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Angela Mastelić,1 Vedrana Čikeš Čulić,1 Nikolina Režić Mužinić,1 Milena Vuica-Ross,2 David Barker,3 Euphemia Y Leung,4,5 Jóhannes Reynisson,3 Anita Markotić1 1Department of Medical Chemistry and Biochemistry, University of Split School of Medicine, Split, Croatia; 2Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; 3School of Chemical Sciences, The University of Auckland, 4Auckland Cancer Society Research Centre, The University of Auckland, 5Molecular Medicine and Pathology Department, The University of Auckland, Auckland, New Zealand Abstract: Tumor progression may be driven by a small subpopulation of cancer stem cells (CSCs characterized by CD44+/CD24- phenotype). We investigated the influence of a newly developed thienopyridine anticancer compound (3-amino-5-oxo-N-naphthyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, 1) on the growth, survival and glycophenotype (CD15s and GM3 containing neuraminic acid substituted with acetyl residue, NeuAc) of breast and prostate cancer stem/progenitor-like cell population. MDA-MB-231 and Du-145 cells were incubated with compound 1 alone or in combination with paclitaxel. The cellular metabolic activity was determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The type of cell death induced by 48-h treatment was assessed using a combination of Annexin-V-FITC and propidium iodide staining. Flow cytometric analysis was performed to detect the percentage of CD44+/CD24- cells, and GM3 and CD15s positive CSCs, as well as the expression of GM3 and CD15s per one CSC, in both cell lines. Compound 1 produces a dose- and time-dependent cytotoxicity, mediated mainly by apoptosis in breast cancer cells, and slightly (2.3%) but statistically significant lowering breast CSC subpopulation. GM3 expression per one breast CSC was increased, and the percentage of prostate GM3+ CSC subpopulation was decreased in cells treated with compound 1 compared with non-treated cells. The percentage of CD15s+ CSCs was lower in both cell lines after treatment with compound 1. Considering that triple-negative breast cancers are characterized by an increased percentage of breast CSCs and knowing their association with an increased risk of metastasis and mortality, compound 1 is a potentially effective drug for triple-negative breast cancer treatment. Keywords: breast, prostate, cancer stem cells, CD44+/CD24-, GM3, CD15s

The complex structure of glycosphingolipids (GSLs) supports their important role in cell function as modulators of growth factor receptors and glutamine transporters in plasma membranes. The aberrant composition of clustered GSLs within signaling platforms, so-called lipid rafts, inevitably leads to tumorigenesis due to disturbed growth factor signal transduction and excessive uptake of glutamine and other molecules needed for increased energy and structural molecule cell supply. GSLs are also involved in plasma membrane processes such as cell adhesion, and their transition converts cells from epithelial to mesenchymal with features required for cell migration and metastasis. Glutamine activates the mechanistic target of rapamycin complex 1 (mTORC1), resulting in nucleotide synthesis and proliferation. In addition, glutamine contributes to the cancer stem cell GD2 ganglioside-positive phenotype in the triple-negative breast cancer cell line MDA-MB-231. Thieno[2,3-b]pyridine derivative possesses higher cytotoxicity against MDA-MB-231 than against MCF-7 cells and induces a shift to aerobic metabolism and a decrease in S(6)nLc4Cer GSL-positive cancer stem cells in the MDA-MB-231 cell line. In this review, we discuss findings in MDA-MB-231, MCF-7, and other breast cancer cell lines concerning their differences in growth factor receptors and recent knowledge of the main biochemical pathways delivering distinct glycosphingolipid patterns during tumorigenesis and therapy.

Abstract Smart charging of electric vehicles can alleviate grid congestion and reduce charging costs. However, various electric vehicle models currently lack the technical capabilities to effectively implement smart charging since they cannot handle charging pauses or delays. These models enter sleep mode when charging is interrupted, preventing resumption afterwards. To avoid this, they should be continuously charged with their minimum charging power, even when a charging pause would be desirable, for instance with high electricity prices. This research examines this problem to inform various stakeholders, including policymakers and manufacturers, and stimulates the adoption of proactive measures that address this problem. Here, we demonstrate through technical charging tests that around one-third of tested car models suffer from this issue. Through model simulations we indicate that eliminating paused and delayed charging problems would double the smart charging potential for all applications. Lastly, we propose concrete legal and practical solutions to eliminate these problems.

