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Background: The incorporation of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has redefined therapeutic strategies for advanced ovarian cancer. This study evaluates the efficacy of bevacizumab combined with standard chemotherapy by comparing progression-free survival (PFS) and overall survival (OS) outcomes with a historical cohort of patients treated with standard chemotherapy alone. Methods: We conducted an analysis of 71 patients with advanced epithelial ovarian cancer treated at the University Clinical Center in Niš, Serbia, from April 2017 to March 2023. All patients received standard chemotherapy paired with bevacizumab and were monitored for progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimates. Subgroup analyses were performed based on age, ECOG performance status, presence of metastases, and pleural effusion. Additionally, a historical cohort of 30 patients treated with standard chemotherapy alone was used for comparison, and Cox regression analysis was conducted to identify factors influencing treatment outcomes. Results: The study findings indicate significant improvements in median PFS (20 months vs. 15 months) and OS (58 months vs. an undetermined upper limit) compared to the historical cohort. Subgroup analysis of the bevacizumab-treated group revealed that younger patients (<65 years) and those without metastases or pleural effusion exhibited notably better survival outcomes. The hazard ratio for PFS in patients younger than 65 was 0.65 (95% CI: 0.45-0.93), suggesting a substantial reduction in disease progression risk compared to older patients. Conclusion: Bevacizumab, when used alongside standard chemotherapy, significantly extends both PFS and OS in patients with advanced ovarian cancer. These benefits are particularly pronounced in younger patients. The results underscore the necessity of integrating bevacizumab into the treatment regimen for advanced ovarian cancer, advocating for tailored therapeutic strategies based on individual risk profiles and clinical characteristics. This study reinforces the pivotal role of bevacizumab in enhancing the current ovarian cancer treatment landscape and highlights the potential for further personalizing oncological care.

Tapentadol is a unique opioid analgesic due to its dual mechanism of action. Compared to other opioids with a classical mechanism of action, its analgesic potential is not far behind them, and its advantages are: a better safety profile in terms of a lower potential for drug-drug interactions and a lower potential for causing adverse events, and it is safe to use in sensitive populations. Tapentadol in the form of a immediate release formulation is an adequate drug of choice for achieving a pharmacotherapeutic analgesic response in acute pain conditions, while in the form of a extended release formulation it is an adequate pharmacotherapeutic analgesic solution for chronic pain syndromes of various etiology. Due to the specificity of the mechanism of action, tapentadol adequately relieves both pain components - nociceptive and neuropathic, and has an indication area for mixed pain syndrome as well. Based on this, the need for the use of co-analgesics is reduced, and thus the incidence of possible interactions and adverse events is reduced.

Inflammatory bowel disease (IBD) is marked by chronic inflammation of the gastrointestinal tract and encompasses two major subtypes, Crohn's disease (CD) and ulcerative colitis (UC). IBD is frequently accompanied by extraintestinal manifestations (EIMs), with axial and peripheral spondyloarthritis (SpA) being the most common. Enthesitis, an inflammation of the bone insertions of capsules, ligaments, and tendons, represents an initial lesion in SpA. However, enthesitis remains an underestimated and often obscured EIM. The early detection of subclinical entheseal involvement in IBD patients using ultrasound (US) could provide an opportunity for timely intervention. US is a more feasible and affordable approach than magnetic resonance imaging (MRI). While previous meta-analyses have reported on the incidence and prevalence of SpA in IBD, specific attention to enthesitis has been lacking. Therefore, this narrative review aims to assess the current knowledge on existing IBD-SpA cohorts, focusing specifically on enthesitis.

Objective: Tapentadol is a drug of choice for neuropathic cancer pain. DN4 questionnaire quickly determines neuropathic pain component. The aim of this study is to determine the correlation between neuropathic malignant pain component by applying tapentadol antidolorose pharmacotherapy in combination with palliative radiotherapy of osseous neuropathic metastatic changes in breast cancer patients before and after palliative radiotherapy. Methods: The first patients group comprised 30 patients with primary breast cancer and proved painful bone secondary deposits with neuropathy for which tapentadol was prescribed, and they underwent palliative radiotherapy. The second group comprised 30 patients with primary breast cancer and proved painful bone metastases with neuropathy treated only with palliative antidolorose radiotherapy. Key findings : After two-months-follow up, tapentadol group patients had lower DN4 score values (Z=2,021; p=0.043). Significantly lower number of tapentadol group patients was without neuropathic pain after a three-month-follow up (χ ²=5,711; p=0.017). Significantly greater number of tapentadol group patients had best ECOG score 0 ( χ² =7,486; p=0.023). There was statistically significant positive correlation between tapentadol dose and DN4 score in patients after a month (ρ=0,471; p=0.009) and three months after the radiotherapy completion (ρ=0,610; p<0.001). Tapentadol is an opioid analgesic efficient for neuropathy relief in these patients and DN4 questionnaire is an efficient pharmacotherapy tool.

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.

The COVID-19 pandemic remains a serious public health problem globally. During winter influenza seasons, more aggressive SARS-CoV-2 infections and fatalities have been documented, indicating that influenza co-infections may significantly impact the disease outcome of COVID-19. Both influenza and SARS-CoV-2 viruses share many similarities in their transmission and their cellular tropism for replication in the human respiratory tract. However, the complex intricacies and multi-faceted dynamics of how the two pathogens interact to ensure their survival in the same lung microenvironment are still unclear. In addition, clinical studies on influenza co-infections in COVID-19 patients do not provide conclusive evidence of how influenza co-infection mechanistically modifies disease outcomes of COVID-19. This review discusses various viral as well as host factors that potentially influence the survival or synergism of these two respiratory pathogens in the infected lung microenvironment.

