bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Between Integration and Patient Experience in Hospital-Based Health Systems: An Exploration of Horizontal and Vertical Forms of Integration
Authors: Torres Jillian S. , Diana Mark L.
Published: September 2024

Goal:

The U.S. hospital sector is experiencing record levels of integration, with more than half of U.S. physicians and nearly three quarters of all hospitals affiliated with one of slightly more than 630 health systems. However, there is growing evidence to suggest that health system integration is associated with more expensive and lower quality care. The goal of this research is to explore the associations between forms of health system integration and hospital patient experience scores.

Methods:

A cross-section of data for the year 2019 was assembled and analyzed from the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patient experience survey. Data from theCompendium of US Health Systems, published by the Agency for Healthcare Research and Quality (AHRQ), and the American Hospital Association (AHA) Annual Survey were used to obtain independent variables and hospital-level covariates. A series of multivariable regressions was used to explore the associations between forms of health system integration and hospital patient experience scores across three domains: overall impression of the hospital; experiences with staff; and the hospital environment. Forms of both horizontal integration (i.e., number of hospitals owned by hospital-based health systems) and vertical integration (i.e., physician-hospital integration, nursing home ownership, accountable care organization [ACO] participation, group purchasing, contract management, offering insurance products, and investor ownership) were explored.

Principal Findings:

Although horizontal integration was not associated with any meaningful differences in patient experience scores, health systems with physician–hospital integration were associated with overall impression scores that were 2 percentage points higher than systems without physician integration. Similarly, contract management and membership in a group purchasing organization were associated with overall impression and environment scores that were 2 to 3 percentage points higher than hospitals that did not engage in those forms of integration. By contrast, investor ownership was associated with a 5% lower score for overall patient experience compared with other forms of ownership.

Practical Applications:

The findings of this study suggest that hospitals in more vertically integrated systems may have higher patient experience scores than independent hospitals and those that belong exclusively to horizontally integrated systems. Thus, there are elements of vertical integration that could benefit patients and be worth pursuing. Conversely, higher degrees of horizontal integration in the form of multihospital ownership may not be of any benefit to patients and should be pursued with caution.
Recognition of Scrotal Ulceration After Hyperthermic Intraperitoneal Chemotherapy
Authors: Ninomiya Mark , Ellis Elizabeth , Gabrielsen J. Scott
Published: September 2024

Scrotal ulceration after hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) is a rare but severe complication. This is a case report of a patient presenting with painful nonhealing scrotal ulceration after 2 treatments of HIPEC with MMC. After failing conservative management, biopsy demonstrated ulceration with thrombosis of adjacent vessels. Excision of the affected area with scrotoplasty completely resolved his pain. Scrotal ulceration after HIPEC is a debilitating complication. While preventative measures are not well understood, early recognition and surgical excision of scrotal ulceration after HIPEC can lead to rapid resolution of symptoms.
Severity of Lower Urinary Tract Symptoms Predicts Neurologic Quality of Life in Patients With Multiple Sclerosis
Authors: Kong Lily , Blubaum Aleksandar C. , Blakely Stephen A. , Miravalle Augusto A. , Flynn Brian J.
Published: September 2024

Introduction:

Lower urinary tract symptoms (LUTSs) are underreported in patients with multiple sclerosis (MS). We aim to define the incidence of LUTSs in patients with MS and their effect on neurologic quality of life.

Materials and Methods:

We identified patients presenting to the neurology clinic for routine follow-up for multiple sclerosis. Each patient responded to validated questionnaires regarding urinary quality of life using the Bladder Control Scale (BLCS) from the Multiple Sclerosis Quality-of-Life Inventory (MSQLI) and overall Quality of Life in Neurological Disorders (NeuroQOL). A retrospective chart review was performed to assess for the presence of lower urinary tract symptoms. Overall neurologic quality of life was measured in the presence and absence of LUTS, and P-values were calculated using the Student t test. A urinary quality-of-life score was correlated with an overall neurologic quality-of-life score using the Spearman rank correlation coefficient.

Results:

The study included 91 patients who completed the validated questionnaires. Of the 91 patients, 85 (93%) described the presence of at least 1 lower urinary tract symptom. The most common symptoms were urgency (84%), frequency (69%), incontinence (54%), and retention (38%). Seventy-two (79%) patients reported that LUTS negatively affected urinary quality of life. The presence of LUTS negatively affected the overall neurologic quality of life. Urinary quality of life was predictive of the overall neurologic quality of life (−0.22, P = .04).

Conclusions:

LUTSs are very common in patients with MS, and they not only significantly affect but also predict the overall neurologic quality of life.
New Insights Into Pharmacology of GABAA Receptor Alpha Subunits–Selective Modulators
Authors: Moraru Miruna Valeria , Stoleru Smaranda , Zugravu Aurelian , Coman Oana Andreia , Fulga Ion
Published: September 2024

Background:

Benzodiazepines have long held a leading position in medical therapeutics, known for their multiple common therapeutic properties and primarily being prescribed for anxiety and insomnia. However, their lack of specificity and various side effects have led to a reevaluation of their long-term use, resulting in a rapid growth in the literature focusing on targeted therapies.

