bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Cochlear Implant Electrode Arrays Misplaced in the Internal Auditory Canal: A Systematic Review
Authors: Johnson Benjamin R. , Benaim Ezer H. , Thompson Nicholas J. , Marouf Azmi , Dedmon Matthew M. , Anderson Melissa R. , Selleck A. Morgan , Brown Kevin D. , Dillon Margaret T.
Published: June 2024

Objective

Misplacement of electrode arrays in the internal auditory canal (IAC) presents a unique clinical challenge. Speech recognition is limited for cochlear implant (CI) users with misplaced arrays, and there are risks with revision surgery including facial and/or cochlear nerve injury.

Databases Reviewed

PubMed, Embase, and Scopus.

Methods

A literature search was performed from inception to September 2023. The search terms were designed to capture articles on misplaced arrays and the management options. Articles written in English that described cases of array misplacement into the IAC for children and adults were included. The level of evidence was assessed using Oxford Center for Evidence Based Medicine guidelines. Descriptive statistical analyses were performed.

Results

Twenty-eight cases of arrays misplaced in the IAC were identified. Thirteen (46%) were patients with incomplete partition type 3 (IP3), and 7 (25%) were patients with common cavity (CC) malformations. Most misplaced arrays were identified postoperatively (19 cases; 68%). Of these cases, 11 (58%) were managed with array removal. No facial nerve injuries were reported with revision surgery. Eight cases (42%) were left in place. Several underwent mapping procedures in an attempt improve the sound quality with the CI.

Conclusion

Electrode array misplacement in the IAC is a rare complication that reportedly occurs predominately in cases with IP3 and CC malformations. Removal of misplaced arrays from the IAC reportedly has not been associated with facial nerve injuries. Cases identified with IAC misplacement postoperatively can potentially be managed with modified mapping techniques before proceeding with revision surgery.
Cochlear Implant Device Failures Falling Under the 2020 FDA Voluntary Field Corrective Action: A Systematic Review and Meta-analysis
Authors: Govindan Aparna , Saade Mia , Perez Enrique R. , Wanna George B. , Cosetti Maura K. , Schwam Zachary G.
Published: June 2024

Objective

To compare the rate of device failure for those cochlear implants (CIs) involved in the 2020 Food and Drug Administration (FDA) voluntary field corrective action (VFCA).

Databases Reviewed

Medline, Embase, and Scopus.

Methods

A systematic review was performed according to the PRISMA guidelines. Publications reporting institutional experiences with implants affected by the VFCA were included. Outcomes assessed included etiology of, rate of, and time to failure and pre-/post-device failure speech perception testing. All outcomes reported in at least two independent studies were included in a meta-analysis.

Results

Six studies met criteria for analysis. The overall pooled failure rate was 23.7% (95% CI, 11.6–38.4%). The pooled device, inconclusive, and medical failure rates were 21.5%, 0.2%, and 0.7%, respectively. Pediatric failure rates were higher than those of adults (46.9% [95% CI, 11.2–84.5%] versus 32.6% [95% CI, 8.2–63.7%]). WRS declined with primary implant failure (55.1% [95% CI, 48.0–62.1%] to 34.1% [95% CI, 30.2–38.0%]) but improved after reimplantation (34.1% [95% CI, 30.2–38.0%] to 50.1% [95% CI, 45.2–55.1%]).

Conclusions

The rate of pooled reported failure for CIs falling under the 2020 VFCA in the literature thus far is 23.7%. The overwhelming majority of these failures were device related, the rates of which were higher in children. Speech perception improved significantly after reimplantation.
The Genetic Landscape of Primary Breast Marginal Zone Lymphoma Identifies a Mutational-driven Disease With Similarities to Ocular Adnexal Lymphoma
Authors: Ivanova Vanesa-Sindi , Menter Thomas , Zaino Joel , Mertz Kirsten D. , Hamelin Baptiste , Dirnhofer Stefan , Kloboves-Prevodnik Veronika , Tzankov Alexandar , Gašljević Gorana
Published: June 2024

Extranodal marginal zone lymphomas (eMZL) can occur in any organ and site of the body. Recent research has shown that they differ from organ to organ in terms of their mutational profile. In this study, we investigated a cohort of primary breast marginal zone lymphomas (PBMZL) to get a better insight into their morphologic and molecular profile. A cohort of 15 cases (14 female and 1 male) was characterized by immunohistochemistry (IHC) for 19 markers, fluorescence in situ hybridization (FISH), and high throughput sequencing (HTS) using a lymphoma panel comprising 172 genes. In addition, PCR for the specific detection of Borrelia spp. and metagenomics whole genome sequencing were performed for infectious agent profiling. Follicular colonization was observed in most cases, while lymphoepithelial lesions, though seen in many cases, were not striking. All 15 cases were negative for CD5, CD11c, and CD21 and positive for BCL2 and pan B-cell markers. There were no cases with BCL2, BCL10, IRF4, MALT1, or MYC translocation; only 1 had a BCL6 rearrangement. HTS highlighted TNFAIP3 (n=4), KMT2D (n=2), and SPEN (n=2) as the most frequently mutated genes. There were no Borrelia spp., and no other pathogens detected in our cohort. One patient had a clinical history of erythema chronicum migrans affecting the same breast. PBMZL is a mutation-driven disease rather than fusion-driven. It exhibits mutations in genes encoding components affecting the NF-κB pathway, chromatin modifier-encoding genes, and NOTCH pathway-related genes. Its mutational profile shares similarities with ocular adnexal and nodal MZL.
Antibody-mediated autoimmunity in symptom-based disorders: position statement and proceedings from an international workshop
Authors: Mountford Rebecca , Adler Brittany L. , Andersson David , Bashford-Rogers Rachael , Berwick Richard , Bevan Stuart , Caro Xavier , Chung Tae Hwan , Clark J. David , Dawes John M. , Dong Xinzhong , Helyes Zsuzsanna , Kingery Wade , van Middendorp Joost J. , Neiland Harvey , Maurer Margot , Scheibenbogen Carmen , Schmack Katharina , Schreiner Thomas , Svensson Camilla I. , Tékus Valéria , Goebel Andreas
Published: June 2024

