Cura por vacío (VAC), a propósito de un caso en Atención Primaria / Vacuum assisted closure (VAC), about a case in primary care

El síndrome compartimental agudo requiere de la descompresión quirúrgica, mediante fasciotomía, esta técnica debe ser urgente y será clave para evitar la instauración de graves secuelas. El posterior abordaje de estas heridas de difícil y lenta cicatrización suponen un reto para los profesionales de la salud y un problema para la salud pública debido a los altos costes y elevada morbilidad. La terapia de presión negativa (TPN) o cura por vacío (VAC, "vacuum assisted closure") es un tratamiento no invasivo que consigue la curación de las heridas favoreciendo la vascularización, la aparición del tejido de granulación y eliminación del exceso de exudado[AU]

Acute compartment syndrome requires surgical decompression by fasciotomy, this technique must be urgent and will be key to avoid the establishment of serious sequels. The subsequent approach to these wounds, which are difficult and slow to heal, is a challenge for health professionals and a problem for public health due to high costs and high morbidity. Negative pressure therapy (NPWT) or vacuum assisted closure (VAC) is a non-invasive treatment that achieves wound healing by promoting vascularization, the appearance of granulation tissue and elimination of excess exudate[AU]

A síndrome compartimental aguda requer descompressão cirúrgica, por fasciotomia, esta técnica deve ser urgente e será fundamental para evitar o estabelecimento de sequelas graves. O tratamento subsequente destas feridas difíceis e de cicatrização lenta é um desafio para os profissionais de saúde e um problema desaúde pública devido aos elevados custos e à elevada morbilidade. A terapia por pressão negativa (NPWT) ou o encerramento assistido por vácuo (VAC) é um tratamento não invasivo que permite a cicatrização de feridas através da promoção da vascularização, do aparecimento de tecido de granulação e da remoção do excesso de exsudado[AU]

Mix and measure II: joint high-energy laboratory powder diffraction and microtomography for cement hydration studies.

Portland cements (PCs) and cement blends are multiphase materials of different fineness, and quantitatively analysing their hydration pathways is very challenging. The dissolution (hydration) of the initial crystalline and amorphous phases must be determined, as well as the formation of labile (such as ettringite), reactive (such as portlandite) and amorphous (such as calcium silicate hydrate gel) components. The microstructural changes with hydration time must also be mapped out. To address this robustly and accurately, an innovative approach is being developed based on in situ measurements of pastes without any sample conditioning. Data are sequentially acquired by Mo Kα1 laboratory X-ray powder diffraction (LXRPD) and microtomography (µCT), where the same volume is scanned with time to reduce variability. Wide capillaries (2 mm in diameter) are key to avoid artefacts, e.g. self-desiccation, and to have excellent particle averaging. This methodology is tested in three cement paste samples: (i) a commercial PC 52.5 R, (ii) a blend of 80 wt% of this PC and 20 wt% quartz, to simulate an addition of supplementary cementitious materials, and (iii) a blend of 80 wt% PC and 20 wt% limestone, to simulate a limestone Portland cement. LXRPD data are acquired at 3 h and 1, 3, 7 and 28 days, and µCT data are collected at 12 h and 1, 3, 7 and 28 days. Later age data can also be easily acquired. In this methodology, the amounts of the crystalline phases are directly obtained from Rietveld analysis and the amorphous phase contents are obtained from mass-balance calculations. From the µCT study, and within the attained spatial resolution, three components (porosity, hydrated products and unhydrated cement particles) are determined. The analyses quantitatively demonstrate the filler effect of quartz and limestone in the hydration of alite and the calcium aluminate phases. Further hydration details are discussed.

Diabetic ketoacidosis in youth with diabetes mellitus during the COVID-19 pandemic.