Areas of Uncertainty:

Despite many efforts, uncertainties persist and there are heterogeneous findings across studies regarding the pharmacological effects attributed to gamma-aminobutyric acid type A (GABAA) receptor subunits. Selective compounds targeting GABAA receptor alpha subunits are currently under active research and definitive conclusions have not been reached yet. Some compounds have not progressed to clinical trials, while others, if advanced, have been halted. These challenges emphasize the difficulty in translating preclinical findings into clinical use.

Data Sources:

A literature review was conducted using the PubMed database, searching for articles discussing GABAA receptor subunits. The search was refined by including only selective compounds with potential anxiolytic and cognitive enhancement properties.

Results:

Findings reveal compounds with promising anxiolytic and antidepressant effects with minimal sedation and absence of tolerance development. Moreover, some compounds show potential in alleviating cognitive dysfunction. There is a broad spectrum of potential therapeutic applications for selective compounds, ranging from neurological disorders such as epilepsy and neuropathic pain to cognitive dysfunction–related conditions. Currently, the leading selective compounds with the most promising results in ongoing clinical trials are basmisanil and darigabat. Basmisanil holds further exploration potential in the treatment of cognitive impairment and related conditions, while darigabat shows progress in the advancement of adjunctive therapy of focal onset seizures and for the treatment of panic disorder, respectively.

Conclusions:

Future drug discovery efforts are encouraged to focus on positive allosteric modulators that selectively target the α2, α3 subunits and negative/positive allosteric modulators that target the α5 subunit of the GABAA receptor. The pursuit of ligands possessing only anxiolytic effects or those enhancing cognition continues to be an important focus for future research, with promising advancements depicted in recent studies.
Prophylactic Mesh-related Reoperations and Mesh-related Problems During Subsequent Relaparotomies: Long-term Results From the PRIMA Trial
Authors: van den Berg Rudolf , van den Dop L. Matthijs , Timmermans Lucas , van den Berg Michiel , Pierik Robert E.G.J.M. , Zwaans Willem A.R. , Reim Daniel , Buijk Steven E. , van Brussel Jerome P. , Lange Johan F. , Jeekel Johannes J. , Tanis Pieter J.
Published: September 2024

Objective:

This study aimed to evaluate all mesh-related problems during reoperations after mesh-reinforcement 15 years after the start of the PRIMA trial. SUMMARY BACKGROUND DATA Prophylactic mesh reinforcement during closure of a midline laparotomy has proven to reduce the incidence of incisional hernia, especially in high-risk patients, but long-term mesh-related morbidity is largely unknown.

Methods:

Patients receiving a prophylactic onlay or retro-rectus mesh in the PRIMA trial between 2009 and 2012 were included on an as-treated basis from participating centers that made reoperation notes available. Main outcomes were the incidences of complications requiring mesh explantation, mesh-related ileus, and mesh-related problems during laparotomy for other diagnoses.

Methods:

Out of 373 patients randomized to prophylactic mesh reinforcement, 242 were included: 127 with onlay and 115 patients with retrorectus mesh. Median follow-up is 27 months (IQR 12-78). Thirty-four patients underwent reoperation for any reason during entire follow-up, 22 after onlay (17.3%) and 12 after retrorectus mesh (10.4%). Reoperation rate for complications that required mesh explantation was 4/127 (3.1%) after onlay and 0/115 (0%) after retrorectus mesh. Mesh-related ileus occurred in none of the onlay group, and 3/115 (2.6%) in the retrorectus group. During subsequent laparotomies for other primary diagnoses, adhesions to the mesh were noted in 3/10 patients in the onlay group and 1/5 patients in the retro-rectus group. Overall, the mesh was removed in 10/127 (7.9%) in the onlay group and 7/115 (6.1%) patients in the retro-rectus group.

Conclusions:

In high-risk patients receiving a prophylactic mesh during midline laparotomy closure, low incidences of mesh-related complications requiring reoperation and mesh-related problems during unrelated subsequent laparotomies were found, for both the onlay and retrorectus techniques.
Platelet-rich plasma enhances rib fracture strength and callus formation in vivo
Authors: Camarena Adrian , Kang Lillian , Mirando Anthony J. , Augustine Emily , McMillian Najerie S. , Stinson Natasha C. , Agarwal Suresh M. , Becker Matthew L. , Hilton Matthew J. , Fernandez-Moure Joseph S.
Published: September 2024

BACKGROUND

Rib fractures are a common traumatic injury affecting more than 350,000 patients a year. Early stabilization has shown to be effective in reducing pulmonary complications. Platelet-rich plasma (PRP) is a growth factor–rich blood product known to improve soft tissue and bone healing. We hypothesized that the addition of PRP to a rib fracture site would accelerate callus formation and improve callus strength.

METHODS

Platelet-rich plasma was isolated from pooled Lewis rat blood and quantified. Thirty-two Lewis rats underwent fracture of the sixth rib and were treated with 100 μL PRP (1 × 106 platelets/μL) or saline. At 2 weeks, ribs were harvested and underwent a 3-point bend, x-ray, and microcomputed tomography, and callus sections were stained with 4′,6-diamidino-2-phenylindole and Alcian blue and picrosirius red. At 6 weeks, ribs were harvested and underwent a 3-point bend test, x-ray, microcomputed tomography, and Alcian blue and picrosirius red staining.

