Aim: In individuals with COVID-19, the study assessed the relationship between cytokine expression and pulmonary dysfunction. These correlations may help to suggest strategies for prevention and therapies of coronavirus disease outbreak. Patients and methods: 50 healthy participants and 100 COVID-19 patients participated in this study. COVID-19 participants were subdivided into moderate and severe groups based on the severity of their symptoms. In both patients and controls, measurements of white blood cells (WBCs), lymphocytes, C-reactive protein (CRP), interleukin (IL)-1, IL-4, IL-6, IL-18, and IL-35 were estimated. All the patients performed chest CT and CO-RADS score was assessed. Results: All patients had increased WBCs count and CRP, IL-1, IL-4, IL-6, IL-18, and IL-35 levels than healthy controls. While WBCs, CRP, and cytokines like IL-1β and IL-6 showed significantly higher levels in the severe group as compared to moderate patients, IL-4, IL-35, and IL-18 showed comparable levels in both disease groups. Furthermore, CO-RADS score was positively connected with WBCs, CRP, and cytokine levels (IL-35, IL-18, IL-6, IL-4 and IL-1β) in both groups, and lymphocyte levels in all patient groups considerably decreased as compared to the controls. CO-RADS score, also demonstrated a positive correlation with lymphocytes in the moderate COVID-19 patients, whereas in the severe patients, it demonstrated a negative correlation with lymphocytes. Conclusion: Severe COVID-19 patients, compared to individuals with moderate illness and healthy controls, patients had lower lymphocyte counts and increased CRP with greater WBCs counts. In contrast to moderate COVID-19 patients, severe COVID-19 patients had higher levels of IL-1β and IL-6, but IL-4, IL-18, and IL-35 between both illness categories at close levels. CO-RADS 5 was the most frequent category in both moderate and severe cases. Patients with a typical CO-RADS involvement had a higher CRP and white blood cell count with a lower lymphocyte count than the others. Cytokine levels were considered a surrogate markers of severe lung affection in COVID 19 patients.

Background: At altitudes beyond 2500 m the risk of developing high altitude pulmonary edema (HAPE) grows with the increases in pulmonary arterial pressure. HAPE is characterized by severe pulmonary hypertension, though the incidence and relevance of individual risk factors are not yet predictable. However, the systolic pulmonary pressure (SPAP) and peak in tricuspid regurgitation velocity (TVR) are crucial factors when diagnosing pulmonary hypertension by echocardiography. Methods: The SPAP and TVR of 27 trekkers aged 20-65 years en route in the Solu Khumbu region of Nepal was assessed. Echocardiograph measurements were performed at Lukla (2,860 m), Gorak Shep (5170 m), and the summit of Kala Patthar (5,675 m). The altitude profile and the participant’s characteristics were also compiled for correlation with the measured data. Results: The results showed a highly significant increase of SPAP and TVR after ascending Kala Patthar. The study revealed a lower increase of SPAP and TVR in the group of older participants, although the initial respective measurements in Gorak Shep were significantly higher for this group. A similar finding occurred in those using Diamox® as prophylaxis. There was an inverse relationship between TVR and SPAP, the peripheral capillary oxygen saturation and heart rate. Conclusions: The echocardiograph results indicate that older people are a risk group for developing a HAPE. The prophylactic use of acetazolamid led to higher initial SPAP values in Gorak Shep, and a lower increase of SPAP as well as TRV after ascending Kala Patthar. Arterial oxygen saturation measurements can provide an indicator for the self-assessment for the risk of developing HAPE and provide a rule of thumb for the altitude profile but does not replace a HAPE diagnosis. The collected data variables concerning backpack weight, sex, workload (actual ascent speed), and pre-existing diseases were not statistically significant factors related to SPAP and TVR (p=<0.05).

Endothelial autocrine signaling is essential to maintain vascular hemostasis. There is limited in-formation about the role of endothelial autocrine signaling in regulating severe pulmonary vas-cular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe PAH mouse model, Egln1Tie2Cre (Tie2Cre-mediated disruption of Egln1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cells (PVECs) hyperproliferation and the pathogenesis of PAH. PVECs isolated from Egln1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhib-ited hyperproliferative phenotype in coincident with upregulation of proliferation specific tran-scriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in culture human PVECs. Endo-thelial specific deletion of Cxcl12 (Egln1/Cxcl12Tie2 Cre) or AMD3100 treatment in Egln1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in Egln1Tie2Cre mice (Egln1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine sig-naling in regulating PVECs hyperproliferation and pulmonary vascular remodeling in PAH.

Pulmonary arteriovenous malformation (PAVMs) in children are rare lesions characterized by abnormal low resistance vascular structures connecting a pulmonary artery to a pulmonary vein, resulting in an intrapulmonary right-to-left shunt. The insidious onset and variable signs&nbsp;and symptoms make diagnosis difficult, especially in children. PAVMs&nbsp; can be single or multiple, congenital or acquired, and up to 47-80% of cases are associated with hereditary hemorrhagic telangiectasia (HHT).We present the&nbsp; case of a 12-year-old female teenager referred to our center for epistaxis, headache, fatigue and weakness, with evidence of mild oxygen desaturation.&nbsp; Bubble test showed a right-to-left shunt and pulmonary angio-CT confirmed the diagnosis. Percutaneous selective embolization was performed with full recovery of normal arterial oxygen saturation. When differentiating between mild oxygen desaturation and exercise intolerance in children and adolescents, physicians should be aware of the possibility of PAVMs as a cause.&nbsp;

Pulmonary arterial hypertension is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors, and likely gene x environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 36% of pediatric-onset idiopathic PAH (IPAH) compared to ~11% of adult-onset IPAH. De novo variants are frequently associated with PAH in children, and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, the increased etiologic heterogeneity, poorer prognosis and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

Background and objective: Addressing the global morbidity associated with pulmonary disease is an important need for the respiratory community. However, there is also a growing momentum to show the efficacy of new tools of diagnosis. Despite this, there are few physiotherapeutic tools that help identify and categorize these conditions. The aim was to analyze the variables of physiotherapy index of the ventilatory workload (PIVW) in people with chronic obstructive pulmonary disease (COPD) during stability and exacerbation in an outpatient setting. Material and Methods: Analyzed retrospectively of 198 clinical records were reviewed. The PIVW was extracted in stability and exacerbation of these patients with COPD. After applying the exclusion and inclusion criteria; 54 patients were classified. Through the statistical analysis of chi-square, a significant association was reported for each of the variables and the total PIVW score. Results: when analyzing the baseline with the peak of PIVW, there was a significant increase in patients COPD exacerbation. Similarly, the variables that constitute the loads, translations and supports underwent a significant increase from baseline to exacerbation (p<0.0001), except for the additional oxygen contribution, where the frequency of patients was the same in basal and exacerbation as well. Conclusions: the PIVW, serves to determine ventilatory problemas in outpatients, characterizing the specific changes of loads, translators or assistance.

Background: Tuberculosis (TB) manifests itself primarily in the lungs as pulmonary disease (PTB) and sometimes disseminates to other organs to cause extra-pulmonary TB, such as lymph node TB (LNTB). This study aimed to investigate the role of host genetic polymorphism in immunity related genes to find a genetic basis for such differences. Methods: Sixty-three, Single nucleotide polymorphisms (SNPs) in twenty-three, TB-immunity related genes including eleven innate immunity (SLCA11, VDR, TLR2, TLR4, TLR8, IRGM, P2RX7, LTA4H, SP110, DCSIGN and NOS2A) and twelve cytokine (TNFA, IFNG, IL2, Il12, IL18, IL1B, IL10, IL6, IL4, IL1RA, IL8 and TNFB) genes were investigated to find genetic associations in both PTB and LNTB as compared to healthy community controls. The serum cytokine levels were correlated for association with the genotypes. Results: PTB and LNTB showed differential genetic associations. The genetic variants in the cytokine genes (IFNG, IL12, IL4, TNFB and IL1RA and TLR2,4 associated with PTB susceptibility and cytokine levels but not LNTB (p &lt; 0.05). Similarly, genetic variants in LTA4H, P2RX7, DCSIGN and SP110 showed susceptibility to LNTB and not PTB. Pathway analysis showed abundance of cytokine related variants for PTB and apoptosis related variants for LNTB. Conclusions: PTB and LNTB outcomes of TB infection have a genetic component and should be considered for any future susceptibility and functional studies.

Pulmonary hypertension (PH) has a high mortality, and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type 2 and type 17 responses in C57BL/6 mice. Here, we focused on type 2 response related cytokines, specifically Resistin-like-molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM2.5) or saline was used in C57BL/6 and BALB/c wild type or RELMα-/- mice. Vascular remodeling was assessed by histology, right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM2.5, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were more prominent in the C57BL/6 strain. Compared to wild type mice, RELMα-/- had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV IL-33 and RV ST2-IL-33-receptor were significantly increased in BALB/c wild type mice, but not in BALB/c-RELMα-/- or in C57BL/6-wild type or C57BL/6-RELMα-/- mice. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα-/- were not different from their respective wild type controls. In BALB/c mice, RELMα was a key contributor to antigen/PM2.5 induced pulmonary vascular remodeling, RV thickening and RV cytokine responses, highlighting the significance of the genetic background. The RELMα-/- animals demonstrated significantly decreased expression of RELMβ and RELM which makes these mice comparable to a situation where human RELMα levels would be significantly modified, as humans only have one RELM molecule.

Background: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoid malignancy. The majority of patients are asymptomatic and HCL is usually diagnosed incidentally during a routine blood cell counts. In symptomatic patients, typical symptoms are related to pancytope-nia and splenomegaly. In this review we present, rare clinical symptoms in patients with HCL. Methods: A literature search was conducted of PubMed, Web of Science, and Google Scholar for articles concerning hairy cell leukemia, leukemia cutis, bone lesions, neurological manifesta-tions, pulmonary symptoms, ocular manifestations, cardiac manifestation, rare symptoms. Publications from January 1980 to August 2024 were scrutinized. Additional relevant publica-ions were obtained by reviewing the references from the chosen articles. Results: Extra medul-lary and extra nodal manifestations of classic HCL are rare. However, leukemic involvement in the skin, bone, central nervous system, gastrointestinal tract, heart, kidney, liver, lung, ocular and other organs have been reported.

Lupus, also known as systemic lupus erythematosus (SLE), is a chronic autoimmune disease that can lead to inflammation and damage to multiple organs and tissues in the body. The symptoms vary from patient to patient, which makes the disease manifest very differently, resulting in difficulty in diagnosing and treating patients. Some may experience fatigue, hair loss, joint pain, and more. In the past, a general approach of blanket immunosuppression was commonly used to treat lupus. These immunosuppressive drugs would broadly target the immune system and focus on reducing symptoms. However, recent research has shown that selective immunotherapies such as monoclonal antibodies (anifrolumab and belimumab) which target specific components of the immune system are more effective in managing lupus because of their ability to reach specific cells in the immune system rather than easing symptoms. Anifrolumab blocks the activity of type I interferons, while belimumab neutralizes BLyS to reduce the production of autoantibodies, the root cause of SLE.¹⁻² This paper will introduce the immunology of the disease, explore how the more traditional approach of blanket immunosuppressive drugs work compared to the newer selective immunotherapies, and review the results from the clinical trials of anifrolumab and belimumab.

Prostate cancer lung metastasis represents a clinical conundrum due to their implication of advanced disease progression and the complexities they introduce in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, the review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, the review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

Tumid Lupus Erythematosus has been the subject of heated debate as to its correct nosographic classification. In particular, its definition has changed over time, depending on the different studies performed. In this review we address the initial definition of TLE, the changes that have taken place in the understanding and placement within the classification of Lupus Erythematosus (LE), and focus on clinical, histopathological, immunophenotypical and differential diagnosis aspects.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by debilitating symptoms including skin and visceral fibrosis, systemic skin hardening, Raynaud's phenomenon and other vascular dysfunctions, and immune abnormalities. The disease poses a significant medical challenge with no cure currently available. As such, SSc is designated as an intractable disease in Japan, with patients receiving government subsidies for medical expenses. Oxidative stress (OS) is implicated in the pathogenesis of SSc and the antioxidant combination Tweendee X®︎ (TwX) has shown promising results in mitigating OS-related conditions. HOCl-induced SSc-mice are known to exhibit similar skin and visceral fibrosis, vascular disorders, and autoimmunity observed in human. In a study done using these mice, Twx demonstrated a significant reduction in lung and skin fibrosis compared to untreated HOCl-induced SSc mice. TwX also significantly reduced advanced oxidized protein products (AOPP) in serum, Col-1 gene expression and the activation of B cells involved in autoimmunity. SSc is a disease state in which autoimmune abnormalities, fibrosis, and vascular disorders are intertwined, and therefore for a treatment to be effective it needs to address multiple issues. Thus the efficacy of TwX may stem from its strong antioxidant capacity to regulate OS, which cannot be achieved by a single antioxidant on its own. In other studies, targeting other OS-related conditions, TwX was safe and proved to be effective at prevent dementia in humans with mild cognitive impairment and to significantly improve cognitive impairment in Alzheimer's (AD) mouse models. TwX may offer a new approach to antioxidant treatment for SSc, to address multiple abnormalities that are characteristic of the disease.

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by a variety of both signs and symptoms; it mainly affects women of childbearing age, with an estimated prevalence of 24/100,000 people in Europe and North America. SLE is often described as an antibodies-driven disease as its clinical manifestations are usually associated with the presence or the absence of specific antibodies. Objectives To evaluate clinical manifestations in patients with SLE and to assess the relationship with the presence of specific antibodies by using real-world data. Methods A retrospective study was performed; the 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus were used to classify patients with SLE. Data concerning serological profiles (which included Antinuclear antibodies – ANA, anti dsDNA, anti-Ro/SS-A, anti-La/SS-B, anti-Sm) were gathered along with medical records of clinical manifestations. Complement levels were also tested for possible clinical correlations. χ² or Fisher's exact tests were utilized to establish associations between autoantibodies and symptoms. The odds ratios (OR) and their 95% confidence intervals (CI) were computed. No correction was made for multiple testing; only a p-value 0.01 ≤ was considered significant. Results One-hundred and twenty-seven patients (n=127, mean age 53.43 ±14.02) were enrolled in this study. Anti-dsDNA antibodies were found to be statistically significant for both malar rash and proteinuria; anti-Ro/SSA antibodies showed an association with photosensitivity and pericarditis; furthermore, a strong association was found between anti-Ro antibodies and proteinuria, but only if anti-dsDNA antibodies were present as well. Patients who tested positive for anti-La/SSB antibodies correlated with a threefold increase in the risk of developing pericarditis. Lastly, anti-Smith appeared to be associated with NPSLE as well as an increased risk for both autoimmune haemolytic anemia and thrombocytopenia. Conclusions In our study, many associations confirmed those found in previous studies; however, new relationships between antibodies and clinical manifestations were found thus indicating the need for additional evaluations to assess these correlations further.

