compliance), and vasopressor consumption. DerSimonian–Laird random effects models were used to calculate mean differences (MDs) and log risk ratios (log RRs) with 95% confidence intervals (CIs). The Cochrane Risk-of-Bias tool 2.0 was applied to assess the risk of bias in included studies. The protocol of this meta-analysis has been registered in PROSPERO.

Results:

We included 14 studies (1121 patients) that employed different individualized PEEP strategies. Compared with control groups, individualized PEEP groups exhibited a significantly improved intraoperative PaO2/FiO2 (MD=56.52 mmHg, 95% CI: [33.98–79.06], P<0.001) and reduced incidence of PPCs (log RR=−0.50, 95% CI: [−0.84 to −0.16], P=0.004). Individualized PEEP reduced driving pressure while improving respiratory compliance. Intraoperative vasopressor consumption was similar between both groups. The weighted mean PEEP in the individual PEEP groups was 13.2 cmH2O [95% CI, 11.7–14.6]. No evidence indicated that one individualized PEEP strategy is superior to others.

Conclusions:

Individualized PEEP seems to work positively for lung protection in the Trendelenburg position and pneumoperitoneum in patients undergoing general anesthesia.
What is the effect of bariatric surgery on health-related quality of life in people with obesity? Observational cohort analysis of the United Kingdom National Bariatric Surgery Registry
Authors: Buckell John , Small Peter K. ,   NBSR Collaborators, Jebb Susan A. , Aveyard Paul , Khan Omar , McGlone Emma Rose
Published: August 2024

Background:

Previous small studies investigating health-related quality of life (HRQoL) following bariatric surgery have demonstrated heterogenous effects. This study aimed to use National Bariatric Surgery Registry (NBSR) records to investigate the relationship between weight and HRQoL in people undergoing bariatric surgery in the UK.

Materials and methods:

In this observational study using United Kingdom National Bariatric Surgery Registry (NBSR) records between 1st June 2017 and 23rd November 2022, patients undergoing primary bariatric surgery with one baseline and at least one follow-up visit within 1 year from surgery were eligible for inclusion. Models estimated the relationship between EuroQol Five Dimension 5-level (EQ-5D) and BMI at baseline and longitudinally. Further analyses were stratified by type 2 diabetes, type of operation (adjustable gastric band, sleeve, or bypass), and domain of EQ-5D.

Results:

Five thousand five hundred eighty-seven observations of 2160 patients were analysed. At baseline, the mean BMI was 45.7±7.8 kg/m2 and the mean EQ-5D was 0.78±0.22. A 1 kg/m2 higher BMI was associated with 0.005 (95% CI [−0.006 to −0.004]) lower EQ-5D. In the month following surgery, EQ-5D increased to 0.91±0.2 while BMI decreased to 39.8±7.1 kg/m2 (P<0.001 for both); subsequently, EQ-5D plateaued (0.90±0.17 at 12 months) while BMI continued to decrease (31.5±6.2 kg/m2 at 12 months, P<0.001). Each 1 kg/m2 decrease in BMI was associated with a 0.006 (95% CI [−0.007 to −0.005]) increase in EQ-5D. Remission of T2D was independently associated with increase in EQ-5D (0.037, 95% CI [0.015–0.059]); type of operation was not. Decreases in BMI were associated with improvements in all five domains of EQ-5D.

Conclusions:

In this large dataset, greater weight loss and T2D remission were independently associated with greater improvements in HRQoL following bariatric surgery. The HRQoL-BMI relationship for people undergoing bariatric surgery differs to that which has previously been estimated following behavioural interventions. The use of the estimates generated here will be important for clinical and political decision-making.
MRI-serum–based score accurately identifies patients undergoing liver transplant without rejection avoiding the need for liver biopsy: A multisite European study
Authors: Schaapman Jelte , Shumbayawonda Elizabeth , Castelo-Branco Miguel , Caseiro Alves Filipe , Costa Tania , Fitzpatrick Emer , Tupper Katie , Dhawan Anil , Deheragoda Maesha , Sticova Eva , French Marika , Beyer Cayden , Rymell Soubera , Tonev Dimitar , Verspaget Hein , Neubauer Stefan , Banerjee Rajarshi , Lamb Hildo , Coenraad Minneke
Published: August 2024

Serum liver tests (serum tests) and histological assessment for T-cell–mediated rejection are essential for post-liver transplant monitoring. Liver biopsy carries a risk of complications that are preferably avoided in low-risk patients. Multiparametric magnetic resonance imaging (mpMRI) is a reliable noninvasive diagnostic method that quantifies liver disease activity and has prognostic utility. Our aim was to determine whether using mpMRI in combination with serum tests could noninvasively identify low-risk patients who underwent liver transplants who are eligible to avoid invasive liver biopsies. In a multicenter prospective study (RADIcAL2), including 131 adult and pediatric (children and adolescent) patients with previous liver transplants from the Netherlands, Portugal, and the United Kingdom, concomitant mpMRI and liver biopsies were performed. Biopsies were centrally read by 2 expert pathologists. T-cell–mediated rejection was assessed using the BANFF global assessment. Diagnostic accuracy to discriminate no rejection versus indeterminate or T-cell–mediated liver transplant rejection was performed using the area under the receiver operating characteristic curve. In this study, 52% of patients received a routine (protocol) biopsy, while 48% had a biopsy for suspicion of pathology. Thirty-eight percent of patients had no rejection, while 62% had either indeterminate (21%) or T-cell–mediated rejection (41%). However, there was a high interobserver variability (0 < Cohen’s Kappa < 0.85) across all histology scores. The combined score of mpMRI and serum tests had area under the receiver operating characteristic curve 0.7 (negative predictive value 0.8) to identify those without either indeterminate or T-cell–mediated rejection. Combining both imaging and serum biomarkers into a composite biomarker (imaging and serum biomarkers) has the potential to monitor the liver graft to effectively risk stratify patients and identify those most likely to benefit from a noninvasive diagnostic approach, reducing the need for liver biopsy.
Liver transplantation for pediatric genetic and metabolic disorders
Authors: Hassan Sara , Anouti Ahmad , Tan Queenie K-G , Wangensteen Kirk , Aqul Amal
Published: August 2024

