Disease Severity Research Articles

Predictors of the severity of the course of COVID-19: demographic factors, clinical signs and laboratory markers.

Introduction. The Coronavirus Disease 2019 (COVID-19) pandemic has had a significant impact on global healthcare, with high mortality and severe complications remaining a major concern. Understanding the predictors of COVID-19 severity may improve patient management and outcomes. While considerable research has focused on the pathogenesis of the virus and vaccine development, the identification of reliable demographic, clinical and laboratory predictors of severe disease remains critical.Hypothesis. Specific demographic factors, clinical signs and laboratory markers can reliably predict the severity of COVID-19. A comprehensive analysis integrating these predictors could provide a more accurate prognosis and guide timely interventions.Aim. The aim of this study is to identify and evaluate the demographic, clinical and laboratory factors that can serve as reliable predictors of severe COVID-19, thereby aiding in the prediction and prevention of adverse outcomes.Methodology. The methods of analysis, synthesis, generalization and descriptive statistics were used to achieve this objective.Results. The analysis showed that demographic factors such as age over 60 and male sex are significant predictors of severe COVID-19. Clinical predictors include respiratory symptoms, especially dyspnoea, and comorbidities such as hypertension, coronary artery disease, chronic obstructive pulmonary disease, respiratory failure, asthma, diabetes mellitus and obesity. Laboratory markers with high prognostic value include elevated levels of C-reactive protein, interleukin-6, ferritin, neutrophil/lymphocyte ratio, d-dimer, aspartate aminotransferase enzyme and decreased lymphocyte count.Conclusion. The study concludes that a holistic approach incorporating demographic, clinical and laboratory data is essential to accurately predict the severity of COVID-19. This integrated model may significantly improve patient prognosis by facilitating early identification of high-risk individuals and allowing timely, targeted interventions. The results highlight the importance of comprehensive patient assessment in managing and mitigating the impact of COVID-19.

Virome Characterization of Native Wild-Rice Plants Discovers a Novel Pathogenic Rice Polerovirus With World-Wide Circulation.

Pandemics originating from zoonotic viruses have posed significant threats to human health and agriculture. Recent discoveries have revealed that wild-rice plants also harbour viral pathogens capable of severely impacting rice production, a cornerstone food crop. In this study, we conducted virome analysis on ~1000 wild-rice individual colonies and discovered a novel single-strand positive-sense RNA virus prevalent in these plants. Through comprehensive genomic characterization and comparative sequence analysis, this virus was classified as a new species in the genus Polerovirus, designated Rice less tiller virus (RLTV). Our investigations elucidated that RLTV could be transmitted from wild rice to cultivated rice via a specific insect vector, the aphid Rhopalosiphum padi, causing less tiller disease symptoms in rice plants. We generated an infectious cDNA clone for RLTV and demonstrated systemic infection of rice cultivars and induction of severe disease symptoms following mechanical inoculation or stable genetic transformation. We further illustrated transmission of RLTV from stable transgenic lines to healthy rice plants by the aphid vector, leading to the development of disease symptoms. Notably, our database searches showed that RLTV and another polerovirus isolated from a wild plant species are widely circulating not only in wild rice but also cultivated rice around the world. Our findings provide strong evidence for a wild plant origin for rice viruses and underscore the imminent threat posed by aphid-transmitted rice Polerovirus to rice cultivar.

An altered natural killer cell immunophenotype characterizes clinically severe pediatric RSV infection.

Respiratory syncytial virus (RSV) infects nearly all children by 2 years of age and is a leading cause of pediatric hospitalizations. A subset of children with RSV infection (RSV+ children) develop respiratory failure requiring intensive care, but immune mechanisms distinguishing severe pediatric RSV infection are not fully elucidated. Natural killer (NK) cells are key innate immune effectors of viral host defense. In this study of 47 critically ill RSV+ children, we coupled NK cell immunophenotype and cytotoxic function with clinical parameters to identify an NK cell immune signature of severe pediatric RSV disease. Airway NK cells were increased in intubated RSV+ children with severe hypoxemia and prolonged duration of mechanical ventilation and were correlated with clinical severity scores. Peripheral blood NK cells were decreased in RSV+ patients and had altered activating receptor expression, with increased expression of CD69 and decreased expression of NKG2D. Ex vivo, circulating NK cells from RSV+ patients exhibited functional impairment characterized by decreased cytotoxicity as well as aberrant immune synapse assembly and lytic granule trafficking. NK cell frequency and phenotype correlated with clinical measures that defined disease severity. These findings implicate a role for NK cells in mediating RSV immunopathology and suggest that an altered NK cell immunophenotype is associated with severe RSV disease in young children.