Systemic sclerosis (also known as scleroderma) is a chronic fibrosing autoimmune disease with both skin and multisystem organ involvement. Scleroderma has the highest mortality among all rheumatic diseases. The pathophysiology mechanism of systemic sclerosis is a progressive self-amplifying process, which implicates the widespread microvascular damage, followed by a dysregulation of innate and adaptive immunity and inflammation, and diffuse fibrosis of the skin and visceral organs. Fibrosis of internal organs is a hint for systemic sclerosis, moreover associated with interstitial lung disease (SSc-ILD) is a complex process. We report a case of a 56 years old female, diagnosed with Systemic Sclerosis 16 years ago. The systemic and clinical manifestations, respiratory functional tests, radiological aspects and specific therapy were discussed.

Non-systemic oral drugs, which do not get absorbed through the gastrointestinal membrane, are an important group of compounds for targeting diseases residing within the gastrointestinal lumen. However, they require a set of design principles not sufficiently covered by traditional druglikeness metrics, such as Lipinski’s Rule of 5. These druglikeness metrics fail to accurately identify true negative outcomes; such is the requirement for novel cheminformatic based approaches for the discovery of non-systemic small molecules. One such example of these newer metrics is the fraction of SP3-hybridised carbon atoms (fSP3) which has shown promising application as an identifier of poor oral-bioavailability. Herein, we discuss the application of fSP3 in the drug discovery process in a number of case studies, including our own work discovering non-systemic fructose scavengers for the treatment of fructose malabsorption.

Background: To assess the prevalence of Hypertension (HTN) in Burning Mouth Syndrome (BMS) patients and to investigate its relationship with sociodemographic factors, pain and the psychological profile. Methods: A case-control study was conducted by enrolling 242 BMS patients and 242 controls matched for age and gender. Sociodemographic and clinical characteristics were recorded, and all the participants completed the numeric rating scale (NRS), the short-form of the McGill pain questionnaire (SF-MPQ), the Hamilton rating scale for anxiety and depression (HAM-A, HAM-D), the Pittsburgh sleep quality index (PSQI) and the Epworth sleepiness scale (ESS). Results: The BMS patients presented a statistically significant higher prevalence of HTN compared to the controls (55% versus 33.5%; p-value: &lt;.001**) and higher median scores of the NRS, SF-MPQ, HAM-A, HAM-D, PSQI and ESS (p &lt; .001**). Multivariate regression analysis in the BMS patients indicated positive correlations between HTN and age, systemic diseases, drug consumption and anxiety (p-value: &lt;.001**) and these predictors were responsible for 11.3% of the HTN variance in the BMS patients, when considered together. Conclusions: The prevalence of HTN was significantly higher in the BMS patients, since ageing, the presence of comorbidities, drug consumption and anxiety were potential predictors. Further studies are needed to better investigate the relationship between BMS and HTN.

Systemic sclerosis is an autoimmune disease characterized by organ fibrosis and vasculopathy. Almost all patients suffer from Raynaud’s phenomenon (RP). Currently, several imaging techniques are available; nailfold video capillaroscopy (NVC) is the most widely available, but flow quantification is not possible with NVC. Novel imaging techniques are of interest in this population. We performed a single-center feasibility study using Micro Vascular Imaging (MVI) as a novel imaging technique for flow quantification of small fingertip vessels. We compared a group of 20 healthy controls (HCs) with 20 Systemic Sclerosis (SSc) patients. In HCs, flow measurements assessed with MVI were statistically significantly higher in individual fingers and combined for all fingers (p&lt;0.0001). As a cut-off value to discriminate HCs from SSc, a peak systolic (PS) flow velocity of &lt;6.9 cm/s and an end-diastolic (ED) flow velocity of &lt;2.68 cm/s was determined. Test characteristics for PS flow velocity showed moderate sensitivity (0.69, 95% CI 0.58-0.78) but high specificity (0.88, 95% CI 0.79-0.93). Similar test characteristics for ED flow velocity were obtained. The optimal cut-off point was estimated at &lt;2.68 cm/s, sensitivity was moderate (0.65, 95% CI 0.53-0.75), specificity was 0.80 (95% CI 0.70-0.87). Here, we present the first study on the use of MVI to assess blood flow in the fingertips with high specificity in SSc patients. Future studies need to investigate correlations with the risk for organ complications, such as digital ulcers or pulmonary arterial hypertension.

Various studies have addressed the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, cancer has a systemic impact which targets various organs thus challenging the overall physiology of the host. So, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern the systemic role of neutrophils, we monitored their number and function at different stages of tumor growth in Dalton’s lymphoma mice model. Notably, we observed a gradual increase in neutrophil count in blood and their infiltration in vital organs of tumor bearing mice. In parallel, we observed damaged histoarchitecture with significant alterations in biochemical parameters that aggravated with tumor progression. We next examined systemic impact of neutrophil by assessing neutrophil elastase, myeloperoxidase, and matrix metalloproteinases (MMP-8 and MMP-9) wherein we found their upregulated expression and activity in tumor condition. Taken together, our results demonstrate high infiltration and hyperactivation of neutrophils which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.

The human oral microbiome refers to an ecological community of symbiotic and pathogenic microorganisms found in the oral cavity. The oral cavity is a suitable environment that provides various kinds of biological niches such as teeth, tongue, and oral mucosa. The oral cavity is the gateway between the external environment and the human body, maintaining oral homeostasis, protecting the mouth, and preventing disease. On the flip side, the oral microbiome plays an important role in triggering, development, and progression of oral and systemic diseases. Currently, disease diagnosis through the analysis of the human oral microbiome has been realized with the recent development of innovative detection technology, and is overwhelmingly promising compared to the previous era. It has been found that patients with oral diseases and systemic diseases have variations in the oral microbiome compared to normal subjects. This narrative review provides insight into the pathophysiological role that oral microbiome plays in influencing oral and systemic diseases, and updates the knowledge related to the oral microbiome over the past 30 years. A wide range of updates was provided with the latest knowledge of the oral microbiome to help researchers and clinicians in both academic and clinical aspects. The microbial community information can be utilized in non-invasive diagnosis and help develop a new paradigm in precision medicine, which will benefit human health in the era of post-metagenomics.

The standard care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment for symptoms. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive settings are even more common, paving the way to a paradigm change of focal treatments role. In fact, according to immunophenotype, radiotherapy can be considered with radical intent in these settings of patients. The aim of this literature review is to analyse available clinical data on prognosis of bone metastases from breast cancer and benefits of available treatments for developing a practical guide for clinicians.

Focusing on the implementation of the 2003 UNESCO Convention for the Safeguarding of the Intangible Cultural Heritage (ICH), this article highlights the fact that the cataloging procedures, the way records are stored, and the metadata models used during recording, visualization, and storage of ICH expression elements, vary from country to country. Especially in these days of great uncertainty, war conflicts, and the systemic risks that may arise, it is vital to clarify what techniques will be used in the storage of ICH to ensure its unhindered preservation and dissemination over time across the globe. Using the systems thinking approach indicated for cases of great complexity, the process followed in Greece for depositing a new element in its local repository is described to demonstrate the need for a well-defined process by UNESCO, which must be followed worldwide and which has not been defined so far. What are the potential challenges not only in determining the type of data but also in choosing the best metadata model to use in each case when capturing this data? What technologies must be used for storing digital cultural heritage in such a way that will preserve it over time, defying physical and technological hazards? The article finally suggests how Blockchain Technologies (BT) can be effectively used to store the global ICH and ensure its continuity in future generations by creating a decentralized worldwide network between the heritage stakeholders.

Pulmonary arterial hypertension (PAH) is a complex and devastating disease that the underlying cellular and molecular mechanisms are largely remains unknown. This study aimed to elucidate the key hub genes and pathways in PAH by bioinformatics analysis. In the current study, we performed WGCNA analysis to systematically identify the hub genes for PAH using transcriptome microarray data. From the Gene Expression Omnibus (GEO) database, one microarray dataset (GSE113439) was downloaded for this study. There were 26 samples in this data set, including 15 PHA samples and 11 normal controls. Based on weighted correlation network analysis, 11 modules were identified and the MEgreenyellow module showed a significantly positive correlation with PAH (r = 0.93, P = 1e−06). The genes in greenyellow module were mainly significantly enriched in mitophagy related pathways by KEGG analyses. Combined with the protein–protein interaction (PPI) and co-expression networks, ten hub genes were identified as candidate biomarkers for PAH in the greenyellow module, including CTNNB1, NIPBL, ROCK2, ROCK1, SCAF11, JAK1, BIRC6, KIF5B, PPP1R12A and XRN1. These hub genes might be potential targets for clinical therapy against PAH. The molecular mechanisms involved in these genes that affected the prognosis of PAH should be further validated through biological and basic studies.

Midkine (MDK) is a multifunctional heparin-binding growth factor, and has been shown to regulate cell growth, survival and migration. It also plays important roles in several inflammatory diseases such as sepsis. However, the role of MDK in the lungs has not yet been elucidated. In the present study, we investigated the role of MDK in pulmonary inflammation experiments using a mouse lipopolysaccharide (LPS)-induced pneumonia model and human bronchial cells. Wild-type and MDK-deficient mice were injected intratracheally with LPS, and several inflammatory parameters were analyzed. In the wild-type mice, mRNA expression of MDK in lung tissues was significantly increased after intratracheal LPS injection. The MDK-deficient mice showed significantly lower counts of total cells and neutrophils, as well as lower concentrations of neutrophil chemokines, KC and MIP-2 in bronchoalveolar lavage fluid, compared to wild-type mice. Moreover, mRNA expressions of TNF-α, KC and MIP-2 in lung tissues, as well as histopathological lung inflammation score, were significantly lower in the MDK-deficient mice. Furthermore, in in vitro experiments using bronchial epithelial cells, LPS stimulation increased mRNA expression of MDK, and MDK knockdown by siRNA decreased LPS-induced TNF-α and CXCL8 upregulation. These findings suggest that deficiency of MDK attenuates LPS-induced pulmonary inflammation.

Idiopathic pulmonary fibrosis [IPF] is a chronic progressive disease characterised by the accumulation of scar tissue in the lung parenchyma. It primarily occurs in middle-aged and elderly adults and results in significant morbidity and mortality worldwide. The disease occurs due to repetitive lung epithelial injury, subsequent fibroblast activation and myofibroblast differentiation, resulting in excessive extracellular matrix deposition. This leads to scar formation and subsequent loss of lung function. Current treatment options for patients with IPF include the two anti-fibrotic drugs, pirfenidone and nintedanib, which can slow disease progression; however, there are currently no known cures for the disease. As such, novel methods and drug targets are warranted. In this review, we provide an up-to-date account of the importance of specific cytokines and the potential role of regulatory immune cells. We discuss their role in the pathogenesis of IPF and address some of the key gaps in knowledge.

Fatigue and dyspnea are the most commonly presented long-term complaints in individuals previously infected with SARS-CoV-2. The purpose of the study was to comprehensively evaluate diaphragm muscle function in COVID-19 survivors, as well as investigate whether potential diaphragm dysfunction will contribute to physical functioning impairment. 46 patients qualified to pulmonary rehabilitation were examined. Diaphragm muscle function parameters were evaluated using ultrasonography, while severity of dyspnea, aerobic capacity and amount of energy used by the body during physical activity were assessed by 6-minute walk test, mMRC scale and Metabolic Equivalent Task (MET), respectively. We identified 69.5% patients with diaphragm atrophy and 6.5% with diaphragm paralysis. Percentage of atrophy was not related to age, gender, BMI index, oxygen therapy use during COVID-19 infection course and severity of disease. Patients with presence of cough, fever and without loss of smell during COVID-19 course had a significantly greater values of diaphragm inspiratory thickness, while patients with cough and no smell disorders had a significantly lower percentage of diaphragm atrophy. Diaphragm functional parameters were strongly associated with selected variables of person's exercise tolerance, such as distance in 6-minute walk test, saturation level, fatigue and exertion in Borg scale. In conclusion, diaphragm muscle dysfunction is a serious long-term post-COVID aftermath and can be viewed as a major contributing factor of prolonged functional impairments.

Introduction: The predictive value of the risk stratification scales in elderly patients with IPAH might differ from that in younger. It is unknown whether young and older IPAH patients have the same survival dependence on PAH-specific therapy numbers. The aim of the study was to evaluate the prognostic relevance of risk stratification scales and PAH medication numbers in elderly in comparison with young IPAH patients. Material and methods: 119 patients from a prospective single-center PAH registry were divided on to group I <60 years old (n=89) and group II ≥60 years old (n=30). ESC/ERS, REVEAL, and REVEAL 2.0 risk stratification scores were assessed at baseline, as well as H2FpEF- score and survival at follow-up. Results: During a mean follow-up period of 2.9 years (1.63; 6.0) 42 (35.3%) patients died; at 1, 2, 3, 5, 7, and 10 years survival was 95%, 88.6%, 78.5%, 61.7%, 48.5% and 33.7%, respectively. No survival difference was observed between the two groups despite the use of monotherapy in elderly patients. The best predictive value exhibited the REVEAL in group II (IPAH patients ≥60 years) - AUC 0.73 (0.56-0.91), p = 0.03; and in patients with LHD comorbidities in the entire cohort - AUC 0.73 (0.59-0.87), p<0.009. Factors independently associated with death in the entire cohort were CKD (p=0.01, HR 0.2), the right-to-left ventricle dimension ratio (p=0.0047, HR 5.97), and NT-proBNP >1400 pg/ml (p=0.008, HR 3.18). Conclusion: Risk stratification in elderly IPAH patients requires a fundamentally different approach than that of younger patients, taking into account the initial limitations in physical performance and comorbidities that interfere with current assessment scores. The REVEAL score reliably stratifies patients at any age and LHD comorbidities. The initial monotherapy seems to be reasonable in patients over 60 years. Selection tools for initial combination PAH therapy in older IPAH patients with comorbidities need to be validated in prospective observational studies.