Nontyphoid salmonella can cause severe infections in newborns and is therefore declared a pathogen of major health significance at this age. The aim of the study was molecular and antimicrobial characterization of β-lactamase-producing Salmonella Mikawasima outbreak clone on a Neonatal ward, University Hospital of Split (UHS), Croatia during the COVID-19 pandemic. From April 2020, until April 2023, 75 nonrepetitive strains of Salmonella Mikawasima were isolated from stool specimens and tested for antimicrobial resistance. All 75 isolates were resistant to ampicillin and gentamicin, while 98% of isolates were resistant to amoxicillin/clavulanic acid. A high level of resistance was observed to third-generation cephalosporins (36% to ceftriaxone and 47% to ceftazidime). Extended-spectrum β-lactamase production was phenotypically detected by double-disk synergy test in 40% of isolates. Moderate resistance to quinolones was detected; 7% of isolates were resistant to pefloxacin and ciprofloxacin. All isolates were susceptible to carbapenems, chloramphenicol, and co-trimoxazole. Fourteen representative isolates, from 2020, 2021, 2022, and 2023, were analyzed with PFGE and all of them belong to the same clone. Whole-genome sequencing (WGS) analysis of three outbreak-related strains (SM1 and SM2 from 2020 and SM3 from 2023) confirmed that these strains share the same serotype (Mikawasima), multilocus sequence typing profile (ST2030), resistance genes [ bla TEM-1B, aac(6')-Iaa, aac(6')-Im, and aph(2'')-Ib) ] and carry incompatibility group C (IncC) plasmid. Furthermore, the gene bla SHV-2 was detected in SM1 and SM2. In summary, WGS analysis of three representative strains clearly demonstrates the persistence of β-lactamase-producing Salmonella Mikawasima in UHS during the 4-year period.

Aim: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbred polygenic model of childhood absence epilepsy (CAE), which, as their non-epileptic control (NEC) rats, are derived from Wistar rats. While the validity of GAERS in reproducing absence seizures is well established, its use as a model for CAE psychiatric comorbidities has been subject to conflicting findings. Differences in colonies, experimental procedures, and the use of diverse controls from different breeders may account for these disparities. Therefore, in this study, we compared GAERS, NEC, and Wistar bred in the same animal facility with commercially available Wistar (Cm Wistar) as a third control., Methods: We performed hole board (HB) and elevated plus maze (EPM) tests that were analyzed with standard quantitative and T-pattern analysis in male, age-matched Cm Wistar and GAERS, NEC, and Wistar, bred under the same conditions, to rule out the influence of different housing factors and provide extra information on the structure of anxiety-like behavior of GAERS rats., Results: Quantitative analysis showed that GAERS and NEC had similar low anxiety-like behavior when compared to Cm Wistar but not to Wistar rats, although a higher hole-focused exploration was revealed in NEC. T-pattern analysis showed that GAERS, NEC, and Wistar had a similar anxiety status, whereas GAERS and NEC exhibited major differences with Cm Wistar but not Wistar rats. EPM results indicated that GAERS and NEC also have similar low anxiety compared to Cm Wistar and/or Wistar rats. Nevertheless, the analysis of the T-pattern containing open-arm entry showed GAERS and Wistar to be less anxious than NEC and Cm Wistar rats., Conclusion: To summarize, comorbid anxiety may not be present in male GAERS rats. This study also highlighted the importance of including a control Wistar group bred under the same conditions when evaluating their behavior, as using Wistar rats from commercial breeders can lead to misleading results., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Non-coding RNAs, particularly small Cajal-body associated RNAs (scaRNAs), play a significant role in spliceosomal RNA modifications. While their involvement in ischemic myocardium regeneration is known, their role in cardiac development is unexplored. We investigated scaRNA20's role in iPSC differentiation into cardiomyocytes (iCMCs) via overexpression and knockdown assays. We measured scaRNA20-OE-iCMCs and scaRNA20-KD-iCMCs contractility using Particle Image Velocimetry (PIV), comparing them to control iCMCs. We explored scaRNA20's impact on alternative splicing via pseudouridylation (Ψ) of snRNA U12, analyzing its functional consequences in cardiac differentiation. scaRNA20-OE-iPSC differentiation increased beating colonies, upregulated cardiac-specific genes, activated TP53 and STAT3, and preserved contractility under hypoxia. Conversely, scaRNA20-KD-iCMCs exhibited poor differentiation and contractility. STAT3 inhibition in scaRNA20-OE-iPSCs hindered cardiac differentiation. RNA immunoprecipitation revealed increased Ψ at the 28th uridine of U12 RNA in scaRNA20-OE iCMCs. U12-KD iCMCs had reduced cardiac differentiation, which improved upon U12 RNA introduction. In summary, scaRNA20-OE in iPSCs enhances cardiomyogenesis, preserves iCMC function under hypoxia, and may have implications for ischemic myocardium regeneration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rajasingh Johnson reports financial support was provided by National Heart Lung and Blood Institute. Johnson Rajasingh reports financial support was provided by American Heart Association. Selene Perales reports financial support was provided by American Heart Association. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no potential conflict of interest relevant to this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pulmonary fibrosis, severe alveolitis, and the inability to restore alveolar epithelial architecture are primary causes of respiratory failure in fatal COVID-19 cases. However, the factors contributing to abnormal fibrosis in critically ill COVID-19 patients remain unclear. This study analyzed the histopathology of lung specimens from eight COVID-19 and six non-COVID-19 postmortems. We assessed the distribution and changes in extracellular matrix (ECM) proteins, including elastin and collagen, in lung alveoli through morphometric analyses. Our findings reveal the significant degradation of elastin fibers along the thin alveolar walls of the lung parenchyma, a process that precedes the onset of interstitial collagen deposition and widespread intra-alveolar fibrosis. Lungs with collapsed alveoli and organized fibrotic regions showed extensive fragmentation of elastin fibers, accompanied by alveolar epithelial cell death. Immunoblotting of lung autopsy tissue extracts confirmed elastin degradation. Importantly, we found that the loss of elastin was strongly correlated with the induction of neutrophil elastase (NE), a potent protease that degrades ECM. This study affirms the critical role of neutrophils and neutrophil enzymes in the pathogenesis of COVID-19. Consistently, we observed increased staining for peptidyl arginine deiminase, a marker for neutrophil extracellular trap release, and myeloperoxidase, an enzyme-generating reactive oxygen radical, indicating active neutrophil involvement in lung pathology. These findings place neutrophils and elastin degradation at the center of impaired alveolar function and argue that elastolysis and alveolitis trigger abnormal ECM repair and fibrosis in fatal COVID-19 cases. Importantly, this study has implications for severe COVID-19 complications, including long COVID and other chronic inflammatory and fibrotic disorders.