A 2-day closed workshop was held in Liverpool, United Kingdom, to discuss the results of research concerning symptom-based disorders (SBDs) caused by autoantibodies, share technical knowledge, and consider future plans. Twenty-two speakers and 14 additional participants attended. This workshop set out to consolidate knowledge about the contribution of autoantibodies to SBDs. Persuasive evidence for a causative role of autoantibodies in disease often derives from experimental “passive transfer” approaches, as first established in neurological research. Here, serum immunoglobulin (IgM or IgG) is purified from donated blood and transferred to rodents, either systemically or intrathecally. Rodents are then assessed for the expression of phenotypes resembling the human condition; successful phenotype transfer is considered supportive of or proof for autoimmune pathology. Workshop participants discussed passive transfer models and wider evidence for autoantibody contribution to a range of SBDs. Clinical trials testing autoantibody reduction were presented. Cornerstones of both experimental approaches and clinical trial parameters in this field were distilled and presented in this article. Mounting evidence suggests that immunoglobulin transfer from patient donors often induces the respective SBD phenotype in rodents. Understanding antibody binding epitopes and downstream mechanisms will require substantial research efforts, but treatments to reduce antibody titres can already now be evaluated.
U-Turn Design Metatarsal Artery Flap
Authors: Reingrittha Pissanu , Kittipibul Krittin , Kulkittaya Somchai , Jitprapaikulsarn Surasak
Published: June 2024

Background

In distal forefoot defect, finding wound closure is challenging because of the distal site and small blood vessels involved. One possible resolution is the utilization of a metatarsal artery flap in a ‘U-turn’ design. This method offers several advantages, including its long length and a viable option for distal forefoot defect.

Methods

Thirty-six patients with forefoot injuries from metatarsophalangeal (MTP) joint to distal interphalangeal (DIP) joint due to trauma were consecutively recruited and completed the study. Outcomes were analyzed descriptively, and risk prediction modeling for edge necrosis was performed.

Results

The mean ± SD follow-up time was 27.3 months ±1.9. The median (IQR) MTP-to-DIP joint wound width and length were 1.8 (1.4, 3.0) and 3.2 cm (2.9, 6.2), respectively. The median (IQR) width, length, and width-to-length ratio flap dimensions were 3.6 (2.8, 6.0), 4.7 cm (4.3, 9.3), and 1.5 (1.2, 1.7), respectively. The mean ± SD operative time was 32.9 min ± 5.7. The median (IQR) intraoperative blood loss was 5.0 mL (4.0, 5.0). The mean ± SD hospital length of stay postoperatively was 4.0 days ±1.0. The mean ± SD Foot and Ankle Outcome Score and Foot Function Index were 64.1 ± 2.5 and 7.8% ± 3.3, respectively. All patients had good or excellent aesthetic satisfaction. Spontaneously resolving edge necrosis occurred in 13.9%. The mean ± SD time-to-start-ambulation was 1.7 weeks ±0.5. At the 2-year follow-up visit, all patients had reduced U-turn flap pivot point redundancy without shoe size impact, needing reoperation, or donor site morbidity. Edge necrosis was significantly associated with length-to-width ratio (P= 0.014) but not with Foot and Ankle Outcome Score or Foot Function Index.

Conclusions

Metatarsal artery flap of U-turn design was reliable and was associated with a short recovery time, alternative resolution for forefoot area due to short operation time, minimal blood loss, short hospital length of stay, and excellent availability.
An Innovative Approach to Classifying and Treating Axillary Scar Contracture
Authors: Chen Fuhuan , Wu Jiang , Zhang Xulong , Chen Zhaohan , Yue Xiaotong , Chen Baoguo
Published: June 2024

Background

Axillary cicatricial contracture is a debilitating condition that can greatly impair shoulder joint function. Therefore, timely correction of this condition is imperative. In light of Ogawa's prior classification of axillary cicatricial contracture deformities, we have proposed a novel classification system and reconstruction principles based on a decade of treatment experience. Our proposed system offers a more comprehensive approach to correcting axillary cicatricial contracture deformities and aims to improve patient outcomes.

Methods

Our study included 196 patients with a total of 223 axillary cicatricial contracture deformities. The range of shoulder abduction varied between 10 and 120 degrees. Our treatment approach included various methods such as the lateral thoracic flap, transverse scapular artery flap, cervical superficial artery flap, medial upper arm flap, latissimus dorsi flap, Z-shape modification, and the use of local flaps combined with skin grafting. After 2 weeks, the sutures were removed, and patients were instructed to start functional exercises. To categorize the deformities, we divided them into 2 types: axillary-adjacent region cicatricial contracture (type I) and extended area contracture (type II).