OBJECTIVES: We sought to determine if the early months of the coronavirus disease 2019 (COVID-19) pandemic influenced pediatric diabetic ketoacidosis (DKA) hospitalization characteristics. METHODS: This is a cross-sectional study of youth with laboratory-confirmed DKA admitted to a large tertiary children's hospital in the USA. Data were collected from admissions in March through July 2019 and March through July 2020, respectively. We evaluated the clinical characteristics of hospitalization, including demographic data and DKA severity. We used univariable ordinal logistic regression followed by multiple ordinal logistic regression to adjust for potential confounders. RESULTS: We included 137 children with diabetes admitted for DKA in the relevant period in 2019 and 173 patients admitted for DKA in the same period in 2020. Hemoglobin A1C (HbA1c) upon admission was higher in 2020 (median=12.2 %) than in 2019 (11.5 %, p=0.018). Children who were admitted with DKA in 2020 were less likely to be autoantibody positive than those in 2019 (83 vs. 91 %, p=0.028). In the univariable model, being admitted in 2020 was significantly associated with more severe DKA (p=0.038), as was HbA1c (p=0.001). After adjusting for HbA1c upon admission, admission year was no longer significantly associated with more severe DKA. CONCLUSIONS: In this study of pediatric diabetes of any type and duration of diabetes, youth admitted for DKA at the start of the COVID-19 pandemic, compared with those admitted during the year before, were more likely to have autoantibody-negative diabetes and had significantly higher HbA1c. Additionally, higher HbA1c seemed to mediate more severe DKA during the pandemic.

Identification of type 1 diabetes risk phenotypes using an outcome-guided clustering analysis.

AIMS/HYPOTHESIS: Although statistical models for predicting type 1 diabetes risk have been developed, approaches that reveal the heterogeneity of the at-risk population by identifying clinically meaningful clusters are lacking. We aimed to identify and characterise clusters of islet autoantibody-positive individuals who share similar characteristics and type 1 diabetes risk. METHODS: We tested a novel outcome-guided clustering method in initially non-diabetic autoantibody-positive relatives of individuals with type 1 diabetes, using the TrialNet Pathway to Prevention study data (n=1123). The outcome of the analysis was the time to development of type 1 diabetes, and variables in the model included demographic characteristics, genetics, metabolic factors and islet autoantibodies. An independent dataset (the Diabetes Prevention Trial of Type 1 Diabetes Study) (n=706) was used for validation. RESULTS: The analysis revealed six clusters with varying type 1 diabetes risks, categorised into three groups based on the hierarchy of clusters. Group A comprised one cluster with high glucose levels (median for glucose mean AUC 9.48 mmol/l; IQR 9.16-10.02) and high risk (2-year diabetes-free survival probability 0.42; 95% CI 0.34, 0.51). Group B comprised one cluster with high IA-2A titres (median 287 DK units/ml; IQR 250-319) and elevated autoantibody titres (2-year diabetes-free survival probability 0.73; 95% CI 0.67, 0.80). Group C comprised four lower-risk clusters with lower autoantibody titres and glucose levels (with 2-year diabetes-free survival probability ranging from 0.84-0.99 in the four clusters). Within group C, the clusters exhibit variations in characteristics such as glucose levels, C-peptide levels and age. A decision rule for assigning individuals to clusters was developed. Use of the validation dataset confirmed that the clusters can identify individuals with similar characteristics. CONCLUSIONS/INTERPRETATION: Demographic, metabolic, immunological and genetic markers may be used to identify clusters of distinctive characteristics and different risks of progression to type 1 diabetes among autoantibody-positive individuals with a family history of type 1 diabetes. The results also revealed the heterogeneity in the population and complex interactions between variables.

PET/CT targeted tissue sampling reveals intravenously administered HGN194 IgG1 affects HIV distribution after rectal exposure.

Neutralizing monoclonal antibodies hold great potential for prevention of human immunodeficiency virus (HIV) acquisition. IgG is the most abundant antibody in human serum, has a long half-life, and potent effector functions, making it a prime candidate for an HIV prevention therapeutic. We combined Positron Emission Tomography (PET) imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-GFP HIV (PA-GFP-BaL) and fluorescently labeled HGN194 IgG1 to determine whether intravenously instilled IgG influences viral interaction with mucosal barriers and viral penetration in colorectal tissue two hours after rectal viral challenge. Our results show that IgG1 did not alter the number of virions found throughout the colon or viral penetration into the epithelium of the rectum or descending colon. A minor increase in virions was observed in the transverse colon of IgG1 treated animals. Overall, the number of viral particles found in the mesenteric lymph nodes was low. However, IgG1 administration resulted in a significant reduction of virions found in mesenteric lymph nodes. Taken together, our results show that HGN194 IgG1 does not prevent virions from penetrating into the colorectal mucosa but may perturb HIV virion access to the lymphatic system.

