bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review and individual patient data meta-analysis on glucose- 6 – phosphate dehydrogenase activities measured by a semi-quantitative handheld Biosensor
Authors: Ley Benedikt , Vasquez Laura Rojas , Sitsabasan Avyinaeesh , Adhikari Bipin , Adhikari Nabaraj , Alam Mohammad Shafiul , Das Santasabuj , Ghimire Prakash , Lacerda Marcus V. G. , Price Ric N. , Rijal Komal Raj , von Seidlein Lorenz , Talukdar Arunansu , Thriemer Kamala , Satyagraha Ari Winasti , Sadhewa Arkasha , Rajasekhar Megha , Commons Robert J.
Published: December 2024

Measurement of glucose-6-phosphate dehydrogenase (G6PD) activity guides hypnozoitocidal treatment ofP. vivaxmalaria. The G6PD Standard (SDBiosensor, Republic of Korea) here referred to as “Biosensor” is a quantitative point-of-care diagnostic that measures G6PD activity in U/gHb . The manufacturer recommends cutoffs to define G6PD deficient (≤4.0U/gHb), intermediate (4.1-≤6.0U/gHb) and normal (>6.0U/gHb) individuals. The aim of this individual patient data (IPD) meta- analysis was to evaluate these cutoffs (CRD42023406595).

A systematic review identified studies reporting population-level G6PD activity measured by Biosensor, published between January 2017 and May 2023. IPD were collated and standardised. The adjusted male median (AMM) was defined as 100% activity and calculated across all studies (universal AMM) and separately for each setting. The proportion of participants classified as deficient or intermediate were compared using the manufacturer-recommended cutoffs and 30% and 70% of the universal AMM and setting-specific AMM. Associations between G6PD activity and blood sampling method, malaria status, and age were assessed.

Eleven studies with 9,724 participants from eight countries were included in this analysis. The universal AMM was 7.7U/gHb and the setting-specific AMMs ranged from 6.2U/gHb to 9.9U/gHb. When using the universal AMM, 4.2% of participants were classified as deficient and 11.9% as intermediate or deficient. The corresponding values were 3.9% and 10.8% for setting-specific cutoffs, and 7.2% and 18.3% for manufacturer-recommended definitions for deficients and intermediates respectively. The manufacturer-recommended cutoff for deficient individuals fitted the distribution of G6PD activities better than definitions based on the percentage of AMM. There was no significant association between malaria status or blood sampling method and G6PD activity. Measured G6PD activity decreased in children 1 to 5 years and plateaued thereafter.

The manufacturer’s recommended cutoff is conservative but more reliable at categorising G6PD deficient individuals than those based on calculations of 30% activity using the AMM. The observed decrease in G6PD activity in children between 1 to 5 years of age warrants further investigation.
Causation and prevention in epidemiology: assumptions, derivations, and measures old and new
Authors: Allard Robert
Published: December 2024

Epidemiologic measures quantifying the causative or the preventive effect of a particular agent with respect to a given disease are frequently used, but the set of assumptions on which they rest, and the consequences of these assumptions, are not widely understood. We present a rigorous derivation of these measures from the sufficient-causes model of disease occurrence and from the definition of causation as the bringing forward of the occurrence time of an event. This exercise brings out the fact that an understanding of the assumptions underpinning all measures of effect, and of the extent to which they may or may not be met, is necessary to their prudent interpretation. We also introduce a new measure, discarding 1) the sufficient-causes model and 2) the assumption that the agent can only be either causative or preventive, relative to a given disease, but not both. Some may consider this more acceptable than having to decide, on slim or no evidence, that the agent has only one kind of effect on the disease. In any case, I submit that epidemiology should eventually discard the concept of causation, as has been done in some other basic sciences, and replace it with the adequate modeling of disease-producing processes, in individuals and populations.
Antiviral activity of Tecovirimat against Mpox virus clades 1a, 1b, 2a and 2b
Authors: Postal Jeanne , Guivel-Benhassine Florence , Porrot Françoise , Grassin Quentin , Crook Jack M. , Vernuccio Riccardo , Caro Valérie , Vanhomwegen Jessica , Guardado-Calvo Pablo , Simon-Lorière Etienne , Dacheux Laurent , Manuguerra Jean-Claude , Schwartz Olivier
Published: December 2024

The recent Mpox virus (MPXV) outbreak was caused by a novel and more pathogenic clade 1b virus. We compared the antiviral efficacy of Tecovirimat in cell culture, against the two ancestral clades 1a and 2a, the clade 2b that circulated in 2022, and the recent clade 1b virus. We report that Tecovirimat similarly inhibits the replication of all four MPXV clades, at nanomolar concentrations (nM). Our results suggest that Tecovirimat remains a therapeutic option against the latest clade 1b virus.
Genome sequencing reveals the impact of non-canonical exon inclusions in rare genetic disease
Authors: Pitsava Georgia , Hawley Megan , Auriga Light , de Dios Ivan , Ko Arthur , Marmolejos Sofia , Almalvez Miguel , Chen Ingrid , Scozzaro Kaylee , Zhao Jianhua , Barrick Rebekah , Mew Nicholas Ah , Fusaro Vincent A. , LoTempio Jonathan , Taylor Matthew , Mestroni Luisa , Graw Sharon , Milewicz Dianna , Guo Dongchuan , Murdock David R. , Bujakowska Kinga M. ,   UCI-GREGoR Consortium, Xiao Changrui , Délot Emmanuèle C. , Berger Seth I. , Vilain Eric
Published: December 2024

Introduction

Advancements in sequencing technologies have significantly improved clinical genetic testing, yet the diagnostic yield remains around 30-40%. Emerging sequencing technologies are now being deployed in the clinical setting to address the remaining diagnostic gap.