Pediatric genetic and metabolic liver diseases comprise a broad spectrum of conditions and represent the second most common indication for liver transplantation following biliary atresia. The decision to transplant can be challenging and requires consideration of several factors including hepatic involvement, extra-hepatic manifestations, and anticipated post-transplant outcomes. This review examines pediatric genetic and metabolic liver diseases, their pathophysiology, clinical presentation, and the role of liver transplantation.
Liver transplantation for pediatric liver malignancies
Authors: Sakamoto Seisuke , Harikrishnan Sakthivel , Uchida Hajime , Yanagi Yusuke , Fukuda Akinari , Kasahara Mureo
Published: August 2024

In the last few decades, collaboration between international pediatric oncology groups has resulted in significant improvement in survival after liver transplantation (LT) for pediatric liver tumors, and LT has become the accepted standard of care for unresectable pediatric liver tumors—either living donor liver transplantation or deceased donor liver transplantation. Hepatoblastoma and HCC are the common pediatric liver malignancies treated by LT, and LT is now the accepted treatment modality for unresectable nonmetastatic cases. The long-term survival rate is more than 80% in hepatoblastoma transplants. Furthermore, with the advent of living donor liver transplantation, the waitlist mortality, availability of a better graft quality with shorter ischemic times, and performance of LT with the appropriate timing between chemotherapy have all improved. Up to 80% of pediatric HCCs are unresectable, and studies have shown that LT for pediatric HCC has better outcomes than liver resection. Furthermore, LT has also shown better results than liver resection for cases of HCC not meeting Milan criteria. Given the rarity of pediatric liver malignancies and challenges in optimal management, a multidisciplinary treatment approach, research models building on what is already known, and consideration of newer treatment modalities are required for further improving the treatment of pediatric liver malignancies.
Social Determinants of Health and Disparities in Pregnancy Outcomes
Authors: Onishi Kazuma , Abuhamad Alfred , Saade George , Grobman William , Silver Robert , Greenland Philip , Simhan Hyagriv , Bairey Merz Noel C. , Haas David , Samuel Parry , Kawakita Tetsuya
Published: August 2024

OBJECTIVE:

To examine the extent to which racial and ethnic disparities in adverse pregnancy outcomes between non-Hispanic Black women and non-Hispanic White women may be explained by social determinants of health (SDoH).

METHODS:

This study was a secondary analysis of a prospective cohort study (nuMoM2b [Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be]) that enrolled 10,038 nulliparous individuals with singleton pregnancies. This analysis included only individuals who identified as non-Hispanic Black or non-Hispanic White. We used the nonlinear extension of the Oaxaca-Blinder decomposition based on logistic regression to estimate the percentage contribution of SDoH to racial and ethnic disparity in preterm birth (PTB) and preeclampsia. Eleven SDoH variables in the models covered various SDoH domains (ie, sociodemographic, psychological, behavioral, social relationship, and health care access and quality).

RESULTS:

Of 10,038 individuals, 1,321 non-Hispanic Black and 5,762 non-Hispanic White individuals composed the study population. Compared with non-Hispanic White individuals, non-Hispanic Black individuals had 3.9% (95% CI, 2.0–5.7) and 4.1% (95% CI, 2.2–6.0) higher frequencies of PTB and preeclampsia, respectively. A large proportion of disparities between non-Hispanic White women and non-Hispanic Black women in PTB (56.4%; 95% CI, 2.9–100.0) and preeclampsia (71.2%; 95% CI, 17.5–100.0) may be explained by SDoH.

CONCLUSION:

A large percentage of the racial and ethnic disparities between non-Hispanic Black and non-Hispanic White individuals in PTB and preeclampsia were explained by SDoH. These findings underscore the contribution of SDoH to racial and ethnic disparities in adverse pregnancy outcomes and point to intervention targets to reduce racial health disparities.
Ectopic Olfactory Neuroblastoma Arising in the Nasopharynx
Authors: Zhang Mingxia , Ren Qinzhan , Liu Junqi , Qi Yan , Wang Wei , Wang Zhenlin
Published: August 2024