For quite a long time efforts have been made to develop processes for producing iron i.e. steel without employing conventional procedures - from ore, coke, blast furnace, iron, electric arc furnace, converter to steel. The insufficient availability and the high price of the coking coals have forced many countries to research and adopt the non-coke-consuming reduction and metal manufacturing processes (non-coke metallurgy, direct reduction, direct processes). This paper represents a survey of the most relevant processes from this domain by the end of 2000, which display a constant increase in the modern process metallurgy.

Introduction: Osteoarthritis (OA) is a degenerative chronic process that primarily affects the elderly, but there are also reports of OA in the young and sports-active population. Symptoms of OA usually include pain, joint stiffness, and crepitation. Physical, radiologic, and laboratory tests are required for diagnosis. The main goal of OA treatment is to restore normal function to the joint affected by OA. Methods: A literature search on PubMed was used to collect facts about the relationship between sports and OA and possible treatment methods. All forms of articles were considered in the literature search. Articles that were not written in English were not included. Literature from the library of the Faculty of Medicine in Mostar was an additional source of information. Results: OA occurs more frequently in people who play or have played professional sports. On the other hand, daily exercise has a positive effect on cartilage metabolism. Most articles reported the occurrence of OA in former professional athletes. The joint most commonly affected by OA was the knee. Injuries were a predictive factor for the occurrence of OA, and most studies talk about anterior cruciate ligament injuries. Running and football were the most commonly studied sports. Treatment options include conservative treatment, surgical methods, and biological therapy. Conclusion: Frequent strain and injury in athletes can cause cartilage damage and potentially lead to the development of OA. The benefits of exercise far outweigh the risks of developing OA. In addition, some studies report a significant stimulating effect of exercise on cartilage cell metabolism. Treatment of OA consists of the use of analgesics, intra-articular therapy, and physiotherapy. Surgical methods are considered when conservative approaches are unsuccessful. Biological therapy and similar treatments are the new potential treatments.

The essential role of immunoglobulin G (IgG) in immune system regulation and combatting infectious diseases cannot be fully recognized without an understanding of the changes in its N-glycans attached to the asparagine 297 of the fragment crystallizable (Fc) domain that occur under such circumstances. These glycans impact the antibody stability, half-life, secretion, immunogenicity, and effector functions. Therefore, in this study, we analyzed and compared the total IgG glycome—at the level of individual glycan structures and derived glycosylation traits (sialylation, galactosylation, fucosylation, and bisecting N-acetylglucosamine (GlcNAc))—of 64 patients with influenza, 77 patients with coronavirus disease 2019 (COVID-19), and 56 healthy controls. Our study revealed a significant decrease in IgG galactosylation, sialylation, and bisecting GlcNAc (where the latter shows the most significant decrease) in deceased COVID-19 patients, whereas IgG fucosylation was increased. On the other hand, IgG galactosylation remained stable in influenza patients and COVID-19 survivors. IgG glycosylation in influenza patients was more time-dependent: In the first seven days of the disease, sialylation increased and fucosylation and bisecting GlcNAc decreased; in the next 21 days, sialylation decreased and fucosylation increased (while bisecting GlcNAc remained stable). The similarity of IgG glycosylation changes in COVID-19 survivors and influenza patients may be the consequence of an adequate immune response to enveloped viruses, while the observed changes in deceased COVID-19 patients may indicate its deviation.

Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease widespread in Europe and Asia. HFRS is caused by negative-sensed single-stranded RNA orthohantaviruses transmitted to humans through inhaling aerosolized excreta of infected rodents. Symptoms of HFRS include acute kidney injury, thrombocytopenia, hemorrhages, and hypotension. The immune response raised against viral antigens plays an important role in the pathogenesis of HFRS. Inhibitory co-receptors are essential in regulating immune responses, mitigating immunopathogenesis, and reducing tissue damage. Our research showed an increased soluble form of inhibitory co-receptors TIM-3, LAG-3, and PD-1 in HFRS patients associated with disease severity. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient’s serum and the potential correlation with key clinical parameters. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient’s serum and their possible association with relevant clinical parameters. Using multiplex immunoassay, we found elevated levels of TIM-3, LAG-3, and PD-1 proteins in the serum of HFRS patients. Furthermore, increased levels were associated with creatinine, urea, lactate dehydrogenase concentrations, and platelet count. These findings suggest that these proteins play a role in regulating the immune response and disease progression.