RESULTS

At 2 weeks, PRP increased callus diameter (9.3 mm vs. 4.3 mm, p = 0.0002), callus index (4.5 vs. 2.1, p = 0.0002), bone volume/total volume (0.0551 vs. 0.0361, p = 0.0024), cellularization (2,364 vs. 1,196, p < 0.0001), and cartilage (12.12% vs. 3.11%, p = 0.0001) and collagen (6.64% vs. 4.85%, p = 0.0087) content compared with controls. At 6 weeks, PRP increased fracture callus diameter (5.0 mm vs. 4.0 mm, 0.0466), callus index (2.5 vs. 2.0, p = 0.0466), BV/TV (0.0415 vs. 0.0308, p = 0.0358), and higher cartilage (8.21% vs. 3.26%, p < 0.0001) and collagen (37.61% vs. 28.00%, p = 0.0022) content compared with controls. At 6 weeks, PRP samples trended toward improved mechanical characteristics; however, these results did not reach significance (p > 0.05).

CONCLUSION

Rib fractures are a common injury, and accelerated stabilization could improve clinical outcomes. Platelet-rich plasma significantly increased callus size, calcium deposition, and cartilage and collagen content at 2 and 6 weeks and trended toward improved strength and toughness on mechanical analysis at 6 weeks compared with controls, although this did not reach significance. These findings suggest that PRP may be a useful adjunct to accelerate and improve fracture healing in high-risk patients.
Psychotherapies for the treatment of personality disorders: the state of the art
Authors: Emmelkamp Paul M.G. , Meyerbröker Katharina
Published: September 2024

Purpose of review

To provide an update of systematic reviews, meta-analyses and recent clinical outcome studies for personality disorder (PD) in order to investigate the state of the art of the evidence of psychotherapy for personality disorders

Recent findings

Few outcome studies in patients with Cluster A and Cluster C PD have been conducted, which limits the conclusions which can be drawn. Most recently published research has been conducted with borderline PD. There is limited evidence that dialectical behavior therapy (DBT), mentalization based therapy and schema therapy are more effective than treatment as usual. There is no convincing evidence that long and intensive therapy is more effective than short and less intensive therapy. Drop-out is rather high for patients with borderline PD. Group therapy results in more drop-outs than individual therapy

There is a clear need of studies evaluating whether psychotherapies developed for PDs are more effective than CBT for patients with Cluster C PD. Given that studies with patients with Cluster B PD suggest that longer treatment of DBT and mentalization-based treatment is not more effective than shorter treatment this needs to be studied with other evidence-based therapies as well. Serious efforts are needed to evaluate therapies for patients with Cluster A PDs.
Self-driving development of perfusion processes for monoclonal antibody production
Authors: Müller Claudio , Vuillemin Thomas , Gadiyar Chethana Janardhana , Bielser Jean-Marc , Souquet Jonathan , Fagnani Alessandro , Sokolov Michael , von Stosch Moritz , Feidl Fabian , Butté Alessandro , Cruz Bournazou Mariano Nicolas
Published: September 2024

It is essential to increase the number of autonomous agents bioprocess development for biopharma innovation to shorten time and resource utilization in the path from product to process. While robotics and machine learning have significantly accelerated drug discovery and initial screening, the later stages of development have seen improvement only in the experimental automation but lack advanced computational tools for experimental planning and execution. For instance, during development of new monoclonal antibodies, the search for optimal upstream conditions (feeding strategy, pH, temperature, media composition, etc.) is often performed in highly advanced high-throughput (HT) mini-bioreactor systems. However, the integration of machine learning tools for experiment design and operation in these systems remains underdeveloped. In this study, we introduce an integrated framework composed by a Bayesian experimental design algorithm, a cognitive digital twin of the cultivation system, and an advanced 24 parallel mini-bioreactor perfusion experimental setup. The result is an autonomous experimental machine capable of 1. embedding existing process knowledge, 2. learning during experimentation, 3. Using information from similar processes, 4. Notifying events in the near future, and 5. Autonomously operating the parallel cultivation setup to reach challenging objectives. As a proof of concept, we present experimental results of 27 days long cultivations operated by an autonomous software agent reaching challenging goals as are increasing the VCV and maximizing the viability of the cultivation up to its end.
Vascular HIF2 signaling prevents cardiomegaly, alveolar congestion and capillary remodeling during chronic hypoxia
Authors: Teresa Albendea-Gomez , Susana Mendoza-Tamajon , Rosana Castro-Mecinas , Beatriz Escobar , Susana Ferreira Rocha , Sonia Urra-Balduz , Angel Nicolas-Avila Jose , Eduardo Oliver , Maria Villalba-Orero , Silvia Martin-Puig
Published: September 2024

