Major Organ Research Articles

Pigmentary Changes in Systemic Sclerosis are Associated with More Severe Cutaneous Sclerosis and Severity of Other Systems: A Cross-sectional Study from India.

Pigmentary changes of the skin in systemic sclerosis in the form of diffuse hyperpigmentation and salt-and-pepper pigmentation are well documented in the literature; however, its association with disease severity and extent of underlying internal organ involvement has not been well studied. To assess the correlation between morphology and extent of pigmentary changes with the degree of cutaneous sclerosis and frequency and degree of major organ involvement. This was a cross-sectional descriptive study conducted in a tertiary care teaching hospital from December 2014 to November 2016. Consecutive patients of systemic sclerosis attending the outpatient department were screened, and patients satisfying the diagnosis as per the American Rheumatism Association criteria were recruited. Skin sclerosis was quantified using modified Rodnan skin score (MRSS), whereas pigmentary changes were calculated in terms of percentage of body surface area involved by rule-of-nine method. Investigations were carried out depending on organ involvement and as per respective specialty consultations with focus on pulmonary, cardiac, and gastrointestinal systems. Of the 50 patients recruited, all had cutaneous involvement in the form of binding down of skin, followed by pigmentary changes. MRSS was significantly higher in patients with any pigmentary alteration (P = 0.03) compared to those without any pigmentary changes. There was a rising trend in between the MRSS severity and the proportion of patients with hyperpigmentation, and it was statistically significant (P = 0.04). Among systemic involvement, lung was involved in the form of interstitial lung disease in 94% patients (n = 47). However, skin pigmentation of any type was associated with lower high-resolution computed tomography scores (P = 0.02). This study shows that in systemic sclerosis patients presenting with pigmentary skin manifestations, cutaneous sclerosis is significantly higher.

Synthesis and tissue distribution of bufadienolides in Bufo bufo gargarizans

This study explored the biosynthesis of bufadienolides(BDs) in Bufo bufo gargarizans to solve the dilemma of the decreasing resources of B. bufo gargarizans and provide a theoretical basis for the sustainable utilization of the resources. Ultra-high performance liquid chromatography-Orbitrap-mass spectrometry(UHPLC-Orbitrap-MS) was employed to detect the synthesis sites of BDs in B. bufo gargarizans, and the results were verified by desorption electrospray ionization-mass spectrometry imaging(DESI-MSI) and homogenate incubation experiments. BDs in B. bufo gargarizans had the highest content in the liver and the highest concentration in the gallbladder, in addition to the parotid gland and skin, which suggested that the liver could synthesize BDs. The results of DESI-MSI also showed that BDs were mainly enriched in the liver rather than the immature parotid gland. The incubation experiment of liver homogenates demonstrated the liver of B. bufo gargarizans had the ability to synthesize BDs. This study showed that the liver was a major organ for the synthesis of BDs in B. bufo gargarizans during metamorphosis, development, and growth, which provided strong theoretical support for the biosynthesis of BDs and the sustainable utilization of B. bufo gargarizans resources.

The Discovery of Gut Microbial Metabolites as Modulators of Host Susceptibility to Acetaminophen-Induced Hepatotoxicity.

The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is a major organ exposed to gut microbial metabolites, and it serves as the nexus for maintaining healthy interactions between the gut microbiota and the host. At the same time, the liver is the primary target of potentially harmful gut microbial metabolites. In this review, we provide an up-to-date list of gut microbial metabolites that have been identified to either increase or decrease host susceptibility to acetaminophen (APAP)-induced liver injury. The signaling pathways and molecular factors involved in the progression of APAP-induced hepatotoxicity are well-established, and we propose that the mouse model of APAP-induced hepatotoxicity serves as a model system for uncovering gut microbial metabolites with previously unknown functions. Furthermore, we envision that gut microbial metabolites identified to alter APAP-induced hepatotoxicity likely have broader implications in other liver diseases. SIGNIFICANCE STATEMENT: This review provides an overview of the role of the gut microbiota in modulating the host susceptibility to acetaminophen (APAP)-induced liver injury. It focuses on the roles of gut bacterial small molecule metabolites as mediators of the interaction between the gut microbiota and the liver. It also illustrates the utility of APAP-induced liver injury as a model to identify gut microbial metabolites with biological function.