Degenerative mitral valve disease (DMVD) consists of progressive degeneration of the mitral valve that can occur either in isolation or in association with the tricuspid valve, leading to incomplete coaptation of its leaflets and subsequent valve regurgitation. It's the most common cardiac condition in small animals, accounting for about 75% of cases of heart disease in dogs, mainly affecting elderly small-breed dogs. Breeds with a genetic predisposition such as Cavalier King Charles Spaniels and Bull Terriers tend to develop the disease early. It can be classified into 4 stages: A, B, C, and D, with B having subdivisions (B1 and B2). Animals in stages A, B1, and B2 are asymptomatic, showing clinical signs only from stage C onwards. The report details the case of a 13-year-old Fox Terrier diagnosed at stage B2 of the disease, progressing to stage C within two years. A cardiologist conducted annual monitoring.

Fungal-bacterial co-colonization and co-infections are emerging among TB-suspected patients, yet the underlying mechanisms that enable and arise from their interactions are poorly understood. Understanding how environmental microbes such as fungi and bacteria co-evolve and develop traits to evade host immune responses and resist treatment is critical to controlling opportunistic co-infections. Our previous work has demonstrated that fungal-bacterial interactions can have dramatic impacts on fungal pathogenesis and drug resistance. Here, we, therefore, hypothesize that cross-kingdom synergistic interactions between environmental fungi and bacteria may influence both fungal and bacterial virulence, antimicrobial resistance patterns and aetiology. Through this, we aimed to establish the prevalence of fungal–bacterial microbial communities associated with chronic primary or opportunistic pulmonary infections. Concordantly, through surveilling 302 clinical samples from 151 patients, we established the prevalence of TB (0.7%) to be lower than that of fungi (1.3%) and non-TB bacterial (4.6%) mono-aetiologies Figure 2. However, our main observation was the unexpected taxonomic diversity with a striking twist of fungal-bacterial di-kingdom aetiological conformities. Interestingly, the majority of the patients presented with at least a di or mono-kingdom aetiological pairings. Importantly, fungi and non-TB bacteria formerly regarded as atypical opportunists are now frequently isolated as possible aetiology for chronic pulmonary infection. Hence, we revealed many di-kingdom aetiological pairings here but their significance remains a question of further examination. Among which Acremonium spp + K. pneumoniae (n=5), Acremonium spp +Streptococcus pneumoniae (n=4), Acremonium spp + C. albicans + K. pneumoniae (n=3) were among the most dominant aetiological pairings observed. Interestingly, Acremonium spp + K. pneumoniae pairings were also seen to be the most commonly associated with pulmonary TB both during and after treatment. Isolation from the same infection niche as seen here calls for further investigations into any interaction signatures that may exist between these organisms. Taken together, our data suggest that fungal-bacterial co-existence may influence their virulence attributes and antimicrobial resistance patterns, with relevance to patient outcomes. Therefore, our data reveals an array of fungal-bacterial pairings that may influence the prognosis of chronic pulmonary disease. Importantly, suggesting that the diversity of pulmonary infective fungi and bacteria, and their complex population structures may pose challenges to the analysis and interpretation of conventional data. Thus, there is a need to redirect our diagnostic approaches to encompass polymicrobial aetiology in order to enhance our suspicion index for better management of opportunistic fungal-bacterial co-infections.

Background: To our knowledge, the sudden onset of symptomatic pulmonary hypertension after COVID-19 vaccination has not been described. Both cases presented here resulted in functional limitations and likely permanent organ damage. Case Summary: We report two cases of acute onset pulmonary hypertension in previously healthy adult males within three weeks of receiving the second dose of the Pfizer (BNT162b2) mRNA COVID-19 vaccine from different lots. Both patients experienced the sudden onset of severe fatigue and dyspnea on exertion with negative COVID-19 PCR testing. The diagnosis was made by serial transthoracic echocardiography in the first case and by both transthoracic echocardiography and right heart catheterization in the second. Discussion: Pulmonary hypertension is a serious disease characterized by damage to lung vasculature and restricted blood flow through narrowed arteries from the right to left heart. The onset of symptoms is typically insidious, progressive and incurable, leading to right heart failure and premature death. The World Health Organization (WHO) classifies pulmonary hypertension into 5 categories and recently re-defined as a resting mean pulmonary artery pressure greater than 20 mmHg. Sudden onset pulmonary hypertension would only be expected in the settings of surgical pneumonectomy or massive pulmonary emboli with compromise of at least 50% of the lung vasculature.

Background: Currently, many detection methods have high sensitivity to the diagnosis of lung cancer. However, some postoperative patients with pulmonary nodule were eventually diagnosed as benign nodules. The ideal evaluation of an individual with a pulmonary nodule would expedite therapy for a malignant nodule and minimize testing for those with a benign nodule.Methods: This case-control study is designed to explore the relationship between ACE1 rs4646994 polymorphism and the risk of lung cancer in patients with pulmonary nodules, 400 individuals with lung cancer and benign pulmonary nodules were included. A DNA extraction kit was used to extract plasm DNA from peripheral blood. The relationship between ACE1 rs4646994 and the risk of lung cancer in patients with pulmonary nodules was determined by chi-square test, logistic regression analysis and cross analysis. Results: The results showed that the DD genotype of ACE1 rs4646994 may increase the risk of lung cancer in patients with pulmonary nodules, and this correlation was more significant in the female subgroup. In the age stratification analysis, it was found that the risk of lung cancer was significantly increased in the DD genotype of ACE1 rs4646994 in the older subgroup (&gt; 45 years). In addition, the possibility of EGFR mutation in lung adenocarcinoma patients with ACE1 rs4646994 DD genotype was lower than that of II or ID genotype carriers. Conclusions: Our study indicated that ACE1 rs4646994 polymorphism increases the risk of lung cancer in patients with pulmonary nodules from China.

Transmembrane protein 100 (TMEM100) plays an important role in angiogenesis, vascular morphogenesis, integrity and cardiovascular development. TMEM100 is a downstream target of the BMP9/10 and BMPR2/ALK1 signaling pathways. Our recent study demonstrates TMEM100 is a lung endothelium enriched gene. Endothelial-specific deletion of Tmem100 impairs lung endothelial cells regeneration. Activation of Tmem100 signaling represents a novel strategy for lung vascular repair and regeneration. It is interesting and important to understand the roles of TMEM100 in the physiological and pathological conditions. In this review, we summarized the current knowledge of TMEM100.

Patients under immunosuppressive therapy for kidney diseases or on maintenance hemodialysis are more susceptible to infection than the general population since loss of renal function per se was an immunocompromised condition. Of relevance, CT imaging plays a crucial role in the detection and management of pulmonary infectious diseases. We hence presented diverse CT findings of pulmonary infections in the above said patients collected during our arduous work against a wide range of pathogens including klebsiella pneumoniae, staphylococcus aureus, candida parapsilosis, aspergillus, cryptococcus, mucor, pneumocystis carinii, cytomegalovirus, mycobacterium and nocardia. Notably, the pulmonary pathological changes were either primary pneumonia or secondary to the catheter-associated bloodstream infection. For a descriptive purpose, pulmonary manifestations of Wegener’s granuloma, lung cancer and diffuse alveolar hemorrhage/infection in vasculitis were also examined. As such, we retrospectively elaborated most likely CT features of each individual pathogen and briefly covered the differential diagnosis as well. Arguably, combination of pattern recognition with knowledge of the clinical setting could make a presumptive diagnosis and early treatment even more convenient. From the experience of first-line nephrologists, our work could make a substantial contribution to the expeditious and efficacious management of pulmonary infections in the pertinent patient population.

Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that anti-inflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg⁹ bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.

Objective: To estimate for the first time the burden of serious fungal infections in Romania; Methods: Data derived from the World Health Organization (WHO), National Institute of Statistics, Romanian public health agencies and non-profit health organizations and published annual reports on local epidemiology were used in the present study. When no data was available, specific at-risk populations were used to calculate frequencies of serious fungal diseases, using previously published epidemiological parameters. All data refer to the year 2016; 3) Results: The estimated number of serious fungal infections in Romanian population was 435,930 in 2016. Recurrent vulvovaginal candidiasis accounts for up to 80% of total cases (more than 350,000 women annually). Concerning the HIV related infections, among 14349 infected persons, Pneumocystis pneumonia occurred in about 10% of late presenters (30 cases in 2016), while cryptococcal meningitis is rarely diagnosed (less than 20 cases). Annually, the total number of oesophageal candidiasis and oral thrush cases in HIV-positive patients may be as high as 1229 and 3066, respectively. In immunocompromised and cancer patient population, the annual incidence of candidaemia is 295, and at least 158 invasive aspergillosis cases and 4 mucormycosis cases occur yearly. With 4,966 critical care beds and approximately 200,000 abdominal surgeries performed, the estimated annual incidence of candidaemia and Candida peritonitis is 689 and 344, respectively. The annual incidence of pulmonary tuberculosis is still high in Romania (12,747 cases). Thus, the prevalence of post-TB chronic pulmonary aspergillosis is estimated to be 8.98/100,000 (1768 cases). The prevalence of chronic obstructive pulmonary disease (COPD) and asthma in adults is 6% and 6.5%, respectively. Therefore, allergic bronchopulmonary aspergillosis prevalence is estimated at 29,387 and severe asthma with fungal sensitisation at 38,731 cases annually. 4) Conclusions: Not being on the list of reportable diseases, the number of patients presenting with severe mycoses in Romania can only be roughly estimated. Based on local reports and prevalence estimation, we consider that at least 2.2% of Romanians suffer a serious form of fungal disease.

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost)-incorporated nanoparticles and imatinib, a PDGF-receptor tyrosine kinase inhibitor, -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of PAH and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for treatment of PAH.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein. Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

Large Language Models (LLMs) have proved significant proficiency when comes to code generation especially in Structured Query Language (SQL) for databases and recent successful Text-to-SQL method involves fine-tuning pre-trained LLMs for SQL generation tasks. Transforming natural language text into SQL queries, has been attempted to solve with various learning techniques including Few-shot learning[1], fine tuning. In this paper we propose Supervised fine-tuning (SFT) as a better alternative for learning technique for text-to-SQL generation task using Code-Llama that pushes state of art accuracy on spider test suite to 89.6% on dev set which represent first instance of surpassing the earlier best-in-class with 5.5% higher score and 86.8% of exact match accuracy on dev set. Furthermore, we demonstrate that properly prompted LLM along with SFT provides far fewer hallucinations and much more robust LLM that can be used as a general tool for any text-to-SQL generation use case.

Systemic inflammation and immunodeficiency are the key components of Cirrhosis Associated Immune Dysfunction (CAID); its severity is dynamic and progressive and is associated with the greater deterioration of the liver function. There are two different immune phenotypes: the low-grade systemic inflammation phenotype and the high-grade systemic inflammation phenotype. Each of these phenotypes is related with the function of liver cirrhosis; thus, the presence of high-grade inflammation is correlated with the severity of the hepatic insufficiency, the bacterial translocation, and the organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation plays a relevant role in the persistent systemic inflammation in patients with cirrhosis; the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.

A new approach based on input-output (IO) analysis has emerged to estimate the carbon footprints of companies and their products from cradle to gate. While they rely on the same principles as the GHG Protocol, they use a distributed iterative framework to improve the footprint estimations and reduce their uncertainty. While optimal estimations would result if all the world’s companies would enter such a system, this paper shows how such a distributed system could apply to the real world where many enterprises would stay out of the system. We show how it would increase the quality of the estimations with respect the GHG Protocol by integrating scope 1 and scope 2 data of the value chains in the footprint estimations and reducing the part of remaining scope 3 data. To help analyzing uncertainty, we show how to use the scope 1/2/3 decomposition to estimate the biases and the standard deviations of the computed production intensities. We illustrate the model on macroeconomic data for 44 sectors and two regions (Europe and Rest of World), using the Inter-Country Input-Output database (ICIO). Such a system would necessarily rely on Information and Communication Technology since the companies would be permanently interconnected in a large-scale meshed network, using an application protocol for data exchange.

Introduction: Advanced glycation end-products (AGEs) may play a relevant role as inducers in the chronic inflammatory pathway present in immune-mediated diseases, such as systemic lupus erythematosus (SLE). AGEs concentrations have been associated, with discrepant results to date, with some parameters such as disease activity or accrual damage, suggesting their potential usefulness as biomarkers of the disease. Objectives: To confirm differences in AGEs levels measured by cutaneous autofluorescence between SLE patients and healthy controls (HC) and study their correlation with various disease parameters. Methods: Cross-sectional study, where AGEs levels were measured by skin autofluorescence, and SLE patients’ data were compared with those of sex- and age-matched HC in a 1:3 proportion through a multiple linear regression model. Correlations of AGEs levels with demographic and clinical data were analyzed through ANOVA tests. Both analyses were adjusted for confounders. Results: AGEs levels in SLE patients were significantly higher than in HC (p<0.001). We found statistically significant positive correlation with SLE disease activity index (SLEDAI) and damage index (SDI), physician and patient global assessment, C-reactive protein, leukocyturia, complement C4, IL6 and oral ulcers. We also found a negative statistically significant correlation with current positivity of anti-nuclear and anti-Ro60 antibodies. Conclusions: AGEs seem to have a role in LES pathophysiology, becoming a new management and prognosis biomarker in this disease. The association with specific antibodies and disease manifestations may indicate a specific clinical phenotype related to higher AGEs levels.

we describe an atypical case of Whipple disease involving exclusively the spinal cord in an adolescent receiving immunosuppressive therapy for systemic lupus erythematosus. The diagnosis was particularly difficult since lupus and Whipple disease can present similar clinical features and the patient’s prolonged contact with sewage was initially not mentioned. A literature review of the clinical, imaging, diagnostic, and therapeutic challenges of Whipple disease is also performed.

A Systemic Lupus Erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by a complex interplay of genetic, molecular, and cellular factors. It is considered a multifactorial disorder influenced by genetic susceptibility, environmental triggers, and dysregulated immune responses. Understanding the molecular and cellular mechanisms driving SLE pathogenesis has been instrumental in developing targeted therapies to manage the disease and improve patient outcomes. In this essay, we will delve into the intricate molecular and cellular processes underlying SLE and examine the key lessons learned from human therapies.