Hypoxia is associated with the onset of cardiovascular diseases including cardiac hypertrophy and pulmonary arterial hypertension (PAH). Endothelial HIF2 signaling mediates pulmonary arterial remodeling and subsequent right ventricular systolic pressure (RVSP) elevation during chronic hypoxia, encouraging novel therapeutic opportunities for PAH based on specific HIF2 inhibitors. Nevertheless, HIF2 relevance beyond the pulmonary endothelium or in the cardiac adaptation to hypoxia remains elusive. Wilms tumor 1 lineage contributes to heart and lung vascular compartments including pericytes, endothelial and smooth muscle cells. Here we describe the response to chronic hypoxia of a novel HIF2 mutant mouse model in the Wt1 lineage (Hif2/Wt1cKO).Hif2/Wt1cKO is protected against pulmonary remodeling and increased RVSP induced by hypoxia, but displays alveolar congestion, inflammation and hemorrhages associated with microvascular instability. Furthermore, lack of HIF2 in the Wt1 lineage leads to cardiomegaly, capillary remodeling, right and left ventricular hypertrophy, systolic dysfunction and left ventricular dilation, suggesting pulmonary-independent cardiac direct roles of HIF2 in hypoxia. These structural defects are partially restored upon reoxygenation, while functional parameters remain altered. Our results suggest that cardiopulmonary HIF2 signaling prevents excessive vascular proliferation during chronic hypoxia and define novel protective roles of HIF2 to warrant stable microvasculature and organ function.
DeepDiveR – A software for deep learning estimation of palaeodiversity from fossil occurrences
Authors: Cooper Rebecca Brown , Allen Bethany J , Silvestro Daniele
Published: September 2024

The incompleteness of the fossil record, in particular variation in preservation and sampling through space and time, presents a barrier to estimating changes in biodiversity which standard statistical methods struggle to account for. Here we present DeepDiveR, an R package for the DeepDive program enabling estimation of biodiversity from fossil occurrence data. The method uses a simulation-trained deep neural network to generate predictions of biodiversity change through time, while accounting for temporal, spatial and taxonomic heterogeneities in preservation. DeepDiveR can be readily used to explore the extinct biodiversity of different clades. We demonstrate the pipeline to build and customise analyses, including consideration of changes in biogeography. We also further develop the model to integrate information about modern diversity in the case of extant clades and introduce a function that automatically adjusts the parameterization of the simulations to generate training data that reflect the distribution of empirical datasets. To demonstrate the software, we analyse the fossil record of the order Carnivora through the Cenozoic, finding a peak in diversity in the Late Miocene and a 37% species loss since the Pleistocene. Our implementation includes the generation summary statistics and plots that allow for an evaluation of the model performance and diversity estimations and a configuration file that captures all parameters required to guarantee the full reproducibility of the results.
Proliferation symmetry breaking in growing tissues
Authors: Li Xinzhi , Datta Aniruddha , Banerjee Shiladitya
Published: September 2024

Morphogenesis of developing tissues results from anisotropic growth, typically driven by polarized patterns of gene expression. Here we propose an alternative model of anisotropic growth driven by self-organized feed-back between cell polarity, mechanical pressure, and cell division rates. Specifically, cell polarity alignment can induce spontaneous symmetry breaking in proliferation, resulting from the anisotropic distribution of mechanical pressure in the tissue. We show that proliferation anisotropy can be controlled by cellular elasticity, motility and contact inhibition, thereby elucidating the design principles for anisotropic morphogenesis.
Targeted long-read sequencing as a single assay improves diagnosis of spastic-ataxia disorders
Authors: Rudaks Laura Ivete , Stevanovski Igor , Yeow Dennis , Reis Andre L. M. , Chintalaphani Sanjog R. , Cheong Pak Leng , Gamaarachchi Hasindu , Worgan Lisa , Ahmad Kate , Hayes Michael , Hannaford Andrew , Kim Samuel , Fung Victor S. C. , Halmagyi Michael , Martin Andrew , Manser David , Tchan Michel , Ng Karl , Kennerson Marina L. , Deveson Ira W. , Kumar Kishore Raj
Published: September 2024

The hereditary spastic-ataxia spectrum disorders are a group of rare disabling neurological diseases. The genetic testing process is complex, and often requires multiple different assays to evaluate the many potential causative genes and variant types, including short tandem repeat expansions, single nucleotide variants, insertions/deletions, structural variants and copy number variants. This can be a protracted process and, even after all avenues are exhausted, many individuals do not receive a genetic diagnosis.

Aiming to streamline and improve this process, we developed a targeted long-read sequencing strategy with capacity to characterise genetic variation of all types and sizes within 469 disease-associated genes, in a single assay. We applied this to a cohort of 34 individuals with genetically undiagnosed spastic-ataxia spectrum disorders. An additional five individuals with a known genetic diagnosis were included as positive controls.

We identified causative pathogenic variants that would be sufficient for genetic diagnosis in 14/34 (41%) unsolved participants. The success rate was 5/11 (45%) in those who were naïve to genetic testing and 9/23 (39%) in those who were undiagnosed after prior genetic testing, completed on a clinical basis. Short tandem repeat expansions inFGF14were the most common cause, present in 7/34 (21%). Two individuals (2/34, 6%) had biallelic pathogenic short tandem repeat expansions inRFC1and one individual had a monoallelic pathogenic short tandem repeat expansion inATXN8OS/ATXN8. Causative pathogenic sequence variants other than short tandem repeat expansions were found in four individuals, including a heterozygous missense variant inVCP, a heterozygous in-frame deletion inSTUB1, a homozygous splicing variant inANO10, and compound heterozygous missense and nonsense variants inSPG7. In addition to these solved cases, a pathogenic or likely-pathogenic variant with uncertain clinical implications was identified in a further three individuals, including a single individual who was found to have a short tandem repeat expansion inBEAN1in addition to biallelic expansions inFGF14within the range of 200-249 repeats.