Methods

We tested whether short-read genome sequencing could increase diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive clinical genetic testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing.

Results

We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not interrogated by the original testing. In 9 cases, they were deep intronic variants, 5 of which led to abnormal splicing and cryptic exon inclusion, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis.

Conclusion

Genome sequencing overcomes multiple limitations of clinical genetic testing, such as inability to call intronic variants and technical limitations. Our findings highlight cryptic exon inclusion as a common mechanism via which deep intronic variants cause Mendelian disease. However, they also reinforce that reanalysis of exome datasets can be a fruitful approach.
Functional network dynamics in photosensitive epilepsy depend on stimulation frequency and photosensitivity type
Authors: Timar Lili , Deplazes Sina , Bothmann Julia , Renzel Roland , Ledergerber Debora , Dubcek Tena , Imbach Lukas
Published: December 2024

Objective

To describe the underlying dynamical mechanisms of photosensitive epilepsy (PSE) and different photosensitivity types.

Methods

This retrospective study included healthy controls (HC), non-PSE patients with epilepsy (PWE), and PSE patients. All participants were stimulated with flickering white light (1-60Hz) under 10-20 EEG monitoring.

Results

We observed significantly higher occipital Photoparoxysmal response (PPR) power in PSE patients compared to HC for stimulation frequencies 10Hz-20Hz. This activity was highest in Type 4, which shows a type-specific variation of the PPR. However, the excitability of the visual cortex, investigated by the occipital transient (P100) and steady-state visual evoked potentials (ssVEP), remained unchanged in most PSE types compared to HC and to PWE. The ssVEP power only increased significantly in Type 4 compared to HC. Instead, PSE patients showed apparent differences in functional connectivity in the PPR band (3-4Hz) with hypoconnected centro-parietal regions and hyperconnected anterior and anterio-posterior areas compared to HC and PWE for stimulation frequencies 10Hz-20Hz.

Conclusion

PSE is a network effect modulated by hyperconnected anterior and anterio-posterior regions, accompanied by a hyperexcitable visual cortex.

Significance

We provide novel evidence that altered network dynamics in PSE patients are likely a prerequisite for the propagation of the PPR and type-specific responses.
Mouse brain organoids modelin vivoneurodevelopment and function and capture differences to human
Authors: Lloyd-Davies Sánchez Daniel J , Lindhout Feline W , Anderson Alexander J , Pellegrini Laura , Lancaster Madeline A
Published: December 2024

In the last decade since their emergence, brain organoids have offered an increasingly popular and powerful model for the study of early development and disease in humans. These 3D stem cell-derived models exist in a newer space at the intersection ofin vivoand 2Din vitromodels. Functional benchmarking has so far remained largely uncharacterised however, leaving the extent to which these models may accurately portrayin vivoprocesses still yet to be fully realised. Here we present a standardised unguided protocol to generate brain organoids from mice, the most commonly-usedin vivomammalian model; and in parallel establish a guided protocol for generating region-specific choroid plexus mouse organoids. Both unguided and guided mouse organoids progress through neurodevelopmental stages with anin vivo-like tempo and recapitulate species-specific characteristics of neural and choroid plexus development, respectively. Neuroepithelial cells generate neural progenitors that give rise to different neural subtypes including deep-layer neurons, upper-layer neurons, and glial cells. We further adapted protocols to prolong mouse cerebral organoid (CO) cultures as slices at the air-liquid interface (ALI), enhancing accessibility for long-term studies and functional investigations. In mature mouse ALI-COs, we observed mature glia, as well as synaptic structures and long-range axon tracts projecting to distant regions, suggesting an establishment and maturation of neural circuitry. Indeed, functional analyses with high-density multi-electrode arrays (HD-MEAs) indicate comparable activity toex vivoorganotypic mouse brain slices. Having established protocols for both region-specific and unpatterned mouse brain organoids, we demonstrate that their neurodevelopmental trajectories, and resultant mature features, closely mimic thein vivomodels to which they are benchmarked across multiple biochemical, morphological, and functional read-outs. We propose that mouse brain organoids are a valuable model for functional studies, and provide insight into how closely brain organoids of other species, such as human, may recapitulate their own respectivein vivodevelopment.
Induction of an early IFN-γ cellular response and high plasma levels of SDF-1α are inversely associated with COVID-19 severity and residence in rural areas in Kenyan patients
Authors: Wanjiku perpetual Njeri , Orindi Benedict , Kimotho John , Sayed Shahin , Shah Reena , Saleh Mansoor , Mwacharo Jedidah , Maronga Christopher , Olouch Vivianne , Karanu Ann , Shah Jasmit , Nneka Zaitun , Ochola-Oyier Lynette Isabella , Abdi Abdirahman I. , Dunachie Susanna , Bejon Philip , Nduati Eunice , Ndungu Francis M.
Published: December 2024