Olfactory neuroblastoma (ONB) is an uncommon malignant tumor typically located in the upper nasal cavity. Olfactory neuroblastoma originating in the nasopharynx is extremely rare and tends to be misdiagnosed. The authors describe a rare case of ONB arising ectopically in the nasopharynx. The patient was a 65-year-old woman with recurrent epistaxis and a feeling of fullness in the right ear. After evaluation, endoscopic surgery was performed. The pathological result proved to be ONB. Postoperative magnetic resonance imaging showed that the tumor was completely resected. The patient proceeded to have 66 Gy of postoperative intensity-modulated radiotherapy and was followed for 36 months without tumor recurrence. Olfactory neuroblastoma originating from the nasopharynx is more rare condition compared with ONB located in other areas in the literature. The symptoms of ONB ectopic to the nasopharynx are similar to those of other nasopharyngeal tumors, which were likely to be misdiagnosed. The treatment principle is the same as that of nonectopic ONB, which is surgery combined with radiotherapy. Surgery can be performed using an endoscopic transnasal approach.
Frequent Occurrence of Alzheimer Disease in Patients With IgE-mediated Allergies
Authors: Bożek Andrzej , Pawłowicz Robert , Spyra Aleksandra , Tekiela Natalia , Miodonska Martyna , Grzanka Alicja
Published: August 2024

Alzheimer disease and allergic diseases are common health problems. The aim of the study was to check the hypothesis that older patients with IgE-mediated allergies have a higher prevalence of Alzheimer disease. It was a retrospective, multicenter cohort observation. In total, 7129 people were examined, including 3566 women and 2558 men (mean 64.9±6.9 y). The diagnosis of Alzheimer disease is based on the ICD-10 code and appropriate medical documentation. The proportion of patients with confirmed Alzheimer disease in the group of patients with diagnosed allergy compared to the group of those without allergy was as follows: 13.9% (168) versus 8.2% (484) with P=0.001. There was a positive correlation between the presence of Alzheimer disease and high serum total IgE, eosinophilia, and asthma or the presence of atopic polymorphic disease (P<0.05). IgE-dependent allergic diseases, in particular allergic asthma, and the presence of high serum IgE levels may favor the development of Alzheimer disease.
Mandatory or Voluntary COVID-19 Vaccination: Insights into the Knowledge, Attitude and Perception among Healthcare Workers at a Nursing College in South Africa
Authors: Mokoena Lindokuhle , Singh Tanusha
Published: August 2024

Vaccine hesitancy has emerged as a significant global challenge impacting healthcare institutions, workplaces and governments alike. Despite concerted efforts by the government and numerous other institutions in South Africa, low vaccination rates persist (33% as of November 13, 2023), reflecting the persistence of this global challenge. This challenge is particularly pronounced in educational institutions such as institutions of higher learning in South Africa, where many people converge, increasing the risk of viral exposure. This study aims to assess the knowledge, attitudes, and perceptions of healthcare workers (HCWs) at a Nursing College regarding voluntary and mandatory COVID-19 vaccination. Employing a quantitative approach, a survey with closed-ended Likert-type questions was administered to 504 individuals at the College. The sample size of 218 respondents was calculated based on a margin of error of 5%, a confidence level of 95%, and an additional 25% contingency for potential incomplete data, resulting in a final representative sample of 270 respondents. The Statistical Package for Social Sciences (SPSS) was used for the analysis. Findings indicate a high uptake of voluntary COVID-19 vaccinations among HCWs, with some being mandated. Most HCWs demonstrated a strong commitment to safeguarding themselves and others. Despite concerns, HCWs thought the COVID-19 vaccines were effective, and their views were supported by a low level of infection among the participants, underscoring its efficacy in preventing transmission. Effective communication emerged as a critical factor in addressing post-vaccination behaviours and enhancing vaccine acceptance. However, the findings also highlighted the need for tailored outreach strategies to specific audiences, such as pregnant women, and the importance of addressing concerns about adverse effects through clear and open communication. Several factors influencing the choice between mandatory and voluntary vaccination were identified, including eligibility concerns, religious convictions, and financial considerations. Notably, concerns about safety and knowledge gaps outweighed these factors, suggesting the need for targeted educational initiatives to bolster vaccine acceptance. In conclusion, this study provides valuable insights into the dynamics of vaccination acceptance among an influential occupational group, with implications for the acceptance of other vaccines. Vaccination efforts can be strengthened by addressing concerns, enhancing communication strategies, and tailoring outreach efforts to promote public health in light of future outbreaks.

Author summary

Conception and design of the study: LM, TS

Data acquisition: LM

Data analysis: LM

Interpretation of the data: LM, TS

Drafting of the paper: LM

Critical revision of the paper: TS

Both authors approved the final manuscript
Using Glittr.org to find, compare and re-use online materials for training and education
Authors: van Geest Geert , Haefliger Yann , Zahn-Zabal Monique , Palagi Patricia M.
Published: August 2024