Identification of hsa_circ_0018905 as a New Potential Biomarker for Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating autoimmune disease characterized by early onset, for which the interaction of genetic and environmental factors is crucial. Dysregulation of the immune system as well as myelinization-de-myelinization has been shown to correlate with changes in RNA, including non-coding RNAs. Recently, circular RNAs (circRNAs) have emerged as a key player in the complex network of gene dysregulation associated with MS. Despite several efforts, the mechanisms driving circRNA regulation and dysregulation in MS still need to be properly elucidated. Here, we explore the panorama of circRNA expression in PBMCs purified from five newly diagnosed MS patients and five healthy controls (HCs) using the Arraystar Human circRNAs microarray. Experimental validation was then carried out in a validation cohort, and a possible correlation with disease severity was tested. We identified 64 differentially expressed circRNAs, 53 of which were downregulated in PBMCs purified from MS compared to the HCs. The discovery dataset was subsequently validated using qRT-PCR with an independent cohort of 20 RRMS patients and 20 HCs. We validated seven circRNAs differentially expressed in the RRMS group versus the HC group. hsa_circ_0000518, hsa_circ_0000517, hsa_circ_0000514, and hsa_circ_0000511 were significantly upregulated in the MS group, while hsa_circ_0018905, hsa_circ_0048764, and hsa_circ_0003445 were significantly downregulated; Among them, the expression level of hsa_circ_0018905 was significantly decreased in patients showing a higher level of disability and in progressive forms of MS. We described the circRNAs expression profile of PBMCs in newly diagnosed MS patients and proposed hsa_circ_0018905 as potential MS biomarker.

Adapted Low-FODMAP Diet in IBS Patients with and without Fibromyalgia: Long-Term Adherence and Outcomes

Background/Objectives: A low-FODMAPs Diet (LFD) is considered a “second line” dietary strategy for irritable bowel syndrome (IBS) but, after a period of strict restriction of all FODMAP foods, it has to be adapted and tailored to each patient (AdLFD). Fibromyalgia often coexists with IBS in up to 65% of cases. Our aims were to evaluate if comorbid fibromyalgia influenced the long-term clinical outcomes and adherence to an AdLFD in IBS patients. Methods: IBS patients with or without fibromyalgia who had started an AdLFD were enrolled. Patients had been evaluated before starting the LFD (T0). After a mean follow-up of 62.5 ± 22.7 months (T1), they were re-evaluated using questionnaires on disease severity, bowel habits, psychological status, and adherence to AdLFD. Results: In total, 51 IBS patients entered the study. Nineteen of them had comorbid fibromyalgia. Thirty patients reported a reduction in symptom severity at T1 in comparison with T0. Despite some slight differences in single IBS Symptom Severity Score items, comorbid fibromyalgia did not influence the IBS-SSS total score at T1. Patients with comorbid fibromyalgia showed a higher Hospital Anxiety and Depression Scale (HADS) score at baseline. A total of 44 patients showed good long-term adherence to the AdLFD. All patients improved their HADS score and had long-term adherence to the AdLFD. Conclusions: Comorbid fibromyalgia showed only a slight influence on long-term outcomes of an AdLFD on IBS symptoms, without affecting the relief of global symptoms. No influence on long-term adherence to AdLFD was detected. Hence, this approach can be taken into account in fibromyalgia patients for a nonpharmacological management of IBS symptoms. However, multicentric studies on larger samples would be welcome in the future.

Economic and societal burden of myasthenia gravis in Denmark, Finland, and Sweden: A population-based registry study.