Results

For each subtype, a specific treatment method was chosen based on a designed algorithm decision tree. Out of the total cases, 133 patients underwent treatment with various types of local flaps, including Z-plasty, whereas 63 patients received treatment involving skin grafting and different types of local flaps. At the time of discharge, the abduction angle of the shoulder joint ranged from 80 to 120 degrees. Among the 131 patients who were followed up, 108 of them adhered to a regimen of horizontal bar exercises. After a 1-year follow-up period, the abduction angle of the shoulder joint had significantly improved to a range of 110–180 degrees.

Conclusions

We have proposed a novel classification method for the correction of axillary cicatricial contracture deformity. This approach involves utilizing distinct correction strategies, in conjunction with postoperative functional exercise, to ensure the effectiveness of axillary reconstruction.
Examining Craniofacial and Velopharyngeal Structures in Premature Infants: A Window Into the Womb
Authors: Loomis-Goltl Evy I. , Power Samantha J. , Neuberger Ilana , Barhaghi Krystle , Kotlarek Katelyn J.
Published: June 2024

Background:

Very little is known about how the velopharynx and levator veli palatini muscle develop in utero. The purpose of this study was to describe craniofacial, velopharyngeal, and levator veli palatini dimensions in a group of infants born prematurely and imaged before 40 weeks gestation.

Methods:

A retrospective, descriptive study design was utilized to examine the MRI scans of 6 infants less than 40 weeks’ gestation. Imaging was initially completed for medically necessity and pulled from patients’ charts retrospectively for the purpose of this study. Craniofacial, velopharyngeal, and levator veli palatini dimensions were analyzed.

Results:

All linear measures were consistently shorter across all variable categories. While effective VP ratio was less favorable for speech in infants under 40 weeks’ gestation, angle measures such as LVP angle of origin, NSB angle, SNA angle, and SNB angle were relatively unchanged.

Conclusions:

Linear craniofacial, VP, and LVP variables tend to be smaller in infants under 40 weeks’ gestation than those reported within the first 6 months of life while angulation is relatively similar. Future research in this area may be relevant to better diagnosis of craniofacial conditions in utero.
Spectrum-effect relationship between components and antitumor activity of Lonicerae Japonicae Flos based on orthogonal partial least squares regression
Authors: Liu Tianliang , Yang Linlin , Dong Chengming , Qi Daming , Ji Baoyu , Gao Qiguo
Published: June 2024

Lonicerae Japonicae Flos is a significant food and traditional Chinese medicine, known as plant antibiotics. It has rich chemical constituents and significant pharmacological effects. The antitumor activity of Lonicerae Japonicae Flos has been clarified, but the study on its spectrum-effect relationship has not been reported. The compounds responsible for its antitumor activity are still unknown. In this study, processed products of Lonicerae Japonicae Flos at different temperatures were taken as experimental materials, and SMMC-7721, A549, and MGC80-3 cells were tested. The orthogonal partial least squares regression method was used to analyze the common compounds in different processed products and the antitumor activity. The results show that processed products have a stronger inhibitory effect on A549 cells and MGC80-3 cells than SMMC-7721 cells. Compounds such as secologanic acid, isochlorogenic acid A, serotonin, and chlorogenic acid play an important role in their antitumor effects.
Obesity-related neuropathy: the new epidemic
Authors: Elafros Melissa A. , Reynolds Evan Lee , Callaghan Brian C.
Published: June 2024

Purpose of review

To examine the evidence evaluating the association between obesity and neuropathy as well as potential interventions.

Recent findings

Although diabetes has long been associated with neuropathy, additional metabolic syndrome components, including obesity, are increasingly linked to neuropathy development, regardless of glycemic status. Preclinical rodent models as well as clinical studies are shedding light on the mechanisms of obesity-related neuropathy as well as challenges associated with slowing progression. Dietary and surgical weight loss and exercise interventions are promising, but more data is needed.

High-fat-diet rodent models have shown that obesity-related neuropathy is a product of excess glucose and lipid accumulation leading to inflammation and cell death. Clinical studies consistently demonstrate obesity is independently associated with neuropathy; therefore, likely a causal risk factor. Dietary weight loss improves neuropathy symptoms but not examination scores. Bariatric surgery and exercise are promising interventions, but larger, more rigorous studies are needed. Further research is also needed to determine the utility of weight loss medications and ideal timing for obesity interventions to prevent neuropathy.
Orthostatic Hemifacial Spasm in Idiopathic Intracranial Hypertension
Authors: Patrick Madison M. , Postma Galen K. , Bielling Rachel A.H. , Trokthi Brenda , Carey Andrew R. , Maitland Charles G.
Published: June 2024

Background:

Among the symptoms seen in idiopathic intracranial hypertension (IIH), hemifacial spasm (HFS) is rare. Orthostatic-induced HFS preceding lumbar puncture (LP) is previously unreported. We treated two patients with unusual IIH presentations. This case series reviews the few reports of HFS in IIH and proposes a mechanism for spasm occurrence.