A wealth of excellent training and educational materials for the computational life sciences are scattered around the Internet, but they can be hard to find. Many materials reside in public Git repositories that are hosted on platforms such as GitHub and GitLab.Glittr.orgis a manually curated database of Git repositories, which enables users to find educational materials that would otherwise be hard to identify. With the application, users can search and compare educational materials based on topic and author, but also on engagement metrics such as stargazers (bookmarks) and recency (days since last commit).Glittr.orgcurrently contains 664 entries, which are assigned to six different categories within the domain of computational life sciences. By analysing the database, we reveal insights in the availability of materials per topic, collaboration patterns of developers, and licensing practices. This knowledge helps to understand in which areas open educational materials are scant, the importance of Git for collaboration on educational materials and how licensing can be improved to enhance sharing and reuse. Taken together, we show thatGlittr.orgcontains a wealth of connected and openly available metadata. Therefore, it enhances adherence to the FAIR (Findable, Accessible, Interoperable, Reusable) principles, which benefits learners, teachers and trainers in the entire life sciences community and beyond.
Protein Language Models in Directed Evolution
Authors: Maguire Russell , Bloznelyte Kotryna , Adepoju Fikayo , Armean-Jones Matthew , Dewan Shafiat , Fozzard Stella , Gupta Akash , Ibrahimi Ece , Jones Frances Patricia , Lalli Preet , Schooneveld Anna , Thompson Sean , Berman David , Addison Will , Rossoni Luca , Taylor Ian
Published: August 2024

The dominant paradigms for integrating machine-learning into protein engineering arede novoprotein design and guided directed evolution. Guiding directed evolution requires a model of protein fitness, but most models are only evaluatedin silicoon datasets comprising few mutations. Due to the limited number of mutations in these datasets, it is unclear how well these models can guide directed evolution efforts. We demonstratein vitrohow zero-shot and few-shot protein language models of fitness can be used to guide two rounds of directed evolution with simulated annealing. Our few-shot simulated annealing approach recommended enzyme variants with 1.62 × improved PET degradation over 72 h period, outperforming the top engineered variant from the literature, which was 1.40 × fitter than wild-type. In the second round, 240in vitroexamples were used for training, 32 homologous sequences were used for evolutionary context and 176 variants were evaluated for improved PET degradation, achieving a hit-rate of 39 % of variants fitter than wild-type.
Multi-layered dosage compensation of the avian Z chromosome
Authors: Papanicolaou Natali , Lentini Antonio , Wettersten Sebastian , Hagemann-Jensen Michael , Krüger Annika , Zhang Jilin , Coucoravas Christos , Petrosian Ioannis , Xin Xian , Ceyhan Ilhan , Rorbach Joanna , Wright Dominic , Reinius Björn
Published: August 2024

Sex-chromosome dosage represents a challenge for heterogametic species to maintain correct proportion of gene products across chromosomes in each sex. While therian mammals (XX/XY system) achieve near-perfect balance of X-chromosome mRNAs through X-upregulation and X-inactivation, birds (ZW/ZZ system) have been found to lack efficient compensation at RNA level, challenging the necessity of resolving major gene-dosage discrepancies in avian cells. Through allele-resolved multiome analyses, we comprehensively examined dosage compensation in female (ZW), male (ZZ), and rare intersex (ZZW) chicken. Remarkably, this revealed that females exhibit upregulation of their single Z through increased transcriptional burst frequency similar to mammalian X-upregulation, and that Z-protein levels are further balanced via enhanced translation efficiency in females. Global analyses of transcriptional kinetics elements in birds demonstrate remarkable conservation of the genomic encoding of burst kinetics between mammals and birds. Our study uncovers new mechanisms for achieving sex-chromosome dosage compensation and highlights the importance of gene-dosage balance across diverse species.
Analysis of hepatic lentiviral vector transduction; implications for preclinical studies and clinical gene therapy protocols
Authors: Hu Peirong , Hao Yajing , Tang Wei , Diering Graham H. , Zou Fei , Kafri Tal
Published: August 2024

Lentiviral vector-transduced T-cells were approved by the FDA as gene therapy anti-cancer medications. Little is known about the host genetic variation effects on the safety and efficacy of the lentiviral vector gene delivery system. To narrow this knowledge-gap, we characterized hepatic gene delivery by lentiviral vectors across the Collaborative Cross (CC) mouse genetic reference population. For 24 weeks, we periodically measured hepatic luciferase expression from lentiviral vectors in 41 CC mouse strains. Hepatic and splenic vector copy numbers were determined. We report that CC mouse strains showed highly diverse outcomes following lentiviral gene delivery. For the first time, moderate correlation between mouse strain-specific sleeping patterns and transduction efficiency was observed. We associated two quantitative trait loci (QTLs) with intra-strain variations in transduction phenotypes, which mechanistically relates to the phenomenon of metastable epialleles. An additional QTL was associated with the kinetics of hepatic transgene expression. Genes comprised in the above QTLs are potential targets to personalize gene therapy protocols. Importantly, we identified two mouse strains that open new directions in characterizing continuous viral vector silencing and HIV latency. Our findings suggest that wide-range patient-specific outcomes of viral vector-based gene therapy should be expected. Thus, novel escalating dose-based clinical protocols should be considered.
Analysis of Risk Factors and the Establishment of a Predictive Model for Thrombosis in Patients with immune thrombocytopenia
Authors: Liang Hui , Duan Lingxue , Long Manyu , Tie Songyuan , Sun Changyan , Ma Sha , Wang Jing , Wang Shuya
Published: August 2024

Objectives

To explore the risk factors for thrombi occurring in patients with immune thrombocytopenia (ITP) and establish a risk prediction model to better predict the risk of thrombosis in patients with ITP.

Methods

We retrospectively analyzed 350 ITP patients who had been hospitalized in The First People’s Hospital of Yunnan Province between February to June 2024. For all patients, we recorded demographic characteristics and clinical data, analyzed the risk factors for thrombosis in ITP patients and then developed a risk prediction model.