Health care resource utilization (HCRU) and the economic burden of myasthenia gravis (MG) are significant, but existing studies rarely include comprehensive nationwide data. We examined HCRU and direct and indirect costs associated with MG overall and by disease severity in Denmark, Finland, and Sweden. Data were collected retrospectively from nationwide health and social care registries. All individuals ≥18 years of age with ≥2 International Classification of Diseases diagnoses of MG between 2000 and 2020 were included. HCRU, direct (inpatient and outpatient contacts, medication) and indirect costs (early retirement, sick leave, death), and associated factors were calculated. The full study cohort comprised 8622 people with MG (pwMG). Mean annual numbers of all-cause secondary health care contacts for pwMG were 3.4 (SD = 8.3), 7.0 (SD = 12.3), and 2.9 (SD = 3.9), with mean annual total costs of €12,185, €9036, and €5997 per person in Denmark, Finland, and Sweden, respectively. Inpatient periods, involving 77%-89% of study participants in the three countries, contributed most to direct costs, whereas the majority of indirect costs resulted from early retirement in Denmark and Finland, and sick leave periods in Sweden. Mean annual total costs were highest with very severe MG (€19,570-€33,495 per person across the three countries). Female sex and comorbidities, such as mental and behavioral disorders and severe infections, were also associated with higher total costs. This population-based study shows a high level of HCRU and a significant direct and indirect economic burden of MG across three Nordic countries, especially for severe forms of MG.

Co-introduction into a delicate island ecosystem: metastrongyloid nematodes (superfamily Metastrongyloidea) of veterinary and medical importance circulating in aquatic and terrestrial environments of Tenerife (Canary Islands).

Metastrongyloid nematodes typically reside as adults in the cardiopulmonary systems of their mammalian definitive hosts, potentially causing severe diseases. Of particular concern are Angiostrongylus cantonensis and A. costaricensis, which can cause eosinophilic meningitis and abdominal angiostrongyliasis, respectively, in their accidental human hosts. Several metastrongyloid species of medical and veterinary importance have been documented in the Canary Islands. However, the gastropod species acting as intermediate hosts for some of these nematodes in the archipelago remained unknown. This study aimed to investigate the occurrence of metastrongyloid nematodes in terrestrial and aquatic gastropods, including both endemic and non-native species, on Tenerife. Foot samples from terrestrial and aquatic gastropods were analyzed using a multiplex PCR targeting the Internal Transcribed Spacer 1 (ITS1), allowing the specific detection of A. cantonensis, A. vasorum, Aelurostrongylus abstrusus, Crenosoma striatum, Troglostrongylus brevior, and Crenosoma vulpis. Five metastrongyloid species, namely C. striatum, A. cantonensis, Ae. abstrusus, A. vasorum, and an unidentified metastrongyloid, were identified within both non-native and endemic terrestrial gastropods. In the aquatic snail Physella acuta, only A. cantonensis and C. striatum were detected. This study confirms the introduction of various metastrongyloids associated with non-native mammalian fauna and provides new data on the occurrence of these nematodes in non-native and endemic gastropod species, including their presence in aquatic environments on the Canary Islands.

Does serum albumin at the onset of necrotisıng enterocolitis predict severe disease in preterm infants?

To investigate whether laboratory markers obtained at the onset of necrotising enterocolitis (NEC) predict the severity of the disease in preterm infants. Prospective cohort study conducted in a tertiary referance hospital. A total of 88 preterm infants were included in the study. Of those, 60 infants had the diagnosis of severe NEC, while the remaining 28 infants constituted the non-severe NEC group. Severe NEC was defined as surgical NEC or NEC-related mortality. Infants with and without severe NEC were compared in terms of demographic, clinical and laboratory characteristics. At the onset of disease, infants with severe NEC noted to have lower platelet count and serum ALB levels (p = 0.011, p = 0.004; respectively), whereas higher CRP, and serum lactate levels (p = 0.009, p = 0.008; respectively). Multiple binary logistic regression analyses showed that CRP (1.03(1.01-1.05), p = 0.024) and serum albumin level (0.16(0.04-0.64), p = 0.010) were statistically significant independent risk factors for severe NEC. The optimal cut-off value for the serum ALB level was found to be 23g/L with 52% sensitivity (95%CI: 37-68%) and 84% specificity (95%CI: 60-97%) (AUC 0.727; p = 0.002). Serum ALB level at NEC onset might be a reliable biomarker for severe disease in preterm infants.

Comparison of Longitudinal Outcomes in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis.

Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are both genetic diseases of mucociliary clearance resulting in progressive lung disease with onset in early life. PCD is often considered to be milder in childhood than CF, based on minimal evidence. Similar to CF, genotype-phenotype associations exist in PCD: pathogenic variants in CCDC39 and CCDC40, causing inner dynein arm/microtubular defects (IDA/MTD) are associated with more severe disease. To compare longitudinal outcomes in matched children with PCD and CF. We hypothesized that children with PCD with IDA/MTD defects would have lower lung function but better nutritional indices than matched children with CF with minimal function genotypes (i.e., those associated with pancreatic insufficiency). Children with PCD enrolled in a prospective, multicenter, observational study were matched with CF patients from the CF Foundation Patient Registry by birth cohort, age, sex, race/ethnicity and year of study visit. The association of disease group overall and by severity class (PCD-IDA/MTD versus all other defects and CF-minimal versus residual function) with longitudinal outcomes up to age 17 was evaluated with cubic spline mixed effects models. Groups included 136 children with PCD (40 IDA/MTD, 96 other) and 476 with CF (446 minimal function, 30 residual function). Below age 14, the PCD group had similar or lower estimated mean FEV1 % predicted compared to CF (e.g., at age 10, -5.4 % predicted lower (95% CI: -7.7, -3.1)). Compared to the CF-minimal function (pancreatic insufficient) group, the PCD-IDA/MTD group had similar BMI; estimated mean FEV1 % predicted was significantly lower by age 10 (mean difference -10.6% (95% CI: -14.7, -6.4), increasing to -15.7% (95% CI: -20.3, -11.2) at age 14. The CF cohort had increased prevalence of Pseudomonas aeruginosa cultured on one or more occasions compared to children with PCD (67% vs 27%, p<0.001); there was no difference in prevalence of P. aeruginosa between children with PCD-IDA/MTD and PCD-other. In childhood, average lung function abnormalities in PCD are not milder than CF, particularly for those with IDA/MTD ciliary defects. New guidelines and treatments to improve outcomes in PCD are urgently needed.

Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy

Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype–phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient’s phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype–phenotype correlations.

Phyllosphere of Agathis australis Leaves and the Impact of the Soil-Borne Pathogen Phytophthora agathidicida

Leaf surface microbial communities play an important role in forest ecosystems and are known to be affected by environmental and host conditions, including diseases impacting the host. Phytophthora agathidicida is a soil-borne pathogen that causes severe disease (kauri dieback) in one of New Zealand’s endemic trees, Agathis australis (kauri). This research characterised the microbial communities of the A. australis phyllosphere (i.e. leaf surface) using modern molecular techniques and explored the effects of P. agathidicida on those communities. Fresh leaves were collected from trees where P. agathidicida was and was not detected in the soil and characterisation of the leaf surface microbial community was carried out via high-throughput amplicon sequencing of the internal transcribed spacer (ITS) and 16S ribosomal RNA regions. Nutrients in leaf leachates were also measured to identify other possible drivers of microbial diversity. The dominant phyllosphere microbial phylum was Proteobacteria followed by Acidobacteria. The phyllosphere microbial richness of A. agathis associated with P. agathidicida-infected soils was found to be generally lower than where the pathogen was not detected for both prokaryote (bacterial) and fungal phyla. Leaf leachate pH as well as boron and silicon had significant associations with bacterial and fungal community structure. These findings contribute to the development of a comprehensive understanding of A. australis leaf surface microbial communities and the effects of the soil pathogen P. agathidicida on those communities.

The effects of supervised aerobic training on dyslipidaemia among diabetic older patients