Methods:

Case 1: A woman in her mid-40s with previously controlled IIH developed daily headache, pulsatile tinnitus, right-sided trigeminal paresthesia, and right-sided HFS. The latter 2 symptoms occurred exclusively when moving from a sitting to a standing position. Imaging was unremarkable; opening pressure (OP) on LP was 46 cmH2O with normal cerebrospinal fluid (CSF) components. Case 2: A woman in her late 40s presented with severe daily headache, pulsatile tinnitus, and left-sided HFS following weight gain. Imaging was unremarkable; OP on LP was 32 cmH2O with normal CSF components.

Results:

HFS episodes persisted following LP in both patients. Increasing and initiating acetazolamide, respectively, resolved all symptoms.

Conclusions:

Earlier suggested mechanisms of HFS are based on elevated intracranial pressure (ICP) shifting the facial nerve into proximity of a vascular structure. HFS appearing upon standing and continuing after LP, and thus a lower ICP, contradicts this. We propose a mechanism based on the degree of ICP change. This theory is grounded in the lack of intracranial compliance in IIH, wherein substantial pressure changes occur following small volume changes.
Glycation resistance and life-history traits: lessons from non-conventional animal models
Authors: Duval Cyrielle , Criscuolo François , Bertile Fabrice
Published: June 2024

Glycation reactions play a key role in the senescence process and are involved in numerous age-related pathologies, such as diabetes complications or Alzheimer’s disease. As a result, past studies on glycation have mostly focused on human and laboratory animal models for medical purposes. Very little is known about glycation and its link to senescence in wild animal species. Yet, despite feeding on high-sugar diets, several bat and bird species are long-lived and seem to escape the toxic effects of high glycaemia. The study of these models could open new avenues both for understanding the mechanisms that coevolved with glycation resistance and for treating the damaging effects of glycations in humans. Our understanding of glycaemia’s correlation to proxies of animals’ pace of life is emerging in few wild species; however, virtually nothing is known about their resistance to glycation, nor on the relationship between glycation, species’ life-history traits and individual fitness. Our review summarizes the scarce current knowledge on the links between glycation and life-history traits in non-conventional animal models, highlighting the predominance of avian research. We also investigate some key molecular and physiological parameters involved in glycation regulation, which hold promise for future research on fitness and senescence of individuals.
Is the perception of odour pleasantness shared across cultures and ecological conditions? Evidence from Amazonia, East Africa, New Guinea, Malaysia and Poland
Authors: Sorokowski Piotr , Misiak Michał , Roberts S. Craig , Kowal Marta , Butovskaya Marina , Omar-Fauzee Mohd Sofian , Huanca Tomás , Sorokowska Agnieszka
Published: June 2024

What makes an odour pleasant or unpleasant? The inherent properties of the constituent chemical compounds, or the nose of the beholder, driven by idiosyncratic differences and culture-specific learning? Here, 582 individuals, including Tanzanian Hadza hunter–gatherers, Amazonian Tsimane’ horticulturalists, Yali from the Papuan highlands and two industrialized populations (Poles, Malaysians), rated the pleasantness of 15 odour samples. We find considerable similarities in odour assessments across cultures, but our data do not fully support a claim regarding the universality of smell preferences. Despite cross-cultural similarities in olfactory assessments, probably driven by odour properties, we suggest that odour availability in ecological and cultural niches bears an undeniable effect on human odour preferences.
A red flag: an experimental analysis of the function of pink colouration in males of
Calopteryx haemorrhoidalis asturica
(Odonata: Calopterygidae)
Authors: Yu Xin , Rivas-Torres Anais , Cordero-Rivera Adolfo
Published: June 2024

Males display phenotypic characteristics that may be associated with their quality, allowing non-random mating and post-copulatory female choice. In the damselfly
Calopteryx haemorrhoidalis asturica
, males have a conspicuous pink colouration in the underside of abdominal segments 8–10, which they exhibit during pre- and post-copulatory courtship. We hypothesized that this colouration functions to increase male mating success and/or to elicit females to oviposit. We estimated mating and oviposition success of 27 males, and on the following day, treated males had their segments 8–10 painted black and control males the seventh segment. We recorded the number of male–male fights and courtships, whether the courtship ended in copulation, and whether the female remained in the territory and laid eggs. Our results indicate that the mating success of male
C. h. asturica
was not significantly affected by the removal of the pink colouration of the abdominal tip, but this colouration clearly affected their success in enticing females to oviposit. Courtship frequency, fat content and muscle mass were positively correlated to male mating rate, and the number of aggressive encounters was negatively correlated. Our study yields experimental evidence for the function of pink colouration of male
C. h. asturica
, in the context of post-copulatory sexual selection.
3D revisualization: a new method to revisit segmented data
Authors: Hu Yuzhi , Limaye Ajay , Lu Jing
Published: June 2024

3D visualization and segmentation are increasingly widely used in physical, biological and medical science, facilitating advanced investigative methodologies. However, the integration and reproduction of segmented volumes or results across the spectrum of mainstream 3D visualization platforms remain hindered by compatibility constraints. These barriers not only challenge the replication of findings but also obstruct the process of cross-validating the accuracy of 3D visualization outputs. To address this gap, we developed an innovative revisualization method implemented within the open-source framework of
Drishti
, a 3D visualization software. Leveraging four animal samples alongside three mainstream 3D visualization platforms as case studies, our method demonstrates the seamless transferability of segmented results into
Drishti
. This capability effectively fosters a new avenue for authentication and enhanced scrutiny of segmented data. By facilitating this interoperability, our approach underscores the potential for significant advancements in accuracy validation and collaborative research efforts across diverse scientific domains.
The topology of spatial networks affects stability in experimental metacommunities
Authors: Arancibia Paulina A.
Published: June 2024