The aim of this study was to explore adherence to the Consolidated Standards of Reporting Trials (CONSORT) reporting standards in abstracts of randomized controlled trials on glaucoma. A cross-sectional observational study was conducted on the aforementioned abstracts, indexed in MEDLINE/PubMed between the years 2017 and 2021. In total, 302 abstracts met the inclusion criteria and were further analyzed. The median score of CONSORT-A items was 8 (interquartile range, 7-10) out of 17 (47.0%). Most analyzed studies were conducted in a single center (80.5%) and the abstracts were predominantly structured (95.0%). Only 20.5% of the abstracts adequately described the trial design, while randomization and funding were described by 6.0% of the abstracts. Higher overall scores were associated with structured abstracts, a multicenter setting, statistically significant results, funding by industry, a higher number of participants, and having been published in journals with impact factors above four ( p < 0.001, respectively). The results of this study indicate a suboptimal adherence to CONSORT-A reporting standards, especially in particular items such as randomization and funding. Since these factors could contribute to the overall quality of the trials and further translation of trial results into clinical practice, an improvement in glaucoma research reporting transparency is needed.

Objective: The aim of this study was to establish the effects of prolonged formulation of tapentadol in combination with palliative radiotherapy on bone metastatic changes in oncology patients with primary breast cancer and proven bone metastases., Patients and Methods: The research was conducted as a prospective study at the Clinic for Oncology, University Clinical Center Nis, Nis, Serbia, during a three-month interval of monitoring the patients. The first group comprised 30 patients with mentioned malignancy for which tapentadol was prescribed, and they underwent palliative radiotherapy for bone metastatic changes. The second group comprised 30 patients with the same disease treated only with pain relief radiotherapy to metastatic changes. All the patients were interviewed using the Pain Detect questionnaire., Results: Significantly more patients from the first group had severe pain in comparison to patients from the control group (χ2=16.596; p<0.001) at the second measurement and also at the third measurement (χ2=15.357; p<0.001). At the third measurement, pain with a neuropathic component was significantly more present in patients from the control group (χ2=8.541; p=0.014). There was a significant pain reduction in both groups - Tapentadol group (χ2=59.513; p<0.001) and control group (χ2=60.000; p<0.001) - and also a significant reduction of neuropathic pain component: Tapentadol group (χ2=56.267; p<0.001) and control group (χ2=60,000; p<0.001). There was a statistically significant positive correlation between tapentadol dose and pain intensity according to the numerical pain scale at all three measurements., Conclusions: Tapentadol prolonged-release formulation is an effective pharmacotherapy solution, along with palliative radiotherapy, for pain relief in patients with skeletal metastatic breast cancer. Palliative radiotherapy in these patients does not provide adequate neuropathic pain component relief.

Neutrophil adhesion to endothelia, entry into tissues and chemotaxis constitute essential steps in the immune response to infections that drive inflammation. Neutrophils bind to other cells and migrate via adhesion receptors, notably the α M β 2 integrin dimer (also called Mac-1, CR3 or CD11b/CD18). Here, the response of neutrophils to integrin engagement was examined by monitoring the activity of peptidylarginine deiminase 4 (PAD4). Histone H3 deimination was strongly stimulated by manganese, an integrin-activating divalent cation, even in the absence of additional inflammatory stimuli. Manganese-induced cell attachment resulted in neutrophil swarm formation that paralleled histone deimination, whereas antibodies that impair integrin binding prevented both cell adhesion and histone deimination. Manganese treatment led to putative deimination of profilin, a protein that functions as an actin-organizing hub, as detected by two-dimensional gel electrophoresis and citrulline immunoblotting. Cl-amidine, a covalent inhibitor of PAD4, and GSK484, a specific PAD4 inhibitor, blocked profilin deimination. Neutrophil migration toward leukotriene B4 and toward synovial fluid from a rheumatoid arthritis patient were inhibited by chloramidine, thus supporting the contribution of deimination to chemotaxis. The data, based on a simplified system for integrin activation, imply a mechanism whereby integrin attachment coordinates neutrophil responses to inflammation and orchestrates deimination of nuclear and cytoskeletal proteins. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Immunotherapeutic targeting of surface regulatory proteins and pharmacologic inhibition of critical signaling pathways has dramatically shifted our approach to the care of individuals with B cell malignancies. This evolution in therapy reflects the central role of the B cell receptor (BCR) signaling complex and its co-receptors in the pathogenesis of B lineage leukemias and lymphomas. Members of the Fc receptor-like gene family ( FCRL1-6 ) encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Among them, FCRL1 expression peaks on naïve and memory B cells and is unique in terms of its intracellular co-activation potential. Recent studies in human and mouse models indicate that FCRL1 contributes to the formation of the BCR signalosome, modulates B cell signaling, and promotes humoral responses. Progress in understanding its regulatory properties, along with evidence for its over-expression by mature B cell leukemias and lymphomas, collectively imply important yet unmet opportunities for FCRL1 in B cell development and transformation. Here we review recent advances in FCRL1 biology and highlight its emerging significance as a promising biomarker and therapeutic target in B cell lymphoproliferative disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mamidi, Huang, Honjo, Li, Tabengwa, Neeli, Randall, Ponnuchetty, Radic, Leu and Davis.)

Background: Digital health has the potential to improve the quality of care, reduce health care costs, and increase patient satisfaction. Patient acceptance and consent are a prerequisite for effective sharing of personal health information (PHI) through health information exchanges (HIEs). Patients need to form and retain trust in the system(s) they use to leverage the full potential of digital health. Germany is at the forefront of approving digital treatment options with cost coverage through statutory health insurance. However, the German population has a high level of technology skepticism and a low level of trust, providing a good basis to illuminate various facets of eHealth trust formation., Objective: In a German setting, we aimed to answer the question, How does an individual form a behavioral intent to share PHI with an HIE platform? We discussed trust and informed consent through (1) synthesizing the main influence factor models into a complex model of trust in HIE, (2) providing initial validation of influence factors based on a qualitative study with patient interviews, and (3) developing a model of trust formation for digital health apps., Methods: We developed a complex model of the formation of trust and the intent to share PHI. We provided initial validation of the influence factors through 20 qualitative, semistructured interviews in the German health care setting and used a deductive coding approach to analyze the data., Results: We found that German patients show a positive intent to share their PHI with HIEs under certain conditions. These include (perceived) information security and a noncommercial organization as the recipient of the PHI. Technology experience, age, policy and regulation, and a disposition to trust play an important role in an individual's privacy concern, which, combined with social influence, affects trust formation on a cognitive and emotional level. We found a high level of cognitive trust in health care and noncommercial research institutions but distrust in commercial entities. We further found that in-person interactions with physicians increase trust in digital health apps and PHI sharing. Patients' emotional trust depends on disposition and social influences. To form their intent to share, patients undergo a privacy calculus. Hereby, the individual's benefit (eg, convenience), benefits for the individual's own health, and the benefits for public welfare often outweigh the perceived risks of sharing PHI., Conclusions: With the higher demand for timely PHI, HIE providers will need to clearly communicate the benefits of their solutions and their information security measures to health care providers (physicians, nursing and administrative staff) and patients and include them as key partners to increase trust. Offering easy access and educational measures as well as the option for specific consent may increase patients' trust and their intention to share PHI., (©Julia Busch-Casler, Marija Radic. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.08.2023.)