Radial extracorporeal shock wave therapy for the management of spasticity in cerebral palsy: study protocol for a randomized controlled trial.

Background: Spasticity is the most common motor disorder in cerebral palsy (CP), and its management is complex, posing a significant challenge for the rehabilitation team. Radial extracorporeal shock wave therapy (rESWT) has emerged in recent years as an effective, non-invasive, and low-risk alternative for the management of spasticity in CP patients, with only minor side effects such as small bruises or discomfort during application. There is great variability in rESWT administration protocols, ranging from a single session up to the 12 sessions. The most extensively studied protocol involves 3 rESWT sessions with a one-week interval between session. According to current literature, the effect of rESWT has not been investigated by extending the time interval between sessions beyond 1 week to determine if therapeutic effects on spasticity can be prolonged over time. Methods: Following a power calculation using the minimal clinical important difference of our primary outcome (R2 of Modified Tardieu Scale), 72 patients will be included in the study. Enrolment is based upon inclusion/exclusion criteria outlined in the Methods section. Participants will be randomized in 3 groups. Each patient will receive 2000 impulses in the Triceps Sural muscle (distributed by all the plantar flexor muscles: soleus and gastrocnemius), at a 2.2 Bars pressure and a frequency of 8 Hz. The Control Group will receive 3 rESWT sessions with a time interval of 1 week between each session. The Experimental Group A will receive 3 rESTW sessions with a time interval of 2 weeks between each session and the Experimental Group B will receive 3 rESTW sessions with a time interval of 4 weeks between each session. Discussion: This study will provide further information regarding the effect of rESWT on spasticity in patients with CP. If an increase in the time interval between rESWT sessions allows for the prolongation of therapeutic benefits on spasticity, it will be clinically relevant fact. With the same treatment dosage, patients will be able to benefit from its effects for a longer period of time. Clinical trial registration: ClinicalTrials.gov, identifier NCT05702606.

Anaesthetic mortality in cats: A worldwide analysis and risk assessment.

BACKGROUND: Patient safety is essential in small animal anaesthesia. This study aimed to assess anaesthesia-related deaths in cats worldwide, identify risk and protective factors and provide insights for clinical practice. METHODS: A prospective multicentre cohort study of 14,962 cats from 198 veterinary centres across different countries was conducted. Data on anaesthesia-related deaths, from premedication up to 48 hours postextubation, were collected. Logistic regression was used to analyse patient demographics, American Society of Anesthesiologists (ASA) classification, procedure type and anaesthetic drugs. RESULTS: The anaesthesia-related mortality was 0.63%, with 74.5% of deaths occurring postoperatively. Cats with cachexia, a higher ASA status or who underwent abdominal, orthopaedic/neurosurgical or thoracic procedures exhibited elevated mortality. Mechanical ventilation use was associated with increased mortality. Mortality odds were reduced by the use of alpha2-agonist sedatives, pure opioids in premedication and locoregional techniques. LIMITATIONS: Limitations include non-randomised sampling, potential biases, unquantified response rates, subjective death cause classification and limited variable analysis. CONCLUSIONS: Anaesthetic mortality in cats is significant, predominantly postoperative. Risk factors include cachexia, higher ASA status, specific procedures and mechanical ventilation. Protective factors include alpha2-agonist sedatives, pure opioids and locoregional techniques. These findings can help improve anaesthesia safety and outcomes. However, further research is required to improve protocols, enhance data quality and minimise risks.

Decoding functional proteome information in model organisms using protein language models.