Cadmium Exposure Induces Apoptosis and Necrosis of Thyroid Cells via the Regulation of miR-494-3p/PTEN Axis.

Cadmium (Cd) exposure is a persistent pollution problem, necessitating caution in using cadmium-expelling complexing agents. Currently, there is no targeted therapy to treat Cd poisoning. The thyroid gland is a major endocrine organ that directly regulates thyroid hormones involved in various physiological processes and is a target organ for Cd accumulation. Herein, the effects of Cd exposure on swine thyroid glands were investigated. Six-week-old male pigs were randomly divided into the Cd and control groups. The control group was fed a normal diet containing 0mg Cd/kg, while the Cd group was fed a diet containing 20mg Cd/kg (CdCl2) for 40days. The regulation mechanism of phosphatase and tensin homolog (PTEN) microRNA-494-3p (miR-494-3p) was evaluated to determine the toxic effects of Cd exposure on free radicals' cleaner. Notably, heat shock proteins (HSPs) were triggered as defense agents against Cd. Cd exposure increased the enzyme activity of superoxide dismutase1(SOD1) and SOD2, catalase (CAT), and glutathione (GSH), and the endoplasmic reticulum stress in thyroid cells. Histopathological staining, RT-qPCR, and Western Blot assays were further employed to detect possible apoptosis and necroptosis of thyroid cells induced by Cd exposure. The assays revealed increased thyroid inflammatory injury, fibrosis, and apoptosis caused by Cd exposure. This study demonstrates the role of microRNAs in regulating Cd toxicity in pig thyroid tissue and provides evidence of Cd's negative effects. It further provides an assessment of the toxicological impact of Cd as an environmental endocrine disruptor (ED) that threatens public health and safety, which forms a basis for the development of Cd poisoning treatment therapies.

Scleroderma-overlap syndromes: capillaroscopy, laboratory, and clinical manifestations and follow-up compared to scleroderma patients.

Overlap syndrome (OS) is a group of systemic connective tissue diseases (CTDs) that meet the criteria of two or more CTDs. In this study, we evaluated clinical, laboratory, and capillaroscopic manifestations of patients with scleroderma OS (SSc-OS) and its subgroups and follow-up progression compared to patients with limited SSc (LcSSc). In a 10-year cross-sectional study, we evaluated 135 adult patients (70 with SSc-OS and 65 with LcSSc) with the same skin score for their baseline and follow-up clinical, laboratory, high-resolution chest tomography (HRCT), echocardiography, and nailfold capillaroscopy data and compared them. Of the 135 patients, 70 had SSc-OS, including 45 (64.3%) cases of SSc-SS (Sjögren's syndrome), 11 (15.7%) of SSc-RA (rheumatoid arthritis), 9 (12.9%) of SSc-myositis and 5 (1.7%) of SSc-SLE (systemic lupus erythematosus), and 65 had LcSSc. Lung and heart involvement and pulmonary arterial hypertension (PAH) did not differ between the two groups (p > 0.05). Musculoskeletal involvement and non-specific pattern of capillaroscopy were higher (p = 0.035 and p = 0.001), and digital ulcer (DU) and scleroderma patterns of capillaroscopy were lower in the SSc-OS group (p = 0.000).No significant relationship was found between capillaroscopic patterns and organ involvement in the two groups (p-value > 0.05). In the follow-up (3.71 ±2.63 years), new DU and progression of lung involvement (p = 0.002) and the progression in capillaroscopic patterns was lower in SSc-OS (p = 0.000). In the follow-up, new DU was not seen in the SSc-OS, with lower progression of lung involvement, skin score, and capillary damage. In SSc-OS patients, the most common subgroup was SSc-SS. Scleroderma OS was associated with lower major organ involvement and capillaroscopy progression than LcSSc. Major organ involvement in patients with SSc-OS was significantly lower than in LcSSc patients. In the follow-up, new DU was not seen in the SSc-OS with lower progression of lung involvement, skin score, and capillary damage.

Oxidative Stress, Inflammation, and Mitochondrial Dysfunction: A Link between Obesity and Atrial Fibrillation.