Introduction COVID-19 was less severe in Sub-Saharan Africa (SSA) compared with Europe and North America. It is unclear whether these differences could be explained immunologically. Here we determined the levels of ex vivo SARS-CoV-2 peptide-specific IFN-γ producing cells, and levels of plasma cytokines and chemokines over the first month of COVID-19 diagnosis among Kenyan COVID-19 patients from urban and rural areas. Methods Between June 2020 and August 2022, we recruited and longitudinally monitored 188 COVID-19 patients from two regions in Kenya, Nairobi (urban, n = 152) and Kilifi (rural, n = 36), with varying levels of disease severity ­– severe, mild/moderate, and asymptomatic. IFN-γ secreting cells were enumerated at 0-, 7-, 14- and 28-days post diagnosis by an ex vivo enzyme-linked immunospot (ELISpot) assay following in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with overlapping peptides from several SARS-CoV-2 proteins. A multiplexed binding assay was used to measure the levels of 22 plasma cytokines and chemokines. Results Higher frequencies of IFN-γ-secreting cells against the SARS-CoV-2 spike peptides were observed on the day of diagnosis among the asymptomatic compared to the patients with severe COVID-19. Higher concentrations of 17 of the 22 cytokines and chemokines measured were positively associated with severe disease, and in particular interleukin (IL)-8, IL-18 and IL-1ra (p<0.0001), while a lower concentration of SDF-1α was associated with severe disease (p<0.0001). Concentrations of 8 and 16 cytokines and chemokines including IL-18 were higher among Nairobi asymptomatic and mild patients compared to their respective Kilifi counterparts. Conversely, the concentrations for SDF-1α were higher in rural Kilifi compared to Nairobi (p=0.012). Conclusion In Kenya, as seen elsewhere, pro-inflammatory cytokines and chemokines were associated with severe COVID-19, while an early IFN-γ cellular response to overlapping SARS-CoV-2 spike peptides was associated with reduced risk of disease.  Living in urban Nairobi (compared with rural Kilifi) was associated with increased levels of pro-inflammatory cytokines/chemokines.
Development and Feasibility Evaluation of a Telehealth System (Impak Sihat) to Empower Rural Population in Malaysia on the Quality Use of Medicines
Authors: Nazar Nor Ilyani Mohamed , Rahman Norny Syafinaz Ab , Alias Nor Elina , Zaini Syahrir , Kamil Tg Karmila Tg Mohd , Jamani Nurjasmine Aida , Elnaem Mohamed Hassan
Published: December 2024

The global rise of chronic diseases necessitates quality use of medicines (QUM) and adherence for effective management. Insufficient QUM understanding among patients adversely affects healthcare outcomes in Malaysia. High rates of irrational medication use, particularly in rural areas, are influenced by various factors. Continuous engagement from healthcare providers is essential, potentially facilitated by a tailored telehealth system. This study aimed to design a customized telehealth system for Malaysia’s rural population and assess patient experiences and acceptance. The study comprised three phases: i) a qualitative pre-development phase exploring internet access and health information-seeking behaviours; ii)development of the telehealth system (Impak Sihat-healthy impact) based on identified needs; and iii) a post-development feasibility evaluation of the Impak Sihat system through community demonstration and validated questionnaires. Fifteen respondents were interviewed during the pre-development phase, achieving saturation and revealing insights on health issues, internet usage, social media preferences, and technology literacy. A customized telehealth system was developed, addressing the identified needs with relevant content and resources. Following system development, a feasibility study with 77 participants indicated acceptable scores of 73 to 87% across six domains. However, older age was significantly linked to lower scores in the ‘User-friendly features and ease of learning and understanding’ domain (p<0.01). The telehealth system effectively meets Malaysia’s rural population’s needs and has been successfully developed. To optimize this system’s effectiveness, considerations regarding older age, socioeconomic status, internet reliability, and information confidentiality must be addressed.
Verification of the semiquantitative assessment of vertebral deformity for subsequent osteoporotic fracture prediction and screening for the initiation of osteoporosis treatment: A case-control study using a clinical-based setting
Authors: Yoshii Ichiro , Sawada Naoya , Chijiwa Tatsumi
Published: December 2024

Background Semiquantitative grading of the vertebral body (SQ) is an easy screening method for vertebral body deformation. The validity of the SQ as a risk factor and as a screening tool for incident osteoporotic fractures (OF) was investigated using retrospective case-control data Methods Outpatients followed up for >= two years as patients with osteoporosis were recruited. All of them were tested with X-ray images of the lateral thoracolumbar view and other tests at baseline. Patients were classified according to the SQ grade, and potential risk factors were compared for each SQ group. Cox regression analyses were conducted regarding the incident OFs separated into vertebral and non-vertebral fractures (VF and NVF). Statistical differences in the possible risk factors among the groups were examined, and the likelihood of the incident OFs in the variables was examined. After propensity score matching procedures of the confounding factors (PSM), the possibility of incident VFs was compared between the SQ grade groups. Results In the crude dataset, the probabilities of incident VF in SQ Grade 3 and NVF in SQ Grade 1 or higher were significantly higher than in the other grades. Using a Cox regression analysis multivariant mode, the SQ grade was the only statistically significant factor for an incident VF, but not for NVF. However, no significant difference was shown after PSM for VFs. Conclusions These results suggested that the SQ classification was inappropriate for predicting an incident OFs. However, the grading showed significantly higher risk, therefore that is available for screening.
Different Methods of Ankle-Brachial Index Calculation on the Prevalence of Peripheral Arterial Disease and Arterial Calcification in Subjects with Type 2 Diabetes Mellitus from a Public Hospital in Peru
Authors: Espinoza-Enciso Luis Fernando , Hernández-Gozar Iván Gonzalo , Zuñiga-Baldarrago Kevin Clared , Lozano-Purizaca Robert , Briceño-Alvarado Manolo , Yovera-Aldana Marlon
Published: December 2024

Objective

To determine the frequency of peripheral arterial disease (PAD) and arterial calcification (AC) using three methods of ankle-brachial index (ABI) in patients with type 2 diabetes mellitus.