BackgroundHigher prevalence rates of diabetes and its complications have been reported among individuals with poor physical activity and a sedentary lifestyle. This study explored the influence of six months of moderate-intensity supervised aerobic training on the serum lipid profile, hs-CRP level, and variable-related correlations in prediabetic and type 2 diabetes patients (T2DM).DesignThe study was based on a two-arm parallel group pretest‒posttest comparative design.MethodsA total of 50 subjects who were diagnosed with diabetes for more than five years and aged 30–70 years were included in this study. The subjects were classified into two groups on the basis of their glycated haemoglobin (HbA1c%) values: Group 1 (patients with the prediabetes; HbA1c % ≤ 6.5, n = 25) and Group 2 (patients with the T2DM; HbA1c % ≥ 6.5, n = 25). Blood sugar, HbA1c %, insulin, lipid profile, and highly sensitive CRP (hs-CRP) were measured via colorimetric and immunoassay techniques at baseline and six months postintervention with moderate aerobic exercise.ResultsThe results revealed that participation in moderate aerobic training interventions for six months resulted in a significant reduction in BMI, fasting blood sugar, glycosylated haemoglobin, hs-CRP, and lipid profile parameters such as T-Cholest, TG, and LDL-C as well as significant improvement in the level of insulin with a reduction in the values of HOMA-IR towards normal values in the patients with prediabetes (P < 0.01) in group 1 and patients with diabetes in group 2 (P < 0.001). The change in VO2max with good physical fitness significantly improved with the exercise program after six months. The reduced levels of hs-CRP, HOMA-IR, and lipid profile and improved levels of insulin were significantly positively correlated with the levels of glycated haemoglobin (HbA1c%) in the patients with prediabetes (P < 0.01) and those with diabetes (P < 0.001) following six months of moderate aerobic training interventions. Moreover, hs-CRP was positively correlated with T-Cholest, TG, and LDL-C (p = 0.01) and negatively correlated with HDL-C. The data revealed improved glycemic control factors, lipid profiles, and hs-CRP levels as cardio-predictive markers in patients with both prediabetes and diabetes as well. These findings suggest that the anti-inflammatory effect of physical activity gained from moderate exercise training for six months may counteract increased cardiovascular complications associated with increased CRP levels and lipid profiles in prediabetes and T2DM patients.ConclusionsModerate aerobic training for six months favourably affects glycemic parameters, lipid profiles, and inflammatory hs-CRP indicators and improves VO2max, an indicator of physical fitness, in prediabetic and diabetic patients. The data obtained suggest the positive effect of moderate exercise training as a protective modulator of cardiovascular disorders, including the dyslipidaemic profile, glycaemic control, and hs-CRP inflammatory markers, in prediabetes and T2DM patients. Thus, regular exercise, owing to its anti-inflammatory effects and ability to improve cardiorespiratory fitness, lipid profiles, blood glucose levels, and insulin resistance, may help reduce the severity of cardiovascular diseases in prediabetes and T2DM patients and healthy controls.Trial registrationRetrospectively registered with ClinicalTrials.gov PRS under trial identifier ID: NCT06246435 dated 30/01/2024.

Modelling water use efficiency (WUE) for estimating the severity of Ganoderma boninense-derived basal stem rot disease in oil palm

Modelling water use efficiency (WUE) for estimating the severity of Ganoderma boninense-derived basal stem rot disease in oil palm

Multifractal Analysis in Age-Based Classification for COVID-19 Patients’ CT-Scan Images with Different Noise Levels

Recently, many number of people various countries contracted the COVID-19 (C-19) disease. The identification of this harmful disease and other pneumonia diseases is an important process in the medical world. CT-Scan is mainly prescribed to predict the severity of lung diseases affected by C-19 and other pneumonia diseases. Generally, a CT-Scan image is represented as a grayscale image (GI). Biomedical-oriented GIs are more complex and they are too difficult to recognize the status of lung diseases directly from the experimental images. To address this type of medical problem, a multifractal approach can be applied to analyze and illustrate the GIs in detail. Therefore, the multifractal dimensional analysis is used to diagnose and explore the vehemence of the contamination levels in the lungs. In this study, the complexity of CT-Scan images of C-19 patients is analyzed in order to perform a comparison in terms of age and noise levels. It was also discovered that the intricate of CT-Scan images is considerably varied for patients aged 50 and above when compared to younger subjects. This comparative study indicates that the deadly virus affects elderly persons compared to youngsters. The proposed age-based classification is supported by image processing techniques, qualitative measures, and statistical tools. The obtained results are demonstrated graphically by Generalized Fractal Dimensions (GFD) spectrum, 3D visualization, ANOVA table, and box plots to expose the rate of discrimination of complexity in CT-Scan lung images.