Our results demonstrate the utility of targeted long-read sequencing in the genetic evaluation of patients with spastic-ataxia spectrum disorders, highlighting both the capacity to increase overall diagnostic yield and to streamline the testing pathway by capturing all known genetic causes in a single assay.
Performance of Open-Source LLMs in Challenging Radiological Cases – A Benchmark Study on 1,933 Eurorad Case Reports
Authors: Kim Su Hwan , Schramm Severin , Adams Lisa C. , Braren Rickmer , Bressem Keno K. , Keicher Matthias , Zimmer Claus , Hedderich Dennis M. , Wiestler Benedikt
Published: September 2024

Recent advancements in large language models (LLMs) have created new ways to support radiological diagnostics. While both open-source and proprietary LLMs can address privacy concerns through local or cloud deployment, open-source models provide advantages in continuity of access, and potentially lower costs. In this study, we evaluated the diagnostic performance of eleven state-of-the-art open-source LLMs using clinical and imaging descriptions from 1,933 case reports in the Eurorad library. LLMs provided differential diagnoses based on clinical history and imaging findings. Responses were considered correct if the true diagnosis was included in the top three LLM suggestions. Llama-3-70B evaluated LLM responses, with its accuracy validated against radiologist ratings in a case subset. Models were further tested on 60 non-public brain MRI cases from a tertiary hospital to assess generalizability. Llama-3-70B demonstrated superior performance, followed by Gemma-2-27B and Mixtral-8x-7B. Similar performance results were found in the non-public dataset, where Llama-3-70B, Gemma-2-27B, and Mixtral-8x-7B again emerged as the top models. Our findings highlight the potential of open-source LLMs as decision support tools for radiological differential diagnosis in challenging, real-world cases.
Widespread Associations between Behavioral Metrics and Brain Microstructure in ASD Suggest Age Mediates Subtypes of ASD
Authors: Ressa Haylee J. , Newman Benjamin T. , Jacokes Zachary , McPartland James C. , Kleinhans Natalia M. , Druzgal T. Jason , Pelphrey Kevin A. , Van Horn John Darrell ,   GENDAAR Research Consortium
Published: September 2024

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviors. Our lab has previously found that g-ratio, the proportion of axon width to myelin diameter, and axonal conduction velocity, which is associated with the capacity of an axon to carry information, are both decreased in ASD individuals. By associating these differences with performance on cognitive and behavioral tests, this study aims to first associate a broad array of behavioral metrics with neuroimaging markers of ASD, and to explore the prevalence of ASD subtypes using a neuroimaging driven perspective. Analyzing 273 participants (148 with ASD) ages 8 to 17 through an NIH-sponsored Autism Centers of Excellence network (MH100028), we observe widespread associations between behavioral and cognitive evaluations of autism and between behavioral and microstructural metrics, alongside different directional correlations between different behavioral metrics. Stronger associations with individual subcategories from each test rather than summary scores suggest that different neuronal profiles may be masked by composite test scores. Machine learning cluster analyses applied to neuroimaging data reinforce the association between neuroimaging and behavioral metrics and suggest that age-related maturation of brain metrics may drive changes in ASD behavior. This suggests that if ASD can be definitively subtyped, these subtypes may show different behavioral trajectories across the developmental period. Clustering identified a pattern of restrictive and repetitive behavior in some participants and a second group that was defined by high sensory sensitivity and language performance.
Shifting Routes: Plant Specific Insert trafficking and function in Arabidopsis seedlings under abiotic stress
Authors: Moura Inês , Neves João , Séneca Ana , Pissarra José , Pereira Susana , Pereira Cláudia
Published: September 2024

Due to plants’ inability to escape adverse conditions, they must adapt and adjust their endomembrane system through protein sorting and distribution. Cardosins A and B are key models for studying intracellular trafficking. They are aspartic proteinases in thistle flowers that mediate different vacuolar pathways despite sharing high sequence similarity, and both are responsive to stress conditions. The Plant Specific Insert (PSI) is a 100 amino acid domain found in these proteins. It is known that stress can impact protein sorting, shifting it from the conventional pathway (ER-Golgi) to a Golgi-independent route. In this work we assessed changes in the expression and localization of PSI from Cardosin B (PSI B) in Arabidopsis plants overexpressing PSI B-mCherry submitted to different abiotic stress conditions (saline, hydric, oxidative, metals). Aside from potential PSI B localization changes, we focused on characterizing the homozygous line, alongside assessing several biometric parameters and biochemical endpoints. The results revealed that the PSI B line responded differently depending on the stress conditions. Biometric and biochemical analyses emphasized the roles of PSI B in enhancing plant fitness and supporting adaptation to abiotic stress. Besides, confocal microscopy allowed us to find PSI B accumulation in Endoplasmic Reticulum-derived vesicles (ER bodies), indicating a shift from the common PSI B-mediated route. These findings underscore the role of PSI B in enhancing plant fitness and adaptation to abiotic stress through altered protein trafficking.