The adipose tissue has long been thought to represent a passive source of triglycerides and fatty acids. However, extensive data have demonstrated that the adipose tissue is also a major endocrine organ that directly or indirectly affects the physiological functions of almost all cell types. Obesity is recognized as a risk factor for multiple systemic conditions, including metabolic syndrome, type 2 diabetes mellitus, sleep apnea, cardiovascular disorders, and many others. Obesity-related changes in the adipose tissue induce functional and structural changes in cardiac myocytes, promoting a wide range of cardiovascular disorders, including atrial fibrillation (AF). Due to the wealth of epidemiologic data linking AF to obesity, the mechanisms underlying AF occurrence in obese patients are an area of rich ongoing investigation. However, progress has been somewhat slowed by the complex phenotypes of both obesity and AF. The triad inflammation, oxidative stress, and mitochondrial dysfunction are critical for AF pathogenesis in the setting of obesity via multiple structural and functional proarrhythmic changes at the level of the atria. The aim of this paper is to provide a comprehensive view of the close relationship between obesity-induced oxidative stress, inflammation, and mitochondrial dysfunction and the pathogenesis of AF. The clinical implications of these mechanistic insights are also discussed.

Pragmatic targets for moderate/severe SLE and their implications for clinical care and trial design: sustained DORIS or LLDAS for at least 6 months is sufficient while their attainment for at least 24 months ensures high specificity for damage-free progression

ObjectivesTreatment targets in systemic lupus erythematosus (SLE) have been validated in unselected—in terms of severity—cohorts, which limits their generalisability. We assessed remission (Definition of Remission in SLE (DORIS)) and Lupus...

In vivo functional immunoprotection correlates for vaccines against invasive bacteria

Vaccination has significantly reduced the incidence of invasive infections caused by several bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. However, no vaccines are available for many other invasive pathogens. A major hurdle in vaccine development is the lack of functional markers to quantify vaccine immunity in eliminating pathogens during the process of infection. Based on our recent discovery of the liver as the major organ of vaccine-induced clearance of blood-borne virulent bacteria, we here describe a new vaccine evaluation system that quantitatively characterizes the key features of effective vaccines in shuffling virulent bacteria from the blood circulation to the liver resident macrophage Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) in mouse septic infection model. This system consists of three related correlates or assays: pathogen clearance from the bloodstream, pathogen trapping in the liver, and pathogen capture by KCs/LSECs. These readouts were consistently associated with the serotype-specific immunoprotection levels of the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) against lethal infection of S. pneumoniae, a major invasive Gram-positive pathogen of community-acquired infections in humans. Furthermore, the reliability and sensitivity of these correlates in reflecting vaccine efficacy were verified with whole cell vaccines of Klebsiella pneumoniae and Escherichia coli, two major Gram-negative pathogens in hospital-acquired invasive infections. This system may be used as effective readouts to evaluate the immunoprotective potential of vaccine candidates in the preclinical phase by filling the current technical gap in vaccine evaluation between the conventional in vitro approaches (e.g. antibody production and pathogen neutralization/opsonophagocytosis) and survival of immunized animals.