Methodology

A descriptive cross-sectional study using data from the Foot at Risk Program of the Endocrinology Department at Hospital María Auxiliadora from 2015 to 2020. We calculated the ABI for each lower limb using the lowest, highest, or average systolic pressure from the dorsalis pedis or posterior tibial artery in the ipsilateral leg. We defined PAD if any ABI from either leg was <0.9; AC if ABI was >1.3; and the rest were classified as normal. We calculated the prevalence of PAD and AC for each ABI method and assessed differences between ABI categories based on clinical variables using the chi-square or Fisher’s exact test.

Results

We included 643 subjects with a mean age of 61.4 years, 69.8% female. The prevalence of PAD was 7.8%, 15.4%, and 28.2% using the highest, average, or lowest systolic pressure as the numerator in the ABI, respectively. The highest prevalence of PAD occurred with the lowest pressure and the lowest with the highest pressure. AC was observed in 18.2%, 11%, and 16.2%, and normal values were 74%, 73.6%, and 55.7%. In all three methods, PAD was associated with older age and AC was associated with longer duration of diabetes.

Conclusions

Using different ABI methods, we observed a prevalence of PAD ranging from 7.8% to 28%, and a prevalence of CA between 11% and 18% among patients with type 2 diabetes mellitus at a public hospital in Peru. Further research is necessary to verify if the new ABI calculation methods provide improved accuracy in predicting complications.
The significance of molecular heterogeneity in breast cancer batch correction and dataset integration
Authors: Moir Nicholas , Pearce Dominic A. , Langdon Simon P. , Simpson T. Ian
Published: December 2024

Breast cancer research benefits from a substantial collection of gene expression datasets that are commonly integrated to increase analytical power. Gene expression batch effects arising between experimental batches, where signal differences confound true biological variation, must be addressed when integrating datasets and several approaches exist to address these technical differences. This brief communication study clearly demonstrates that popular batch correction techniques can significantly distort key biomarker expression signals. Through the implementation of ComBat batch correction and evaluation of integrated expression values, we profile the extent of these distortions and consider an additional mitigatory batch correction step. We demonstrate that leveraginga prioriknowledge of sample molecular subtype classification can optimally remove batch effect distortion while preserving key biomarker expression variation and transcriptional legitimacy. To the best of our knowledge, this study presents the first analysis of the interplay between dataset molecular composition and the concomitant robustness of integrated, batch-corrected biological expression signal.
Radiomics with super-voxel segmentation improves HPV prediction accuracy significantly in oropharyngeal cancer
Authors: Altinok Oya , Schabath Matthew B. , Guvenis Albert
Published: December 2024

Human papillomavirus (HPV) status has been shown to be prognostic among patients with oropharyngeal cancer (OPC); Specifically, patients with HPV-positive tumors often have a superior prognosis and response to treatment compared to HPV-negative tumors which may be attributed greater tumor heterogeneity. This study assessed if analyzing tumor subregions (i.e., habitats) using super-voxel segmentation can effectively capture intratumor heterogeneity and improve predicting HPV positivity compared to a conventional whole-tumor approach. Using publicly available data from The Cancer Imaging Archive (TCIA) of 192 patients (85% HPV positive) with OPC, we utilized radiomics to predict HPV status comparing a super-voxel segmentation approach and a whole tumor approach. For the subregion approach, the number of supervoxels (subregions) generated per patient varied based on tumor size (mean = 30 supervoxels/patient [SD = 10]). 18 radiomic features were extracted from each supervoxel based on gray-level frequency distribution and aggregated using variance to summarize heterogeneity. For the whole tumor approach, the same radiomic features were generated across the entire tumor without sub-segmentation. As such, 18 radiomic features were utilized to predict HPV status in both models. The dataset was divided into a training set (70%) and an independent test set (30%). An optimizable ensemble model based on a decision tree with GentleBoost was applied to both the subregion and the whole tumor models to predict HPV status from radiomics features. The proposed super-voxel-based approach yielded an AUC of 0.94 in the training set and 0.91 in the test set which outperformed whole tumor analysis (AUC of 0.77 and 0.75, respectively). These findings demonstrate the value of incorporating heterogeneity measure and super-voxel segmentation in oropharyngeal cancer radiomics, which enable a significantly more accurate prediction of the HPV Status.
Trends, correlates, and recent pattern of antibiotic misuse in acute rotavirus diarrhea in urban and rural Bangladesh
Authors: Saqeeb Kazi Nazmus , Tafsir Hasan S. M. , Khan Soroar Hossain , Khan Md Alfazal , Faruque ASG , Ahmed Tahmeed
Published: December 2024

Background

The indiscriminate use of antibiotics in pediatric populations has emerged as a critical global public health concern. A notable example of this is the misuse of antibiotics for treating rotavirus infections, particularly in developing countries. Despite this, there is a dearth of comprehensive research from this region. To address this gap, this study systematically examined the trends and factors associated with antibiotic misuse for acute rotavirus diarrhea among children aged 6-23 months in Bangladesh over a 15-year period. The study also explored sources of prescription, and types of antibiotics utilized in both urban and rural settings of Bangladesh.