Forecasting severe respiratory disease hospitalizations using machine learning algorithms

BackgroundForecasting models predicting trends in hospitalization rates have the potential to inform hospital management during seasonal epidemics of respiratory diseases and the associated surges caused by acute hospital admissions. Hospital bed requirements for elective surgery could be better planned if it were possible to foresee upcoming peaks in severe respiratory illness admissions. Forecasting models can also guide the use of intervention strategies to decrease the spread of respiratory pathogens and thus prevent local health system overload. In this study, we explore the capability of forecasting models to predict the number of hospital admissions in Auckland, New Zealand, within a three-week time horizon. Furthermore, we evaluate probabilistic forecasts and the impact on model performance when integrating laboratory data describing the circulation of respiratory viruses.MethodsThe dataset used for this exploration results from active hospital surveillance, in which the World Health Organization Severe Acute Respiratory Infection (SARI) case definition was consistently used. This research nurse-led surveillance has been implemented in two public hospitals in Auckland and provides a systematic laboratory testing of SARI patients for nine respiratory viruses, including influenza, respiratory syncytial virus, and rhinovirus. The forecasting strategies used comprise automatic machine learning, one of the most recent generative pre-trained transformers, and established artificial neural network algorithms capable of univariate and multivariate forecasting.ResultsWe found that machine learning models compute more accurate forecasts in comparison to naïve seasonal models. Furthermore, we analyzed the impact of reducing the temporal resolution of forecasts, which decreased the model error of point forecasts and made probabilistic forecasting more reliable. An additional analysis that used the laboratory data revealed strong season-to-season variations in the incidence of respiratory viruses and how this correlates with total hospitalization cases. These variations could explain why it was not possible to improve forecasts by integrating this data.ConclusionsActive SARI surveillance and consistent data collection over time enable these data to be used to predict hospital bed utilization. These findings show the potential of machine learning as support for informing systems for proactive hospital management.

Impaired incretin homeostasis in non-diabetic moderate to severe chronic kidney disease

Background: Incretins are regulators of insulin secretion and glucose homeostasis metabolized by dipeptidyl peptidase-4 (DPP-4). Chronic kidney disease (CKD) may modify incretin release, metabolism, or response. Methods: We performed two-hour oral glucose tolerance testing (OGTT) in 59 people with non-diabetic CKD (estimated glomerular filtration rate [GFR]&lt;60 ml/min per 1.73 m2) and 39 matched controls. We measured total (tAUC) and incremental area under the curve (iAUC) of plasma total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide (GIP). Fasting DPP-4 levels and activity were measured. Linear regression was used to adjust for demographic, body composition, and lifestyle factors. Results: Mean (standard deviation [SD]) eGFR was 38 ±13 and 89 ±17ml/min per 1.73 m2 in CKD and controls, respectively. GLP-1 tAUC and GIP iAUC were higher in CKD than controls with a mean of 1531 ± 1452 versus 1364 ± 1484 pMxmin, and 62370 ± 33453 versus 42365 ± 25061 pgxmin/ml, respectively. After adjustment, CKD was associated with 15271 pMxmin/ml greater GIP iAUC (95% confidence intervals [CI]: 387, 30154) compared to controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122, 95% CI: -619, 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6, 95% CI: 0.3, 2.8 mg/dl) and 120 minutes (mean difference, 0.84, 95% CI: 0.2, 1.5 mg/dl) in CKD compared to controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups. Conclusions: Overall, incretin response to oral glucose is preserved or augmented in moderate to severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression are enhanced.

Disabling foot pain and its impact on daily living among people with psoriatic arthritis in Singapore: a cross-sectional observational investigation