Understanding the drivers of community stability has been a central goal in ecology. Traditionally, emphasis has been placed on studying the effects of biotic interactions on community variability, and less is understood about how the spatial configuration of habitats promotes or hinders metacommunity stability. To test the effects of contrasting spatial configurations on metacommunity stability, I designed metacommunities with patches connected as random or scale-free networks. In these microcosms, two prey and one protist predator dispersed, and I evaluated community persistence, tracked biomass variations, and measured synchrony between local communities and the whole metacommunity. After 30 generations, scale-free metacommunities had lower global biomass variability and higher persistence, suggesting higher stability. Synchrony between patches was lower in scale-free metacommunities. Patches in scale-free metacommunities showed a positive relationship between variability and patch connectivity, indicating higher stability in isolated communities. No clear relationship between variability and patch connectivity was observed in random networks. These results suggest the increased heterogeneity in connectivity of scale-free networks favours the prevalence of isolated patches of the metacommunity, which likely act as refugia against competition—the dominant interaction in this system—resulting in higher global stability. These results highlight the importance of accounting for network topology in the study of spatial dynamics.
Levels of 5α-reductase gene in intestinal lavage fluid decrease with progression of colorectal cancer
Authors: Fujii Tadashi , Nakagawa Yoshihito , Funasaka Kohei , Hirooka Yoshiki , Tochio Takumi
Published: June 2024

Introduction. Colorectal cancer (CRC) is a leading cause of cancer deaths, closely linked to the intestinal microbiota and bile acid metabolism. Secondary bile acids, like deoxycholic and lithocholic acid, are associated with increased CRC risk due to their disruption of vital cellular functions. In contrast, isoallolithocholic acid (isoalloLCA) shows potential health benefits, highlighting the complex role of bile acids in CRC. A specific primer set was previously developed to amplify homologs of the 5α-reductase gene (5ar), which are involved in the biosynthesis of isoalloLCA, thereby enabling the estimation of abundance of 5ar (5ar levels) in the intestine.

Hypothesis/Gap Statement. We hypothesized that 5ar levels in the intestine are associated with CRC.

Aim. This study aimed to investigate intestinal 5ar levels and compare them across different stages of the adenoma–carcinoma sequence, providing insights into novel strategies for monitoring CRC risk.

Methodology. DNA was extracted from intestinal lavage fluids (ILF) collected during 144 colonoscopies. Next-generation sequencing (NGS) was employed to examine the sequence of 5ar homologues, using a specific primer set on DNA from seven selected ILFs – four from carcinoma patients and three from individuals with non-neoplastic mucosa. Additionally, we used quantitative PCR (qPCR) to measure 5ar levels in all 144 DNA samples.

Results. We conducted 144 colonoscopies and categorized patients according to the adenoma–cancer sequence: 52 with non-neoplastic mucosa, 69 with adenomas and 23 with carcinoma. Analysis of 292,042 NGS-derived 5ar sequences revealed the seven most prevalent amplicon sequence variants, each 254 base pairs in length. These closely matched or were identical to 5ar sequences in Bacteroides uniformis, Phocaeicola vulgatus and Phocaeicola dorei. Furthermore, qPCR analysis demonstrated significantly lower 5ar levels in the carcinoma group compared to those in the non-neoplastic mucosa group (P = 0.0004). A similar, though not statistically significant, trend was observed in the adenoma group (P = 0.0763), suggesting that 5ar levels decrease as CRC progresses.

Conclusion. These findings indicate that PCR-based monitoring of 5ar levels in intestinal samples over time could provide a non-invasive, rapid and cost-effective method for assessing an increased risk of CRC.
START Diabetes Prevention: A Multi-Level Strategy for Primary Care Clinics
Authors: Tseng Eva , Marsteller Jill A. , Clark Jeanne M. , Maruthur Nisa M.
Published: June 2024

Background

Prediabetes, a high-risk state for developing diabetes, affects more than 1 in 3 adults nationally. However, <5% of people with prediabetes are receiving any treatment for prediabetes. Prior intervention studies for increasing prediabetes treatment uptake have largely focused on individual barriers with few multi-level interventions that address clinician- and system-level barriers.

Objective

To measure the effectiveness of a multi-level intervention on uptake of prediabetes treatment in a primary care clinic.

Design

Pragmatic study of the START (Screen, Test, Act, Refer and Treat) Diabetes Prevention intervention.

Participants

The START Diabetes Prevention intervention was implemented in a suburban primary care clinic outside of Baltimore compared to a control clinic in the same area over a 12-month period.

Intervention

START Diabetes Prevention intervention included a structured workflow, shared decision-making resources and electronic health record clinical decision support tools.

Main Measures

Uptake of prediabetes treatment, defined as Diabetes Prevention Program referral, metformin prescription and/or medical nutrition referral within 30 days of any PCC visit.

Key Results

We demonstrated greater uptake of preventive treatment among patients with prediabetes in the intervention clinic vs. control clinic receiving usual care (11.6% vs. 6.7%, p<0.001). More patients in the intervention vs. control clinic reported their PCC discussed prediabetes with them (60% vs. 48%, p=0.002) and more felt overall that they understood what their doctor was telling them about prediabetes and that their opinion was valued. The START Diabetes Prevention Strategy had greater acceptability and usefulness to PCCs at the study end compared to baseline.