Background: Relative-tachycardia (RT), a phenomenon of unproportionately high heart-rate elevation in response to fever, has been previously attributed to unfavourable outcomes in severe-inflammatory-response-syndrome (SIRS). Relative heart-rate to body-temperature ratio (RHR) and its prognostic associations in patients with severe and critical coronavirus disease 2019 (COVID-19) have not been investigated., Methods: We retrospectively analyzed heart-rate and body-temperature data at admission in patients who were hospitalized due to COVID-19 at a tertiary center from March 2020 to June 2021. After excluding patients with known heart rate affecting medications (beta-blockers and other antiarrhythmics) and atrial fibrillation, a total of 3490 patients were analyzed. Patients were divided into quartiles based on RHR on admission, with patients belonging to the 1st quartile designated as having relative-bradycardia (RB) and patients belonging to 4th quartile designated as having RT. Comparisons with baseline clinical characteristics and the course of treatment were done., Results: There were 57.5% male patients. Median age was 69 years. Most patients had severe or critical COVID-19 at admission. Median heart-rate at the time of hospital admission was 90/min, median body-temperature was 38 °C, and median RHR was 2.36 with interquartile-range 2.07-2.65. RB in comparison to middle-range RHR was significantly associated with older age, higher comorbidity burden, less severe COVID-19 and less pronounced inflammatory profile, and in comparison to RT additionally with higher frequency of hyperlipoproteinemia but lower frequency of obesity. RT in comparison to middle-range RHR was significantly associated with younger age, more severe COVID-19, lower comorbidity burden, lower frequency of arterial hypertension, higher frequency of diabetes mellitus, and more pronounced inflammatory profile. In multivariate analyses adjusted for clinically meaningful parameters, RB patients experienced more favorable survival compared to RT, whereas RT patients experienced higher mortality in comparison to RB and middle-range RHR patients, independently of older age, male sex, higher comorbidity burden and higher COVID-19 severity., Conclusions: Heart rate and axillary temperature are an indispensable part of a clinical exam, easy to measure, at effectively no cost. RT at admission, as a sign of excessive activation of the sympathetic nervous system, is independently associated with fatal outcomes in COVID-19 patients., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) has become a major concern worldwide due to multidrug resistance and the ability to spread locally and globally. Infections caused by KPC-KP are great challenge in the healthcare systems because these are associated with longer hospitalization and high mortality. The emergence of colistin resistance has significantly reduced already limited treatment options. This study describes the molecular background of colistin-resistant KPC-KP isolates in the largest hospital in southern Croatia. Thirty-four non-duplicate colistin-resistant KPC-KP isolates were collected during routine work from April 2019 to January 2020 and from February to May 2021. Antimicrobial susceptibility was determined using disk diffusion, broth microdilution, and the gradient strip method. Carbapenemase was detected with an immunochromatographic test. Identification of bla KPC and mcr genes or mutations in pmrA, pmrB, mgrB, phoP, and phoQ genes were performed by polymerase chain reaction (PCR) and positive products were sequenced. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used for epidemiological analysis. All isolates were multidrug-resistant, with colistin minimum inhibitory concentrations (MICs) from 4 to >16 mg/L, and all harbored bla KPC-2 and had a single point mutation in the mgrB gene resulting in a premature stop codon, with the exception of one isolate with four point mutations corresponding to stop codons. All isolates were negative for mcr genes. PFGE analysis identified a single genetic cluster, and MLST revealed that all isolates belonged to sequence type 101 (ST101). These results show emergence of the high-risk ST101/KPC-2 clone of K. pneumoniae in Croatia as well as appearance of colistin resistance due to mutations in the mgrB gene. Molecular analysis of epidemiology and possible resistance mechanisms are important to develop further strategies to combat such threats., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To standardly assess and describe nailfold videocapillaroscopy (NVC) assessment in children and adolescents with juvenile rheumatic and musculoskeletal diseases (jRMD) vs healthy controls (HCs)., Material and Methods: In consecutive jRMD children and matched HCs from 13 centres worldwide, 16 NVC images per patient were acquired locally and read centrally per international consensus standard evaluation of the EULAR Study Group on Microcirculation in Rheumatic Diseases. A total of 95 patients with JIA, 22 with JDM, 20 with childhood-onset SLE (cSLE), 13 with juvenile SSc (jSSc), 21 with localized scleroderma (lSc), 18 with MCTD and 20 with primary RP (PRP) were included. NVC differences between juvenile subgroups and HCs were calculated through multivariable regression analysis., Results: A total of 6474 images were assessed from 413 subjects (mean age 12.1 years, 70.9% female). The quantitative NVC characteristics were significantly lower or higher in the following subgroups compared with HCs: for density: lower in jSSc, JDM, MCTD, cSLE and lSc; for dilations: higher in jSSc, MCTD and JDM; for abnormal shapes: higher in JDM and MCTD; for haemorrhages: higher in jSSc, MCTD, JDM and cSLE. The qualitative NVC assessment of JIA, lSc and PRP did not differ from HCs, whereas the cSLE and jSSc, MCTD, JDM and cSLE subgroups showed more non-specific and scleroderma patterns, respectively., Conclusions: This analysis resulted from a pioneering registry of NVC in jRMD. The NVC assessment in jRMD differed significantly from HCs. Future prospective follow-up will further elucidate the role of NVC in jRMD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Despite trends toward longer-lasting health, the complexity of older people's health problems is increasing, raising the need for interprofessional care in all settings. A lack of coordination among providers risks fragmented care, leading to a repetition or gaps in services, conflicting treatment recommendations, medication errors and higher costs. Accordingly, new integrated models of care are needed that are based on patient needs. Case and Care Management (CCM) is currently being tested in Germany in a variety of settings to improve care., Aim of the Study: The aim of the present study was to analyze the results of health economic evaluations of CCM interventions in Germany in populations over 60 years of age compared to standard care., Material and Methods: The study is based on a systematic literature review conducted via Pubmed and Livivo and supplemented by a comprehensive hand search. The primary studies included for analysis were assessed using the CHEERS statement and narratively synthesized., Results: A total of five cost-effectiveness studies were included, predominantly based on randomized controlled trials. Results regarding cost effectiveness were mixed. Individual studies found significant differences on effectiveness and cost endpoints., Conclusions: The mixed, small number of studies does not currently provide a clear picture of whether CCM interventions have health economic advantages over standard care. Further research is indicated. Innovation fund projects on the topic area are expected to generate new evidence in the future., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the concomitant release of granule contents that damage surrounding tissues into sharp focus. Neutrophil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. Interestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promotes lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) and increases the risk of allergic responses. Recent observations point to the fact that reduced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19.