Results

Stepwise logistic regression analysis indicated that a high complement D-dimer level, a low PLT and a high Padua score were independent risk factors for thrombosis in ITP patients. According to multivariate analysis, a predictive model for thrombus risk was successfully established; the area under the ROC curve(AUC) was 0.673 (95% CI: 0.615-0.730) and the maximum Youden index, sensitivity and specificity were 0.272, 47.0% and 80.2%, respectively.

Conclusion

A high complement D-dimer level, low PLT level, and a high Padua score were shown to be independent risk factors for thrombosis in ITP patients. We developed a risk prediction model based on these three risk factors that could predict the risk of thrombosis in ITP patients to some extent.
Comment to: “Topology of molecular deformations induces triphasic catch bonding in selectin–ligand bonds”
Authors: Quapp Wolfgang , Bofill Josep Maria
Published: August 2024

We contradict diverse mathematical claims of a paper by Casey O. Barkan and Robijn F. Bruinsma in PNAS 2024, 121, No. 6, e2315866121, former BioRxiv preprint from Sept.12,2023. It deals with the physical mechanisms of protein-ligand catch bonding for the family of selectin proteins. Selectins exhibit slip, catch–slip, and slip–catch–slip bonding.
Glucokinase activity controls peripherally-located subpopulations of β-cells that lead islet Ca2+oscillations
Authors: Jin Erli , Briggs Jennifer K. , Benninger Richard K.P. , Merrins Matthew J.
Published: August 2024

Oscillations in insulin secretion, driven by islet Ca2+waves, are crucial for glycemic control. Prior studies, performed with single-plane imaging, suggest that subpopulations of electrically coupled β-cells have privileged roles in leading and coordinating the propagation of Ca2+waves. Here, we used 3D light- sheet imaging to analyze the location and Ca2+activity of single β-cells within the entire islet at >2 Hz. In contrast with single-plane studies, 3D network analysis indicates that the most highly synchronized β-cells are located at the islet center, and remain regionally but not cellularly stable between oscillations. This subpopulation, which includes ‘hub cells’, is insensitive to changes in fuel metabolism induced by glucokinase and pyruvate kinase activation. β-cells that initiate the Ca2+wave (‘leaders’) are located at the islet periphery, and strikingly, change their identity over time via rotations in the wave axis. Glucokinase activation, which increased oscillation period, reinforced leader cells and stabilized the wave axis. Pyruvate kinase activation, despite increasing oscillation frequency, had no effect on leader cells, indicating the wave origin is patterned by fuel input. These findings emphasize the stochastic nature of the β-cell subpopulations that control Ca2+oscillations and identify a role for glucokinase in spatially patterning ‘leader’ β-cells.

Highlights

• Studies of islet Ca2+oscillations by 3D light-sheet imaging provide a more complete picture of β- cell subpopulations than prior 2D studies.

• Highly synchronized β-cells (including ‘hub cells’) are a regionally-stable subpopulation located at the islet center that is insensitive to metabolic perturbation.

• Glucokinase activation patterns the Ca2+wave axis, which originates from stochastic β-cell subpopulations on the islet periphery that change between oscillations.

• The stochasticity of ‘leader’ β-cells, and the stability of ‘hubs’, is geographically consistent with the peripheral location of α/δ-cells in mouse islets.
The p.H222P lamin A/C mutation induces heart failure via impaired mitochondrial calcium uptake in human cardiac laminopathy
Authors: Seguret Magali , Jouve Charlene , Ruiz-velasco Andrea , Deshayes Lucille , Guesmia Zoheir , Pereira Celine , Wahbi Karim , Fauconnier Jeremy , Bonne Gisele , Muchir Antoine , Hulot Jean-Sebastien
Published: August 2024

Background: Mutations in the LMNA gene, which encodes lamin A/C, cause a variety of diseases known as laminopathies. Some mutations are particularly associated with the occurrence of dilated cardiomyopathy and heart failure, but the genotype-phenotype relationship and underlying mechanisms are unclear. Here, we used induced pluripotent stem cells (hiPSCs) from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro) to investigate the mechanisms leading to contractile dysfunction. Methods: LMNA p.H222P mutant and a CRISPR/Cas9 corrected isogenic control hiPSCs clones were differentiated into cardiomyocytes (hiPSC-CMs). Immunofluorescence staining was performed on hiPSC-CMs to quantify their sarcomere organization (SarcOrgScore) using a Matlab code. Ring-shaped cardiac 3D organoids were generated to compare the contractile properties of the two clones. Calcium transients in mutant and corrected hiPSC-CMs were measured by live confocal imaging. Mitochondrial respiration parameters were measured by Seahorse. Results: hiPSC-CMs were generated from the LMNA mutant and the corrected hiPSCs with no difference in the differentiation yield (proportion of troponin-positive cells: 95.0% for LMNA p.H222P vs. 95.1% for Ctrl-iso1, p=0.726). hiPSC-CMs displayed well-formed sarcomeres and their organization was similar between the two cell lines. However, cardiac 3D organoids generated with LMNA p.H222P hiPSC-CMs showed an impaired contractility compared to control organoids. Calcium transient recordings in LMNA p.H222P mutant cardiomyocytes showed a significantly higher calcium transient amplitude with a significantly slower calcium re-uptake. Transcriptomic analyses suggested a global mitochondrial dysfunction and in particular an impaired mitochondrial calcium uptake with a significantly decreased expression of the mitochondrial calcium uniporter (MCU). This decrease in MCU expression was confirmed by western blot and was accompanied by an increased MICU1:MCU, as well as an increased PDH Ser232 and PDH Ser300 phosphorylation, indicating a decreased mitochondrial calcium uptake in the LMNA mutant hiPSC-CMs. Measurement of mitochondrial respiration showed lower basal and maximal respiration in LMNA p.H222P hiPSC-CMs. Consistently, the ATP levels were significantly lower in LMNA p.H222P hiPSC-CMs as compared to isogenic controls. Conclusions: LMNA p.H222P mutant hiPSC-CMs exhibit contractile dysfunction associated with mitochondrial dysfunction with impaired MCU complex activity, decreased mitochondrial calcium homeostasis and reduced mitochondrial energy production.
Genetic Polymorphisms Associated with Insulin Resistance Risk in Normal BMI Indians
Authors: Thummala Sabitha , Khan Ghori Junaid Ahmed , Saikia Katherine , Fathima Sarah , Kruthi Nithya , Balamurali AR , Ranganathan Rahul
Published: August 2024