Protein language models have been tested and proved to be reliable when used on curated datasets but have not yet been applied to full proteomes. Accordingly, we tested how two different machine learning-based methods performed when decoding functional information from the proteomes of selected model organisms. We found that protein language models are more precise and informative than deep learning methods for all the species tested and across the three gene ontologies studied, and that they better recover functional information from transcriptomic experiments. The results obtained indicate that these language models are likely to be suitable for large-scale annotation and downstream analyses, and we recommend a guide for their use.

Sensitive Detection and Quantification of Oxygenated Compounds in Complex Samples Using GC-Combustion-MS.

This work introduces a new element-selective gas chromatography detector for the accurate quantification of traces of volatile oxygen-containing compounds in complex samples without the need for specific standards. The key to this approach is the use of oxygen highly enriched in 18O as the oxidizing gas in a combustion unit (800 °C) that allows us to directly and unambiguously detect the natural oxygen present in the GC-separated compounds through its incorporation into the volatile species formed after their combustion and their subsequent degradation to 16O in the ion source. The unspecific signal due to the low 16O abundance in the oxidizing gas could be compensated by measuring the m/z 12 that comes as well from the CO2 degradation. Equimolarity was proved with several O-containing compounds with different sizes and functionalities. A detection limit of 28 pg of injected O was achieved, which is the lowest ever reported for any GC detector, which barely worsened to 55 and 214 pg of O when the oxygenate partially or completely coeluted with a very abundant matrix compound. Validation was attained by the analysis of a SRM to obtain accurate (99-103%) and precise (1-4% RSD) results. Robustness was tested after spiking a hydrotreated diesel with 10 O-compounds at the ppm level, which could be discriminated from the matrix crowd and quantified (mean recovery of 102 ± 9%) with a single generic standard. Finally, it was also successfully applied to easily spot and quantify the 33 oxygenates naturally present in a complex wood bio-oil sample.

Exercise prescription for the prevention and treatment of chronic diseases in primary care: Protocol of the RedExAP study.

BACKGROUND: Existing evidence supports the effectiveness of exercise in preventing and treating chronic diseases, yet its integration into clinical practice remains limited. This study protocol aims to address the evidence-practice gap by exploring barriers to exercise prescription in primary care and developing a clinical practice guideline (CPG). METHODS: Employing a qualitative approach, focus groups will be conducted to investigate primary care professionals' challenges in prescribing exercise and patients' adherence to recommendations. Phenomenological analysis will facilitate data interpretation. Data triangulation, expert analysis, and quality criteria will ensure study reliability. The CPG development process is outlined, emphasizing transdisciplinary collaboration and patient involvement. CONCLUSION: The RedExAP study responds to the imperative for evidence-based exercise integration in primary care. The study's combined qualitative exploration and CPG development present the potential to improve health outcomes and cost-effectiveness. By elucidating primary care professionals' and patients' perspectives, the study contributes to enhancing exercise prescription adoption. The innovative transdisciplinary approach aligns with the 2030 Agenda, promoting better population health and greater social well-being, showing promise in alleviating chronic disease burdens. This study's findings lay the groundwork for advancing evidence-based exercise interventions within primary care to transform chronic disease management.

Understanding the effects of omega-3 fatty acid supplementation on the physical properties of brain lipid membranes.

A deficiency in omega-3 fatty acids (ω3 FAs) in the brain has been correlated with cognitive impairment, learning deficiencies, and behavioral changes. In this study, we provided ω3 FAs as a supplement to spontaneously hypertensive rats (SHR+ ω3). Our focus was on examining the impact of dietary supplementation on the physicochemical properties of the brain-cell membranes. Significant increases in ω3 levels in the cerebral cortex of SHR+ ω3 were observed, leading to alterations in brain lipid membranes molecular packing, elasticity, and lipid miscibility, resulting in an augmented phase disparity. Results from synthetic lipid mixtures confirmed the disordering effect introduced by ω3 lipids, showing its consequences on the hydration levels of the monolayers and the organization of the membrane domains. These findings suggest that dietary ω3 FAs influence the organization of brain membranes, providing insight into a potential mechanism for the broad effects of dietary fat on brain health and disease.