Methods

Data from the icddr,b’s Diarrhea Disease Surveillance System (DDSS) were analyzed for 4870 children with laboratory-confirmed acute rotavirus diarrhea treated at Dhaka (urban) and Matlab (rural) hospitals between 2004 and 2018. Relevant sociodemographic and epidemiological data was obtained from the database. To assess changes in antibiotic use over the years chi-square test for trend was employed. Separate logistic regression models specific to each site were developed to identify factors linked to antibiotic use in cases of rotavirus diarrhea.

Results

Over the study period, the percentage of children with rotavirus diarrhea treated with antibiotics significantly rose in both urban (from 43% to 75.5%) and rural (from 35% to 69%) settings (p<0.001). In urban areas, a majority of children (57.5%) received antibiotics at a physician’s clinic for their illness, whereas almost all rural children (86.3%) obtained antibiotics from a pharmacy before being treated at icddr,b. Macrolides were identified as the most frequently prescribed antibiotics (46.6% in urban areas and 38% in rural areas). The urban regression model, revealed that factors such as severity of illness (OR = 1.8; 95% CI 1.5, 2.2), mother’s education (OR = 2.1; 95% CI 1.6, 2.8), father’s education (OR = 1.8; 95% CI 1.4, 2.3), household monthly income > $100 (OR = 1.5; 95% CI 1.2, 1.9), and the distance from home to the nearest health facility (OR = 1.4; 95% CI 1.1, 1.9) were all significantly positively correlated with the use of antibiotic among children suffering from rotavirus diarrhea. Similar results were observed in the rural regression model.

Conclusions

The increasing trend of antibiotic misuse for rotavirus diarrhea in Bangladesh, coupled with the tendency of healthcare providers to prescribe antibiotics inappropriately and the higher incidence of misuse among affluent, educated families, is alarming. Future research is therefore imperative to elucidate the hindrances and catalysts to the prudent administration of antibiotics across diverse societal groups, encompassing both healthcare personnel and family members.
Targeted Muscle Reinnervation (TMR) or Regenerative Peripheral Nerve Interface (RPNI) for pain prevention in patients with limb amputation: a protocol for a systematic review and meta-analysis
Authors: del Moral Preciado Jesús , Gámiz David Gurpegui , Calatayud Bernardo Hontanilla
Published: December 2024

Introduction

Regenerative Peripheral Nerve Interface (RPNI) and Targeted Muscle Reinnervation (TMR) are two reinnervation techniques which have shown clear superiority over classical amputation. It is mainly due to a lower incidence of painful neuromas, residual limb pain and phantom limb pain associated with these new procedures.

However, they have never been compared to each other. Neither has their effectiveness been evaluated based on patients demographics, age, sex, comorbidities (diabetes, coronary heart disease, peripheral arterial disease, chronic kidney disease, congestive heart failure), amputations cause, type of amputation, amputation level, previous surgeries and if there was or not previous nerve division into fascicles. Therefore, the objective of this systematic review and meta-analysis is to compile all the evidence to date and provide a comprehensive view of what each technique offers.

Methods and design

The review will be conducted according to this protocol, following the recommendations of the ‘Cochrane Handbook for Systematic Reviews’. A comprehensive electronic search will be performed in: Cochrane Register of Controlled Trials (CENTRAL), Web of Science, Scopus, PubMed and MedRixb. This review will include randomized, quasi-randomized, and observational studies written in English and Spanish. We will use Covidence for assessing all titles and abstracts identified during the literature search. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points.

Ethics and dissemination

The proposed systematic review will collect and analyse data from published studies; therefore, it raises no ethical issues. The results of the review will be disseminated by publication in a peer-review journal and submitted for presentations at conferences.

PROSPERO registration number

CRD42024617299.

STRENGTHS AND LIMITATIONS OF THIS STUDY

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This will be the first systematic review to include a comparison between RPNI and TMR.

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Through a comprehensive search and selection of high-quality articles, the best available evidence of RPNI and TMR against classical amputation will be gathered.

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Gray literature and unpublished studies will be sourced from MedRixb aiming to reduce the impact of a possible publication bias.

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Exclusion of non-English/Spanish papers may lead to language bias.

PICO QUESTION

Population

Any adults (aged over 18 years) and gender with a superior or inferior limb amputation.

Intervention

Targeted Muscle Reinnervation (TMR) or Regenerative Peripheral Nerve Interface (RPNI).

Comparators

Classical amputation.

TMR vs RPNI.

Outcomes

1) Incidence of neuroma, 2) Incidence of residual limb pain (RLP), 3) Severity of Pain 4) Incidence of phantom limb pain (PLP), and 5) Surgical complications (dehiscence, infection, haematoma and seroma).
Uncovering the Biological Toll of Neighborhood Physical Disorder: Links to Metabolic and Inflammatory Biomarkers in Older Adults
Authors: Yu Jiao , Cudjoe Thomas K.M. , Mathis Walter S. , Chen Xi
Published: December 2024

Background

Neighborhood physical disorder has been linked to adverse health outcomes, yet longitudinal assessments of its relationship with metabolic and inflammatory biomarkers in older adults remain limited. This study examined the association between patterns of neighborhood physical disorder exposure and biomarkers among older adults.