Background

Insulin resistance (IR) contributes significantly to the onset of metabolic disorders, such as type 2 diabetes mellitus and cardiovascular diseases. Identifying genetic markers associated with IR can offer insights into its mechanisms and potential therapeutic targets.

Objective

This study investigated the association between four single nucleotide polymorphisms (SNPs) and insulin resistance among 191 individuals in the Indian population.

Methods

A literature review identified four SNPs linked to IR. Participants were divided into groups based on insulin resistance and sensitivity, determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA2-IR). DNA was extracted for genotyping using Illumina Infinium Global Screening Array (GSA) V3. Case-control analysis assessed SNP-genotype associations with insulin resistance and other clinical parameters.

Results

Among 191 participants, 57 were insulin-resistant and 134 were insulin-sensitive. Significant associations (P < 0.05) were found between selected SNPs and IR. SNP rs920590 showed the strongest association, with the T allele associated with increased IR risk (odds ratio = 4.01, 95% CI 1.55-10.34; p < 0.0014). Additionally, serum LDL cholesterol, serum triglycerides, HbA1c, Insulin fasting and fat mass show significant differences in cases and controls.

Conclusion

This study validates genetic markers linked to insulin resistance (IR) in the Indian population and elucidates their roles in IR pathogenesis. Understanding these markers can inform personalised therapeutic strategies for metabolic disorders.
Insulin Resistance Risk in Normal BMI Individuals: Investigating the Role of Genetic Polymorphisms in RNF138, ABCA1, and ESRRG-GPATCH2 Genes - A Case-Control Study in the Indian Population
Authors: Thummala Sabitha , Fathima Sarah , Kruthi Nithya , Ghori Junaid Ahmed Khan , Saikia Katherine , Belde Vivek , Balamurali AR , Ranganathan Rahul
Published: August 2024

Background

India, characterised as the “diabetes capital” of the world, faces a rapidly increasing diabetes crisis with over 65 million cases diagnosed. Despite the growing prevalence, the genetic underpinnings of insulin resistance (IR) among Indians with normal BMI remain understudied. This research aims to fill the knowledge gap by investigating the association of specific gene variants (RNF138, ABCA1, andESRRG-GPATCH2) with IR risk in this demographic.

Methods

A total of 191 participants (90 men, 101 women) were recruited for this cross-sectional study. Participants were categorized into cases (HOMA2-IR > 2) and controls (HOMA2-IR < 2) based on Homeostasis Model Assessment Insulin Resistance values. Genotyping for rs4799327 (RNF138), rs2275543 (ABCA1), and rs1497828 (ESRRG-GPATCH2) was performed using the Illumina Infinium Global Screening Array. Statistical analyses, including odds ratios (ORs), 95% confidence intervals (CIs), and inheritance model analysis, were conducted to assess the association between genotypes and IR.

Results

Significant associations were found between IR and genetic variants rs4799327 in RNF138 and rs1497828 inESRRG-GPATCH2(dominant inheritance model) and rs2275543 in ABCA1 (additive model). The study highlights a notable susceptibility to IR linked to these genetic markers among normal BMI individuals in the Indian population.

Conclusions

This study underscores the importance of genetic factors in the risk of developing insulin resistance among Indians with normal BMI, suggesting a complex interplay of genetics beyond traditional risk factors. These findings necessitate further research into the functional significance of these associations and their potential implications for targeted interventions and preventive strategies in high-risk populations.

Trial registration

Not applicable.
Study the Prevalence of Multidrug resistant bacteria from air samples collected from Mumbai & Suburban areas
Authors: Shah Janvi , Ghosh Sourav
Published: August 2024

Introduction

Air comprises mixture of airborne bacteria & air pollutants in near surface of atmosphere. Air pollution is one of the major threat around the world due to change in physical and chemical parameters because of natural and anthropogenic activities; leading to climate change.

Materials and Methods

A systematic analysis of AQI included air pollutants PM2.5, PM10, CO, SO2, NO2, O3, NH3using SAMEER app developed by CPCB and meteorological parameters including wind speed and relative humanity. The overuse of antibiotics since last two decades has lead pathogenic bacteria gaining resistance.