OUTCOME OF AZITHROMYCIN AND MONOSODIUM GLUTAMATE ON HISTOLOGIC AND BIOCHEMICAL ALTERATIONS IN RATS’ LIVER

Background: Monosodium glutamate (MSG), a commonly used flavouring, mediated hepatotoxic and pro-inflammatory responses. Azithromycin (AZT), an antibiotic with anti-inflammatory activity, may be co-consumed with MSG to present unknown outcomes on the liver, a major organ for the detoxification of xenobiotics. Aim: This study evaluated the effect of AZT and MSG on histologic and biochemical changes in rats’ liver. Methods: Thirty rats in five groups were for seven successive days orally exposed to groups 1, (distilled water 1 mL Kg−1), 2, (MSG 8000 mg/kg), 3, overdose AZT, OAZT (AZT 412.5 mg Kg−1), 4, therapeutic concentration AZT, TAZT, (AZT 82.5mg Kg−1), and 5, (TAZT 82.5 mg Kg−1 + MSG 8000 mg Kg−1). Liver function markers in therats’ serum and liver tissue, and changes in the liver histologic were assessed by acceptable protocols. The mean of numeric data were tested for significance at p value less than 0.05 by analysis of variance (ANOVA). Results: MSG treatment significantly (p<0.05) increased hepatic and serum alanine aminotransferase activity (ALT), aspartate aminotransferase activity (AST), alkaline phosphatase activity (ALP), total bilirubin concentration (T-BIL), and direct bilirubin concentration (D-BIL) but decreased albumin concentration (ALB) compared to control and others. TAZT treatment caused a significant (p<0.05) decrease in these effects unlike MSG and OATZ treatments while TAZT + MSG co-treatment significantly (p<0.05) reversed these effects compared to MSG-treated rats. Rats’ liver sections for rats in groups 2 and 3 showed severe hepatocellular degeneration and necrosis compared to others while those in group 4 (TAZT) showed the normal hepatic histo-architecture comparable to those in group 1 (control). Those in group 5 showed marked cellular swelling and leukocytic infiltration in only the centrilobular areas, suggesting active restorative responses. Conclusion: Thus, TAZT significantly mitigated the compromised histologic and biochemical integrities of liver function due to MSG treatment in rats via probable normalization of their enzymatic and non-enzymatic indicators of liver function. This suggests that TAZT could be useful in managing histologic and biochemical malfunction of rats’ liver due to MSG assault. Peer Review History: Received: 12 October 2023; Revised: 9 November; Accepted: 13 December, Available online: 15 January 2024 Academic Editor: Dr. Marwa A. A. Fayed, University of Sadat City, Egypt, maafayed@gmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Idoko Alexander, Caritas University, Enugu, Nigeria, idokoalexander1@gmail.com Dr. Dennis Amaechi, MrsFoluBabade Mini Estate, Flat 5 by Old Soldiers Quarter, Sabongari/Bwari, Abuja- Federal Capital Territory, Nigeria. amaechitoexcel@yahoo.com

Atypical Complications during the Course of COVID-19: A Comprehensive Review.

COVID-19 is primarily a respiratory disease, but numerous studies have indicated the involvement of various organ systems during the course of illness. We conducted a comprehensive review of atypical complications of COVID-19 with their incidence range (IR) and their impact on hospitalization and mortality rates. We identified 97 studies, including 55 research articles and 42 case studies. We reviewed four major body organ systems for various types of atypical complications: (i) Gastro-intestinal (GI) and hepatobiliary system, e.g., bowel ischemia/infarction (IR: 1.49-83.87%), GI bleeding/hemorrhage (IR: 0.47-10.6%), hepatic ischemia (IR: 1.0-7.4%); (ii) Neurological system, e.g., acute ischemic stroke/cerebral venous sinus thrombosis/cerebral hemorrhage (IR: 0.5-90.9%), anosmia (IR: 4.9-79.6%), dysgeusia (IR: 2.8-83.38%), encephalopathy/encephalitis with or without fever and hypoxia (IR: 0.19-35.2%); (iii) Renal system, e.g., acute kidney injury (AKI)/acute renal failure (IR: 0.5-68.8%); (iv) Cardiovascular system, e.g., acute cardiac injury/non-coronary myocardial injury (IR: 7.2-55.56%), arrhythmia/ventricular tachycardia/ventricular fibrillation (IR: 5.9-16.7%), and coagulopathy/venous thromboembolism (IR: 19-34.4%). This review encourages and informs healthcare practitioners to keenly monitor COVID-19 survivors for these atypical complications in all major organ systems and not only treat the respiratory symptoms of patients. Post-COVID effects should be monitored, and follow-up of patients should be performed on a regular basis to check for long-term complications.