Pregnancies with type 1 diabetes mellitus (T1DM) have a high incidence of large-for-gestational-age neonates (LGA) despite optimal glycemic control. In recent years, glycemic variability (GV) has emerged as a possible risk factor for LGA, but the results of the conducted studies are unclear. This study analyzed the association between GV and LGA development in pregnancies with T1DM. This was a prospective cohort study of patients with T1DM who used continuous glucose monitoring (CGM) during pregnancy. Patients were followed from the first trimester to birth. GV parameters were calculated for every trimester using the EasyGV calculator. The main outcomes were LGA or no-LGA. Logistic regression analysis was used to assess the association between GV parameters and LGA. In total, 66 patients were included. The incidence of LGA was 36%. The analysis extracted several GV parameters that were significantly associated with the risk of LGA. The J-index was the only significant parameter in every trimester of pregnancy (odds ratios with confidence intervals were 1.33 (1.02, 1.73), 3.18 (1.12, 9.07), and 1.37 (1.03, 1.82), respectively. Increased GV is a risk factor for development of LGA. The J-index is a possible novel GV parameter that may be assessed in all three trimesters of pregnancy together with glycated hemoglobin and time-in-range.

Background: Individuals with opioid use disorder (OUD) use the emergency department (ED) at high rates. Medication treatment for OUD (MOUD) is associated with reduced ED utilization. However, individuals receiving MOUD still utilize ED services at higher rates than the general population. The objective of this study is to compare the psychosocial and clinical characteristics of those who do and do not utilize ED services based on the Healthy People 2030 framework regarding social determinants of health (SDoH) among a sample of individuals receiving MOUD., Methods: Participants receiving buprenorphine for OUD at an outpatient addiction clinic completed a cross-sectional survey between July and September 2019. A 6-month prospective medical record review was conducted. The primary outcome was ED visit (yes/no) during the 6-month study period. Demographic, psychosocial, and clinical characteristics were gathered from survey measures and chart abstraction. Chi square and T-tests tested differences by ED utilization., Results: Participants (n=142) were 54.9% female and 68.8% Black, with an average age of 43.2 years (SD=12.5). Of the participants, 38.7% visited the ED in the study period, primarily for infectious or musculoskeletal causes. Participants with an ED visit were more likely to be Black (p=.011), have less social support (p=.030), more medical comorbidities (p=.008) including chronic pain (p=.045), and more visits with an addiction provider in the study period (p=.009)., Conclusions: Factors associated with ED utilization among individuals receiving buprenorphine for OUD include low social support and medical comorbidities, including chronic pain. More research is needed on modifiable SDoH that influence ED utilization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

Childhood absence epilepsy (CAE) is characterized by absence seizures, which are episodes of lack of consciousness accompanied by electrographic spike-wave discharges. About 60% of children and adolescents with absence seizures are affected by major neuropsychological comorbidities, including anxiety. Endocannabinoids and monoamines are likely involved in the pathophysiology of these CAE psychiatric comorbidities. Here, we show that the synthetic cannabinoid receptor type 1/2 (CB1/2R) agonist WIN 55,212-2 (2 mg/kg) has a strain-dependent effect on anxiety-like and motor behavior when assess in the hole board test and cerebral monoaminergic levels in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and their non-epileptic control (NEC) rat strain. Using quantitative and Temporal pattern (T-pattern) analyses, we found that WIN 55,212-2 did not affect the emotional status of GAERS, but it was anxiolytic in NEC. Conversely, WIN 55,212-2 had a sedative effect in GAERS but was ineffective in NEC. Moreover, vehicle-treated GAERS more motivated to explore by implementing more complex and articulated strategies. These behavioral changes correlate with the reduction of 5-HT in the hippocampus and substantia nigra (SN) and noradrenaline (NA) in the entopeduncular nucleus (EPN) in vehicle-treated GAERS compared to NEC rats, which could contribute to their low anxiety status and hypermotility, respectively. On the other hand, the increased level of NA in the EPN and 5-HT in the SN is consistent with an activation of the basal ganglia output-mediated motor suppression observed in WIN 55,212-2-treated GAERS rats. These data support the view of a strain-dependent alteration of the endocannabinoid system in absence epilepsy by adding evidence of a lower emotional responsiveness and a basal ganglia hypersensitivity to cannabinoids in GAERS compared to NEC rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Deurwaerdère, Casarrubea, Cassar, Radic, Puginier, Chagraoui, Crescimanno, Crunelli and Di Giovanni.)

Introduction: Medicine stands at the threshold of a new era heralded by the vast potential of cell engineering. Like advances made possible by genetic engineering, current prospects for purposeful control of cell functions through cell engineering may bring breakthroughs in the treatment of previously intractable diseases., Areas Covered: Engineering of cytotoxic T cells for expression of chimeric antigen receptors (CARs) instructs them to attack and destroy malignant cells and thus provides an exciting new approach in oncology. A decade of practical experience and first-in-human trials encourage the search for new and broader uses of CAR technology, including in autoimmune diseases., Expert Opinion: Systemic lupus erythematosus is an example of a broader category of autoimmune diseases, for which cell engineering will provide a powerful new therapeutic approach. This article describes different types of CAR T cell strategies that will provide new treatment options for patients with autoimmune diseases and replace conventional therapies.