While the pathology of acute hemorrhagic fever with renal syndrome (HFRS) has been widely researched, details on the chronic HFRS sequelae remain mainly unexplored. In this study, we analyzed the clinical and laboratory characteristics of 30 convalescent HFRS patients 14 years after the disease contraction, mainly emphasizing several endothelial dysfunction parameters. Convalescent HFRS patients exhibited significantly higher serum levels of erythrocyte sedimentation rate, von Willebrand factor, uric acid, C-reactive protein and immunoglobulin A when compared to healthy individuals. Furthermore, 24 h urine analyses revealed significantly lower sodium and potassium urine levels, as well as significantly higher proteinuria, microalbumin levels and β2-microglobulin levels when compared to healthy individuals. First morning urine analysis revealed significantly higher levels of hematuria in convalescent HFRS patients. None of the additional analyzed endothelium dysfunction markers were significantly different in post-HFRS patients and healthy individuals, including serum and urine P-selectin, E-selectin, soluble intercellular adhesion molecule 1, vascular intercellular adhesion molecule 1 (sVCAM-1) and vascular endothelial growth factor (VEGF). However, binary logistic regression revealed a weak association of serum sVCAM-1 and urine VEGF levels with HFRS contraction. Generally, our findings suggest mild chronic inflammation and renal dysfunction levels in convalescent HFRS patients 14 years after the disease contraction.

ABSTRACTDuring the SARS-CoV-2 pandemic, the lack of standardized measurements of the immune response after vaccination or recovery from COVID-19 resulted in incomparable results and hindered correlation establishment. Prioritizing reliable and standardized methods to monitor pathogen-specific immunity is crucial, not only during the COVID-19 pandemic but also for future outbreaks. During our study of the humoral immune response, we used a SARS-CoV-2 wild-type neutralization assay, ensuring the measurement of the immune response directed to all SARS-CoV-2 antigens in their proper conformation. A head-to-head comparison of the neutralizing antibody (NAb) responses elicited by four vaccines used in Europe during 2021 (BNT162b2, mRNA-1273, ChAdOx nCoV-19, and Ad26.COV2.S) and their comparison to NAb responses in convalescents showed that while the amount was comparable, NAbs induced by natural infection were of higher quality. Namely, NAbs produced by disease were better activators of the complement system than NAbs induced by vaccination. Furthermore, the contribution of spike protein-specific IgGs to the SARS-CoV-2 neutralization was lower in convalescents compared to vaccinees, indicating that those who recovered from COVID-19 were armed with antibodies of additional specificities and/or classes that contributed to virus neutralization. These findings suggest that a higher stringency of public policy measures targeting individuals who have recovered from COVID-19, in comparison to those who have been vaccinated, may not have been fully justified.

Background and Objectives: eBEACOPP is the most effective chemotherapy regimen for younger patients with early unfavorable (EU) and advanced-stage (AS) Hodgkin lymphoma (HL), albeit with significant toxicities. The 14-day/cycle prednisone course contributes to side effects, including osteoarticular events like avascular bone necrosis (AVN). Our center has been using eBEACOPP since 2009 for AS and 2014 for EU patients. In 2016, we reduced prednisone treatment to 7–10 days to lessen AVN risk. We analyzed the effects of this approach. Materials and Methods: We retrospectively collected data on patients who received at least two cycles of eBEACOPP for first-line HL treatment. Results: A total of 162 patients (33 EU, 129 AS) were included. Their median age was 31 (range 19–59 years), and 88 were males. A total of 94 patients received full corticosteroid courses, and 68 received reduced corticosteroid courses. The overall response rate (ORR) was 98%. Different corticosteroid dosings had no significant effect on ORR, febrile neutropenia episodes, or hospital admissions. After a median follow-up (mFU) of 58 months, the 5yPFS for the entire cohort was 98% vs. 95% for the standard course vs. the short corticosteroids course, respectively (p = 0.37), while the 5yOS was 98% vs. 99% for the standard course vs. short corticosteroids course, respectively (p = 0.87). In AS patients intended to be treated with six eBEACOPP cycles, 5yPFS and 5yOS were 100% vs. 97% and 100% vs. 99% for standard vs. short corticosteroid courses, respectively (p = 0.56 and p = 0.17). In EU patients, 5yPFS was 97% (standard) vs. 95% (short) (p = 0.98) and 5yOS 100% vs. 93.3% (p = 0.87). Osteoarticular events were numerically lower in patients receiving the shorter prednisone course, both in the whole cohort and in the subgroup of patients treated with six cycles of eBEACOPP, but this difference failed to reach statistical significance. Conclusions: eBEACOPP provides excellent and durable first-line disease control. Shortening the corticosteroid course does not compromise efficacy, potentially reducing toxicity. However, longer follow-ups and larger studies are needed for confirmation.