Heterozygous PAI-1 Deficiency’s Role in Pathological Aging in the Human Cardiovascular System

Background and Objective: Plasminogen activator inhibitor (PAI-1) is a member of the fibrinolytic system and a marker and a mediator of cellular senescence. Experimental evidence in humans suggests that higher levels of PAI-1 are associated with increased pathological aging in several major organ systems of the human body. To better understand the role of PAI-1 in humans, specifically in the cardiovascular system, we studied the effects of a loss-of-function mutation in SERPINE1, the gene encoding PAI-1, in an Old Order Amish community in Berne, Indiana. Overall, carriers of the null SERPINE1 variant had greater leukocyte telomere lengths, lower fasting insulin levels, and less prevalent diabetes mellitus. To further the conclusions previously published, our goal is to continue to analyze data collected alongside demographic data to determine if there is a link between PAI-1 deficiency and protection against aging-related changes in the human cardiovascular system. We hypothesized that the differences between the cardiovascular endpoints between carriers and non-carriers will be most significant in older groups.
 Methods: Participants included 177 members of the community, 43 of which were carriers for the SERPINE1 mutation. To test our hypothesis, we divided participants into tertiles and compared the results of selected cardiovascular parameters of those with and without the mutation in each tertile.
 Results: Our analysis revealed a statistically significant difference in brachial pulse pressures between carriers of the null mutation and normal individuals in the third tertile, corresponding to individuals ages 55 to 82. Those heterozygous for the mutation in this age group had a lower brachial pulse pressure, suggesting there are protective effects of PAI-1 haploinsufficiency against endothelial senescence as people age.
 Potential Impact: By identifying the age group with the most pronounced effects of PAI-1 deficiency, we can further investigate the means by which these results manifest in humans and better understand where in the aging process they are most significant.

Single-nuclei transcriptome analysis of channel catfish spleen provides insight into the immunome of an aquaculture-relevant species.

The catfish industry is the largest sector of U.S. aquaculture production. Given its role in food production, the catfish immune response to industry-relevant pathogens has been extensively studied and has provided crucial information on innate and adaptive immune function during disease progression. To further examine the channel catfish immune system, we performed single-cell RNA sequencing on nuclei isolated from whole spleens, a major lymphoid organ in teleost fish. Libraries were prepared using the 10X Genomics Chromium X with the Next GEM Single Cell 3' reagents and sequenced on an Illumina sequencer. Each demultiplexed sample was aligned to the Coco_2.0 channel catfish reference assembly, filtered, and counted to generate feature-barcode matrices. From whole spleen samples, outputs were analyzed both individually and as an integrated dataset. The three splenic transcriptome libraries generated an average of 278,717,872 reads from a mean 8,157 cells. The integrated data included 19,613 cells, counts for 20,121 genes, with a median 665 genes/cell. Cluster analysis of all cells identified 17 clusters which were classified as erythroid, hematopoietic stem cells, B cells, T cells, myeloid cells, and endothelial cells. Subcluster analysis was carried out on the immune cell populations. Here, distinct subclusters such as immature B cells, mature B cells, plasma cells, γδ T cells, dendritic cells, and macrophages were further identified. Differential gene expression analyses allowed for the identification of the most highly expressed genes for each cluster and subcluster. This dataset is a rich cellular gene expression resource for investigation of the channel catfish and teleost splenic immunome.

The effect of colchicine on mucocutaneous and joint manifestations of Behçet's disease

Mucocutaneous lesions are the most common manifestation and hallmark of Behçet’s Syndrome (BS). They show a significant impact on patients' quality of life and more importantly, may occur concurrently with major organ involvement. Colchicine is the first-line therapy for patients with mucocutaneous involvement because of its good tolerability and safety profile. The literature lacks clear data on the duration of treatment of mucocutaneous symptoms and the prognosis of patients who interrupt colchicine therapy. This study was planned to observe differences in mucocutaneous findings, joint findings and disease activity, in the colchicine-free period of the patients who were followed up with the diagnosis of BS without active major organ involvement and who were in remission and discontinued colchicine treatment. Our study demonstrated a significant increase in the rate of patients who developed aphthae after the discontinuation of colchicine treatment, which is the primary endpoint, and in the number of newly developed aphthae, which is the secondary endpoint. A significant increase was observed in the rate of patients who developed erythema nodosum in the first and second months. There was no significant difference in the development of genital ulcers after discontinuation of colchicine. The rate of nodular lesion development in female patients increased during the colchicine-free period. Due to the low number of patients who developed joint complaints, we could not demonstrate the efficacy of colchicine in our study.

The mediator role of treatment response on oral health related quality of life in Behçet's syndrome.