Highlight

PSI B has an active role in enhancing plant fitness, revealing its value in adaptation and tolerance to abiotic stress by adjusting its localization and trafficking under challenging environments.
Comprehensive analysis of the RBP regulome reveals functional modules and drug candidates in liver cancer
Authors: Garbulowski Mateusz , Mosca Riccardo , Gallardo-Dodd Carlos J. , Kutter Claudia , Sonnhammer Erik L. L.
Published: September 2024

RNA binding proteins (RBPs) are essential components of the transcriptomic regulome. Identifying the RBP regulome in cancer cells is crucial to discovering and understanding carcinogenesis mechanisms and providing new therapeutic targets. Here, we aimed to reveal the regulome of liver cancer upon specific perturbations. To this end, we applied a consensus Gene Regulatory Network (GRN) approach using knockdown data for the liver cancer cell line HepG2. By incorporating multiple GRNs from diverse inference methods, we constructed a highly precise GRN. To validate our results, we comprehensively evaluated the consensus GRN, focusing on characterizing the most relevant aspects of the liver cancer regulome. This included utilizing eCLIP-seq and RAPseq data to verify RBP interactions and binding sites. In addition, we performed an enrichment analysis of network modules and drug repurposing based on the inferred GRN. Taken together, our findings demonstrate the critical roles of RBP regulatory interactions in liver cancer that can be employed to improve treatment strategies.
The phospho-ferrozine assay: A tool to study bacterial redox-active metabolites produced at the plant root
Authors: Giacalone David , Schutt Emilly , McRose Darcy L.
Published: September 2024

Soil microbial communities are pivotal to plant health and nutrient acquisition. It is becoming increasingly clear that many interactions, both among and between microbes and plants, are governed by small bioactive molecules or “secondary metabolites” that can aid in communication, competition, and nutrient uptake. Yet, secondary metabolite biogeography – who makes what, where, and why— is in its infancy. Further, secondary metabolite biosynthesis genes are often silent or weakly expressed under standard laboratory conditions, making it incredibly difficult to study these small molecules. To begin to address these dual challenges, we focused on Redox-Active metabolites (RAMs), a specific class of small molecules, and took advantage of recent findings that many RAMs aid in acquiring phosphorus and that their production is frequently stimulated by stress for this macronutrient. We developed a screen for RAM-producing bacteria that leverages phosphorus limitation to stimulate metabolite biosynthesis and uses a colorimetric (ferrozine) iron-reduction assay to identify redox activity. We isolated 557 root-associated bacteria from grasses collected at sites across the United States (Santa Rita Experimental Range (AZ), Konza Prairie Biological Station (KS), and Harvard Forest (MA)) and from commercial tomato plants and screened them for RAM production. We identified 128 soil isolates of at least 19 genera across Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes that produced RAMs under phosphorus stress. Our work reveals that the production of RAMs under phosphorus stress is common across diverse soil bacteria and provides an approach to screen for these small molecules rapidly.

Importance

By secreting secondary metabolites, bacteria at the plant root can defend against diseases and help acquire essential nutrients. However, the genes which synthesize secondary metabolites are typically inactive or are weakly expressed under standard laboratory conditions. This fact makes it difficult to study these small molecules and hinders the discovery of novel small molecules that may play crucial roles in agricultural and biomedical settings. Here, we focus on Redox-Active metabolites (RAMs), a class of secondary metabolites that can help bacteria solubilize phosphorus and are often produced when phosphorus is limited. We developed a screen that rapidly identifies RAM-producing bacteria by utilizing a colorimetric iron-reduction assay in combination with phosphorus limitation to stimulate biosynthesis. The screen reveals that RAM-producing bacteria are far more prevalent in soil than previously appreciated and that this approach can be used to identify RAM producers.
Longitudinal Symptom Burden and Pharmacologic Management of Catatonia in Autism with and without Profound Impairment: An Observational Study
Authors: Smith Joshua Ryan , Lim Seri , Bindra Snehal , Marler Sarah , Rajah Bavani , Williams Zachary J. , Baldwin Isaac , Hossain Nausheen , Wilson Jo Ellen , Fuchs D. Catherine , Luccarelli James
Published: September 2024

Introduction

Catatonia is a highly morbid psychomotor and affective disorder which can affect autistic individuals with and without profound impairment. Catatonic symptoms are treatable with pharmacotherapy and electroconvulsive therapy, but the longitudinal effectiveness of these treatments has not been described.

Methods

We conducted a prospective observational cohort study of patients with autism and co-morbid catatonia who received outpatient care in a specialized outpatient clinic from July 1st, 2021 to May 31st, 2024. Data investigating pharmacologic interventions, and clinical measures including the Bush Francis Catatonia Rating Scale (BFCRS), Kanner Catatonia Severity Scale (KCS), Kanner Catatonia Examination (KCE), and Clinical Global Impression – Improvement (CGI-I) were collected.

Results

Forty-five patients were identified with 39 (86.7%) meeting criteria for profound autism. All patients received pharmacotherapy. 44 (97.8%) were treated with benzodiazepines with a mean maximal daily dose of 17.4 mg (SD=15.8) lorazepam equivalents. Thirty-five patients (77.8%) required more than one medication class for treatment. Fourteen patients (31.1%) attempted to taper off benzodiazepines during the study period; of these, 5 patients (11.1%) were successfully tapered off, and the remaining 9 (17.8%) discontinued the taper due to a return of catatonic symptoms. Statistically significant improvement was observed across all clinical domains except the KCS. However, the majority remained symptomatic over the study period.

Conclusions

Despite clinical improvements while receiving the gold standard for psychopharmacologic management of catatonia, chronic symptoms remained for the majority of catatonia patients over the study period, and few were able to taper and discontinue benzodiazepine treatment.