The objective of this study was to investigate regulatory T cells (Tregs) and monocytes; specifically, the expression of CTLA-4 (CD152) and FOXP3+ in CD4+CD25+ Tregs and the expression of CD40+ and CD192+ monocyte subpopulations in subjects with primary progressive multiple sclerosis (PPMS). Immunological analysis was conducted on peripheral blood samples collected from the 28 PPMS subjects (15 treated with ocrelizumab and 13 untreated PPMS subjects) and 10 healthy control subjects (HCs). The blood samples were incubated with antihuman CD14, CD16, CD40, and CD192 antibodies for monocytes and antihuman CD4, CD25, FOXP3, and CTLA-4 antibodies for lymphocytes. The study results showed that in comparison to HCs both ocrelizumab treated (N = 15) and untreated (N = 13) PPMS subjects had significantly increased percentages of CTLA-4+ and FOXP3+ in CD4+CD25+ Tregs. Further, ocrelizumab treated PPMS subjects, compared to the untreated ones, had significantly decreased percentages of CD192+ and CD40+ nonclassical monocytes. Increased percentages of CTLA-4+ and FOXP3+ in CD4+CD25+ Tregs in both ocrelizumab treated and untreated PPMS subjects indicates the suppressive (inhibitory) role of Tregs in abnormal immune responses in PPMS subjects. Decreased percentages of CD40+ and CD192+ non-classical CD14+CD16++ monocytes for treated compared to untreated PPMS subjects suggest a possible role for ocrelizumab in dampening CNS inflammation.

Hemorrhagic fever with renal syndrome (HFRS) is an acute zoonotic disease caused by viruses of the Orthohantavirus genus. This syndrome is characterized by renal and cardiopulmonary implications detectable with different biomarkers. Here, we explored the role of serum and urine levels of lipocalin-2, endothelin-1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFRS pathology. A total of twenty-eight patients hospitalized due to a Puumala orthohantavirus infection were included, with serum and urine samples collected on patient admission (acute phase) and discharge (convalescent phase). In comparison to healthy individuals, patients exhibited significantly higher acute-phase serum and urine levels of lipocalin-2, serum levels of endothelin-1 and serum and urine levels of NT-proBNP. Patients in the convalescent phase showed a significant decrease in urine lipocalin-2, serum endothelin-1 and serum and urine NT-proBNP levels. We recorded a strong correlation between serum levels of lipocalin-2 and endothelin-1 and urine levels of lipocalin-2 with several kidney injury markers, such as serum creatinine, urea, urine white blood cell count and proteinuria. We also demonstrated an independent correlation of serum and urine lipocalin-2 levels with acute kidney injury in HFRS. All in all, our results show an involvement of NT-proBNP, lipocalin-2 and endothelin-1 in the renal and cardiac pathology of HFRS.

As of now, the COVID-19 pandemic has spread to over 770 million confirmed cases and caused approximately 7 million deaths. While several vaccines and monoclonal antibodies (mAb) have been developed and deployed, natural selection against immune recognition of viral antigens by antibodies has fueled the evolution of new emerging variants and limited the immune protection by vaccines and mAb. To optimize the efficiency of mAb, it is imperative to understand how they neutralize the variants of concern (VoCs) and to investigate the mutations responsible for immune escape. In this study, we show the in vitro neutralizing effects of a previously described monoclonal antibody (STE90-C11) against the SARS-CoV-2 Delta variant (B.1.617.2) and its in vivo effects in therapeutic and prophylactic settings. We also show that the Omicron variant avoids recognition by this mAb. To define which mutations are responsible for the escape in the Omicron variant, we used a library of pseudovirus mutants carrying each of the mutations present in the Omicron VoC individually. We show that either 501Y or 417K point mutations were sufficient for the escape of Omicron recognition by STE90-C11. To test how escape mutations act against a combination of antibodies, we tested the same library against bispecific antibodies, recognizing two discrete regions of the spike antigen. While Omicron escaped the control by the bispecific antibodies, the same antibodies controlled all mutants with individual mutations.