Background: Social determinants of health (SDoH) influence health outcomes differentially across gender. Gender differences in SDoH have been identified at baseline in opioid use disorder (OUD) treatment studies, but less is known about how SDoH and gender intersect with OUD treatment trajectories. This study aims to identify social correlates of OUD treatment outcomes from five key areas of social determinants separately for men and women receiving buprenorphine for OUD., Methods: This is a secondary data analysis of a cross-sectional survey with medical record review conducted with patients recruited from an office based opioid treatment clinic. Participants completed surveys between July-September 2019. A 6-month prospective medical record review was conducted to determine treatment retention, substance use recurrence, and buprenorphine continuation. Chi square, T-tests, and Mann Whitney U tested differences in social factors and OUD outcomes by gender. Gender-stratified multivariable logistic and negative binomial regressions assessed predictors of OUD outcomes., Results: Among study participants (n = 142), women were significantly younger (p < 0.001), more likely to live in a safe neighborhood (p = 0.046), and less likely to be employed (p = 0.005) or have substance use recurrence during the study period (p = 0.033) than men. For women, employment (AOR=0.19, p = 0.031) and education (AOR=0.08, p = 0.040) were negatively associated with treatment retention. For men, no social factors were associated with OUD outcomes., Conclusions: SDoH may impact OUD treatment outcomes differently by gender. Addressing MOUD stigma and implementing patient-centered care strategies may facilitate OUD treatment continuation among employed women in recovery. Gender-related social factors should be considered in OUD treatment research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Following the massive impact of the Covid-19 pandemic on the global economy and on small and medium-sized enterprises (SMEs) in particular, the concept of resilience has experienced a renaissance. As an organizational concept, business model resilience describes the extent to which an organization can maintain or quickly recover its value proposition despite unexpected current or future disruptions (Palzkill-Vorbeck 2018). Although research has been conducted in this area for decades, there is still a lack of a unified framework that brings together the findings from research and links them to organizational practice. The paper addresses this gap by developing a framework for business model resilience and demonstrating its practical relevance for organizational performance during the Covid-19 pandemic in 2020. The framework includes 11 factors that characterize the resilience of an organization's business model. For managers and decision-makers, the framework is an opportunity to assess and improve the resilience of their organizations. For researchers, the framework is an important foundation for transferring the concept of business model resilience into organizational practice., Competing Interests: Conflict of interestM. Radic, P. Herrmann, P. Haberland and C.R. Riese declare that they have no competing interests., (© The Author(s) 2022.)

Ag-specific immunotherapy is a long-term goal for the treatment of autoimmune diseases; however developing a means of therapeutically targeting autoimmune T cells in an Ag-specific manner has been difficult. Through the engineering of an HLA-DR1 chimeric Ag receptor (CAR), we have produced CD8 + CAR T cells that target CD4 + T cells in an Ag-specific manner and tested their ability to inhibit the development of autoimmune arthritis in a mouse model. The DR1 CAR molecule was engineered to contain CD3ζ activation and CD28 signaling domains and a covalently linked autoantigenic peptide from type II collagen (CII; DR1-CII) to provide specificity for targeting the autoimmune T cells. Stimulation of the DR1-CII CAR T cells by an anti-DR Ab induced cytokine production, indicating that the DR1-CAR functions as a chimeric molecule. In vitro CTL assays using cloned CD4 + T cells as target cells demonstrated that the DR1-CII CAR T cells efficiently recognize and kill CD4 + T cells that are specific for the CII autoantigen. The CTL function was highly specific, as no killing was observed using DR1-restricted CD4 + T cells that recognize other Ags. When B6.DR1 mice, in which autoimmune arthritis had been induced, were treated with the DR1-CII CAR T cells, the CII-specific autoimmune CD4 + T cell response was significantly decreased, autoantibody production was suppressed, and the incidence and severity of the autoimmune arthritis was diminished. These data demonstrate that HLA-DR CAR T cells have the potential to provide a highly specific therapeutic approach for the treatment of autoimmune disease., (Copyright © 2021 by The American Association of Immunologists, Inc.)

The global social, economic and political crises related to coronavirus disease 2019 (COVID-19) presumably had more indirect than direct negative impacts on health systems. Drastic lifestyle changes, social isolation and distancing, and individual and global financial crises resulted in robust populations forfeiting healthy habits and seeking comfort in alcoholic beverages, drugs and unhealthy diets. The inevitable consequences are increases in the incidence of nonalcoholic fatty liver disease, viral hepatitis, acute alcoholic hepatitis, liver cirrhosis decompensation and ultimately liver-related mortality. The inaccessibility of regular clinical and sonographic monitoring systems has caused difficulties in the treatment of patients with chronic liver disease (CLD) and has prevented prompt hepatocellular carcinoma detection and treatment. A dramatic reduction in the number of liver donors and the transformation of numerous transplantation centers into COVID-19 units drastically decreased the rate of orthotopic liver transplantation. The indirect, unavoidable effects of the COVID-19 pandemic in the following years have yet to be determined. Substantial efforts in the management of patients with liver disease in order to overcome the inevitable COVID-19-related morbidity and mortality that will follow have yet to be initiated. Several questions regarding the impact of the COVID-19 pandemic on liver disease remain. The most important question for general CLD patients is: How will the modification of clinical practice during this pandemic affect the outcomes of CLD patients? This article reviews the influence of COVID-19 on patients with liver disease during the pandemic, with particular emphasis on the disease course associated with pandemic resolution., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interest for this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins., (© 2021. The Author(s).)