Lay Summary

Catatonia is a condition which can significantly impact the quality of life for autistic individuals with and without profound impairment. Symptoms of catatonia such as aggression and self-injury can improve with treatment. However, over the three-year period of this study, most patients experienced residual symptoms, and few could discontinue psychotropic medication.
Comparison of haemoglobin concentration measurements using HemoCue-301 and Sysmex XN-Series 1500: a survey among anaemic Gambian infants aged 6-12 months
Authors: Bah Mamadou , Verhoef Hans , Camara Abdou , Ngom Morris Nden , Jallow Demba , Bajo Kebba , Bah Foday , Pleij Maarten , Klappe Maaike , Saidykhan Alasana , Okoh Emmanuel , Bah Abdoulie , Cerami Carla
Published: September 2024

Background & Aims

In low-income countries, point-of-care photometers are used in the screening and management of anaemia in individuals, but also in the assessment of population iron status when evaluating efficacy of intervention studies or public health interventions. We aimed to evaluate the accuracy of a commonly used photometer, HemoCue-301, in determining haemoglobin concentration among anaemic children aged 6-12 months in a field setting in rural Africa.

Methods

This report concerns a secondary analysis of data from Gambian infants being screened for an ongoing randomized controlled trial. In those found to be anaemic by HemoCue-301, haemoglobin concentration was measured by Sysmex XN-1500, an automated haematology analyser that was used as a reference. Passing-Bablok regression analysis was used to estimate the regression constant (systematic deviation between two measurement methods that remain consistent across the range of measurements) and proportional bias (systematic deviation between two measurement methods that change in magnitude relative to the value being measured).

Results

Analysis was based on 227 participants. There was strong evidence of absolute bias among moderately anaemic participants (haemoglobin concentration at 8.0g/dL) (absolute bias: 1.12g/dL; 95% CI: 0.91 to 1.37g/dL; proportional bias: 14.0%; 95% CI: 11.4% to 17.1%) in haemoglobin concentrations measured by HemoCue-301 compared to those measured by Sysmex XN-Series1500. Bias was marginal at haemoglobin concentration of 11.0g/dL (absolute bias: −0.08g/dL; 95% CI: −0.18 to 0.07g/dL; proportional bias: −7.3%; 95% CI: −6.5% to 0.6%).

Conclusion

Haemoglobin measurements by HemoCue-301 seem substantially biased in participants with haemoglobin less than 8.0g/dL.
Online group-based Acceptance and Commitment Therapy for stroke survivors: a study of fidelity of delivery within the Wellbeing After Stroke study
Authors: Foote Hannah , Bowen Audrey , Cotterill Sarah , Patchwood Emma
Published: September 2024

Objectives

To explore whether practitioners can deliver the Acceptance and Commitment Therapy-based Wellbeing After Stroke intervention with fidelity to both the clinical protocol and the Acceptance and Commitment therapy model.

Design

Observational fidelity study, embedded within the Wellbeing After Stroke study. Setting: online groups. UK.

Participants

Practitioners employed by the Stroke Association, trained to deliver the intervention.

Measures

1) a bespoke Wellbeing After Stroke fidelity tool to assess fidelity to dose, duration and content of intervention sessions, self-completed by practitioners and a sub-set completed by researchers based on video recordings. We calculated inter-rater reliability of researchers and practitioners. 2) Acceptance and Commitment Therapy-Fidelity Measure to assess fidelity to the Acceptance and Commitment Therapy model, completed by researchers on the sub-set of recorded sessions.

Results

Seven practitioners delivered the Wellbeing After Stroke intervention to three groups of stroke survivors. The planned dose of the intervention was delivered, with duration slightly longer than planned. Practitioners delivered the intervention with high fidelity to protocol: 92–100% of content delivered, as measured by the Wellbeing After Stroke fidelity tool, once reliability was established. Some practitioners delivered the intervention with fidelity to the Acceptance and Commitment Therapy model.

Conclusions

Trained and supervised practitioners can deliver an online, group Acceptance and Commitment Therapy-based intervention to stroke survivors with high fidelity to protocol. Improving training may increase consistency with the Acceptance and Commitment Therapy model. The ACT-Fidelity Measure can be used to measure consistency of delivery of protocolised, group interventions, but adaptations would increase suitability to context.
Evaluating the Risk of Cardiovascular Adverse Events and Appendicitis After COVID-19 Diagnosis in Adults in the United States: Implications of the Start of Follow-Up
Authors: Layton J. Bradley , Lindaas Arnstein , Muthuri Stella G , Lloyd Patricia C. , Richey Morgan M. , Gruber Joann F. , Lyu Hai , McKillop Mollie M. , Kowarski Lisa S. , Bui Christine , Fisher Shelby S. , Clarke Tainya C. , Cheng Angela S. , Wan Zhiruo , Duenas Pablo Freyria , Chen Yangping , Burrell Timothy , Sheng Minya , Shoaibi Azadeh , Chillarige Yoganand , Beers Jeffrey , Anthony Mary S. , Forshee Richard A. , Anderson Steven A.
Published: September 2024

Purpose

This study evaluated the association between coronavirus disease 2019 (COVID-19) diagnosis and adverse events (AEs), including cardiovascular AEs and appendicitis, in US adults before the introduction of COVID-19 vaccines. Real-world studies of AEs after COVID-19 suggest that diagnoses of AEs and COVID-19 frequently occur on the same day and may be a source of bias.