The aim of the study was to analyse the effects of Treatment Response with oral ulcers on oral health related quality of life in Behçet's syndrome (BS). In the cross-sectional study, 339 BS patients (F/M: 179/160, mean age: 36,13±9,81 years) were included. Data were collected by clinical examinations and patient reported outcome measures (PROMs) regarding Oral Health Impact Profile-14 (OHIP-14) questionnaire and self-reported Treatment Responses coded by a 5-point Likert-type scale (1: symptoms were cured- 5: symptoms were worsened). Moderated Mediation analysis (MA) was used to understand how oral ulcer activity (independent variable; X) influenced OHIP-14 score (outcome variables, Y) through self-reported Treatment Response (M1) and age (M2) as possible mediator variables (M) and disease course (mucocutaneous and musculuskeletal involvement vs. major organ involvement) as a possible moderator variable (W) on these relationships. In Moderated MA, OHIP-14 score (Y) was mediated by the presence of oral ulcer (X) (p=0.0000), the negative Treatment Response (M1) (p=0.0001) and being young (M2) (p=0.0053) with mucocutaneous involvement (W)(p=0.0039). Self-reported Treatment Response as an underestimated issue has a Mediator role in relation to oral ulceration on oral health related quality of life in the framework of patient empowerment strategies. Therefore, study results give clues to assist physicians and dentists for better understanding of patients' perspective.

Safety and efficacy of tranexamic acid in major non-cardiac vascular surgery: a systematic review and meta-analysis

Background: Tranexamic acid (TXA) is a synthetic lysine analogue that inhibits fibrinolysis. The effectiveness of TXA in obstetrics, trauma and orthopaedic and cardiac surgery is well established. However, concerns regarding its prothrombotic potential remain, which is an important consideration for vascular surgery. We aimed to evaluate the safety and efficacy of TXA in adults undergoing major non-cardiac vascular surgery. Methods: A pre-specified protocol (PROSPERO CRD42023427282) was followed. Relevant databases (PubMed, MEDLINE, EMBASE) were searched for randomised controlled trials (RCTs). Data extraction and risk of bias assessments were performed in duplicate. A random effects model was used to synthesise data from RCTs. Measures of effect were reported as relative risk (RR) with 95% confidence intervals (CIs). The primary safety outcome was a composite of arterial and venous thromboembolic events (composite of myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis and symptomatic proximal venous thromboembolism). Certainty of evidence was assessed using the GRADE approach. Results: After screening 1989 records, three RCTs were included, cumulatively enrolling 1,560 participants. In all trials, patients received either TXA (intravenously or orally) compared with placebo. There was no evidence of the effect of intravenous TXA on thromboembolic events (RR 1.10, 95% CI 0.89 to 1.36, two RCTs, 1460 participants, low certainty of evidence) or on critical bleeding (composite of life-threatening, critical and major organ bleed) (RR 0.85, 95% CI 0.65 to 1.11, two RCTs, 1460 participants, low certainty of evidence). TXA may reduce postoperative blood loss, especially at 0–4 hours (Cliff’s delta −0.41, 95% CI −0.19 to −0.59) and 0–24 hours (Cliff’s delta −0.37, 95% CI −0.14 to −0.55) after surgery. There was no evidence of an effect of TXA on reducing perioperative red blood cell (RBC) transfusion requirements (RR 0.66, 95% CI 0.11 to 3.95, one RCT, 100 participants). One RCT assessed oral TXA and found no evidence of an effect on type II endoleak post endovascular aneurysm repair. No thrombotic complications were reported in this RCT during the study period. Conclusions: We found no evidence of an effect of TXA on thromboembolic complications. While TXA appears to reduce early postoperative bleeding, the clinical relevance of this is uncertain. Due to limitations of study design and the variety of vascular procedures, the role of TXA in vascular surgery is still unclear. Ongoing trials may reduce this uncertainty. Registration: Prospectively registered on PROSPERO (CRD42023427282)

Diagnosis and Management of Pulmonary Manifestations of Telomere Biology Disorders.