BackgroundPsoriatic Arthritis (PsA)-related foot involvement has been shown to have a profound impact on daily functioning, with most studies having focused on predominantly Caucasian populations. The aim was to describe disabling foot pain (DFP) and its impact on daily living in PsA in Singapore.MethodsA cross-sectional, retrospective study was conducted using clinical data collected during a single-visit to a rheumatology clinic in Singapore. Records for adults with physician-diagnosed PsA were reviewed for sociodemographic information, disease characteristics, global disease activity and burden. Foot-specific measures included clinical assessment and the Manchester Foot Pain and Disability Index used to define DFP and evaluate between-group differences.ResultsForty-two participants with PsA (83% female, 57% Chinese, 31% Malay, 9.5% Indian, mean (SD) age 54-years (16)) attended the rheumatology clinic over the study-period. The median (IQR) disease duration was 2-years (11) and all were taking current DMARDs. Global disease measures demonstrated mild-to-moderate global disease activity and mild functional impairment, and were significantly higher in those with DFP. Despite 90% reporting to be coping well with their condition, self-care and having emotional support (n = 38), this study sample demonstrated high levels of anxiety/depression (29%), sleep disturbance (34%) and fatigue (24%), and a lack of disease- and drug-specific knowledge (64%). Further management was indicated for medication adherence counselling (48%), occupational therapy (43%), physiotherapy (36%) and podiatry (30%). Nearly half had current foot pain with 40% reporting DFP (n = 17), which caused significantly greater difficulty walking 3 km than those without DFP (p < 0.05). Rearfoot enthesitis (plantar fasciitis, Achilles enthesitis) was the most common cause of DFP (67%) with pain lasting longer than 1-year. 72% were overweight or obese, with a high proportion not engaging in any cardiovascular exercise (70%). Three of 42 participants had previously seen a podiatrist.ConclusionsPeople with DFP in PsA experience more severe global disease activity, reduced mobility and higher levels of negative impact on their daily lives in Singapore. In the absence of working in a multidisciplinary-team, there is value in comprehensive assessments that have potential to capture a holistic view of personal impact and improve person-centred care in PsA.

Engineering Macrophage-Derived Exosome to Deliver Pirfenidone: A Novel Approach to Combat Silicotic Pulmonary Fibrosis.

Silicosis is a severe lung disease characterized by diffuse pulmonary fibrosis, for which there is currently no effective treatment. Pirfenidone (PFD) shows great antifibrotic potential but is clinically hindered by low bioavailability and gastrointestinal side effects. To address these limitations, this study develops a PFD delivery system (PFD-Exo) using J774A.1 macrophage-derived exosomes. Firstly, PFD is loaded via sonication, then PFD-Exo is characterized using Raman spectral imaging and UV absorption spectroscopy. Finally, in vitro and in vivo silicosis models are established to evaluate its antifibrotic effects. Results show that PFD-Exo outperforms free PFD in inhibiting TGF-β1-induced transdifferentiation of primary lung fibroblasts in vitro. In a mouse model of silicosis, PFD-Exo is found to be accumulated in the lungs following intratracheal administration and significantly ameliorates pulmonary inflammation and fibrosis while minimizing gastrointestinal side effects. Mechanistic studies reveal that PFD-Exo modulates the TGF-β signaling pathway by downregulating SMAD3 and upregulating SMAD7 and NOGGIN. In conclusion, this study provides the first evidence of macrophage-derived exosomes as an effective PFD delivery system for silicosis treatment and offers a promising strategy for other refractory pulmonary diseases.

Regional Differences in Vascular Graft Degradation and Regeneration Contribute to Dilation.

Severe coronary artery disease is often treated with a coronary artery bypass graft using an autologous blood vessel. When this is not available, a commercially available synthetic graft can be used as an alternative but is associated with high failure rates and complications. Therefore, the research focus has shifted toward the development of biodegradable, regenerative vascular grafts that can convert into neoarteries. We previously developed an electrospun tropoelastin (TE)-polyglycerol sebacate (PGS) vascular graft that rapidly regenerated into a neoartery, with a cellular composition and extracellular matrix approximating the native aorta. We noted, however, that the TE-PGS graft underwent dilation until sufficient neotissue had been regenerated. This study investigated the mechanisms behind the observed dilation following TE-PGS vascular graft implantation in mice. We saw more pronounced dilation at the graft middle compared with the graft proximal and graft distal regions at 8 weeks postimplantation. Histological analysis revealed less degradation at the graft middle, although the remaining graft material appeared pitted, suggesting compromised structural and mechanical integrity. We also observed delayed cellular infiltration and extracellular matrix (ECM) deposition at the graft middle, corresponding with the area's reduced ability to resist dilation. In contrast, the graft proximal region exhibited greater degradation and significantly enhanced cellular infiltration and ECM regeneration. The nonuniform dilation was attributed to the combined effect of the regional differences in graft degradation and arterial regeneration. Consideration of these findings is crucial for graft optimization prior to its use in clinical applications.

Disease models of Leigh syndrome: From yeast to organoids.

Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.