Methods

We included community-dwelling Medicare beneficiaries with 2017 biomarker data from the National Health and Aging Trends Study (n = 4,558). Neighborhood physical disorder from 2011 to 2016 was assessed using interviewer reports of neighborhood characteristics. Latent class analysis was employed to identify longitudinal patterns of exposure. Inverse probability weighted linear regression models were used to examine associations between physical disorder patterns and five biomarkers, including body mass index (BMI), waist circumference, hemoglobin A1C (HbA1c), high-sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6).

Results

Four classes of neighborhood physical disorder emerged: stable low exposure (85%), increased exposure (4%), decreased exposure (8%), and stable high exposure (3%). Regression findings indicate that residing in neighborhoods with stable high exposure was significantly associated with higher levels of BMI (b = 0.06, p<0.05), HbA1c (b= 0.09,p<0.05), hsCRP (b = 0.21, p < 0.05), and IL-6 (b = 0.22, p < 0.05), compared to those with stable low exposure. Older adults with increased exposure and decreased exposure also exhibited elevated risks in multiple metabolic and inflammation biomarkers.

Conclusions

Persistent exposure to neighborhood physical disorder is associated with higher levels of metabolic and inflammatory biomarkers, underscoring the need for targeted clinical screening and neighborhood initiatives to promote healthy aging in place.
Nucleosome Spacing Can Fine-Tune Higher Order Chromatin Assembly
Authors: Chen Lifeng , Maristany M. Julia , Farr Stephen E. , Luo Jinyue , Gibson Bryan A. , Doolittle Lynda K. , Espinosa Jorge R. , Huertas Jan , Redding Sy , Collepardo-Guevara Rosana , Rosen Michael K.
Published: December 2024

Cellular chromatin displays heterogeneous structure and dynamics, properties that control diverse nuclear processes. Models invoke phase separation of conformational ensembles of chromatin fibers as a mechanism regulating chromatin organizationin vivo. Here we combine biochemistry and molecular dynamics simulations to examine, at single base-pair resolution, how nucleosome spacing controls chromatin phase separation. We show that as DNA linkers extend from 25 bp to 30 bp, as examplars of 10N+5 and 10N (integer N) bp lengths, chromatin condensates become less thermodynamically stable and nucleosome mobility increases. Simulations reveal that this is due to trade-offs between inter- and intramolecular nucleosome stacking, favored by rigid 10N+5 and 10N bp linkers, respectively. A remodeler can induce or inhibit phase separation by moving nucleosomes, changing the balance between intra- and intermolecular stacking. The intrinsic phase separation capacity of chromatin enables fine tuning of compaction and dynamics, likely contributing to heterogeneous chromatin organizationin vivo.
Unveiling DNA Origami Interaction Dynamics on Living Cell Surfaces by Single Particle Tracking
Authors: Van Zundert Indra , Spezzani Elena , Brillas Roger R. , Paffen Lars , Yurchenko Angelina , de Greef Tom F. A. , Albertazzi Lorenzo , Bertucci Alessandro , Patiño Tania
Published: December 2024

Due to the unique spatial addressability of DNA origami, targeting ligands (e.g. aptamers or antibodies) can be specifically positioned onto the surface of the nanostructure, constituting an essential tool for studying ligand-receptor interactions at the cell surface. While the design and ligand incorporation into DNA origami nanostructures are well-established, the study of cell surface interaction dynamics is still in the explorative phase, where in depth fundamental understanding on the molecular interactions remains underexplored. This study uniquely captures real-time encounters between DNA origami and cells in-situ using single particle tracking (SPT). Here, we functionalized DNA nanorods (NRs) with antibodies or aptamers specific to the epidermal growth factor receptor (EGFR) and used them to target EGFR-overexpressing cancer cells. SPT data revealed that ligand coated NRs selectively bound to the receptors expressed in target cancer cells, while non-functionalized NRs only display negligible cell interactions. Furthermore, we explored the effect of ligand density on the DNA origami, which revealed that aptamer-decorated NRs exhibit non-linear binding characteristics, whereas this effect in antibody-decorated NRs was less pronounced. This study provides new mechanistic insights into the fundamental understanding of DNA origami behaviour at the cell interface, with unprecedented spatiotemporal resolution, aiding the rational design of ligand-targeted DNA origami for biomedical applications.
PfATP2 is an essential flippase on thePlasmodium falciparumsurface that influences parasite sensitivity to antiplasmodial compounds
Authors: Qiu Deyun , England Eleanor , Lehane Adele M.
Published: December 2024