Telomere biology disorders (TBD) are a group of genetic disorders characterized by premature shortening of telomeres, resulting in accelerated aging of somatic cells. This often leads to major multisystem organ dysfunction, and TBDs have become increasingly recognized as a significant contributor to numerous disease processes within the past 10-15years. Both research and clinical practice in this field are rapidly evolving. A subset of patients with TBD suffers from interstitial lung disease, most commonly pulmonary fibrosis. Often, the clinical presentation is indistinguishable from other forms of lung fibrosis. There are no pathognomonic radiographic or histological features, and a high level of suspicion is therefore required. Telomere evaluation is thus crucial to establishing the diagnosis. This review details the clinical presentation, objective evaluation, indicated genetic testing, and recommended management strategies for patients affected by interstitial lung disease associated with TBDs. Our goal is to empower pulmonologists and other healthcare professionals who care for these patients to provide appropriate and personalized care for this population.

The importance and added value of patient involvement in person-centred medication reviews.

Background: The iSIMPATHY (implementing Stimulating Innovation in the Management of Polypharmacy and Adherence Through the Years) team is conducting person-centred medication reviews using a 7-step review tool focusing on ‘what matters to you’1.
 iSIMPATHY is an EU-funded partnership between Scotland, Ireland and Northern Ireland. One of the main drivers for change is the WHO 3rd global patient safety challenge, Medication Without Harm which aims to reduce severe avoidable medication-related harm by 50% globally in the next 5 years, with one of the key action areas being polypharmacy2. To date over 1400 person-centred medication reviews have been conducted with patients in Northern Ireland. These reviews aim to reduce inappropriate polypharmacy, promote adherence and health literacy and provide patient education.
 Personal and Public Involvement (PPI) feedback was sought prior to the project starting and patient engagement has continued throughout.
 Method: Structured, person-centred medication reviews were conducted in acute medical wards in a secondary care setting in Northern Ireland. Priority was given to those on 10 or more medicines or a high risk medicine, over 50 and resident in a care home or approaching end of life. Data were collected for a cohort of 66 patients who consented to an iSIMPATHY review. Data were analysed to determine the interventions made due to patient involvement in the review as compared with interventions which could be made by completing a kardex (medicine list) review only.
 Results: An average of 9.3 interventions were made per patient, significance was graded using the Eadon system, with 4.4% graded 3 (significant but does not lead to an improvement in patient care), 88.9% graded 4 (significant and results in an improvement in standard of care) and 6.7% graded 5 (very significant and prevents major organ failure or an adverse reaction of similar importance). Interventions included checking and requesting laboratory tests, omitted medicines started, adjustments made for allergy, frailty, renal or liver impairment and identification of adverse drug reactions. Importantly, 88% (n=58) of patients had an intervention made because the medication review was discussed with them. This resulted in 38% additional interventions and included 22% of grade 5 interventions.
 The themes of additional interventions were: adherence and inhaler education (19%), identification of unmet/unknown health need and symptom control (15%), community support services (15%), lifestyle (12%), reduction and stopping unnecessary/inappropriate medicines (10%), identification of important additional information (10%), sick day rules (8%), self-care (7%) and referral to other services (5%).
 Conclusion: Patient involvement in their medication review leads to the identification of new and unmet needs, allows for the provision of counselling on medicines, adherence and lifestyle and prompts discussion and action on the deprescribing of inappropriate and unnecessary medicines. These additional interventions are clinically significant for the patient.
 Next steps: Medication reviews and data collection continues with the aim of scale and spread. For results and learning opportunities search https://www.isimpathy.eu/.
 
 https://www.isimpathy.eu/
 Medication Safety in Polypharmacy Technical Report, World Health Organisation 2019.
 
 https://www.who.int/initiatives/medication-without-harm
 
 Eadon, H. Assessing the quality of ward pharmacists’ interventions. Int. J. Pharm. Pract 1992, 1, 145–147
 

Cancer Immunotherapy with Lipid Nanoparticles Loaded with a Stimulator of Interferon Genes Agonist against Renal Tumor Lung Metastasis.