Conclusions

A low-touch multi-level intervention is effective in increasing prediabetes treatment uptake. The intervention was also acceptable and feasible for clinicians, and enhanced patient understanding and discussions of prediabetes with their clinicians.
Weighted 2D-kernel density estimations provide a new probabilistic measure for epigenetic age
Authors: Perez-Correa Juan-Felipe , Stiehl Thomas , Marioni Riccardo E. , Corley Janie , Cox Simon R. , Costa Ivan G. , Wagner Wolfgang
Published: June 2024

Background

Epigenetic aging signatures can provide insights into the human aging process. Within the last decade many alternative epigenetic clocks have been described, which are typically based on linear regression analysis of DNA methylation at multiple CG dinucleotides (CpGs). However, this approach assumes that the epigenetic modifications follow either a continuous linear or logarithmic trajectory. In this study, we explored an alternative non-parametric approach using 2D-kernel density estimation (KDE) to determine epigenetic age.

Results

We used Illumina BeadChip profiles of blood samples of various studies, exemplarily selected the 27 CpGs with highest linear correlation with chronological age (R2> 0.7), and computed KDEs for each of them. The probability profiles for individual KDEs were further integrated by a genetic algorithm to assign an optimal weight to each CpG. Our weighted 2D-kernel density estimation model (WKDE) facilitated age-predictions with similar correlation and precision (R2= 0.81, median absolute error = 4 years) as other commonly used clocks. Furthermore, our approach provided a variation score, which reflects the inherent variation of age-related epigenetic changes at different CpG sites within a given sample. An increase of the variation score by one unit reduced the mortality risk by 9.2% (95% CI (0.8387, 0.9872), P <0.0160) in the Lothian Birth Cohort 1921 after adjusting for chronological age and sex.

Conclusions

We describe a new method using weighted 2D-kernel density estimation (WKDE) for accurate epigenetic age-predictions and to calculate variation scores, which provide an additional variable to estimate biological age.
Designing pathways for bioproducing complex chemicals by combining tools for pathway extraction and ranking
Authors: Sveshnikova Anastasia , Oftadeh Omid , Hatzimanikatis Vassily
Published: June 2024

The synthesis of many important biochemicals involves complex molecules and many reactions. Therefore, the design and optimization of whole-cell biocatalysts to produce these molecules requires the use of metabolic modeling. Such modeling involves the extraction of the production pathways from biochemical databases and their integration into genome-scale metabolic models of the host organism. However, the synthesis of such complex molecules requires reactions from multiple pathways operating in balanced subnetworks that are not assembled in existing databases. Here we present SubNetX, a novel computational algorithm that extracts reactions from a given reaction database and assembles balanced reaction subnetworks to produce a target biochemical from a selected set of precursor metabolites, energy currencies, and cofactors of the host organism. These subnetworks can be directly integrated into whole-cell metabolic models, and using available methods, we can then reconstruct all alternative biosynthetic pathways and rank them according to design criteria such as yield, pathway length, and other optimization goals. We applied SubNetX to eight selected secondary metabolites and one non-natural chemical used as pharmaceuticals to demonstrate the potential of this pipeline.
InteractORF, predictions of human sORF functions from an interactome study
Authors: Slivak Mathilde , Choteau Sébastien A. , Pierre Philippe , Spinelli Lionel , Zanzoni Andreas , Brun Christine
Published: June 2024

Short Open Reading Frames (sORFs) are ubiquitous genomic elements that have been overlooked for years, essentially due to their short length (< 100 residues) and the use of alternative start codons (other than AUG). However, some may encode functional peptides, so-called sORF-encoded peptides (sPEPs), whose functions remain mainly unknown.

In this study, we propose a system approach to determine the functions of sPEPs in monocytes. We first predicted the interactions of sPEPs with canonical proteins and analyzed the interfaces of interactions as well as the set of canonical proteins interacting with sPEPs. Second, by joining these sPEP-canonical protein interactions with the human interactome, we predicted the first sPEP interactome network to date. Based on its topology, we then predicted the function of the sPEPs. Our results suggest that the majority of sPEPs are involved in key biological functions, including regulatory functions, metabolism, and signaling. Overall, the diversity in the predicted functions of the sPEPs underlines the prevalence of their role in different biological mechanisms, suggesting that they are major regulatory actors.
Diversity and assembly of the microbiome of a leguminous plant along an urbanization gradient
Authors: Murray-Stoker David , Rossi Laura , Johnson Marc T. J.
Published: June 2024

Interactions between plants and bacterial communities are essential for host physiology and broader ecosystem functioning, but plant-microbiome interactions can be disrupted by environmental change like urbanization. Here, we evaluated how urbanization affected the diversity and assembly of soil and white clover (Trifolium repens) microbiome communities. We sampled 35 populations of white clover and associated roots and soil along an urbanization gradient. Soil alpha diversity was greater at the urban and rural limits of the gradient and lower in suburban habitats, while root alpha diversity was not influenced by urbanization. Root and soil bacterial communities had distinct compositions, with greater beta diversity for root compared to soil microbiomes. We found that urbanization directly and indirectly affected soil microbiome assembly, particularly through soil carbon. In contrast, root microbiome assembly was not linked to urbanization, which suggested that the host plant acted as an additional filter on microbiome assembly independent of urbanization. We also found that key pathogenic bacteria likeLegionellaandClostridiumvaried in abundance with urbanization, which has implications for human health. Together, our study underscores the importance of examining how urban-driven environmental change alters the ecology and function of soil and root microbiomes.
The effects of biological knowledge graph topology on embedding-based link prediction
Authors: Bradshaw Michael S. , Gaskell Alisa , Layer Ryan M.
Published: June 2024