Results

The study was carried out to identify the prevalence of MDR bacteria in air from 8 different spatial variations of Mumbai & Suburban areas. 32 isolates from air were collected by settle plate technique. Enumeration and characterization of bacteria was performed. Antibiotic susceptibility test against 10 antibiotics; test showed that all bacterial isolates were sensitive to Tigecycline. The bacteria were highly resistant to Methicillin by 81.25 %. ARI of two isolates was 0.9 & MRI of Vasai, 0.625 was the highest. The prominent pollutant among 8 locations was found to be PM2.5, CO & PM10. PCA & hierarchical cluster analysis showed that MRI is not correlated to 8 parameters but, distinctly related to NH3.

Conclusions

The MDR bacteria travel from soil, plants, water, humans, places, inanimate objects into the air. Hence, it is necessary to maintain the sanitation, ecological balance & usage of antibiotics when necessary.
Comparative Analysis of Stress Responses in Medical Students Using Virtual Reality Versus Traditional 3D-Printed Mannequins for Pericardiocentesis Training
Authors: Rubio-López Alberto , García Carmona Rodrigo , Zarandieta Román Laura , Rubio Navas Alejandro , González Pinto Ángel , Cardinal-Fernández Pablo
Published: August 2024

Background

As medical education evolves, innovative methods like virtual reality (VR) and 3D-printed mannequins are increasingly used to simulate high-stress medical scenarios realistically. This study investigates the effectiveness of VR and 3D-printed mannequins in replicating stress levels during pericardiocentesis training, comparing their impact on the emotional and physiological responses of learners.

Methods

We enrolled 108 final-year medical students who were randomized to train with both VR and 3D-printed mannequins. Heart rate variability (HRV) analysis was employed to assess stress responses. Additionally, a secondary analysis examined the influence of demographic factors, lifestyle, medication use, and academic stress on these responses.

Results

Both VR and traditional mannequin-based training methods proved equally effective in simulating the stress levels encountered in real medical procedures. Our findings indicate significant interactions between stress markers and demographic factors, which highlights the complex nature of stress responses in medical education and underscores the necessity for personalized training approaches.

Conclusion

The study validates the use of VR as a viable alternative to traditional mannequins, capable of simulating the technical skills and emotional pressures of medical procedures such as pericardiocentesis. Incorporating VR into medical training programs may enhance learning outcomes and accessibility, particularly in settings constrained by resources.
Computation of Socio-Economic Status in the AWI-Gen Project
Authors: Hazelhurst Scott , Boua Palwende Romuald , Choudhury Ananyo , Madala Siyanda , Sengupta Dhriti , Tluway Furahini , Ramsay Michèle
Published: August 2024

The socio-economic status (SES) of participants in many public health, epidemiological, and genome-wide association studies is an important trait of interest. It is often used in these studies as a measure of direct interest or as a covariate. There are open methodological issues on how SES is computed. The Africa Wits INDEPTH Partnership for Genomic and Environmental Research (AWI-Gen) explores genomic and environmental factors in non-communicable diseases, particularly cardio-metabolic disease. In Phase I of AWI-Gen, approximately 12,000 participants were recruited at six sites in four African countries. Participants were asked questions about asset ownership. This technical note describes how AWI-Gen computed socio-economic status from the asset register.
Integrated clinical risk prediction of type 2 diabetes with a multifactorial polygenic risk score
Authors: Ritchie Scott C. , Taylor Henry J. , Liang Yujian , Manikpurage Hasanga D. , Pennells Lisa , Foguet Carles , Abraham Gad , Gibson Joel T. , Jiang Xilin , Liu Yang , Xu Yu , Kim Lois G. , Mahajan Anubha , McCarthy Mark I. , Kaptoge Stephen , Lambert Samuel A , Wood Angela , Sim Xueling , Collins Francis S. , Denny Joshua C. , Danesh John , Butterworth Adam S. , Di Angelantonio Emanuele , Inouye Michael
Published: August 2024

Combining information from multiple GWASs for a disease and its risk factors has proven a powerful approach for development of polygenic risk scores (PRSs). This may be particularly useful for type 2 diabetes (T2D), a highly polygenic and heterogeneous disease where the additional predictive value of a PRS is unclear. Here, we use a meta-scoring approach to develop a metaPRS for T2D that incorporated genome-wide associations from both European and non-European genetic ancestries and T2D risk factors. We evaluated the performance of this metaPRS and benchmarked it against existing genome-wide PRS in 620,059 participants and 50,572 T2D cases amongst six diverse genetic ancestries from UK Biobank, INTERVAL, the All of Us Research Program, and the Singapore Multi-Ethnic Cohort. We show that our metaPRS was the most powerful PRS for predicting T2D in European population-based cohorts and had comparable performance to the top ancestry-specific PRS, highlighting its transferability. In UK Biobank, we show the metaPRS had stronger predictive power for 10-year risk than all individual risk factors apart from BMI and biomarkers of dysglycemia. The metaPRS modestly improved T2D risk stratification of QDiabetes risk scores for 10-year risk prediction, particularly when prioritising individuals for blood tests of dysglycemia. Overall, we present a highly predictive and transferrable PRS for T2D and demonstrate that the potential for PRS to incrementally improve T2D risk prediction when incorporated into UK guideline-recommended screening and risk prediction with a clinical risk score.
A modular encapsulation system for precision delivery of proteins, nucleic acids and therapeutics
Authors: Luong T. D. , Martel N. , Rae J. , Lo H. P. , Lim Y-W. , Wu Y. , McMahon K-A. , Fletcher N. , Thurecht K. , Johnston A.P.R. , Ariotti N. , Hall T. E. , Parton R.G.
Published: August 2024