Antimalarials play a crucial role in the fight against malaria. However, resistance of the most virulent malaria parasite,Plasmodium falciparum, to front-line antimalarials is spreading. To identify new antimalarials, millions of compounds have been screened for their ability to inhibit the growth of blood-stageP. falciparumparasites. To gain insight into the mode of action of novel compounds and the ease by which parasites can acquire resistance to them, many have been tested in ‘in vitroevolution experiments’, in which parasites are exposed to the compound for a prolonged period of time. In a recent study, parasite resistance to two compounds, MMV007224 and MMV665852, was associated with amplification of thepfatp2gene, implicating PfATP2, a putative phospholipid flippase, as a parasite drug target or resistance determinant. These two compounds, along with MMV665794 (which is structurally related to MMV007224) had previously been reported to dysregulate pH in parasites. Here, we show that PfATP2 localises to the parasite surface and is essential for parasite growth. We demonstrate that parasites genetically engineered to overexpress PfATP2 display reduced sensitivity to MMV665794, MMV007224 and MMV665852 compared to parasites with a normal expression level of the protein, and that parasites in which PfATP2 is knocked down become hypersensitive to the three compounds. We show that PfATP2 expression level does not affect the cytosolic pH of parasites, or the potency by which MMV665794 or MMV007224 dysregulate parasite pH. We show that PfATP2-overexpressing parasites internalise a fluorescent phosphatidylserine analogue (NBD-PS) at a greater rate than parasites with a normal expression level of PfATP2, and that parasites in which PfATP2 is knocked down have a reduced rate of NBD-PS uptake. Further, we provide evidence that MMV665794 and MMV007224 inhibit both ATP- dependent and ATP-independent NBD-PS internalisation mechanisms, the former at lower concentrations. Together, our data are consistent with PfATP2 serving as a major ATP-dependent phosphatidylserine internalisation mechanism at the parasite plasma membrane, and being a target of MMV665794 and MMV007224.
Balancing Act: A Neural Trade-off Between Coherence and Creativity in Spontaneous Speech
Authors: Patel Tanvi , Macpherson Sarah E. , Hoffman Paul
Published: December 2024

Effective communication involves a delicate balance between generating novel, engaging content and maintaining a coherent narrative. The neural mechanisms underlying this balance between coherence and creativity in discourse production remain unexplored. The aim of the current study was to investigate the relationship between coherence and creativity in spontaneous speech, with a specific focus on the interaction among three key neural networks: the Default Mode Network, Multiple Demand Network, and the Semantic Control Network. To this end, we conducted a two-part analysis. At the behavioural level, we analysed speech samples produced in response to topic cues, computing measures of global coherence (indexing the degree of connectedness to the main topic) and Divergent Semantic Integration (DSI; reflecting the diversity of ideas incorporated in the narrative). Coherence and divergence in speech were negatively correlated, suggesting a trade-off between maintaining a coherent narrative structure and incorporating creative elements. At the neural level, higher global coherence was associated with greater activation in the Multiple Demand Network, emphasising its role in organising and sustaining logical flow in discourse production. In contrast, functional connectivity analyses demonstrated that higher DSI was related to greater coupling between the Default Mode and Multiple Demand Networks, suggesting that creative speech relies on a dynamic interplay between associative and executive processes. These results provide new insights into the cognitive and neural processes underpinning spontaneous speech production, highlighting the complex interplay between different brain networks in managing competing demands of being coherent and creative.
Alternative splicing ofSORBS1affects neuromuscular junction formation and stability in myotonic dystrophy type 1
Authors: Hermitte Caroline , de Calbiac Hortense , Moulay Gilles , Mérien Antoine , Lainé Jeanne , Polvèche Hélène , Cailleret Michel , Vassilopoulos Stéphane , Kabashi Edor , Furling Denis , Martinat Cécile , Gazzola Morgan
Published: December 2024

Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disease characterized by a CTG repeat expansion in the 3’ untranslated region of the gene coding for thedystrophia myotonica protein kinase(DMPK). Presence of expanded CTG repeats in DMPK-mRNAs leads to the sequestration of RNA binding factors such as the Muscleblind like (MBNL) proteins resulting in widespread splicing defects contributing to progressive muscle weakness and myotonia. Here, we show that abnormal splicing ofSORBS1exon 25 found in skeletal muscle of myotonic dystrophy type 1 patients is a critical contributor to neuromuscular junction (NMJ) formation and maintenance. Forced exclusion ofSORBS1exon 25 in mice results in NMJ degeneration with marked denervation and postsynaptic destabilization. In zebrafish, misregulation ofsorbs1exon 25 results in reduced motor function and abnormal AChR cluster morphology. Finally, we observed that forcingSORBS1exon 25 exclusion in hiPSC-derived skeletal muscle cells reduces the formation of large AChR clusters upon agrin stimulation. Thus, our study identifies MBNL regulatedSORBS1alternative splicing during skeletal muscle development as a critical event for NMJ formation and maintenance. The aberrant splicing ofSORBS1exon 25 in DM1 expands our understanding of how splicing dysregulation compromises neuromuscular system communication, shedding light on the broader impact of mRNA splicing regulation on NMJ integrity.
Emergence of Anticipatory Beta Activity to Facilitate Behavioral Stability Following Environmental Changes
Authors: Bracco Martina , Vasudevan Varsha , Rohira Vridhi , Welniarz Quentin , Razafinimanana Mihoby , Richard Alienor , Gitton Christophe , Meunier Sabine , Valero-Cabre Antoni , Schwartz Denis , Popa Traian , Gallea Cecile
Published: December 2024