Citation: Lastname, F.; Lastname, F.; Last-name, F. Title. Phar-maceuticals 2022, 15, x. https://doi.org/10.3390/xxxxx Academic Editor: Firstname Lastname Received: date Accepted: date Published: date Publisher’s Note: MDPI stays neutral with regard to jurisdic-tional claims in pub-lished maps and insti-tutional affiliations. Copyright: © 2023 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons 1Olga Gumkowska-Sroka, 2Kacper Kotyla, 3Ewa Mojs, 2Klaudia Palka, 1,2*Przemysław Kotyla 1. Department of Rheumatology and Clinical Immunology Voivodeship Hospital No5 in Sosnowiec Medical University of Silesia Katowice, Poland 2. Department of Internal Medicine Rheumatology and Clinical Immunology Medical University of Silesia Katowice , Poland 3. 3. Department of Clinical Psychology, Poznan University of Medical Sciences Poznan, Poland *Correspondence: Prof Przemysław Kotyla Department of Internal Medicine Rheumatology and Clinical Immunology Medical University of Silesia, Katowice, Poland- Summary Systemic sclerosis is a connective tissue disease of unknown origin and unpredictable course, with both cutaneous and internal organ manifestations. In spite of enormous progress in rheumatology and clinical immunology, the background of diseases is largely unknown and no specific therapy exists. The therapeutic approach to the disease is aimed to treat and preserve the function of internal organs, and this approach is commonly referred to as an organ-based treatment. However, in modern times data from the other branches of medicine may help to treat disease-related complications, making it possible to find a group of drugs to be utilized in the treatment of the disease. In this review, we present possible therapeutic options aiming to stop the progression of fibrotic processes, restore aberrant immune response, stop improper signalling from proinflammatory cytokines, and halt the production of disease-related autoantibodies.

Background: Neuroendocrine tumors (NET) are a rare group of epithelial neoplasm present in gastrointestinal tract (GI) (67.5%), bronchopulmonary tree (25.3-30%), and in 15% of cases, the primary sites cannot be identified. Although endoscopic screening, improvement in pathological techniques, and early detection have shown improvement in NET survival rates, the prognosis of advanced, metastatic, and poorly differentiated NET is very poor. In this study, we aimed to evaluate the effect of Gastrointestinal and pancreatic (GEPs) NETs grade on overall survival. Method: We searched observational studies describing the overall survival or prognostic factors of primary GEP NETs from May 2011 -May 2021 following PRISMA guidelines. Studies describing the effect of primary grade 3 GEP NETs on overall survival were included. Meta-analysis was performed, and pooled hazard ratio and their 95% confidence interval (95% CI) were obtained. The forest plots were created using random-effects models and sensitivity analysis was performed to account for the heterogeneity. Results: Seven studies with 7692 confirmed patients were included. In our meta-analysis grade 3 GEP NET were associated with higher odds of poor survival (pooled HR: 2.73; 95% CI: 1.36–5.47; p = 0.005), with 92% heterogeneity between studies (p < 0.0001). To account for heterogeneity, sensitivity analysis was performed by removing two outlying studies (Fathi et al. and Foubert et al.) on funnel plots. The results after sensitivity analysis did not change and still showed significant association of grade 3 with poor survival (pooled HR: 4.53; 95% CI: 3.54–5.78; p < 0.00001), with no heterogeneity between studies (p = 0.72; I2 = 0%). Conclusion: Our meta-analysis found that grade 3 GEP NETs are associated with poor survival and additional future studies are needed to identify other risk factors associated with poor survival in GEP NETs to improve mortality.

Cancer has emerged as a systemic disease which targets various organs thus challenging the overall physiology of the host. Recently, we have shown that hyperactive neutrophils infiltrate various organs of tumor bearing host and contribute significantly to gradual systemic deterioration. Therefore, taming neutrophils via potent immunomodulators could be an appropriate therapeutic approach in regulating systemic damage. Tinospora cordifolia (TC), an Ayurvedic panacea, is known for its immense medicinal values in traditional literature and recent reports have also documented its strong immunomodulatory potential. However, whether TC can regulate neutrophils to exert its therapeutic effectiveness has not been deciphered so far. To discern this, we utilized murine model of Dalton’s Lymphoma (DL) wherein, we have earlier reported heightened infiltration of neutrophils and their hyperactivation. Our findings showed that TC treatment significantly reduced neutrophil count in peripheral blood and their infiltration in vital organs of tumor bearing host. Further, it ameliorated neutrophil hyperactivation by down regulating the expression of its key cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), MMP-8, MMP-9 and cathepsin G (CSTG) at early and mid stage of tumor growth. In addition, TC treatment prevented histopathological alterations and restored the normal serum enzyme levels at different stages of tumor growth. Importantly, TC treatment also showed significant reduction in tumor burden which was accompanied by a remarkable increase in survival of the tumor-bearing mice. We conclude that Tinospora cordifolia could limit systemic damage via regulating neutrophil infiltration and hyperactivation which can further lead to cancer control at both prophylactic and therapeutic level.

Objectives: To determine the prevalence of controlled systemic hypertension and its associated risk factors among the hypertensive patients who attended the clinic at Mbeya Zonal Referral Hospital in Tanzania. Methods: A descriptive cross-sectional quantitative study was used determine the prevalence of co to 252 hypertensive patients were recruited during clinic visit from September to November 2020 and participant was randomly selected interviews using structured self-administered questionnaires. Data was analyzed using chi square test to find the risk factors associated with controlled hypertension. Results: Among 252 participants, 94(39.7%) individuals with controlled hypertension giving the prevalence of controlled hypertension. The proportion of females with controlled hypertension was slightly higher than male (49 females to 45 males). The prevalence of uncontrolled hypertension was 152(60.3%) participants. The prevalence of controlled hypertension was higher among patients who have regular clinic visit (p< .05) and have daily adherence to their anti-hypertensive medication. A similar trend was observed among participants without financial challenges to attend clinic, short duration of illness, higher level of education and there was no association between age, sex, marital status, smoking, alcohol consumption, having health insurance and having chronic illness. Conclusion: Prevalence of controlled hypertension is higher among patients who have regular clinic visit and have daily adherence to their anti-hypertensive medication. Also, it is higher among participants without financial challenges to attend clinic so they can have regular clinic visit and checkup. Reinforcement on regular drug intake and clinic visit, good nutrition and reduced salt intake and modifying lifestyles of patient with hypertension is important.

In this study, a dynamic mixture copula is used to estimate the marginal expected shortfall in the South African insurance sector. While other studies assumed nonlinear dependence to be static over time, our model capture time-varying nonlinear dependence between institutions and the market. In order to capture time-varying nonlinear dependence, the generalized autoregressive score (GAS) is used to model the dynamic copula parameters. Furthermore, our study implements a ranking that expresses to what degree individual insurers are systemically important in South Africa. We use daily stock return of five South African insurers listed in the Johannesburg Stock Exchange (JSE) from November 13, 2007 to June 15, 2020. We find that Sanlam and Discovery contribute the most to systemic risk, while Santam is found to be the least contributor to the overall systemic risk in the South African insurance sector. Our findings would be of paramount importance for the South African regulators as they would be informed that not only banks are systemically important, but some insurers also are systemically important financial institutions. Hence, stricter regulation of these institutions in the form of higher capital and loss absorbency requirements could be required based on the individual business activities undertaken by the company.

Recently, environmental degradation has become an international issue due to the extensive economic activities around the globe. This aspect demands the policymakers' and new researchers’ emphasis. Hence, the present article examines the impact of corporate social responsibilities (CSR) to community and environment on the environmental performance (ENP) of the manufacturing industry in China. The article also investigates the mediating role of green innovation and environmental strategy among CSR to community, CSR to environment and ENP of manufacturing industry in China. The article gets the primary data from the selected employees of the manufacturing industry using questionnaires. The article also tests the data's validity and reliability, and association among variables using smart-PLS. The outcomes indicated that CSR to environment has a positive association with ENP. The outcomes also revealed that green innovation and environmental strategy significantly mediate among CSR to community, CSR to environment and ENP. The article guides the policymakers in making policies related to improve ENP using CSR to environment and green innovation.

The subject of this article is the dynamics of water in a soil pedostructure sample whose internal environment is subjected to a potential gradient created by the departure of water through surface evaporation. This work refers entirely to the results and conclusions of a fundamental theoretical study focused on the molecular thermodynamic equilibrium of the two aqueous phases of the soil pedostructure. The new concepts and descriptive variables of the hydro-thermodynamic equilibrium state of the soil medium, which have been established at the molecular level of the fluid phases of the pedostructure (water and air) in a previous article, are recalled here in the systemic paradigm of hydrostructural pedology. They allow access to the molecular description of water migration in the soil and go beyond the classical mono-scale description of soil water dynamics. We obtain a hydro-thermodynamic description of the soil's pedostructure at different hydro-functional scale levels including those relating to the water molecule and its atoms. The experimental results show a perfect agreement with the theory, validating at the same time the systemic approach which was the framework.

Background. Myocardial involvement mediated by chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality. Conventional transthoracic echocardiography (TTE) parameters are poor in the detection of subclinical myocardial dysfunction. Aim.To investigate the contribution of strain in the early detection of cardiac damage in stable COPD patients Methods. Group A and B patients with COPD were enrolled in this study. The COPD assessment test, spirometry, 6-minute walk test, and both conventional TTE and strain were performed in these patients. Results. 80 COPD patients, with a mean age 65.6 ± 8.9 years, were included. The. Left ventricular ejection fraction (LVEF) was 60.7 ± 5.1%. Right atrium and right ventricle (RV) strain were 24.5 ± 6.6% and -19.9 ± 3.7%, respectively. Additionally, left ventricle global longitudinal strain (LV GLS) was -21.1 ± 2. Forty-eight patients had impaired RV strain. Compared to COPD patient with normal RV strain, those with RV reduced starin had a lower 6meter walk distance (6MWD) (p=0.001) and forced expiratory volume in the first second (FEV1) (p=0.012), and a higher CAT score (p=0.012). A reduced RV strain was correlated with a higher risk of hospitalizations for acute exacerbation in the post inclusion year (55% versus 25%; p=0.024). No deaths were recorded during the follow-up period. No significant factors causing neither RA starin alteration nor LV GLS reduction were revealed. Conclusion. Group A and B COPD patients having normal conventional TTE parameters, speckle tracking is a key parameter in the detection of subclinical myocardial dysfunction.

Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD) affecting 6-10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of the disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is focused nowadays on the potential role of the genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the TGF-β pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield safe results that will allow a better understanding of SCD-related PH as a part of the disease’s clinical spectrum. The following review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.

Colorectal cancer is the third most diagnosed cancer in males and in females, representing 8% of estimated new cases and the third cause of cancer-related death in both sexes, accounting for 9% of cancer deaths in men and 8% in women. About 20% of patients diagnosed with CRC present metastatic disease. Although lung metachronous or synchronous metastatic spread without other involved sites has been reported in only a small proportion of patients, considering that this tumor is frequently diagnosed, the clinical approach to CRC pulmonary metastases represents a major issue for thoracic surgeons and CRC oncologists. Among patients diagnosed with pulmonary metastases from CRC, about 9 – 12% are eligible for local treatments with radical intent, including surgical resection, SBRT and ablation therapy. Due to the lack of randomized controlled trials among different local strategies, there is no definitive evidence about the optimal approach, although surgical resection is considered the most effective therapeutic option in this clinical scenario. Oncological achievement of primary radical resection, the biology of primary tumor and metastatic sites, disease free interval and or progression free survival are independent prognostic factors which make it possible to define a cohort of patients which might significantly benefit from pulmonary metastasectomy.

Interstitial lung diseases (ILDs) constitute a group of more than 200 disorders, being idiopathic pulmonary fibrosis (IPF) one of the most frequent. Telomere length (TL) shortening causes loss of function of the lung parenchyma. However, little is known about its role as prognostic factor in ILD patients. With the aim of investigating the role of TL and telomerase activity in the prognosis of patients affected by ILDs, we analysed lung tissue samples from 61 patients. We measured relative TL and telomerase activity by conventional procedures. Both clinical and molecular parameters were associated with overall survival by the Kaplan-Meier method. Patients with IPF had poorer prognosis than patients with other ILDs (p = 0.034). When patients were classified according to TL, those with shortened telomeres reported lower overall survival (p = 0.085); differences reached statistical significance after excluding ILD patients who developed cancer (p = 0.021). In a Cox regression analysis, TL behaved as a risk-modifying variable for death associated with rheumatological disorders (RD) co-occurrence (p = 0.029). Also, in patients without cancer, ferritin was significantly increased in cases with RD and IPF co-occurrence (p = 0.032). In relation to telomerase activity, no significant differences were detected. In conclusion, TL in lung tissue emerges as a prognostic factor in ILD patients, Specifically, in cases with RD and IPF co-occurrence, TL can be considered as a risk-modifying variable for death.

Introduction and Aims: COVID-19-associated invasive pulmonary aspergillosis (CAPA) is common and is associated with poor outcomes in critically ill patients. This prospective observational study aimed to explore the association between CAPA development and the incidence and prognosis of cytomegalovirus (CMV) reactivation in critically ill COVID-19 patients. Materials and Methods: We included all consecutive critically ill adult patients with confirmed COVID-19 infection who were admitted to three COVID-19 intensive care units (ICUs) in an Italian hospital from February 25, 2020, to May 8, 2022. A standardized procedure was employed for early detection of CAPA. Risk factors associated with CAPA and CMV reactivation and the association between CMV recurrence and mortality were estimated using adjusted Cox proportional hazard regression models. Results: CAPA occurred in 96 patients (16,6%) of the 579 patients analyzed. Among the CAPA population 40 (41,7%) patients developed CMV blood reactivation with a median time of 18 days (IQR 7-27). The CAPA+CMV group did not exhibit a significantly higher 90-day mortality rate (62.5% vs. 48.2%) than the CAPA alone group (p=0.166). The CAPA+CMV group had a longer ICU stay, fewer ventilation-free days, and a higher rate of secondary bacterial infections than the control group of CAPA alone. In the CAPA population, prior immunosuppression was the only independent risk factor for CMV reactivation (HR 2.33, 95% C.I. 1.21-4.48, p=0.011). Conclusions: In critically ill COVID-19 patients, CMV reactivation is common in those with a previous CAPA diagnosis. Basal immunosuppression before COVID-19 appeared to be the primary independent variable affecting CMV reactivation in patients with CAPA. Furthermore, the association of CAPA+CMV versus CAPA alone appears to impact ICU length of stay and secondary bacterial infections but not mortality.

Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease characterized by progressive parenchymal fibrosis and respiratory failure. In a model of bleomycin-induced pulmonary fibrosis, the antifibrotic and anti-inflammatory activity of Longidaza (bovhyaluronidase azoxymer), which contains a conjugate of the hyaluronidase enzyme with a high molecular weight synthetic carrier azoxymer bromide, was investigated. Experiments were conducted in male C57BL/6 mice. Longidaza was administered at different doses by intranasal and intramuscular routes. Histology, hematology and enzyme-linked immunosorbent assay were used in the study. The use of Longidaza reduced pulmonary fibrosis as evidenced by an improvement in histopathologic damage to the lungs, a decrease in the area of connective tissue and the levels of profibrotic factors (TGF-β1, hydroxyproline, collagen I) in lung tissue. In addition, Longidaza inhibited the inflammatory response in pulmonary fibrosis, decreased the levels of IL-6, TNF-α, hyaluronic acid in lung tissue and the recruitment of inflammatory cells into lung tissue. The highest therapeutic efficacy was observed with the use of Longidaza at doses of 120 and 1200 U/kg intramuscularly, which was superior to that of the reference drug pirfenidone axunio. The data presented in this study suggest that Longidaza is a new and promising drug for the treatment of IPF that warrants further investigation in patients with fibrotic interstitial lung disease.

Pulmonary aspiration is a serious anaesthetic complication with morbidity and up to 9% of all anaesthesia-related mortality. Aspiration risk is especially focused on fastening time. We aimed to evaluate the prevalence of 'risky stomach' defined by ultrasound imagine of solid contents and/or calculated gastric fluid volume >1.25 mL/kg in elective surgery also comparing this definition with the 0-2 qualitative rating scale used for "empty/risky stomach". This prospective study has 97 patients aged 2-18. Ultrasonographic evaluations of the gastric antrum content is scaled with qualitative assessment in supine and right lateral decubitus (RLD) position. Gastric volume was calculated. In our study, stomach content and volume were evaluated by ultrasound in 97% of children and 5.2% had Grade 2 antrum. In RLD position, antral CSA was 2.36 cm², and the median gastric volume was 0.46 mL/kg. In patients with grade 0 antrum has moderate and positive correlation between antral CSA and BMI, and strong and positive correlation between antral CSA and age like grade 1 antrum. We showed that 0.1%-4.7% of elective children had gastric fluid volumes of >1.25 mL/kg as "risky stomach". Ultrasound for gastric contents could be used routine practice to determine pulmonary aspiration risk in emergency and elective procedures.

(1) Infective endocarditis is a severe inflammatory disease associated with substantial mortality and morbidity. Alkaline phosphatase (AP) levels have been shown to change significantly during sepsis additionally we previously found higher initial AP drop after cardiac surgery is associat-ed with unfavorable outcomes. Therefore, the course of AP after surgery for endocarditis is of special interest. (2) 314 patients with active isolated left-sided infective endocarditis at the De-partment of Cardiac Surgery (Medical University of Vienna, Austria) between 2009 and 2018 were enrolled in this retrospective analysis. Blood samples were analyzed at different time points (baseline, postoperative day 1-7, postoperative days 14, and 30). Patients were categorized ac-cording to relative alkaline phosphatase drop (≥30% vs. <30%). (3) The rate of postoperative renal replacement therapy with or without prior renal replacement therapy (7.4 vs. 21.8%; p=0.001 and 6.7 vs. 15.6%; p=0.015, respectively) and extracorporeal membrane oxygenation (2.2 vs. 19.0%; p=0.000) was observed after a higher initial alkaline phosphatase drop. Short-term (30-day mor-tality 3.0 vs. 10.6%; p=0.010) and long-term mortality (p=0.008) were significantly impaired after a higher initial alkaline phosphatase drop. (4) The higher initial alkaline phosphatase drop was accompanied by impaired short and long-term outcomes after cardiac surgery for endocarditis. Future risk assessment scores for cardiac surgery should consider alkaline phosphatase.

A 57-year-old male with a history of hyperlipidemia and mild pulmonary hypertension presented for a left inguinal hernia repair. Preoperative electrocardiogram showed severe right axis deviation at 177 degrees and abnormal repolarization. Right ventricular hypertrophy secondary to pulmonary hypertension was the primary differential but was quickly ruled out due to the patient being asymptomatic and having great exercise tolerance. Dextrocardia was also ruled out due to normal progression on the precordial leads. The simultaneous severe right axis deviations of P, R, and T waves raised suspicion for erroneous lead placement. The repeat electrocardiogram confirmed the diagnosis.

Pulmonary thromboembolism is a very common cardiovascular disease, with a still high mortality rate. Despite the clear guidelines, this disease still represents a great challenge both in diagnosis and treatment. Heterogeneous clinical picture, often without pathognomonic signs and symptoms, represents a huge differential diagnostic problem even for experienced doctors. The decision on the therapeutic regimen also represents a major dilemma in the group of patients who are hemodynamically stable at initial presentation and have signs of right ventricular (RV) dysfunction proven by echocardiography and positive biomarker values (pulmonary embolism of intermediate-high risk). Studies have shown conflicting results about the benefit of using fibrinolytic therapy in this group of patients until hemodynamic decompensation, due to the risk of major bleeding. The latest recommendations give preference to new oral anticoagulants (NOACs) compared to vitamin K antagonists (VKA), except for certain categories of patients (patients with antiphospholipid syndrome, mechanical valves, pregnancy). When using oral anticoagulant therapy, special attention should be paid to drug-drug interactions, which can lead to many complications, even to the death of the patient. Special population groups such as pregnant women, obese patients, patients with antiphospholipid syndrome and cancer represent a great therapeutic challenge in the application of anticoagulant therapy. In these patients, not only the effectiveness of the drugs must be taken into account, but great attention must be paid to their safety and possible side effects, which is why a multidisciplinary approach is emphasized in order to provide the best therapeutic option.

Cultural recovery of Mucorales from hyphae-laden tissue is poor, and the clinical implications of culture positivity are scarcely studied. Therefore, we compared clinical and histological characteristics of culture-positive and culture-negative histology-proven pulmonary mucormycosis cases among cancer patients. Histology specimens were blindly reviewed by a Thoracic Pathologist and graded on four histopathologic features: hyphal quantity, tissue necrosis, tissue invasion, and vascular invasion. Twenty cases with a corresponding fungal culture were identified; five were culture-positive, and 15 culture-negative. Although no statistically significant differences were found, culture-positive patients were more likely to exhibit a high burden of necrosis and have a high burden of hyphae but tended to have less vascular invasion than culture-negative patients. In terms of clinical characteristics, culture-positive patients were more likely to have acute myeloid leukemia (60% vs. 27%, p=0.19), a history of hematopoietic cell transplant (80% vs. 53%, p=0.31), severe lymphopenia (absolute lymphocyte count ≤500/µL, 100% vs. 73%, p=0.36), and monocytopenia (absolute monocyte count ≤100/µL, 60% vs. 20%, p=0.11). Forty-two-day all-cause mortality was comparable between culture-positive and culture-negative patients (60% and 53%, p=0.80). This pilot study represents the first comprehensive histopathological scoring method to examine the relationship between histopathologic features, culture positivity, and clinical features of pulmonary mucormycosis.

Hydrogels, hydrophilic polymeric compounds, have been recently put under investigation as regenerative medicine applications and delivery systems for antineoplastic drugs, particularly chemotherapeutics (anthracyclines, alkylating agents), target drugs (trastuzumab) and immunotherapies. Porosity, conductivity, biodegradability and physical states are some of the peculiarities that render hydrogels suitable for therapies implementation. Chemically-modifying agents and enzymes can be also coupled to hydrogels for pharmacokinetical parameters improvement and side effects avoidance. Cardiotoxicity is in fact one of the major issues for oncological patients after treatment efficacy. Heart failure, myocarditis and hypertension are causes of morbidity and mortality that can possibly be avoided. Specific reaching of the target tumor site has been achieved by several authors in preclinical in vivo studies but clinical studies are currently under design processes. Polydioxanone, a hydrogel-mimicking agent, is capable to interact with the elastic properties of pulmonary artery. An advantageous characteristic is that can be also reabsorbed within biological systems and can cause a remodeling process of the vessel wall. Hydrogels currently represent a strong topic of interest for researchers and probably will guide future clinical investigations and practice.

Pulmonary embolism (PE) is one of the leading causes of cardiovascular mortality, therefore new parameters regarding risk stratification are sought after. In patients admitted for acute PE we investigated associations between the initial coagulation impairment, expressed by prothrombin time international normalised ratio (INR), and parameters reflecting PE severity. Furthermore, in-hospital, 30-day and long-term mortality were also evaluated. The analysis included 848 patients who were divided into two groups: with normal INR≤1.2, and elevated INR>1.2 (252 patients, 29.7%). The group with elevated INR presented higher incidence of tachycardia and lower systolic blood pressure, higher CRP, d-dimer, and NT-proBNP. This group presented higher estimated systolic pulmonary artery pressure (49 IQR39-62mmHg vs 43 IQR32-53mmHg, p<0.001) and shorter pulmonary artery acceleration time (65 IQR55-85ms vs 81 IQR63-102ms; p<0.001). Patients with elevated INR had more often a sPESI of 1 or higher (78%vs60%, p=0.003). Cox regression model revealed that age, leukocyte level, SBP, neoplasm, and INR are associated with higher risk of death (p<0.001). Finally, elevated INR was associated with higher in-hospital (13%vs3%; p<0.001), 30-day (19%vs6%; p<0.001), and long-term mortality (p<0.001). Summing up, elevated INR on admission is frequent in patients with PE, reflects worse clinical condition and is related to PE severity and prognosis.

Background: The Corona Virus Disease 2019 (COVID-19) is spreading globally now. However, the clinical presentation that predict prognosis of the patients are still largely unknow. Methods: We enrolled 393 patients infected with COVID-19 and 30 patients with common pulmonary bulla and reviewed their clinical features to evaluate the potential prognostic value of pulmonary vesicles, especially in the patients with severe symptoms. One COVID-19 patient with vesicles was treated by bullectomy for last resort, and its characteristics of the patient’s perioperative laboratory tests was analyzed. The pathological findings of bullectomy were described and compared with those of common bulla cases. Results: Patients infected with COVID-19 showed more dependence on ventilator, occurrence of super resistant bacteria, and prone to vesicle formation than common bulla (p<0.05). Disease severity is associated with age, sex, and usage of ventilator, ECMO and antibiotics, super resistance bacteria and vesicle formation (p<0.05). The average mortality rate of COVID-19 patients was 4.10% (25.4% in severe patients, 0.00% in mild patients). Interestingly, the mortality rate further increased in severe patients with pulmonary vesicles than those without pulmonary vesicles (35.7% vs 22.4%, p=0.0442). One COVID-19 patient with vesicles underwent bullectomy and had a poor prognosis, who showed diffuse alveolar damage and extensive necrosis in bullectomy specimen. Conclusions: Patients infected with COVID-19 are more prone to form pulmonary vesicles showed on chest CT scans, as an important poor prognosis factor, especially in the severe patients.

Many lifestyle and occupational habits negatively impact on physical and mental health, increasing the risk of cardiovascular and other diseases. While larger institutions fulfill occupational health requirements to ensure their employees’ wellbeing at work, smaller business workers and entrepreneurs may neglect initial signs of stress or physical decline, putting themselves at increased risk. Early detection of compromised cardiopulmonary health or fitness has the potential to flag up indications for early interventions and reduce the risk of disease onset and progression. This case study highlights the usefulness of respiratory muscle training (RMT) in improving pulmonary and cardiovascular parameters as an early countermeasure to cardiopulmonary decline. We suggest RMT as an easily accessible, cost- and time effective opportunity to support a healthy lifestyle.

Introduction: The rising trend in allergic diseases has occurred in parallel with an increasing prevalence in obesity, and suggesting a possible association. The increased body mass has numerous health consequences, including an impairment function of the respiratory system. The associations between eating habits and hypersensitivity to allergens have not been clarified sufficiently. Aim: to evaluate pulmonary function, nutritional status, eating habits and risk factors of obesity in children and adolescents with allergic rhinitis. Material and Methods: The study was performed in 106 children with allergic rhinitis (mean age 12.1+/-3.4; M/F 60/46) from the Department of Allergology. 43 (40.6%) of children presented only allergic rhinitis and in 63 (59.4%) additionally diagnosed with asthma bronchiale. Clinical data, detailed interview about allergies, assessment of pulmonary function and nutritional status, allergy skin test (Allergopharma) and spirometry (Jaeger) were evaluated. Nutritional habits were assessed by a food frequency questionnaire. The statistical analysis was done using the program Statistica v 10.0. Results: In the study group the mean centile of BMI was 49.4; underweight presented 25.4% of children, 55.6 % normal BMI and 18.8 % presented overweight or obesity. Multiple regression analysis showed a significant (adjusted R-squared: 0.97; p<0.05) association between high BMI and snacking between meals and low physical activity. No statistical association between the severity of diseases and BMI or body composition was observed. Conclusions: 1. The prevalence of excess body mass in the study group reached 13.5%. Eating habits were incorrect, especially obese children significantly more frequently ate snacks between meals than children with normal body weight. 2. Among the studied group of children and adolescents with allergic rhinitis and asthma bronchiale, the significant risk factors of obesity were snacking and low physical activity.

ABSTRACT Two years after first patients approached the emergency rooms of hospitals in Wuhan becouse of respiratory distress,thousend of SARS-CoV-2 infected persons continue to die every day worldwide.SARS-CoV-2-infected patients undergo a process of dehydration and malnutrition before they develop respiratory problems and approach the emergency room of a hospital.This is,in many cases, the consequence of high fever which causes massive loss of fluids. In addition loss of appetite, is responsible for the deficit of protein intake.Most of the virus-infected patients admitted to the emergency room are therefore hypovolemic and hypoproteinemic and suffer of respiratory distress accompanied by ground grass opacities at CT-scan of the lungs.Critically ill patients are treated following the guidelines for treatment of septic shock but with „conservative“ fluid replacement and administration of diuretics to assure sufficient hourly urine production. The combination of conservative fluid administration with reduced protein content in the enterally administered diet, together with administration of diuretics, has severe hemodynamic consequenses in mostly aged,dehydrated,critically ill patients. Many of them will develop acute kidney injury in the next 24 hours.In most of the cases, patients continue to loose weight by loosing skeletal muscle mass. Ischemic damage in the lung capillaries is responsible for the acute respiratory distreass syndrome (ARDS) and for the hallmark of autoptic findings,diffuse alveolar damage (DAD) characterized by hyaline membrane formation,fluid invasion of the alveoli recruitment of some inflammatory cells and progressive arrest of blood flow in the pulmonary vessels.The consequence is progressive congestion , increase of lung weight and progressive hypoxia (progressive severity of ARDS).Sequestration of blood in the lungs worsen hypovolemia and ischemia in different organs.This is most probably responsible for recruitment of inflammatory cells and for persistance of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autoptic studies have been performed mostly in patients who died in the ICU after SARS-CoV-2-infection because of progessive ARDS.In those patients, tubulus epithelium necrosis in the kidney is a frequent finding as it has been the case in the first SARS-CoV-1 pandemic.In the death certification charts, many times weeks after first symptoms have started ,cardiac arrest is the cause of death after respitatory insufficiency.Replacement therapy with sufficient amount of fluid and albumin should be part of the early individualized life-saving supportive measures avoiding mechanical ventilation.