Targeted nanoparticles have the potential to revolutionize therapeutics for medical applications. Here, we demonstrate the utility of a flexible precision nanovesicle delivery system for functional delivery of DNA, RNA, proteins and drugs into target cells. Nanovesicles generated by the membrane sculpting protein caveolin, termed caveospheres, can be loaded with RNA, DNA, proteins or drugs post-synthesis or incorporate genetically-encoded cargo proteins during production without the need for protein purification. Functionalized fluorescently-labeled caveospheres form a modular system that shows high stability in biological fluids, specific uptake by target-positive cells, and can deliver proteins, drugs, DNA, and mRNA directly to the cytoplasm and nuclei of only the target cells. We demonstrate their application as a targeted transfection system for cells in culture, as a system to study endosomal escape, and critically, their efficacy in precision tumor killingin vivo.
PBAE-PEG based lipid nanoparticles for lung cell-specific gene delivery
Authors: Liu Bingxin , Sajiki Yamato , Sridharan Anusha , Stuart William , Cui Xuemei , Siefert Matthew , Araki Koichi , Ziady Assem , Shi Donglu , Whitsett Jeffrey A. , Maeda Yutaka
Published: August 2024

Delivery of modified mRNA encapsulated in lipid nanoparticles, exemplified by their successful use in COVID-19 vaccination, provides a framework for treating various genetic and acquired disorders. Herein, we developed PEGylated(PBAE-PEG) and non-PEGylated(PBAE) PBAE with lipids 4A3-SC8/DOPE/cholesterol/DOTAP to form lipid nanoparticles (LNPs) for mRNA delivery into different types of pulmonary cells in vivo. PBAE-PEG/LNP were highly active in transfecting HEK293T cells and air-liquid interfaced H441 cells in vitro. PBAE-PEG/LNP were used to express Cre-recombinase after administration to mice by intravenous injection, resulting in high transfection levels in pulmonary vascular endothelial cells. Intratracheal injection of both PBAE-PEG/LNP and PBAE/LNPs resulted in efficient and selective transfection of lung epithelial cells, identified by the expression of stabilized Cre-recombinase mRNA in club cells and alveolar type 2 cells. PBAE-PEG/LNP were most effective in transfecting alveolar type 2 cells after intratracheal injection, while PBAE/LNPs administered intratracheally were more effective in transfecting secretory airway cells. Cre-mediated recombination was specific to lung epithelial cells after intratracheal administration. Likewise, intravenous administration resulted in selective transfection of endothelial cells but not other pulmonary cell types, indicating their failure to cross the pulmonary endothelial-to-epithelial barrier. Moreover, 5-methoxyuridine modified mRNA was more efficient than unmodified mRNA in vivo but not in vitro.
Counting on AR: EEG responses to incongruent information with real-world context
Authors: Wimmer Michael , Pepicelli Alex , Volmer Ben , ElSayed Neven , Cunningham Andrew , Thomas Bruce H. , Müller-Putz Gernot R. , Veas Eduardo E.
Published: August 2024

Augmented Reality (AR) technologies enhance the real world by integrating contextual digital information about physical entities. However, inconsistencies between physical reality and digital augmentations, which may arise from errors in the visualized information or the user’s mental context, can considerably impact user experience. This study characterizes the brain dynamics associated with processing incongruent information within an AR environment. We designed an interactive paradigm featuring the manipulation of a Rubik’s cube serving as a physical referent. Congruent and incongruent information regarding the cube’s current status was presented via symbolic (digits) and non-symbolic (graphs) stimuli, thus examining the impact of different means of data representation. The analysis of electroencephalographic (EEG) signals from 19 participants revealed the presence of centro-parietal N400 and P600 components following the processing of incongruent information, with significantly increased latencies for non-symbolic stimuli. Additionally, we explored the feasibility of exploiting incongruency effects for brain-computer interfaces. Hence, we implemented decoders using linear discriminant analysis, support vector machines, and EEGNet, achieving comparable performances with all methods. The successful decoding of incongruency-induced modulations can inform systems about the current mental state of users without making it explicit, aiming for more coherent and contextually appropriate AR interactions.
PI(4)P recruits CIDE proteins to promote the formation of unilocular lipid droplets during adipogenesis and hepatic steatosis
Authors: Wu Jin , Gao Mingming , Wu Xiaoqin , Liu Yang , Du Ximing , Liang Yan , Ma Chengxin , Li Peng , Chen Fung-Jung , Yang Hongyuan
Published: August 2024

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be clearly defined. Phosphoinositides mark cellular organelles and regulate cell signalling and organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate the CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on LD surface via knocking down PI4K2A also impaired the localization and function of CIDE proteins. In adipocytes, depleting PI(4)P dramatically reduced the size of LDs, as well as adipose tissue mass. In severe steatotic liver, depleting PI(4)P reduced LD accumulation. Our results thus identify a key function of LD surface PI(4)P under physiological conditions and unveil how CIDE proteins are recruited to LDs.