Metastatic renal cell carcinoma (RCC) has a poor prognosis, and the major organ of metastasis is the lung. Immunotherapy with immune checkpoint inhibitors (ICIs) is the first-line therapy, but the response rates are low. Thus, the development of a more effective immunotherapy against metastatic RCC would be highly desirable. We previously demonstrated how a stimulator of an interferon gene (STING) agonist-loaded lipid nanoparticles (STING-LNPs) significantly activates natural killer (NK) cells and induces an antitumor effect against cases of melanoma lung metastasis that have shown ICI resistance. In this study, we evaluated the potential of using STING-LNPs in the treatment of lung metastatic RCC (Renca). An intravenous injection of STING-LNPs drastically decreased the amount of Renca tumor colonies. In contrast, monotherapies using ICIs showed no antitumor effect, and even a combination of ICI and STING-LNP therapies failed to enhance the antitumor effects. The main effector cells would be NK cells, and the activation of NK cells by the STING-LNPs may avoid the increased expression of immune checkpoint molecules. These findings provide useful insights into the development of an effective immunotherapy against metastatic RCC.

Cost-of-illness changes before and after the diagnosis of systemic lupus erythematosus: a nationwide, population-based observational study in Korea

Abstract Objectives To estimate the direct healthcare cost progression from before to after systemic lupus erythematosus (SLE) diagnosis and to compare healthcare costs by disease severity. Methods Patients with incident SLE diagnosed between 2008 and 2018 were identified from the Korean National Health Insurance database. Annual direct healthcare costs for 5 years before and after SLE were estimated and compared with those of age-, sex- and calendar month-matched (1:4) controls, without SLE. Direct healthcare costs were compared by disease severity of SLE using regression analysis. Results Among 11 173 patients with SLE and 45 500 subjects without SLE, annual direct healthcare costs per person increased in the year before SLE diagnosis and peaked in the first year after diagnosis. They were 7.7-fold greater in the SLE patients than in the subjects without SLE ($5871 vs $759). Severe SLE was associated with 3.284-fold (95% CI: 3.075, 3.507) higher annual costs than mild SLE during the year after diagnosis. Older age (age 60–79 years), lupus nephritis, interstitial lung diseases, and comorbidities such as avascular necrosis and chronic kidney disease were associated with higher annual direct healthcare costs (times [95% CI]) in the first year after diagnosis: age 60–69: 1.119 (1.034, 1.211); age 70–79: 1.470 (1.342, 1.611); lupus nephritis: 1.794 (1.711, 1.881); interstitial lung diseases: 1.435 (1.258, 1.638); avascular necrosis: 6.208 (4.541, 8.487); and chronic kidney disease: 1.858 (1.673, 2.064). Conclusion Patients with SLE incurred significantly higher direct healthcare costs than subjects without SLE during the first year after diagnosis. Disease severity, older age, major organ involvements and comorbidities were associated with increased healthcare costs.

Investigation of Biopsychosocial Status, Fatigue, Sleep Quality, Alexithymia, Cognitive Functions, and Quality of Life in Behçet's Disease.

The aim of this study was to compare the effects of Behçet's disease in terms of anxiety, biopsychosocial status, fatigue, sleep quality, alexithymia, cognitive level, and quality of life according to major and minor organ involvement. The study was planned as a single-centre cohort study. Fifty patients diagnosed with Behçet's (mean age 43±11.96 years) were included in the study. The patients were divided into two groups as major organ involvement (uveitis, neuro-Behçet's, or vascular type Behçet's disease) and minor organ involvement (mucocutaneous type Behçet's disease). Biopsychosocial status was evaluated with Biopsychosocial Questionnaire (BETY-BQ), anxiety with Beck Anxiety Inventory (BAI), fatigue with Multidimensional Assessment of Fatigue (MAF) Scale, sleep quality with Pittsburgh Sleep Quality Index (PSQI), alexithymia with Toronto Alexithymia Scale-20 (TAS-20), cognition level with Mini-Mental State Examination (MMSE), and quality of life with Short Form-36 (SF-36). In the comparison according to minor and major organ involvement, there was no significant difference between the groups in BETY-BQ, BAI, MAF, PSQI, TAS-20, MMSE and SF-36 (p>0.05). Behçet's disease negatively effects in parameters such as biopsychosocial status, fatigue, sleep quality, alexithymia and quality of life. The presence of major or minor organ involvement in the patients did not change these negative effects.