Expression of CD40 and CD192 markers in different monocyte subpopulations has been reported to be altered in people with MS (pwMS). Also, functional connectivity of the corticospinal motor system pathway alterations has been proved by transcranial magnetic stimulation (TMS). The study objective was to investigate the expression of CD40 and CD192 in classical (CD14++CD16−), intermediate CD14++CD16+ and non-classical (CD14+CD16++) blood monocyte subpopulations in pwMS, undergoing neurophysiological TMS assessment of the corticospinal tract integrity by recording motor-evoked potentials (MEPs). Radiological examination on lesion detection with MRI was performed for 23 patients with relapsing–remitting MS treated with teriflunomide. Then, immunological analysis was conducted on peripheral blood samples collected from the patients and 10 healthy controls (HC). The blood samples were incubated with anti-human CD14, CD16, CD40 and CD192 antibodies. Next, pwMS underwent neurological testing of functional disability (EDSS) and TMS assessment with recording MEPs from upper and lower extremity muscles. The results show that in comparison to HC subjects, both pwMS with normal and altered MEP findings (prolonged MEP latency or absent MEP response) had significantly decreased surface receptor expression measured (MFIs) of CD192 and increased CD40 MFI in classical monocytes, and significantly increased percentages of classical and total monocytes positive for CD40. Knowing CD40’s pro-inflammatory action, and CD192 as a molecule that enables the passing of monocytes into the brain, decreased CD192 in classical monocytes could represent a beneficial anti-inflammatory parameter.

Since its inception in 1987, ISO 9001 has become one of the most implemented quality management systems in organizations around the world. Due to its wide application and international recognition, it is widely regarded as a prerequisite for successful internationalization. In the era of digitalization, transformation of labor and capital markets and emergence of born-global companies, questions are being asked if ISO 9001 is as important as it used to be. This is especially relevant in the context of Small and Medium Enterprises (SME) that form the economic backbone of developed countries. The growing market globalization has changed the landscape in which SMEs compete, and many enter international markets from their inception. The aim of this paper is to answer the question how and under which circumstances SMEs make the decision to get ISO 9001 certification. In order to shed more light on this understudied issue we offer a systematization of the literature on the topic of ISO 9001 and SMEs, with a special emphasis on key determinants and barriers of ISO 9001 implementation in SMEs as well as the key outcomes in terms of SME performance following the ISO 9001 implementation.

Alien species represent a significant component of European entomofauna. Intensive international trade of plants, particularly woody ornamentals, has increased introduction of alien species into Europe in the last two decades, where alien terrestrial invertebrates prevail as one of the most numerous groups of introduced organisms. As of 2010, fourteen species of alien psyllids (Hemiptera: Psylloidea) have been recorded in Europe. Five species have been reported from Croatia, including Acizzia jamatonica (Kuwayama, 1908), as the only species from genus Acizzia Heslop-Harrison, 1961 present in Croatia so far. This paper provides genus status in Croatia, with first records of Australian species Acizzia uncatoides (Ferris & Klyver, 1932) and Acizzia acaciaebaileyanae (Froggatt, 1901).

Probing the cortic ospinal tract integrity by transcranial magnetic stimulation (TMS) could help to understand the neurophysiological correlations of multiple sclerosis (MS) symptoms. Therefore, the study objective was, first, to investigate TMS measures (resting motor threshold-RMT, motor evoked potential (MEP) latency, and amplitude) of corticospinal tract integrity in people with relapsing-remitting MS (pwMS). Then, the study examined the conformity of TMS measures with clinical disease-related (Expanded Disability Status Scale—EDSS) and magnetic resonance imaging (MRI) results (lesion count) in pwMS. The e-field navigated TMS, MRI, and EDSS data were collected in 23 pwMS and compared to non-clinical samples. The results show that pwMS differed from non-clinical samples in MEP latency for upper and lower extremity muscles. Also, pwMS with altered MEP latency (prolonged or absent MEP response) had higher EDSS, general and pyramidal, functional scores than pwMS with normal MEP latency finding. Furthermore, the RMT intensity for lower extremity muscles was predictive of EDSS functional pyramidal scores. TMS/MEP latency findings classified pwMS as the same as EDSS functional pyramidal scores in 70–83% of cases and were similar to the MRI results, corresponding to EDSS functional pyramidal scores in 57–65% of cases. PwMS with altered MEP latency differed from pwMS with normal MEP latency in the total number of lesions in the brain corticospinal and cervical corticospinal tract. The study provides preliminary results on the correspondence of MRI and TMS corticospinal tract evaluation results with EDSS functional pyramidal score results in MS.