Objective: Seasonal variations in body composition and parameters that reflect nutritional status are well established in patients on hemodialysis (HD). However, to our knowledge, no study has assessed the changes in oxidative stress (OS). The aims of this study were to assess seasonal variations in OS, body composition, and other nutritional parameters., Methods: Seasonal variations in fat tissue mass (FTM), fat tissue index (FTI), adipose tissue mass (ATM), lean tissue mass (LTM), lean tissue index (LTI), body cell mass (BCM), overhydration (OH) volume, and OS (blood levels of derivatives of reactive oxygen metabolites [d-ROMs], thiobarbituric reactive substances, plasma protein reduced thiol content [THIOLS], and ferric reducing ability of plasma) were assessed in 45 patients on HD, 70 y of age (60.5-76.5 y)., Results: FTM (P < 0.001), FTI (P < 0.001), and ATM (P < 0.001) significantly increased, whereas LTI (P < 0.001), LTM (P < 0.001), BCM (P < 0.001), and OH volume (P = 0.004) significantly decreased over the season. Additionally, significant seasonal variations in the levels of d-ROMs (P = 0.02) and THIOLS (P = 0.02) were found. Levels of d-ROMs were found to be a significant predictor of LTM and BCM (β = -0.57; 95% confidence interval [CI], -1.08 to -0.06; P = 0.03; β = -0.04; 95% CI, -0.075 to -0.006; P = 0.02). Furthermore, hip circumference was found to be the most significant predictor of the level of d-ROMs (β = 2.66; 95% CI; 0.28-5.04; P = 0.03) and waist-to-height ratio (β = 251; 95% CI, 16.6-477.2; P = 0.03) and serum prealbumin levels of THIOLS (β = 263; 95% CI, 6.8-521.1; P = 0.04)., Conclusion: These results suggest seasonal variations in OS in patients on HD and a possible interaction between OS and nutritional status in these patients., Competing Interests: Declaration of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Lung ultrasound (LUS) is a useful imaging method for identifying COVID-19 pneumonia. The aim of this study was to explore the role of LUS in predicting the severity of the disease and fatality in patients with COVID-19., Methods: This was a single-center, follow-up study, conducted from 1 November 2020, to 22 March 2021. The LUS protocol was based on the assessment of 14 lung zones with a total score up to 42, which was compared to the disease severity and fatality., Results: A total of 133 patients with COVID-19 pneumonia confirmed by RT-PCR were enrolled, with a median time from hospital admission to lung ultrasound of one day. The LUS score was correlated with clinical severity at hospital admission (Spearman's rho 0.40, 95% CI 0.24 to 0.53, p < 0.001). Patients with higher LUS scores were experiencing greater disease severity; a high flow nasal cannula had an odds ratio of 1.43 (5% CI 1.17-1.74) in patients with LUS score > 29; the same score also predicted the need for mechanical ventilation (1.25, [1.07-1.48]). An LUS score > 30 (1.41 [1.18-1.68]) and age over 68 (1.26 [1.11-1.43]) were significant predictors of fatality., Conclusions: LUS at hospital admission is shown to have a high predictive power of the severity and fatality of COVID-19 pneumonia.

Detection of prevalence and development of osteopenia or osteoporosis in patients with inflammatory bowel disease using only bone mineral density could be inappropriate to detect all individuals at risk for osteoporosis. Numerous patients could remain undetected by using only bone mineral density as a screening method, especially in patients with ulcerative colitis. Therefore, trabecular bone score should be used as a complementary method., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aims: The aim of this study was to investigate whether controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as assessed by vibration-controlled transient elastography (VCTE), are associated with chronic vascular complications of diabetes mellitus type 2 (T2DM)., Methods: We studied 442 outpatients with established T2DM, and who underwent VCTE and extensive assessment of chronic vascular complications of diabetes., Results: A quarter of analyzed patients had a previous history of myocardial infarction and/or ischemic stroke, and about half of them had at least one microvascular complication (chronic kidney disease (CKD), retinopathy or polyneuropathy). The prevalence of liver steatosis (i.e., CAP ≥ 238 dB/m) and significant liver fibrosis (i.e., LSM ≥ 7.0/6.2 kPa) was 84.2% and 46.6%, respectively. Significant liver fibrosis was associated with an increased likelihood of having myocardial infarction (adjusted-odds ratio 6.61, 95%CI 1.66-37.4), peripheral polyneuropathy (adjusted-OR 4.55, 95%CI 1.25-16.6), CKD (adjusted-OR 4.54, 95%CI 1.24-16.6) or retinopathy (adjusted-OR 1.81, 95%CI 1.62-1.97), independently of cardiometabolic risk factors, diabetes-related variables, and other potential confounders. Liver steatosis was not independently associated with any macro-/microvascular diabetic complications., Conclusions: Significant liver fibrosis is strongly associated with the presence of macro-/microvascular complications in patients with T2DM. These results offer a new perspective on the follow-up of people with T2DM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this study, we examine sublingual videomicroscopy and nailfold videocapillaroscopy (NVC) features in systemic sclerosis (SSc) patients presenting for routine care. Consented participants met classification criteria for SSc. Sublingual videomicroscopy testing was performed in each subject, followed by a NVC assessment. Sublingual assessment provided a density measurement, red blood cell fraction (RBC fract), and perfused boundary region (PBR) score. NVC evaluator defined nailfold findings as normal; specific changes for "early," "active," and "late" scleroderma pattern; or "non-specific" changes. Microangiopathy evolution score was calculated for each participant. Statistical evaluation was performed by non-parametric tests to assess the correlation of the two tools. Thirty-nine SSc patients with limited cutaneous disease participated in this study. Most participants had late pattern NVC. There was a highly significant association between the total sublingual microvascular density and number of capillaries measured by NVC (r = 0.569, P = 0.0002), and statistically significant negative correlation between sublingual total microvascular density and microangiopathy evolution score (r = 0.532, P = 0.0006). There was significant, negative correlation between the total sublingual microvascular density and disorganization of vascular array and capillary ramification (r = 0.461, P = 0.003) and degree of giant capillaries (r = 0.387, P = 0.01). There was no correlation between RBC fract and PBR with NVC parameters. This study showed a significant correlation between sublingual videomicroscopy and NVC in terms of sublingual total microvascular density and microangiopathy evolution score. These preliminary results further support the serial use of a non-invasive and automated sublingual microvascular function testing and glycocalyx measurement in the clinical setting. KEY POINTS: • Tools that longitudinally assess microvascular function and morphologic features are important for monitoring SSc vasculopathy. • Nailfold and sublingual microscopy can identify a loss of capillary density in SSc patients.

As treatment expansion in the opioid epidemic continues, it is important to examine how the makeup of individuals with opioid use disorder (OUD) is evolving. Treatment programs are increasingly utilizing buprenorphine, an effective OUD medication. This exploratory study examines sex and gender differences in psychosocial, clinical and substance use treatment characteristics of a clinical population in outpatient medication treatment for OUD with buprenorphine. This is a secondary data analysis from a cross-sectional survey study with retrospective medical record review conducted with patients recruited from an office-based opioid treatment clinic between July-September 2019. Participants on buprenorphine for at least 28 days at time of survey completion were included (n=133). Differences between men and women were explored with Pearson χ 2 and Fisher's Exact Tests for categorical variables and T-Tests for continuous variables. The sample was 55.6% women and nearly three-fourths Black (70.7%). Mean days in current treatment episode was 431.6 (SD=244.82). Women were younger and more likely to be unemployed, identify as a sexual minority, and live alone with children than men. More women than men had a psychiatric comorbidity. Women reported more prescription opioid misuse while men had more heroin only opioid use. More men reported comorbid alcohol use and a history of drug overdose. One-third of participants reported recent discrimination in a healthcare setting due to substance use. As buprenorphine-based outpatient treatment programs continue to expand, present study findings support evaluation of the unique needs of men and women in order to better tailor OUD-related services and improve treatment outcomes., Competing Interests: Disclosure of Interest: The authors report no conflicts of interest.