Background: The burden of resistant fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited, and the only orally-available antifungals, the triazoles, demonstrate inter and intra-patient variability, non-linear kinetics, toxicity, drug interactions and increasing antifungal resistance. Therapeutic drug monitoring (TDM) of itraconazole, voriconazole and posaconazole has been necessary to ensure their safety and efficacy, but is considered unnecessary for the newest triazole isavuconazole, use of which is increasing. Aims: To characterise isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre to understand prevalence of isavuconazole antimicrobial resistance. To retrospectively review experience of isavuconazole use in this setting, assessing tolerability and therapeutic drug monitoring. Methods: A retrospective observational analysis of adult patients with respiratory disease in a tertiary hospital setting between Sept 2016 and Aug 2021. Clinical cultures were collected and triazole Minimum inhibitory concentration (MIC) were recorded (based on Clinical &amp; Laboratory Standards Institute (CLSI method)). Isavuconazole trough drug levels were carried out as part of the standard of care. Clinical outcomes of treatment were evaluated, along with drug tolerance and TDM. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp isolates. 80.8% of Aspergillus fumigatus isolates were non-wild type and had isavuconazole MIC &gt; 1mg/L, and 73.0% had MIC above the EUCAST (European Committee on Antimicrobial Susceptibility Testing) epidemiological cut-off (ECOFF) of 2mg/L. There was good correlation between isavuconazole MIC and voriconazole MIC (r =0.7, p=0.0002). 54 patients had isavuconazole therapy over the study period with a median duration of 7.7 months (IQR 0.79 - 16.42). 67% of patients were able to tolerate isavuconazole, despite toxicity with prior azole treatment being the primary indication for use (in 61.8%). Increased age (r=0.29; p=0.03 (95%CI 0.02,0.52)) and gender (r for female sex=-0.31; p=0.027 (95%CI -0.52,0.036) were associated risk factors for development of adverse events (AEs). 127 Isavuconazole TDM levels were performed over the study period with 90% &gt;1mg/L and 72% &gt;2mg/L. Dose change from manufacturer’s dose recommendation, however, was required in 15% of patients to achieve a serum drug concentration above the EUCAST ECOFF or Area of technical uncertainty (ATU) value of 2mg/L. Conclusion: In our study, we show use of Isavuconazole as salvage therapy in chronic pulmonary fungal disease setting with high prevalence of azole resistance. Isavuconazole MICs demonstrated good correlation with voriconazole MICs suggesting the latter could be a useful surrogate marker for isavuconazole susceptibility. Although Isavuconazole achieved excellent serum drug concentrations at standard dose compared to other azole drugs, we highlight the importance of antifungal stewardship and TDM monitoring to optimise therapy in this setting.

This is a methodological contribution to reference mode development in system dynamics model conceptualization. Existing behavior mode taxonomies-developed for various modeling phases-provide no comprehensive method for mode classification based on an exhaustive set of mutually exclusive modes, and derivation of questions the simulation model should answer. Novice modelers need such guidance. The article proposes a conceptual framework for systemic behavior with a hierarchical taxonomy of elementary, composite, and overlaid modes. A structured method identifies the intervals of each respective mode, orders them into episodes and then condenses the variables’ episodes to systemic episodes. Each transition then gives rise to a fundamental question for the model under development. Three classical cases illustrate the application and contrast the proposed taxonomy to others in the extant literature. The article then discusses some validation criteria referring to reference modes and their link to the dynamic hypothesis, current limitations, and questions for further research.

(1) Background: The aim of this study was to analyze the relationship between the serum levels of soluble transferrin receptor (sTfR) and interleukin 4 (IL-4), and disease activity and organ mani-festations in SLE patients. (2) Methods: We studied 200 SLE patients and 50 controls. We analyzed disease activity, organ involvement, serum sTfR, IL-4, and interleukin-6 (IL-6) levels, and antinu-clear and antiphospholipid antibody profiles. (3) Results: The median serum levels of sTfR (p>0.000001) and IL-4 (p<0.00001) were higher in the study group than in the controls. SLE patients, compared to the controls, had significantly lower HGB levels (p<0.0001), a lower iron concentration (p=0.008), a lower value of total iron-binding capacity (TIBC) (p=0.03), and lower counts of RBC (p=0.004), HCT (p=0.0004), PLT (p=0.04), neutrophil (p=0.04), and lymphocyte (p<0.0001). Serum sTfR levels were negatively correlated with lymphocyte (p=0.0005), HGB (p=0.0001) and HCT (p=0.008), and positively correlated with IL-4 (p=0.01). Elevated serum sTfR >2.14 mg/dL was associated with an increased risk of myocardial infarction (OR: 10.6 95 CI 2.71–464.78; p=0.001), ischemic heart disease (OR: 3.25 95 CI 1.02–10.40; p=0.04), lung manifestations (OR: 4.48 95 CI 1.44–13.94; p=0.01), and hematological manifestations (OR: 2.07 95 CI 1.13–3.79; p=0.01), and with a reduced risk of neuropsychiatric manifestations (OR: 0.42 95 CI 0.22–0.80; p=0.008). Serum IL-4 was negatively correlated with CRP (p=0.003), and elevated serum IL-4 levels > 0.17 mg/l were associated with a reduced risk of mucocutaneous manifestations (OR: 0.48 95 CI 0.26–0.90; p=0.02). (4) Conclusions: In SLE patients, elevated serum levels of sTfR were associated with an increased risk of cardiovascular, pulmonary, and hematological manifestations, and with a decreased risk of neuropsychiatric manifestations. In contrast, elevated serum IL-4 levels were associated with a decreased risk of mucocutaneous manifestations.

Reactive oxygen species (ROS) are a major risk factor for the development of oxidation and inflammation. Ryegrass (pasture), a natural dietary fiber source, acts as an antioxidant with well-known anti-inflammatory properties. The current study aimed to examine the alkaline phosphatase (ALP)-dependent Kelch-like-ECH-associated protein 1- Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) signaling pathway that facilitates the anti-oxidative and anti-inflammatory properties of pasture and its protective effects on ileal permeability, systemic inflammation, nutrient absorption, liver dysfunction, growth performance, intestinal organ development, and metabolic syndrome in commercial diet-challenged geese. The lipopolysaccharides (LPS), ALP, ROS, and tight junction proteins were determined from the ileum tissues, and the antioxidant enzymes, immunoglobulins, and metabolic syndrome were determined from liver tissues via Enzyme-linked immunosorbent assay (ELISA) kits. While the Nrf2 and LPS/ROS/Keap1-induced inflammatory cytokines were determined by the quantitative reverse transcription polymerase chain reaction (RT-qPCR) method. The intestinal morphology was examined by Hematoxylin and Eosin (H&E) staining to determine nutrient absorption in ileal tissues. Pasture-dependent ALP activity significantly ameliorated commercial diet-induced LPS and ROS-facilitated ileal barrier dysfunction and systemic inflammation. The pasture supplementation induced nutrient absorption by influencing intestinal organ development. Our biochemical assays showed that the activation of Nrf2 significantly increased antioxidant enzymes and immunoglobulins, and decreased Keap1 and malondialdehyde (MDA) concentrations in the liver tissues after pasture supplementation. The correlation analysis of ALP, LPS, ROS, and Keap1-Nrf2 pathway-dependent antioxidant enzymes with other host markers showed that pasture supplementation induced intestinal barrier function via reducing LPS/ROS-induced intestinal permeability and systemic inflammation in the ileum and liver tissues. Pasture intake might attenuate LPS/ROS-induced gut permeability, systemic inflammation, and metabolic syndrome and augment gut barrier functions, nutrient absorption, immunity, and growth performance, possibly by its Keap1-Nrf2 pathway-dependent antioxidant properties.

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is located in the KIT gene. We report a rare case of a boy, born at term, presenting already at birth with generalized subcutaneous nodules, on the face, scalp, trunk, back, hands, and feet. The spleen, liver and inflammatory markers were normal at birth. Tryptase was significantly elevated. Bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical, and inguinal adenopathy while the skin nodules persisted especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation, however compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement.

Purpose of the study: to reveal how the transfusion and the refraining from it affects the neuro-vascular unit in the congenital heart defects correction with cardiopulmonary bypass. Materials and methods: in vitro research, we formed a model of a neurovascular unit, which contains neu-rons, astrocytes and endothelial cells. This cellular model was cultivated in hypoxia conditions with the oxygen saturation levels of 1, 2, 3, 4%. In addition, this unit was cultivated with the pa-tient's serum adding in two different groups - with minimal and maximal levels of system in-flammatory response that we estimated by IL-6 level. Results: We found that during incubation in hypoxic conditions, the level of transendothelial resistance changed in groups with oxygen levels of 1% and 2% only after 4 hours. When we cultivated neurovascular unit cells with patients' sera, we found a minimal level of transendothelial resistance at 4 hours that increased after 24 hours. Permeability analysis showed that its level significantly decreased in the 1% and 2% oxygen group at 60- and 90-minutes relative to the control group. Conclusion: the system inflammatory response has more expressed but less long effect on the neurovascular unit model than hypoxia.

Globally, gastric cancer is a major cause of cancer mortality, with a 5-year survival rate of 32% for locally advanced and metastatic gastric cancer. This systematic literature review summarized the clinical, safety, and humanistic outcomes associated with systemic regimens given as first line therapy for locally advanced and metastatic gastric cancer. The search included articles published in English in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and the American Society of Clinical Oncology meeting library, from inception to April 2022. Phase II and III randomized controlled trials conducted among western populations diagnosed with stage III and IV locally advanced and metastatic gastric cancer were included. Two investigators independently reviewed the studies, conducted data extraction, and assessed risk of bias in accordance with PRISMA guidelines. Twenty-four randomized controlled trials totaling 8,705 patients were included. Median overall survival ranged from 5.0-13.1 months, median progression-free survival ranged from 2.0-7.7 months, and objective response ranged from 13.0-64.1%. Two studies reported higher quality of life outcomes. Grade 3 and 4 adverse events were reported in most studies. Improvement in clinical outcomes can be seen in recently published randomized controlled trials for locally advanced and metastatic gastric cancer.

Diabetes may cause an increase blood levels of cytokines inducing a rising of C reactive protein (PCR) and fibrinogen stimulating a subclinical inflammation which lead to adhesive molecules expression and to endothelial disfunction. A comprehensive panel of type 1 diabetes mellitus (T1DM) interleukins polymorphisms is not provided yet. As chronic periodontitis (CP) is considered the sixth complication of DM, a clarification is needed about the inflammatory role managed by single nucleotides polymorphisms (SNPs). The goal of this review is to focus on the significant diversity of SNPs in T1DM patients with and without CP. After a digital search on PubMed and Scopus with reference to the last 5 years, 21 items were enrolled. Several ILs were analyzed. T1DM still needs to be thoroughly explored regarding the ILs polymorphisms panel, however the last 5 years have led to the increased independence of this condition, causing autonomous inflammatory effects which requires further investigations. CP and T1DM association in children and adolescents represents a severe gap in literature that should be filled, the scarce presence of studies also about adults serves as a motivation for ulterior clinical researches

The La Oroya metallurgical complex reveals a process of structural or power pathology, where economic and environmental social policies lead to a citizenry without systemic freedom, characterized by environmental contamination (PAMA executed on average 67%, some processes with 0%) and sanitary (plumbosis 8.39 to 10.28 μg / dL), the economic dependence of this industry is also observed, which caused the weakening of the communities to maintain autonomy over their own destinies.The Doe Run Peru, operated the metallurgical complex, creating added value to the extractive-export chain of mineral concentrate, but also took advantage of the legal loopholes, the little coordination between the State institutions and the little authority of the supervisory institutions to get the most out of it, complying with the law in some cases, but without moral quality in some others, such as health in the oroinos.Government institutions must have strong links that provide a normative framework with prospects with sustainable development, where the beneficiary is society and not only certain interest groups. The economic benefits of the metallurgical complex operation are multiple, which begin with labor, the purchase and sale of materials and services, the collection of taxes and energy.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a broad array of clinical signs. In this study, we aimed to use intravenous immunoglobulins (IVIG), called intacglobin, as a monotherapy to manage SLE in three patients. Laboratory investigations for SLE diagnosis were performed, including the detection of anti-nuclear antibodies (ANA) and SLE confirmation by detecting high titers of anti-dsDNA antibodies. C3 and C4 serum levels were assessed, as well as the determination of immunoglobulins. The SLEDAI score was measured to determine whether a significant degree of disease activity existed and as a prognostic value. The evaluation of any chest infection was performed by chest-X-ray. The patients were treated with five–ten g/day of IVIG for six consecutive days, followed by five–ten g/month. Immunological evaluation demonstrated that patients presented with a flare of SLE with high titers of ANA and anti-dsDNA antibodies, low C3 and C4, and elevated immunoglobulin levels. The SLEDAI score falls from 10 to below 3, and chest infections in some patients are cleared up. The postulated mechanisms of action of IVIG demonstrated that it could be used as an immunosuppressor, immunomodulator, and antimicrobial agent in patients with SLE.