Clusterin expression and distribution in spermatozoa as predictor of male fertility.

Clusterin (CLU), one of the main glycoproteins in mammalian semen and the male reproductive tract, plays a role in spermatogenesis and sperm maturation. Given the poor reliability of classic seminal studies in determining male-fertilizing capacity and the differences in CLU abundance between normal and abnormal spermatozoa, we investigated the potential value of mRNA-CLU levels and protein distribution in spermatozoa as markers of sperm quality and predictors of male fertility. This multicenter study included 90 patients undergoing in vitro fertilization (IVF) treatment with their partners, and a control group of 36 fertile males with normal seminograms. We assessed the relationship between IVF treatment outcomes, seminogram variables, mRNA-CLU levels by quantitative real-time-PCR and CLU distribution by immunostaining in spermatozoa. Our study reveals CLU staining in the acrosome (p = 0.002, OR 14.8, 95% CI: 2.7-79.3) and mRNA-CLU levels (p = 0.005, OR 10.85, 95% CI: 2.0-57.4) as independent risk factors for pregnancy failure, irrespective of traditional seminogram variables. Additionally, our results suggest that CLU, and specially its secreted isoform, constitutes a component of the protein pool that human spermatozoa can produce during its maturation process, exhibiting a variable abundance and distribution in spermatozoa from fertile men compared to those in patients with altered seminograms and infertile patients with normal seminograms. Our study is the first to identify mRNA-CLU levels and CLU immunostaining in the spermatozoa acrosome as independent risk factors for pregnancy failure, with distribution patterns correlating with sperm maturity and seminogram alterations.

Extended Synaptotagmins 1 and 2 Are Required for Store-Operated Calcium Entry, Cell Migration and Viability in Breast Cancer Cells.

Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1-STIM1 interaction at ER-PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca2+ entry (SOCE), a major mechanism for Ca2+ influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells.

Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function.

Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin-kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin-angiotensin-aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled "Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions", we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.

Long Non-Coding RNAs and Alzheimer's Disease: Towards Personalized Diagnosis.

Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, is the most common form of dementia. Currently, there is no single test that can diagnose AD, especially in understudied populations and developing countries. Instead, diagnosis is based on a combination of medical history, physical examination, cognitive testing, and brain imaging. Exosomes are extracellular nanovesicles, primarily composed of RNA, that participate in physiological processes related to AD pathogenesis such as cell proliferation, immune response, and neuronal and cardiovascular function. However, the identification and understanding of the potential role of long non-coding RNAs (lncRNAs) in AD diagnosis remain largely unexplored. Here, we clinically, cognitively, and genetically characterized a sample of 15 individuals diagnosed with AD (cases) and 15 controls from Barranquilla, Colombia. Advanced bioinformatics, analytics and Machine Learning (ML) techniques were used to identify lncRNAs differentially expressed between cases and controls. The expression of 28,909 lncRNAs was quantified. Of these, 18 were found to be differentially expressed and harbored in pivotal genes related to AD. Two lncRNAs, ENST00000608936 and ENST00000433747, show promise as diagnostic markers for AD, with ML models achieving > 95% sensitivity, specificity, and accuracy in both the training and testing datasets. These findings suggest that the expression profiles of lncRNAs could significantly contribute to advancing personalized AD diagnosis in this community, offering promising avenues for early detection and follow-up.

Functional states of prelimbic and related circuits during the acquisition of a GO/noGO task in rats.

GO/noGO tasks enable assessing decision-making processes and the ability to suppress a specific action according to the context. Here, rats had to discriminate between 2 visual stimuli (GO or noGO) shown on an iPad screen. The execution (for GO) or nonexecution (for noGO) of the selected action (to touch or not the visual display) were reinforced with food. The main goal was to record and to analyze local field potentials collected from cortical and subcortical structures when the visual stimuli were shown on the touch screen and during the subsequent activities. Rats were implanted with recording electrodes in the prelimbic cortex, primary motor cortex, nucleus accumbens septi, basolateral amygdala, dorsolateral and dorsomedial striatum, hippocampal CA1, and mediodorsal thalamic nucleus. Spectral analyses of the collected data demonstrate that the prelimbic cortex was selectively involved in the cognitive and motivational processing of the learning task but not in the execution of reward-directed behaviors. In addition, the other recorded structures presented specific tendencies to be involved in these 2 types of brain activity in response to the presentation of GO or noGO stimuli. Spectral analyses, spectrograms, and coherence between the recorded brain areas indicate their specific involvement in GO vs. noGO tasks.