Adaptive behavior enables flexible responses to environmental changes. This process is particularly crucial when transitioning between environments with different features, relying on the progressive formation of expectations based on prior experience. In humans, beta oscillations are central to adaptive behavior. Yet, the brain mechanisms underlying the detection of environmental changes, and the iterative update needed to progressively improve behavioral performance remain elusive. Here, we reveal that beta activity emerges in a cerebello-cortical network two seconds before action initiation, as the features of a new environment become known and behavioral outcomes become more predictable. Within this period, the cerebellum and parietal cortex drive prefrontal activity to form expectations. Using a single-trial approach, we establish that beta bursts before action initiation predict performance in the upcoming trial based on previous outcomes. These findings uncover a novel anticipatory mechanism that reflects predictive processes critical for stabilizing performance and adapting to environmental changes.
YAP regulates periosteal expansion in fracture repair
Authors: Nijsure Madhura P , Tobin Brendan , Jones Dakota L , Lang Annemarie , Hallström Grey , Baitner Miriam , Tanner Gabrielle I , Moharrer Yasaman , Panebianco Christopher J , Seidl Elizabeth G , Dyment Nathaniel A , Szeto Gregory L , Wood Levi , Boerckel Joel D
Published: December 2024

Bone fracture repair initiates by periosteal expansion. The periosteum is typically quiescent, but upon fracture, periosteal cells proliferate and contribute to bone fracture repair. The expansion of the periosteum is regulated by gene transcription; however, the molecular mechanisms behind periosteal expansion are unclear. Here, we show that Yes-Associated Protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) mediate periosteal expansion and periosteal cell proliferation. Bone fracture increases the number of YAP-expressing periosteal cells, and deletion of YAP and TAZ from Osterix (Osx) expressing cells impairs early periosteal expansion. Mechanistically, YAP regulates both ‘cell-intrinsic’ and ‘cell-extrinsic’ factors that allow for periosteal expansion. Specifically, we identified Bone Morphogenetic Protein 4 (BMP4) as a cell extrinsic factor regulated by YAP, that rescues the impairment of periosteal expansion upon YAP/TAZ deletion. Together, these data establish YAP mediated transcriptional mechanisms that induce periosteal expansion in the early stages of fracture repair and provide new putative targets for therapeutic interventions.
Motor sequence learning involves better prediction of the next action and optimization of movement trajectories
Authors: Kashefi Mehrdad , Diedrichsen Jörn , Pruszynski J. Andrew
Published: December 2024

Learning new sequential movements is a fundamental skill for many animals. Although the behavioral manifestations of sequence learning are clear, the underlying mechanisms remain poorly understood. Motor sequence learning may arise from three distinct processes: (1) improved execution of individual movements independent of their sequential context; (2) enhanced anticipation of “what” movement should be executed next, enabling faster initiation; and (3) the development of motoric sequence-specific representations that encode “how” movements should be optimally performed within a sequence. However, many existing paradigms conflate the "what" and "how" components of learning, as participants often acquire both the sequence content (what to do) and its execution (how to do it). This overlap obscures the distinct contributions of each mechanism to motor sequence learning. In this study, we disentangled these mechanisms using a continuous reaching task. Performance in trained sequences was compared to random sequences to rule out improvements attributable solely to isolated movement execution. By also varying how many upcoming targets were visible we assessed the role of anticipation in learning. When participants could only see one future target, improvements were mostly due to them learning which target would come next. When they could see four future targets, participants immediately demonstrated fast movement times and increased movement smoothness, surpassing late-stage performance in the one target condition. Crucially, even with full visibility of future targets, participants showed further sequence-specific learning caused by a continuous optimization of movement trajectories. Follow-up experiments revealed that the learned sequence representations were effector-specific and encoded contextual information of four movements or longer. Our paradigm enables a clear dissociation between the "what" and "how" components of motor sequence learning and provides compelling evidence for the development of effector-specific sequence representations that guide optimal movement execution.
Integrative analysis of angiogenic signaling in obesity: capillary features and VEGF binding kinetics
Authors: Lee Yunjeong , Tukei Keith Lionel , Fang Yingye , Kuila Shobhan , Liu Xinming , Imoukhuede Princess I.
Published: December 2024

Obesity is a global health crisis, with its prevalence particularly severe in the United States, where over 42% of adults are classified as obese. Obesity is driven by complex molecular and tissue-level mechanisms that remain poorly understood. Among these, angiogenesis—primarily mediated by vascular endothelial growth factor (VEGF-A)—is critical for adipose tissue expansion but presents unique challenges for therapeutic targeting due to its intricate regulation. Systems biology approaches have advanced our understanding of VEGF-A signaling in vascular diseases, but their application to obesity is limited by scattered and sometimes contradictory data. To address this gap, we performed a comprehensive analysis of the existing literature to synthesize key findings, standardize data, and provide a holistic perspective on the adipose vascular microenvironment. The data mining revealed five key findings: (1) obesity increases adipocyte size by 78%; (2) vessel density in adipose tissue decreases by 51% in obese mice, with vessels being 47–58% smaller and 4–9 times denser in comparison with tumor vessels; (3) capillary basement membrane thickness remains similar regardless of obesity; (4) VEGF-A shows the strongest binding affinity for VEGFR1, with four times stronger affinity for VEGFR2 than for NRP1; and (5) binding affinities measured by radioligand binding assay and surface plasmon resonance (SPR) are significantly different. These consolidated findings provide essential parameters for systems biology modeling, new insights into obesity-induced changes in adipose tissue, and a foundation for developing angiogenesis-targeting therapies for obesity.