Stroke is one of the leading cause of adult disability and the second leading cause of death worldwide. The immune system actively participates in the pathobiological process of AIS, during the index event and during the repair process despite the limited attention drawn to this aspect in the existing stroke guidelines globally. The similar clinical course and similar circulating innate and adaptive immune cell counts in AIS and COVID-19 has created a renewed interest in these easily available biomarkers innate and adaptive immunological changes in AIS with potential diagnostic, prognostic, and therapeutic implications. The current scoping review aimed to assess the significance of circulating neutrophil and lymphocyte counts and their ratio (NLR) in AIS and explore their association with post-stroke recovery trajectory. The Arksey and O'Malley methodological framework was employed to review the published papers on the neutrophil-lymphocyte ratio (NLR) and AIS in late November 2020. Only studies published in English from 2000-2020 were included in this scoping review. Fifty-three published papers were reviewed. This review's key finding is that a canonical inflammatory response occurs in AIS just as in the case of COVID-19 and neurological involvements well described in the recent literature. An excessive circulating innate immune cells (neutrophils) and reduced circulating adaptive immune cells (lymphocytes ) are associated with poorer outcomes during the acute interventions ( reperfusion therapies) as well as the recovery trajectory. Main representatives of innate and adaptive immunity follow a canonical course in AIS and COVID-19. Exaggerated circulating innate ( elevated neutrophils and elevated NLR) and reduced adaptive immune response (lymphopenia) correlate with the worse outcome in AIS and COVID-19. This scoping review's findings make the strongest case for a systems biology-based approach to the standard operating procedures in stroke care urgently.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family has been recently associated with the development of autoimmune diseases, including SLE. IL-33 is an alarmin and a pleiotropic cytokine that affects various types of immune cells via binding to its receptor, ST2. In this study, we determine the impact of intraperitoneal IL-33 treatments in young lupus, NZB/W F1 mice. Mice were treated from the age of 6 to 11 weeks. We then assessed the proteinuria level, renal damage, survival rate, and anti-dsDNA antibodies. The induction of regulatory B (Breg) cells and changes in gene expression were also examined. In comparison to the control group, young NZB/W F1 mice administered with IL-33 had a better survival rate as well as reduced proteinuria level and lupus nephritis. IL-33 treatments significantly induced IgM anti-dsDNA antibody, IL-10 expressing Breg cells, and alternatively induced M2 macrophage gene signatures. These results imply that IL-33 exhibit regulatory roles during lupus onset via the expansion of protective IgM anti-dsDNA as well as regulatory cells such as Bregs and M2 macrophages.

In Safety Management System (SMS), the risk management plays a key role for the prevention of accidents. The aim of this paper is to propose a Safety Management model using a system dynamic approach to update conventional industrial safety into the new industrial safety 4.0 that is time to developed. This study analyzes some safety 4.0 aspects lacked in the Bhopal incidental event by considering different data detected in the industrial Plant. The model proposed in this paper discusses the relationships among the main causes that have contributed to the occurrence of the incidental event studied, such as broken safety devices, inadequate personnel experience, operator decisions, manager production strategy, policy decision, as deduced from the relevant literature about Bhopal incidental dynamic.

Pre-diabetes is a serious health condition where blood sugar levels are higher than normal, but not high enough yet to be diagnosed as type 2 diabetes. Pre-diabetes puts one at an increased risk of developing type 2 diabetes and heart disease Methodology: A cross-sectional study was carried out on 384 patients aged 20-70 years old, attending the dental clinics to assess the risk for diabetes, using the FINDRISC questionnaire, HbA1c blood test and a periodontal examination. Results: The mean age of participants was 38.90±10.74. 32.3% were categorized as no risk, 46.6% low risk, while 19% and 2.1% moderate and high risk of developing diabetes respectively. Tests for serum HbA1c Level showed 46.1 % had normal HbA1c followed by 18.0% and 3.6 % were pre-diabetic and diabetic respectively. 19.3% of participants had periodontal pockets measuring more than 4mm and 15.9% measuring more than 6mm. Conclusion: The study has proven to be useful in identifying patients at high-risk of developing diabetes. Controlling and managing periodontal disease could be a new aspect to include in the standards for diabetes care. Dental settings could be a successful platform to carry out the screening and risk stratification of pre-diabetic patients.

Background: To evaluate the effect of systemic erythropoietin, as well as oral steroids, in the management of recent onset non-arteritic anterior ischemic optic neuropathy (NAION). Method: Ninety-nine eyes of 99 patients diagnosed with NAION within 5 days of onset were included in this single masked randomized clinical trial. Thirty-four patients were randomized into group 1 (systemic erythropoietin), group 2 (oral steroids), and group 3 (control). Group A received 10,000 units of erythropoietin twice a day for three days. Group B received oral prednisone 75 mg daily for two weeks followed by a tapering dose (70 mg for 5 days, 60 mg for 5 days, and 5 mg reductions thereafter every 5 days). Functional and structural outcomes were analyzed at 3 and 6 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measure, and mean deviation (MD) of visual field (VF) test and peripapillary retinal nerve fiber layer thickness (PRNFLT) were secondary outcome measures. Results:The mean BCVA (±SD) at the time of presentation was 1 ± 0.56, 1.01 ± 0.6, and 0.94 ± 0.47 logMAR in groups A, B, and C, respectively (P = 0.140); corresponding values were 0.72 ± 0.45, 0.83 ± 0.46, and 0.78 ± 0.4 logMAR (P = 0.417), and at 6-month follow-up, they were 0.70 ± 0.44, 0.73 ± 0.35, and 0.75 ± 0.39 logMAR, respectively (P = 0.597). Fifty-five percent of patients in group A vesus 34.3% in group B, and 31.2% in group C had an improvement of at least 3 lines in the BCVA values at the 6th-month follow-up visit. (P= 0.04) The mean deviation (MD) at the time of presentation was 19.67 ± 6.2, 20.83 ± 4.83, and 18.94 ± 6.92 decibels (db), respectively (P= 0.483).The corresponding values at month 3 were 18.22 ± 7.5, 19.82 ± 7.15, and 17.65 ± 7.22 db, (P = 0.848); and at month 6 they were 16.56 ± 7.08, 18.15 ± 6.57, and 15.9 ± 5.97 db, respectively. (P = 0.699) PRNFLT at presentation was 189 ± 58, 193 ± 64, and 199 ± 62 micrometers, respectively (P = 0.779), which decreased to 110 ± 45, 127 ± 37, and 119 ± 37 at month 3 (P = 0.423). The corresponding values for month 6 were 88 ± 12, 74 ± 25, and 71 ± 18, respectively (P = 0.041). Conclusion: The findings of our study indicate the beneficial effects of systemic erythropoietin in preserving the function and structure of the optic nerve in recent onset NAION.

The human body supports the growth of a wide array of microbial communities in various niches, such as the oral cavity, gastro-intestinal and urogenital tracts and on the surface of the skin. These host associated microbial communities include yet-un-cultivable bacteria and are influenced by various factors. Together, these communities of bacteria are referred to as the human microbiome. Human oral microbiome consists of both symbionts and pathobionts. Deviation from symbiosis among the bacterial community leads to “dysbiosis”—a state of community disturbance. Dysbiosis occurs due to many confounding factors that predispose to a shift in the composition and relative abundance of microbial communities. Dysbiotic communities have been a major cause for many microbiomes related systemic infections. Such dysbiosis is directed by certain important pathogens called the “keystone pathogens” that could modulate community microbiome variations. One such persistent infection is oral infection, mainly periodontitis, where a wide array of causal organisms has been implied to systemic infections such as cardio vascular disease, diabetes mellitus, rheumatoid arthritis and Alzheimer’s disease. The keystone pathogens co-occur with many yet-cultivable bacteria and their interactions lead to dysbiosis. This has been the focus of recent research. While immune evasion is one of the major modes that lead to dysbiosis, new processes and new virulence factors of bacteria have been shown to be involved in this important process of that determine disease or health state. This review focuses on such dysbiotic communities, their interactions and their virulence factors that predispose the host to other systemic implications.

This study investigates the effects of home-based Kakao health care breathing exercises and stretching on respiratory function and fatigue in COVID-19 cured patients. A total of 35 participants performed four movements of home-based breathing exercise and five respiratory muscle stretching exercises four times a week for four weeks. Respiratory function was measured using FVC, FEV1, FEV1/FVC, and PEF. Fatigue was assessed using the Fatigue Severity Scale (FSS). Data analysis was performed using Independent Samples and Paired Samples T-tests in SPSS 24, with a significance level set at p &lt; 0.05. After four weeks of Home based Kakao health care Breathing Exercise, there were significant increases in respiratory FVC, FEV1, FEV1/FVC, and PEF function values observed in the training group (T.G.) after the exercise intervention (p &lt; 0.05). Such an increase was observed when comparing these values with the pre-exercise measurements. In contrast, there was no statistically significant difference in respiratory function outcomes before and after exercise in the control group (C.G.) (p &gt; 0.05). The FSS scores were statistically significant within the training group (T.G.). (p &gt;0.05). The 4-week Kakao health care Breathing Exercise was found to be capable of improving some respiratory functions in COVID-19-recovered patients, but it showed no significant improvement in fatigue levels.

In recent years, the prevalence of tobacco and electronic cigarette (e-cigarette) use among adolescents has raised significant public health concerns worldwide. This study aims to investigate respiratory symptoms among Polish adolescents. We conducted an online survey among Polish school students from all provinces, collecting data over two months in Spring 2021. Students voluntarily complete the anonymous survey, answering questions about respiratory symptoms, smoking habits (both traditional and electronic cigarettes), and demographic information. Analysis focused on four subgroups: non-tobacco users, traditional cigarette smokers, e-cigarette users, and dual users, totaling 10,388 pupils aged 12-18 years, predominantly attending secondary technical and comprehensive schools. A total of 10388 pupils participated in the study, 55.6 % (5778) of whom were girls and 44.4 % (4610) boys. Adolescents, who admitted using both e-cigarettes and traditional cigarettes experienced more frequent episodes of cough during the day (39.70%) and at night (18.40%) compared to their peers in other groups. Chest discomfort, including pain and pressure, was also reported more often by adolescents, who used e-cigarettes and traditional cigarettes concurrently (27.60%) compared to their peers in other groups. Chest pressure was experienced less commonly by non-smoking adolescents (14.40%) than by smokers (18.90%). Higher severity of cough during the day and at night was observed in the group of adolescents using traditional cigarettes and e-cigarettes concurrently compared to the other groups. The adolescents in the dual user group experienced more severe dyspnoea and wheezing compared to the other groups included in the comparison. The results of this study confirm the correlation between the occurrence of respiratory symptoms in adolescents who smoke cigarettes, use e-cigarettes and in dual users. The respiratory symptoms occur most frequently and are the most severe in the group of adolescents who use e-cigarettes and traditional cigarettes

Pulmonary sarcoidosis is a multisystem granulomatous interstitial lung disease (ILD) with a variable presentation and prognosis. Early accurate detection of pulmonary sarcoidosis may prevent progression to pulmonary fibrosis, a serious and potentially life-threatening form of the disease. However, the lack of a gold-standard diagnostic test and specific radiographic findings pose challenges in diagnosing pulmonary sarcoidosis. Chest computed tomography (CT) imaging is commonly used but requires expert, chest-trained radiologists to differentiate pulmonary sarcoidosis from lung malignancies, infections, and other ILDs. In this work, we developed a multichannel, CT and radiomics-guided ensemble network (RadCT-CNNViT) with visual explainability for pulmonary sarcoidosis vs. lung cancer (LCa) classification using chest CT images. We leverage CT and hand-crafted radiomics features as input channels, and a 3D convolutional neural network (CNN) and vision transformer (ViT) ensemble network for feature extraction and fusion before a classification head. The 3D CNN sub-network captures localized spatial information of lesions, while the ViT sub-network captures long-range, global dependencies between features. Through multichannel input and feature fusion, our model achieved the highest performance with accuracy, sensitivity, specificity, and combined AUC of 0.93±0.04, 0.94±0.04, 0.93±0.08 and 0.97 respectively in a 5-fold cross-validation study with pulmonary sarcoidosis (n=126) and LCa (n=93) cases. The model offers promising potential for improving the diagnosis of pulmonary sarcoidosis. A detailed ablation study showing the impact of CNN+ViT compared to CNN or ViT alone, and CT+radiomics input, compared to CT or radiomics alone, is also presented in this work.

Recurrent respiratory papillomatosis (RRP) is a non- malignant disease, characterized by the production of wart-like growths in respiratory tract, affecting both young and adults (Juvenile-Onset Recurrent Respiratory Papillomatosis, JORRP and Adult-Onset Recurrent Respiratory Papillomatosis, AORRP, respectively). Infection caused by Human Papillomavirus (HPV) is known as the main factors involved in RRP development. Complications of RRP may rarely occur, including lung involvement and malignant transformation. The present systematic review was aimed to evaluate the prevalence of severe complications, as lung involvement and lung tumor in JORRP and AORRP patients, following the guideline for reporting systematic reviews and meta-analysis (PRISMA Statement). Among the 378 studies were found on PubMed and Scopus using the following MESH terms “recurrent respiratory papillomatosis and lung tumor” and “pulmonary tumor and recurrent respiratory papillomatosis”. Basing on inclusion and exclusion criteria, a total of 11 studies were included in the systematic review. We found a pooled prevalence of 8% (95% CI:4%-14%; I2: 87.5%) for lung involvement in RRP patients. In addition, we found a pooled risk difference of 5% in lung involvement between JORRP and AORRP (95% CI: -7%-18%; I2 :85.6%, p-value: 0.41). Among patients with lung involvement, we observed a pooled prevalence of lung tumor of 4% (95% CI:1%- 7%; I2: 67.1%), and a pooled prevalence mortality for this group of 4% (95% CI:2%-6%; I2: 0%). Overall, the positivity rate for HPV-6 and -11 in patients with RRP was 91%. Considering only cases with pulmonary involvement, the pooled prevalence for HPV 11 was 21% (95% CI: 5%-45%; I2: 77.2%). Our results evidenced a low/middle risk of pulmonary involvement and lung tumor in JORRP and AORRP patients, with an increased risk for HPV-11 positive patients. Further studies should be performed to improve knowledge and adopt preventive measures to contrast the progression to severe diseases in RRP patients.