Methods

Cohort and self-controlled risk interval (SCRI) designs were used in 2 US administrative claims data sources—Merative™ MarketScan® (ages 18-64 years) and Medicare (ages ≥ 65 years). AEs included stroke (nonhemorrhagic and hemorrhagic), acute myocardial infarction, myocarditis/pericarditis, deep vein thrombosis, pulmonary embolism (PE), disseminated intravascular coagulation (DIC), unusual-site and common-site thrombosis with thrombocytopenia syndrome, and appendicitis. In cohort analyses, weighted hazard ratios (HRs) and 95% confidence intervals (CIs) compared adults with a COVID-19 diagnosis and matched comparators. In SCRI analysis, relative incidences (RIs) and 95% CIs compared risk and reference windows within individuals. Analyses were performed starting follow-up on Time 0 and Day 1.

Results

For cardiovascular AEs, all estimates starting follow-up on Day 1 were above 1.0 in both data sources. For cohort analyses, the strongest associations were for inpatient PE in both databases: MarketScan, HR=8.65 (95% CI, 6.06-12.35), Medicare HR=3.06 (95% CI, 2.88-3.26). For SCRI analyses, the strongest association in MarketScan was for DIC: RI=32.28 (95% CI, 17.06-61.09) and in Medicare was for myocarditis/pericarditis: RI=4.53 (95% CI, 3.89-5.27). AEs diagnosed concurrently with COVID-19 (ie, on Time 0) were common; including Time 0 in follow-up/risk windows resulted in higher RIs, as well as higher HRs for some AEs. However, some AEs (eg, stroke) were more common on Time 0 in the comparator group resulting in lower HRs.

Conclusion

COVID-19 diagnoses had moderate to strong associations with cardiovascular AEs and weak or inconsistent associations with appendicitis, although estimates varied by design and methodology.
Integration of GWAS and multi-omic QTLs identifies uncharacterized COVID-19 gene-biotype and phenotype associations
Authors: Oliva Meritxell , King Emily , Hammond Reza , Lee John S. , Riley-Gillis Bridget , Resztak Justyna , Degner Jacob
Published: September 2024

To better understand COVID-19 pathobiology and to prioritize treatment targets, we sought to identify human genes influencing genetically driven disease risk and severity, and to identify additional organismal-level phenotypes impacted by pleiotropic COVID-19-associated genomic loci. To this end, we performed ancestry-aware, trans-layer, multi-omic analyses by integrating recent COVID-19 Host Genetics Initiative genome-wide association (GWAS) data from six ancestry endpoints - African, Amerindian, South Asian, East Asian, European and meta-ancestry - with quantitative trait loci (QTL) and GWAS endpoints by colocalization analyses. We identified colocalizations for 47 COVID-19 loci with 307 GWAS trait endpoints and observed a highly variable (1-435 endpoint colocalizations) degree of pleiotropy per COVID-19 locus but a high representation of pulmonary traits. For those, directionality of effect mapped to COVID-19 pathological alleles pinpoints to systematic protective effects for COPD, detrimental effects for lung adenocarcinoma, and locus-dependent effects for IPF. Among 64 QTL-COVID-19 colocalized loci, we identified associations with most reported (47/53) and half of unreported (19/38) COVID-19-associated loci, including 9 loci identified in non-European cohorts. We generated colocalization evidence metrics and visualization tools, and integrated pulmonary-specific QTL signal, to aid the identification of putative causal genes and pulmonary cells. For example, among likely causal genes not previously linked to COVID-19, we identified desmoplakin-driven IPF-shared genetic perturbations in alveolar cells. Altogether, we provide insights into COVID-19 biology by identifying molecular and phenotype links to the genetic architecture of COVID-19 risk and severity phenotypes; further characterizing previously reported loci and providing novel insights for uncharacterized loci.
Public Health Interventions for Fractional Optimal Control of Buruli Ulcer
Authors: Nortey Solomon , Akorly Ernest , Dadzie Mark , Moore Stephen E.
Published: September 2024

Buruli Ulcer, a devastating skin disease caused byMycobacterium Ulcerans, poses considerable public health challenges in endemic areas. This article focuses on the use of fractional optimal control theory to prevent the spread of Buruli ulcers via integrated public health interventions. We formulated a mathematical model using the Atangana-Baleanu-Caputo fractional order derivative operator. We investigated the model’s existence and uniqueness and presented numerical simulations using the predict-evaluate-correct-evaluate (PECE) method of Adam-Bashforth Moulton. We also study the fractional optimal control problem (FOCP) to minimize the spread of the disease in the endemic regions. We employ the Fractional Pontryagin’s Maximum Principle (FPMP) and implement the forward-backward method to determine the extremals of the problem. Four control strategies were implemented: promoting health education on the use of protective clothing, enhancing vaccination rates, improving treatment protocols for infected individuals, and spraying insecticides to reduce water-bug populations. After examining the optimal control dynamics of the Buruli ulcer transmission model via multiple simulations with and without control, we discover that there is a substantial decrease in the population of infected humans and the water-bug population. Hence we conclude that the best strategy to implement is by applying all the control strategies suggested.