Barriers and Strategies to Optimize the Use of Glucagon-Like Peptide 1 Receptor Agonists in People with Type 2 Diabetes and High Cardiovascular Risk or Established Cardiovascular Disease: A Delphi Consensus in Spain.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for glycemic control, with many also demonstrating cardiovascular (CV) benefit, in people with type 2 diabetes (T2D). This study aimed to find a consensus on the barriers and strategies for the optimal use of GLP-1 RAs in people with T2D and high CV risk or established cardiovascular disease (CVD) in Spain. METHODS: A two-round Delphi survey (53 questions) was conducted among members of four national scientific societies in Spain, including physicians experienced in the management of people with T2D. The degree of consensus was evaluated with a 7-point Likert scale, establishing consensus when ≥ 70% of the panelists agreed (6-7) or disagreed (1-2). RESULTS: A total of 97 physicians participated in the first round (endocrinology: 34%, family and community medicine: 21%, internal medicine: 23%, and cardiology: 23%), and 96 in the second round. The main barriers identified were: therapeutic inertia and late use of GLP-1 RAs; lack of a comprehensive approach to CV risk; lack of knowledge on the usefulness of GLP-1 RAs in CVD prevention and treatment; and economic/administrative barriers. Strategies with a highest consensus included: the need to establish simple protocols that integrate awareness of CV risk monitoring; training professionals and patients; and the use of new technologies. CONCLUSION: Physicians identified clinical, healthcare, and economic/administrative barriers that limit the use of GLP-1 RAs in people with T2D and high CV risk or established CVD in Spain, highlighting the importance of integrating these therapies according to clinical practice guidelines.

Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10.

Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.

Effect of adding PCSK9 inhibitors to lipid-lowering interventions on arterial stiffness: A systematic review and meta-analysis.

BACKGROUND: Atherosclerosis, a leading cause of mortality, necessitates effective management of hypercholesterolemia, specifically elevated low-density lipoprotein cholesterol (LDL-C). The emergence of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has revolutionised lipid-lowering. PCSK9i demonstrates substantial LDL-C reduction and cardiovascular benefits, particularly in statin-intolerant or nonresponsive individuals. However, the potential pleiotropic effects of PCSK9i, especially on arterial stiffness, remain a subject of investigation. This systematic review and meta-analysis seek to provide a nuanced understanding of the potential pleiotropic effects of PCSK9i, specifically on arterial health. The primary objective was to analyse the influence of PCSK9i on arterial stiffness, extending beyond traditional lipid-lowering metrics and contributing to a more comprehensive approach to cardiovascular risk reduction. METHODS: A systematic search was conducted across major databases, clinical trial registries and grey literature. Inclusion criteria comprised adults in prospective cohort studies undergoing PCSK9i augmentation in lipid-lowering therapy, with a focus on arterial stiffness measured by pulse wave velocity (PWv). Random-effects meta-analyses, sensitivity analyses and meta-regression models were employed to assess the pooled effect of adding PCSK9i to lipid-lowering interventions on arterial stiffness. RESULTS: Five studies (158 participants) met the inclusion criteria, demonstrating a significant reduction in PWv (mean difference: -2.61 m/s [95% CI: -3.70, -1.52]; ES: -1.62 [95% CI: -2.53, -.71]) upon adding PCSK9i to lipid-lowering interventions. Subgroup analysis and meta-regression models suggested potential sex-based and baseline PWv-dependent variations, emphasising patient-specific characteristics. CONCLUSION: The meta-analysis provides robust evidence that adding PCSK9i to lipid-lowering interventions significantly improves arterial stiffness, indicating broader vascular benefits beyond LDL-C reduction.