Due to the limited information available about rare diseases and their causal variants, knowledge graphs are often used to augment our understanding and make inferences about new gene-disease connections. Knowledge graph embedding methods have been successfully applied to various biomedical link prediction tasks but have yet to be adopted for rare disease variant prioritization. Here, we explore the effect of knowledge graph topology on Knowledge graph embedding link prediction performance and challenge the assumption that massively aggregating knowledge graphs is beneficial in deciphering rare disease cases and improving outcomes. We find that using a filtered version of the Monarch knowledge graph with only 11% of the size of the full knowledge graph results in improved model predictive performance. Additionally, we found that as information is aggregated and re-added to the knowledge graph, performance improvements are driven by the quality of information, not the quantity.
Sequence Complexity and Monomer Rigidity Control the Morphologies and Aging Dynamics of Protein Aggregates
Authors: Takaki Ryota , Thirumalai D.
Published: June 2024

Understanding the biophysical basis of protein aggregation is important in biology because of the potential link to several misfolding diseases. Although experiments have shown that protein aggregates adopt a variety of morphologies, the dynamics of their formation are less well characterized. Here, we introduce a minimal model to explore the dependence of the aggregation dynamics on the structural and sequence features of the monomers. Using simulations we demonstrate that sequence complexity (codified in terms of word entropy) and monomer rigidity profoundly influence the dynamics and morphology of the aggregates. Flexible monomers with low sequence complexity (corresponding to repeat sequences) form liquid-like droplets that exhibit ergodic behavior. Strikingly, these aggregates abruptly transition to more ordered structures, reminiscent of amyloid fibrils, when the monomer rigidity is increased. In contrast, aggregates resulting from monomers with high sequence complexity are amorphous and display non-ergodic glassy dynamics. The heterogeneous dynamics of the low and high-complexity sequences follow stretched exponential kinetics, which is one of the characteristics of glassy dynamics. Importantly, at non-zero values of the bending rigidities, the aggregates age with the relaxation times that increase with the waiting time. Informed by these findings, we provide insights into aging dynamics in protein condensates and contrast the behavior with the dynamics expected in RNA repeat sequences. Our findings underscore the influence of the monomer characteristics in shaping the morphology and dynamics of protein aggregates, thus providing a foundation for deciphering the general rules governing the behavior of protein condensates.

Significance Statement

Protein aggregates exhibit diverse morphology, exemplified by amyloid fibrils, gel-like structures, and liquid-like condensates. Differences in the morphologies in identical proteins play important functional roles in several diseases. Simulations using a minimal model show that such structures are encoded in the sequence complexity and bending rigidity of the monomers. The low-complexity flexible sequences form liquid droplets, whose relaxation dynamics are ergodic. In contrast, rigid low and high-complexity sequences, which form ordered nematic fibril-like structures and amorphous aggregates, exhibit heterogenous, non-ergodic dynamics. The relaxation times under these conditions increase as the waiting time increases, which is a signature of aging. The implications of our findings for aging in intrinsically dis-ordered proteins and repeat RNA sequences are outlined.
Species and Genetic Diversity of Nontuberculous Mycobacteria (NTM) in Suspected Tuberculosis Cases in East Azerbaijan, Iran: A Cross-sectional Analysis
Authors: Roshdi Maleki M
Published: June 2024

Introduction

The outbreak of nontuberculous mycobacterial (NTM) infections has increased worldwide, attracting attention in routine diagnostic settings, particularly among patients with suspected tuberculosis. This study aimed to acquire knowledge of NTM infections in patients with suspected tuberculosis and to evaluate the genetic diversity of the strains.

Methods

In this study, 230 clinical specimens were collected from suspected tuberculosis patients. Following decontamination with N-Acetyl-L-cysteine–sodium hydroxide (NALC-NaOH), the sediments of specimens were inoculated onto Löwenstein–Jensen medium and then incubated at 30°C for 8 weeks. The samples that yielded positive cultures underwent evaluation through sequencing conserved fragments ofIS6110andhsp65. For those samples that were not identified as part of theM. tuberculosiscomplex (MTC) byIS6110PCR, further analysis was conducted using PCR to detect fragments of thehsp65gene.

Results

Twenty-one NTM species were isolated from 230 clinical specimens (14 NTM from pulmonary specimens and 7 from extrapulmonary specimens). Among these, 12 (57.14%) were rapid-growing mycobacteria (RGM) and 9 (42.85%) were slow-growing mycobacteria (SGM). NoM. aviumcomplex (MAC) was identified in any of the specimens. Notably,M. kansasii, M. gordonae, andM. abscessusstrains exhibited significant genetic diversity.