Summary: Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a respiratory illness named coronavirus disease 2019 (COVID-19), which is one of the main global health problems since 2019. Glycans attached to the Fc portion of immunoglobulin G (IgG) are important modulators of IgG effector functions. Fc region binds to different receptors on the surface of various immune cells, dictating the type of immune response. Here, we performed a large longitudinal study to determine whether the severity and duration of COVID-19 are associated with altered IgG glycosylation. Methods: Using ultra-high-performance liquid chromatography analysis of released glycans, we analysed the composition of the total IgG N-glycome longitudinally during COVID-19 from four independent cohorts. We analysed 77 severe COVID-19 cases from the HR1 cohort (74% males, median age 72, age IQR 25-80); 31 severe cases in the HR2 cohort (77% males, median age 64, age IQR 41-86), 18 mild COVID-19 cases from the UK cohort (17% males, median age 50, age IQR 26-71) and 28 mild cases from the BiH cohort (71% males, median age 60, age IQR 12-78). Findings: Multiple statistically significant changes in IgG glycome composition were observed during severe COVID-19. The most statistically significant changes included increased agalactosylation of IgG (meta-analysis 95% CI [0.03, 0.07], adjusted meta-analysis P=

During the ongoing COVID-19 epidemic many efforts have gone into the investigation of the SARS-CoV-2–specific antibodies as possible therapeutics. Currently, conclusions cannot be drawn due to the lack of standardization in antibody assessments. Here we describe an approach of establishing antibody characterisation in emergent times which would, if followed, enable comparison of results from different studies. The key component is a reliable and reproducible assay of wild-type SARS-CoV-2 neutralisation based on a banking system of its biological components - a challenge virus, cells and an anti-SARS-CoV-2 antibody in-house standard, calibrated to the First WHO International Standard immediately upon its availability. Consequently, all collected serological data were retrospectively expressed in an internationally comparable way. The neutralising antibodies (NAbs) among convalescents ranged from 4 to 2869 IU mL-1 in a significant positive correlation to the disease severity. Their decline in convalescents was on average 1.4-fold in a one-month period. Heat-inactivation resulted in 2.3-fold decrease of NAb titres in comparison to the native sera, implying significant complement activating properties of SARS-CoV-2 specific antibodies. The monitoring of NAb titres in the sera of immunocompromised COVID-19 patients that lacked their own antibodies evidenced the successful transfusion of antibodies by the COVID-19 convalescent plasma units with NAb titres of 35 IU mL-1 or higher.

OBJECTIVES:. To describe hospital variation in use of “guideline-based care” for acute respiratory distress syndrome (ARDS) due to COVID-19. DESIGN:. Retrospective, observational study. SETTING:. The Society of Critical Care Medicine’s Discovery Viral Infection and RESPIRATORY ILLNESS UNIVERSAL STUDY COVID-19 REGISTRY. PATIENTS:. Adult patients with ARDS due to COVID-19 between February 15, 2020, and April 12, 2021. INTERVENTIONS:. Hospital-level use of “guideline-based care” for ARDS including low-tidal-volume ventilation, plateau pressure less than 30 cm H2O, and prone ventilation for a Pao2/Fio2 ratio less than 100. MEASUREMENTS AND MAIN RESULTS:. Among 1,495 adults with COVID-19 ARDS receiving care across 42 hospitals, 50.4% ever received care consistent with ARDS clinical practice guidelines. After adjusting for patient demographics and severity of illness, hospital characteristics, and pandemic timing, hospital of admission contributed to 14% of the risk-adjusted variation in “guideline-based care.” A patient treated at a randomly selected hospital with higher use of guideline-based care had a median odds ratio of 2.0 (95% CI, 1.1–3.4) for receipt of “guideline-based care” compared with a patient receiving treatment at a randomly selected hospital with low use of recommended therapies. Median-adjusted inhospital mortality was 53% (interquartile range, 47–62%), with a nonsignificantly decreased risk of mortality for patients admitted to hospitals in the highest use “guideline-based care” quartile (49%) compared with the lowest use quartile (60%) (odds ratio, 0.7; 95% CI, 0.3–1.9; p = 0.49). CONCLUSIONS:. During the first year of the COVID-19 pandemic, only half of patients received “guideline-based care” for ARDS management, with wide practice variation across hospitals. Strategies that improve adherence to recommended ARDS management strategies are needed.