Pulmonary tuberculosis (PTB) is one of the leading causes of death in developing countries. This global health burden is worsened by the emergence of multi-drug resistance, which calls for new interventions to address the pandemic and medicinal plants remain a source for the new interventions. This study aimed to investigate the in vitro immunomodulatory effects of three plants used traditionally for the treatment of PTB in the Eastern Cape Province of South Africa. Eradication of Mycobacterium. tuberculosis in the lung tissue, requires the pro-inflammatory M1 phenotype. Thus, a plant extract with a high potential for anti-tuberculosis effects is expected to produce a high concentration of nitric oxide (NO) as the indicator for the pro-inflammatory M1 phenotype. To test this effect, lipopolysaccharide-activated RAW 264.7 macrophages were cultured and treated with the ethanolic crude extracts of three plants: Anthrixia philycoides, Lippia javaniva, and Sanicula elata at concentrations of 50µg/ml, 100µg/ml, and 200 µg/ml. After 24h, 50µl Griess reagent was added to the plates and absorbance was measure at 540nm. A standard curve of sodium nitrite dissolved in culture media was used to determine the concentration of NO in each sample. The results showed Anthrixia philycoides, and Lippia javanica, as anti-inflammatory when compared with the positive control, while Sanicula elata pro-inflammatory, producing a high amount of NO, compared with the positive control. Our results revealed the polarizing activity of Sanicula elata on macrophages towards M1 phenotype, with evidence of the nitric oxide production, warranting further in-vivo investigations of medicinal plant for anti-TB activity.

Background: Oscillation and pulmonary expansion (OPE) therapy can decrease postoperative pulmonary complications in a general surgical population, but its effect after cardiac surgery has not been reported, to our knowledge. We hypothesized that using an OPE device after cardiac surgery before extubation would decrease pulmonary complications. Methods: This retrospective cohort study included adults undergoing elective open cardiac surgery at our institution from January 2018 through January 2019, who had an American Society of Anesthesiologists score of 3 or greater. For mechanically ventilated patients after cardiac surgery, a new OPE protocol was adopted July 1, 2019, comprising an initial 10-minute OPE treatment administered in-line with the ventilator circuit, then continued treatments for 48 hours after extubation. Severe postoperative respiratory complications (primary outcome measure) included need for antibiotics, increased supplemental oxygen use, and prolonged hospital length of stay (LOS). Demographic, clinical, and outcomes data were compared for patients before (usual care with postextubation hyperinflation) and after protocol implementation (OPE). Results: Of 104 patients, 54 patients received usual care, and 50 received OPE. Usual-care recipients had more men (74% vs 62%; P=.19) and were older (median, 70 vs 67 years; P=.009) than OPE recipients. The OPE group had a significantly shorter hospital LOS than the usual-care group (mean, 6.2 vs 7.4 days; P=.04). Other measures improved with OPE but did not reach significance: shorter ventilator duration (mean, 0.6 vs 1.1 days with usual care; P=.06) and shorter LOS in the intensive care unit (mean, 2.7 vs 3.4 days; P=.06). On multivariate analysis, intensive care unit LOS was significantly shorter for the OPE group (mean difference, 0.85 days; 95% CI, 1.65 to 0.06; P=.04). The OPE group had a lower percentage of postoperative complications (10% vs 20%). Conclusion: OPE therapy after cardiac surgery is associated with decreased ICU and hospital LOS.

COVID-19 generated a scenario for global health with multiple systemic impairments. This retrospective study evaluated the clinical, radiological, and pulmonary functional evolution in 302 post-COVID-19 patients. Regarding post-COVID-19 pulmonary symptoms, dry cough, dyspnea, and chest pain were the most frequent. Of the associated comorbidities, asthma was more frequent (23.5%). Chest Tomography (CT) initially showed a mean pulmonary involvement of 69.7%, and the evaluation in the subsequent months showed an improvement in the evolutionary image, and with less than six months post-pathology, there was a commitment of 37 .7%, from six to twelve months, 20% and after 12 months, 9.9%. And as for most of the sample, 50.3% of the patients presented CT normalization in less than six months after infection, 23% normalized between six and twelve months, and 5.2% normalized the images after twelve months, with one remaining. Percentage of 17.3% who maintained post-COVID-19 pulmonary residual sequelae. Regarding spirometry, in less than six months after the pathology, 59.3% of the patients already showed a regular exam; 12.3% normalized their function within six to twelve months, and 6.3% concluded a normal exam after twelve months of post-pathology evaluation. Only 3.6% of the patients still showed some alteration in this period.

Little is known about the effect of statin use in lung cancer development in idiopathic pulmonary fibrosis (IPF). We analyzed the database of the National Health Insurance Service to further investigate the clinical impacts of statin on lung cancer development and overall survival (OS) in IPF patients. The analysis included 9,182 individuals diagnosed with IPF, of which 3,372 (36.7%) were statin users. Compared to statin non-users, the time from diagnosis of IPF to lung cancer development and OS were longer in statin users in IPF patients. In Cox proportional hazard regression models, higher statin compliance, statin use, and being female had an inverse association with lung cancer risk, while older age at diagnosis of IPF and smoking history were associated with higher risk of lung cancer in IPF patients. For OS, statin use, female sex, higher exercise frequency, and diabetes were associated with longer survival. In contrast, older age at diagnosis of IPF and smoking history were associated with shorter OS in IPF patients. These data from a large population indicate that statin had an independent protective association with lung cancer development and mortality in IPF patients.

(1) Background: This retrospective study aimed to compare the efficacy and safety of one-stage computed tomography (OSCT)- to that of two-stage computed tomography (TSCT)-guided localization for the surgical removal of small lung nodules. (2) Methods: We collected data from patients with ipsilateral pulmonary nodules who underwent localization before surgical removal at Veteran General Hospital Kaohsiung between October 2017 and January 2022. The patients were divided into the OSCT and TSCT groups. (3) Results: We found that OSCT significantly reduced the localization time and risky time compared to TSCT, and the success rate of localization and incidence of pneumothorax were similar in both groups. However, the time spent under general anesthesia was longer in the OSCT group than in the TSCT group. (4) Conclusions: The OSCT-guided approach to localize pulmonary nodules in hybrid operation room is a safe and effective technique for the surgical removal of small lung nodules.

Background: This study presents the experience gained in the Newborn Intensive Care Unit (NICU) at “M. S. Curie” Emergency Clinical Hospital for Children in Bucharest after performing a series of bedside surgery interventions on newborns with congenital diaphragmatic hernia (CDH). We evaluate the advantages, complications, immediate and long-term outcome as well as the morbidity. Methods: We conducted a retrospective analysis of the data for all patients operated on-site be-tween 2011 and 2020, in terms of pre- and post-operative stability, procedures performed, com-plications and outcomes. Results: Our study is based on data from ten cases of newborns, term or small for gestation age with birthweights ranging from 2300 to 3300 grams, operated, on average, on the fifth day of life. The main reasons for operating on-site were the hemodynamical instability and the need to ad-minister inhaled Nitic Oxide (iNO) and HFOV ventilation. There were no unforeseen events dur-ing surgery, no immediate postoperative complications and no surgery related mortality. One noticed drawback was the unfamiliarity of the surgery team with the new operating environment. Conclusions: Our experience indicates that bedside surgery improves the likelihood of survival for critically ill neonates suffering from CDH. No immediate complications could be associated with this practice. Keywords: congenital diaphragmatic hernia, severe pulmonary hypertension, bedside surgery, NICU infrastructure

Coronavirus disease 2019 (COVID-19) can lead to systemic coagulation activation and thrombotic complications. We investigated the incidence of objectively confirmed venous thromboembolism (VTE) in 198 hospitalized patients with COVID-19 in a single-center cohort study. Seventy-four patients (37%) were admitted to the intensive care unit (ICU). At time of data collection, 58 (29%) were still hospitalized and 14% had died. During a median follow-up of 5 days (IQR, 3-9), 33 patients (17%) were diagnosed with VTE of whom 22 (11%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7 and 14 days were 15% (95% CI, 9.3-22) and 34% (95% CI, 23-46), respectively. For symptomatic VTE, these were 11% (95% CI, 5.8-17) and 23% (95% CI, 14-33). VTE appeared to be associated with death (adjusted HR, 2.9; 95% CI, 1.02-8.0). The cumulative incidence of VTE was higher in the ICU (25% at 7 days 95% CI, 15-36, and 48% at 14 days, 95% CI, 33-61) than on the wards (any VTE and symptomatic VTE 6.5 % at 7 days (95% CI, 1.5-17) and 10% at 14 days (95% CI, 2.9-24)).The observed risk for VTE in COVID-19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.

The value of QuantiFERON in the diagnosis of tuberculosis and in the monitoring of the response to anti-tuberculosis treatment is unclear. The aims of this study were to evaluate the accuracy of the QuantiFERON-TB Gold In-Tube (QFT-GIT) test in the diagnosis of tuberculosis and in the monitoring of the response to anti-tuberculosis treatment in patients with active pulmonary tuberculosis (PTB). Between January 2013 and December 2015, 128 cases with active PTB and 128 controls with no mycobacterial infection, matched by age (within 3 years) and by the week that they visited Tainan Chest Hospital, were enrolled in the study. Serial testing by QFT-GIT at baseline and after 2 and 6 months of treatment was performed. At these time points, a comparison of the performance of QFT-GIT with that of sputum culture status among study subjects was conducted. Compared to baseline, 116 (87.2%) cases showed a decreased response, whereas 17 (12.8%) showed persistent or stronger interferon-gamma (IFN-γ) responses at 2 months. Their IFN-γ responses declined significantly from baseline to 2 months (median, 6.32 vs. 4.12; P < 0.005). The sensitivity values of the QFT-GIT test for the detection of pulmonary tuberculosis at cut-off points of 0.35 IU/ml, 0.20 IU/ml, and 0.10 IU/ml were 74.4%, 78.2%, and 80.5%, respectively. The specificity values at cut-off points of 0.35 IU/ml, 0.20 IU/ml, and 0.10 IU/ml were 66.2%, 63.9%, and 57.1%, respectively. Our results support the QFT-GIT assay as a potential tool for diagnosing tuberculosis and for monitoring the efficacy of anti-tuberculosis treatment.

The research examines the relationship between self-rated health situation and personal percep-tion of heat waves, and how social linkage of communities would be a moderator variable in residents’ perception of heat waves in Taiwan. This study uses the questionnaire conducted by Sinica “Responsive Capacity under Heat Wave: The Perspectives of the Locals”(2019), using OLS method for estimating the unknown parameters in multiple regression model. The author finds that the correlation of self-rated health situation and perception toward heat is significantly posi-tive. Also, social linkage in communities affects strongly as a moderator variable: While the sat-isfaction to with their community could reduce negative reaction to heat, contacts with neighbors could increase possibility people feel uncomfortable in high-temperature situation. This study ex-hibits the effects of social environment on community, and expects further related researches or practices to strengthen capability to resist heat wavesƒ for Taiwanese residents.

Amebiasis is a disease caused by the unicellular parasite Entamoeba histolytica. In most cases, the infection is asymptomatic but when symptomatic, the infection can cause dysentery and invasive extraintestinal complications. In the gut, E.histolytica feeds on bacteria. Increasing evidences support the role of the gut microbiota in the development of the disease. In this review we will discuss the consequences of E.histolytica infection on the gut microbiota. We will also discuss new evidences about the role of the gut microbiota in regulating the resistance of the parasite to oxi-dative stress and its virulence.

Objective: To explore three novel fasting blood glucose (FBG)-based novel indicators, including FBG-to-albumin ratio (FAR), FBG-to-lymphocytes ratio (FLR), and FBG-to-hemoglobin ratio (FHR), in predicting prognosis and detecting metastasis for patients with pancreatic neuroendocrine neoplasms after resection. Materials and methods: A total of 178 pNEN patients underwent surgical resection were included in this study. Receiver operating characteristic (ROC) curves were used to evaluate the diagnosis values of FAR, FLR, and FHR, and the cut-off values were obtained for further analyses. Univariate and multivariate analyses were conducted to determine the independent predictors. The Kaplan-Meier method was used to evaluate the progression-free survival (PFS) and overall survival (OS) of the pNEN patients. Results: The optimal cut-off values of FAR, FLR, and FHR were 0.17, 2.85, and 0.028, respectively. As for PFS, the area under the curve (AUC) was 0.693 for FAR, 0.690 for FLR, and 0.661 for FHR, respectively. The AUC was 0.770, 0.692, and 0.715 accordingly for OS. The groups with lower FAR, FLR, and FHR were significantly associated with prolonged PFS and OS (p < 0.05). In patients with metastasis, the lower FAR group was correlated with significantly longer PFS and OS (p = 0.022 and 0.002, respectively). The FLR was an independent predictor of PFS in pNEN patients, and the FAR was a predictor of OS. FAR was an independent indicator of PFS in patients with metastasis. Conclusion: Preoperative FAR, FLR, and FHR are effective in predicting the prognosis of pNEN patients and detecting the synchronous metastases.

(1) Background: Little research has been done on professionals' perceptions of institutions and governments during epidemics. We aim to create a profile of physicians who feel they can raise public health issues with relevant institutions during a pandemic. (2) Methods: A total of 1285 Romanian physicians completed an online survey as part of a larger study. We used binary logistic regression to profile physicians who felt able to raise public health issues with relevant institutions; (3) Results: Five predictors could differentiate between respondents who tended to agree with the trust statement and those who tended to disagree: feeling safe at work during the pandemic, considering the financial incentive worth the risk, receiving training on the use of protective equipment, having the same values as colleagues, and enjoying work as much as before the pandemic; (4) Conclusions: Physicians who trust the system to raise public health issues with the appropriate institutions feel they share the same values as their colleagues, say they were trained in the use of protective equipment used during the pandemic, felt they were safe at work during the pandemic, enjoyed their work as much as before the pandemic, and felt the financial bonus justified the risk.

The properties of the annual, semiannual and triennial oscillations (AO, SAO and TO) in the middle atmosphere have been investigated using the TIMED/SABER temperature data. The Lomb-Scargle and wavelet spectra were used to determine the dominant oscillations in the background temperature field. The AO is prominent at the mid-latitudes. The AO amplitudes present an asymmetry between the two Hemispheres, being larger in the mesosphere than in the stratosphere. The SAO dominates the tropical regions, with three amplitude maxima at altitudes of 45, 75, and 85 km. The SAOs in the upper mesosphere (75 km) are out of phase with those in the mesopause (85 km) in the tropical regions, which can generate an enhancement of 11 K at each equinox, contributing to the lower mesospheric inversion layer. The TO is significant in the tropical region, with amplitude being maximum at 35, 45 and 85 km. Result shows that there may be potential interaction by the TO with SAO at 85km at the equator. The relation between ENSO and TO has also been discussed. The ENSO signal may modulate the amplitude of the TO, mainly in the lower stratosphere. The real origin of the TO may lie in the wave-mean-flow interaction.