Conclusions

The prevalence of infections attributed to nontuberculous species surpasses that of tuberculosis. These findings underscore the importance of exploring NTM species in individuals suspected of having TB.
The FBA Solution Space Kernel – Introduction and Illustrative Examples
Authors: Verwoerd Wynand S. , Mao Longfei
Published: June 2024

Background

The solution space of an FBA-based model of cellular metabolism, can be characterised by extraction of a bounded, low dimensional kernel (the SSK) that facilitates perceiving it as a geometric object in multidimensional flux space. The aim is to produce an amenable description, intermediate between the single feasible extreme flux of FBA, and the intractable proliferation of extreme modes in conventional solution space descriptions. Fluxes that remain fixed are separated off while the focus of interest is put on the subset of variable fluxes that have a nonzero but finite range of values. For unbounded fluxes, a finite subrange that geometrically corresponds to the variable flux range is determined and is supplemented by a limited set of rays that encapsulates their unbounded aspects. In this way the kernel emphasises the realistic range of flux variation allowed in the interconnected biochemical network by e.g. limited nutrient uptake, an optimised objective and other model constraints. This work builds on the full presentation of the SSK approach in a research monograph.

Results

It is demonstrated how knowledge of the SSK and accompanying rays can be exploited to explore representative flux states of the metabolic network. Noting that bioengineering interventions such as gene knockouts modify the solution space, new tools based on the SSK analysis are presented here that predict the effects of such interventions on a target flux constructed to represent a desired metabolic output. A simple metabolic model is used first to demonstrate the special concepts and constructions needed to define and compute the SSK. The demonstration model is tweaked to produce typical behaviours of larger models, but with kernels in 1,2 or 3 dimensions that are explicitly displayed to visualise the concepts. General applicability to models where visualisation is inaccessible, is illustrated by showing evaluation of potential bioengineering strategies for a genome scale model.

Conclusions

SSKernel is a flexible interactive tool that facilitates an overview of the FBA solution space as a multidimensional geometric object, in terms of a manageable number of parameters. It allows exploration of effects on this solution space from metabolic interventions, and can be used to investigate bioengineering strategies to manipulate cellular metabolism.
Multiple regulators control the biosynthesis of brasilicardin inNocardia terpenica
Authors: Wolański Marcin , Krawiec Michał , Nieselt Kay , Schwarz Tobias , Dere Dilek , Krismer Bernhard , Cano-Prieto Carolina , Gross Harald , Zakrzewska-Czerwińska Jolanta
Published: June 2024

Brasilicardin A, BraA, is a secondary metabolite produced by the bacteriumNocardia terpenica, and a promising drug due to its potent immunosuppressive activity and low cytotoxicity. Currently, a semisynthetic approach confers production of a complete compound but suffers from insufficient heterologous biosynthesis of BraA intermediates used in the chemical semi-synthesis steps leading to only lab scale quantities of the compound. A better understanding of the involved gene expression regulatory pathways within the brasilicardin biosynthetic gene cluster, Bra-BGC, is a prerequisite to further improve production titers. However, the transcriptional regulation of the Bra-BGC has only been superficially analyzed, till now.

In this study, we comprehensively analyze the functions of several unstudied transcriptional regulators, KstR, SdpR and OmpR, encoded within the close vicinity of the Bra-BGC, and delve into the role of the previously described cluster-situated activator Bra12. We present, that Bra12 and the novel regulator SdpR, bind several DNA sequences located in the promoter regions of the genes essential for BraA biosynthesis. Subsequently, we demonstrate the complex regulatory network through which both regulators are capable of controlling activity of those gene promoters and thus gene expression in Bra-BGC. Furthermore, using the heterologous producer strainAmycolatopsis japonicum, we present, that Bra12 and SdpR regulators play opposite roles in brasilicardin congener biosynthesis. Finally, we propose a comprehensive model of multilevel gene expression regulation in Bra-BGC and propose the roles of locally encoded transcriptional regulators.
Dimeric assembly of F1-like ATPase for the gliding motility ofMycoplasma
Authors: Toyonaga Takuma , Kato Takayuki , Kawamoto Akihiro , Miyata Tomoko , Kawakami Keisuke , Fujita Junso , Hamaguchi Tasuku , Namba Keiichi , Miyata Makoto
Published: June 2024

Rotary ATPases, including F1Fo- and V/A-ATPases, are molecular motors that exhibit rotational movements for energy conversion1. In the gliding bacterium,Mycoplasma mobile, a dimeric F1-like ATPase forms a chain structure with the glycolytic enzyme, phosphoglycerate kinase (PGK), within the cell2, which is proposed to drive the bacterial gliding motility2–4. However, the mechanisms of force generation and transmission remain unclear. Here, we present a 3.2 Å resolution structure of the dimeric ATPase complex obtained using electron cryomicroscopy (cryo-EM). Notably, the structure revealed an assembly distinct from that of known dimeric forms of F1Fo-ATPase5, despite containing conserved F1-ATPase structures. The two ATPase units were interconnected by GliD dimers, previously identified as MMOB16202,6. Gliβ, a homologue of the F1-ATPase catalytic subunit6, exhibited a specific N-terminal region that incorporates PGK into the complex. Structural conformations of the catalytic subunits, catalytically important residues, and nucleotide-binding pattern of the catalytic sites of the ATPase displayed strong similarities to F1-ATPase, suggesting a rotation based on the rotary catalytic mechanism conserved in rotary ATPases1,7–10. Overall, the cryo-EM structure underscores an evolutionary connection in the rotary ATPases and provides insights into the mechanism through which F1-like ATPase drives bacterial gliding motility.