Detailed characterization of medullary and extramedullary reservoirs of osteoclast progenitors (OCPs) is required to understand the pathophysiology of increased periarticular and systemic bone resorption in arthritis. In this study, we focused on identifying the OCP population specifically induced by arthritis and the role of circulatory OCPs in inflammatory bone loss. In addition, we determined the relevant chemokine axis responsible for their migration, and targeted the attraction signal to reduce bone resorption in murine collagen-induced arthritis (CIA). OCPs were expanded in periarticular as well as circulatory compartment of arthritic mice, particularly the CCR2hi subset. This subset demonstrated enhanced osteoclastogenic activity in arthritis, whereas its migratory potential was susceptible to CCR2 blockade in vitro. Intravascular compartment of the periarticular area contained increased frequency of OCPs with the ability to home to the arthritic bone, as demonstrated in vivo by intravascular staining and adoptive transfer of splenic LysMcre/Ai9 tdTomato-expressing cells. Simultaneously, CCL2 levels were increased locally and systemically in arthritic mice. Mouse cohorts were treated with the small-molecule inhibitor (SMI) of CCR2 alone or in combination with methotrexate (MTX). Preventive CCR2/CCL2 axis blockade in vivo reduced bone resorption and OCP frequency, whereas combining with MTX treatment also decreased disease clinical score, number of active osteoclasts, and OCP differentiation potential. In conclusion, our study characterized the functional properties of two distinct OCP subsets in CIA, based on their CCR2 expression levels, implying that the CCR2hi circulatory-like subset is specifically induced by arthritis. Signaling through the CCL2/CCR2 axis contributes to OCP homing in the inflamed joints and to their increased osteoclastogenic potential. Therefore, addition of CCL2/CCR2 blockade early in the course of arthritis is a promising approach to reduce bone pathology.

IMPORTANCE:. At the start of the coronavirus disease 2019 pandemic, medications repurposed for management of coronavirus disease 2019 were used in the absence of clinical trial evidence. OBJECTIVES:. To describe the variation and evolution in use of repurposed medications for coronavirus disease 2019. DESIGN, SETTING, AND PARTICIPANTS:. Observational cohort study of adults hospitalized with coronavirus disease 2019 between February 15, 2020, and April 12, 2021, across 76 United States and international hospitals within the Society of Critical Care Medicine’s Discovery Viral Infection and Respiratory Illness Universal Study coronavirus disease 2019 registry. MAIN OUTCOMES AND MEASURES:. Hospital variation was quantified using multivariable adjusted random effects logistic regression models and unsupervised clustering. Repurposed medications included antivirals, corticosteroids, hydroxychloroquine, immunomodulators, and therapeutic dose anticoagulants. RESULTS:. Among 7,069 adults hospitalized with coronavirus disease 2019, 1,979 (28%) received antivirals, 2,876 (41%) received corticosteroids, 1,779 (25%) received hydroxychloroquine, 620 (9%) received immunomodulators, and 2,154 (31%) received therapeutic dose anticoagulants. Contribution of hospital site to risk-adjusted variation was 46% for antivirals, 30% for corticosteroids, 48% for hydroxychloroquine, 46% for immunomodulators, and 52% for therapeutic dose anticoagulants. Compared with the early pandemic, the later pandemic practice phenotypes converged with increased use of antivirals (odds ratio, 3.14; 95% CI, 2.40–4.10) and corticosteroids (odds ratio, 5.43; 95% CI, 4.23–6.97), with decreased use of hydroxychloroquine (odds ratio, 0.02; 95% CI, 0.01–0.04) and immunomodulators (odds ratio, 0.49; 95% CI, 0.34–0.70). There was no clinically significant change in the use of therapeutic dose anticoagulants (odds ratio, 1.01; 95% CI, 1.01–1.02). There were no differences in risk-adjusted mortality between hospitals with high rates of repurposed medication use compared with hospitals with low rates of use. CONCLUSIONS AND RELEVANCE:. Hospital variation in the use of repurposed medications varied widely across hospitals early in the pandemic and later converged with the emergence of randomized clinical trials. Platforms developed for rapid activation and enrollment in clinical trials of repurposed medications are needed prior to the next pandemic to expedite effective, evidence-based practice.