According to the World Health Organization, bacterium Acinetobacter baumannii is the first on the critical priority list of pathogens in urgent need for new antibiotics. The increasing resistance of A. baumannii to the last-line treatment options, including carbapenems, is a global problem. We report the molecular epidemiology of 12 carbapenem-resistant clinical isolates of A. baumannii collected from hospitalised patients in three neighbouring countries in Southeast Europe: Croatia, Serbia, and Bosnia and Herzegovina, giving an insight into the molecular characterisation and evolutionary history of the acquisition of resistance genes. Besides the blaOXA-23 gene, the endemic presence of OXA-72 oxacillinase of the same origin for more than a decade as the leading mechanism of carbapenem resistance in Southeast Europe was confirmed. To the best of our knowledge, this is the first paper that investigates and analyses the phylogenetic association of the most common mechanisms of resistance to carbapenems in clinical isolates of A. baumannii originating from three neighbouring countries in Southeast Europe.

This study was performed to elucidate genetic relatedness and molecular resistance mechanisms of AmpC-producing multidrug-resistant Proteus mirabilis isolates in University Hospital of Split (UHS), and define efficient antibiotics in vitro. A total of 100 nonrepeated, consecutive, amoxicillin/clavulanate- and cefoxitin-resistant P. mirabilis isolates were collected, mostly from urine (44%) and skin and soft-tissue samples (30%). They were all positive in cefoxitin Hodge test and negative for extended spectrum beta-lactamase production. Pulsed field gel electrophoresis identified four clusters and two singletons, with 79% of isolates in dominant cluster. Molecular characterization and I-C euI analysis of representatives revealed bla CMY-16 gene located on chromosome, and insertion element IS Ecp1 positioned 110 pb upstream of bla CMY-16 starting codon. They also harbored bla TEM-1 , except one with bla TEM-2 . They were all resistant to trimethoprim-sulfamethoxazole, all but one to quinolones, and 81% to all aminoglycosides, while 77% were susceptible (S) and 22% intermediate (I) to piperacillin/tazobactam, and 4% were S and 68% I to cefepime. Only 15% were S to ceftolozane/tazobactam. Meropenem, ertapenem, ceftazidime/avibactam, temocillin, and fosfomycin were 100% efficient in vitro . This is the first report of bla CMY-16 gene in P. mirabilis from hospital samples in Croatia. The findings are in accordance with Italian and Greek reports. The clonal nature of outbreak suggests the high potential of clonal spread. Alternative agents should be considered to spare carbapenem usage.

Objective: Early diagnosis of systemic sclerosis (SSc) is imperative, and Raynaud phenomenon (RP) is an important component of progressive vasculopathy. Nailfold videocapillaroscopy (NVC) is a well-established tool that can quantify structural vascular abnormalities. Digital thermal monitoring (DTM) assesses microvascular functional dysfunction related to thermoregulation. In this study, we investigated the correlation of NVC patterns and DTM variables in patients with SSc., Methods: Patients with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism criteria who consented and enrolled in the clinical care registry had NVC and DTM performed. For NVC, the number of capillaries (density), measurement of apical diameter (dimension), presence or absence of hemorrhages, and number of abnormal shapes were assessed to categorize 3 different qualitative patterns: early, active, and late. For DTM, Doppler ultrasound hyperemic, low frequency, blood velocity of radial artery, and fingertip vascular function were assessed, and a vascular reactivity index (VRI) measurement was automated. Statistical evaluation was performed by nonparametric tests to assess the correlation of NVC and VRI., Results: Thirty-one SSc subjects with interpretable NVC and DTM performed on the same day were included in the study. VRI was progressively higher in SSc patients with early, active, and late NVC patterns of microangiopathy ( P < 0.0001). There was a significant negative correlation between VRI and microhemorrhages scores (r = -0.363, P = 0.044)., Conclusion: Our study suggests that more advanced vasculopathy correlates to reduced microvascular function as detected by DTM and more advanced structural abnormalities detected by NVC. NVC and DTM may provide different aspects of vasculopathy quantification and complement each other as investigative tools., (Copyright © 2021 by the Journal of Rheumatology.)

Background: In 2030 there will be 4 million people in need of care in Germany; however, the nursing care sector is already suffering from a shortage of skilled workers. Innovative approaches are thus required. One possible solution with high future potential is the use of assistive robots that provide support in everyday and work tasks. The aim of this study was to analyze the ethical, legal and social aspects of the use of assistance robots in clinics and care facilities in more detail. The empirical survey addressed decision makers in these organizations who are responsible for making purchasing decisions in the introduction of robotic assistance systems., Material and Methods: Using an online survey, decision makers from more than 160 hospitals and care facilities throughout Germany were interviewed between October and December 2018., Results: The interviewees of the study did not see any absolute exclusion criteria for the use of assistance robots in care with respect to ethical, legal and social aspects. The majority of the participants were not concerned that assistance robots will replace jobs in healthcare. Especially the personalized communication with robots was predominantly seen as positive. With respect to data protection and the decrease of human contact as a consequence of the introduction of assistance robots, the participants were divided. Half of the interviewees also expected a behavioral change due to the presence of a robot., Conclusion: The study showed that from a top management perspective in hospitals and nursing homes, a clarification specifically of legal questions on data protection is necessary and needs to be addressed by politics. Robot manufacturers should also concentrate on the topics of data protection and data security in order to gain acceptance of their solutions.

Since it was first used in 1997, the term "big data" has been popularized; however, the concept of big data is relatively new to medicine. Big data refers to a method and technique to systematically retrieve, collect, manage, and analyze very large and complex sets of structured and unstructured data that cannot be sufficiently processed using traditional methods of processing data. Integrating big data in rare diseases with low prevalence and incidence, like systemic sclerosis is of particular importance. We conducted a literature review of use of big data in systemic sclerosis. The volume of data on systemic sclerosis has grown steadily in the recent years; however, big data methods have not been readily used. This inexhaustible source of data needs to be used more to unleash its full potential., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)