Anti-SARS-CoV-2 IgG titer decreases rapidly after primovaccination, leading to a mandatory booster vaccination. We analysed anti-SARS-CoV-2 Spike RBD IgG levels (positive ≥ 50 AU/mL) in 405 healthcare workers (3010 sera) who received a booster dose (BD) 9 months after two-dose BNT162b2 primovaccination. Median antibody titer at the time of BD (582.6 AU/mL) was 1.7-fold and 16.4-fold lower than the peak titer after the first (961.5 AU/mL) and the second vaccine dose (SVD) (10,232.6 AU/mL), respectively. One month after vaccination, IgG titer increased 40.6-fold after BD compared with a 10.8-fold increase after primovaccination. Three months after vaccination, post-booster antibodies decreased significantly slower (2.2-fold) than after primovaccination (3.3-fold). At six months, antibodies decreased slower after BD (4.5-fold; median 5556.0 AU/mL) than after primovaccination (9.6-fold; median 1038.5 AU/mL). Antibody titers before and one month after BD correlated weakly (r = 0.30) compared with a strong correlation (r = 0.65) between the corresponding post-primovaccination titers. Pre-vaccination COVID-19 had no effect on IgG levels after BD compared with a positive effect after primovaccination. Despite high post-booster IgG levels, 22.5% of participants contracted mild COVID-19. The trend of IgG decline indicates the need for further revaccination, but the vaccine type should be defined according to viral mutations.

While the pathology of acute hemorrhagic fever with renal syndrome (HFRS) has been widely researched, details on the chronic HFRS sequelae remain mainly unexplored. In this study, we analyzed the clinical and laboratory characteristics of 30 convalescent HFRS patients 14 years after the disease contraction, mainly emphasizing several endothelial dysfunction parameters. Convalescent HFRS patients exhibited significantly higher serum levels of erythrocyte sedimentation rate, von Willebrand factor, uric acid, C-reactive protein and immunoglobulin A when compared to healthy individuals. Furthermore, 24 h urine analyses revealed significantly lower sodium and potassium urine levels, as well as significantly higher proteinuria, microalbumin levels and β2-microglobulin levels when compared to healthy individuals. First morning urine analysis revealed significantly higher levels of hematuria in convalescent HFRS patients. None of the additional analyzed endothelium dysfunction markers were significantly different in post-HFRS patients and healthy individuals, including serum and urine P-selectin, E-selectin, soluble intercellular adhesion molecule 1, vascular intercellular adhesion molecule 1 (sVCAM-1) and vascular endothelial growth factor (VEGF). However, binary logistic regression revealed a weak association of serum sVCAM-1 and urine VEGF levels with HFRS contraction. Generally, our findings suggest mild chronic inflammation and renal dysfunction levels in convalescent HFRS patients 14 years after the disease contraction. [ABSTRACT FROM AUTHOR]

We present the case of a 36-year-old woman who works as a kindergarten teacher, often she is kneeling on her knees due to the nature of the job. Since a year ago, she noticed that her right knee was swelling. She had an orthopaedic examination when she could no longer bend her knee. Inspection and palpation revealed the swelling of the anterior and anterior-lateral aspect of the knee. MRI imaging revealed a large, sharply defined, lobulated lesion of the infrapatellar fat pad. After the surgical incision, a lobular lesion was found and surgically removed. Histological analysis confirmed a ganglion cyst. Keywords: Ganglion cyst, Hoffa's fat pad, Knee

CD44 expressed in monocytes and lymphocytes seems to play a crucial role in gastrointestinal inflammation, such as the one occurring in the context of inflammatory bowel diseases. Differentially methylated genes are distinctly expressed across monocyte subpopulations related to the state of Crohn’s disease. Hence, the aim of this study was to detect CD44 expression in leukocyte subpopulations in relation to the type of IBD, therapy, and disease duration. Monocyte subpopulations CD14++CD16−, CD14++CD16++, and CD14+CD16+ as well as other leukocytes were analyzed for their CD44 expression using flow cytometry in 46 patients with IBD and 48 healthy controls. Patients with Crohn’s disease treated with non-biological therapy (NBT) exhibited a lower percentage of anti-inflammatory CD14+CD16++ monocytes, whereas NBT-treated patients with ulcerative colitis had lower expression of CD44 on CD14+CD44+ lymphocytes in comparison to controls, respectively. Conversely, patients with Crohn’s disease treated with biological therapy had a higher percentage of CD44+ granulocytes but lower expression of CD44 on anti-inflammatory monocytes compared to controls. Median fluorescence intensity (MFI) of CD44 on CD44+CD14+ lymphocytes was higher in ulcerative colitis patients treated with biological therapy compared to NBT. The percentage of classical CD14++CD16− monocytes was lower in the