UNLABELLED: The aim of this study was to identify parameters influencing DNA extraction and PCR amplification efficiencies in an attempt to standardize Mucorales qPCR. The Fungal PCR Initiative Mucorales Laboratory Working Group distributed two panels of simulated samples to 26 laboratories: Panel A (six sera spiked with Mucorales DNA and one negative control serum) and Panel B (six Mucorales DNA extracts). Panel A underwent DNA extraction in each laboratory according to the local procedure and were sent to a central laboratory for testing using three different qPCR techniques: one in-house qPCR assay and two commercial assays (MucorGenius and Fungiplex). Panel B DNA extracts were PCR amplified in each laboratory using local procedures: nine in-house qPCR assays and two commercial kits (MucorGenius and MycoGENIE). All data were compiled and anonymously analyzed at the central laboratory. For Panel A, a total of six different automated platforms and five manual extraction methods were used. Positive rates were 64%, 70%, and 89%, for the MucorGenius, Fungiplex, and the in-house qPCR assay, respectively. Using a large volume of serum for DNA extraction provided the highest analytical sensitivity (82.5% for 1 mL compared with 62.7% for smaller volumes, P < 0.01). For Panel B, five in-house qPCR assays and two commercial kits had >78% positivity. Using larger PCR input volumes (≥7 μL) was associated with the highest sensitivity at 95.5% compared to 58.3% when lower input volumes were used (P < 0.01). Using larger sample volumes for nucleic acid extraction and DNA template volumes for PCR amplification significantly improves the performance of Mucorales qPCR when testing serum. IMPORTANCE: Mucormycosis is a life-threatening mold infection affecting immunosuppressed patients but also other patients with diabetes or trauma. Better survival is linked to shorter delays in diagnosis and treatment initiation. Detection of Mucorales-free DNA in serum or plasma using quantitative PCR allows a prompt diagnosis and earlier treatment. Several techniques and protocols of quantitative Mucorales PCR are used in Europe, and improving performance remains a common objective of laboratories participating in the fungal PCR Initiative Working Group. This study, which combined results from 26 laboratories in Europe, showed that the main parameters underpinning sensitivity are the preanalytical variables (volume of serum used for DNA extraction and DNA template volume), irrespective of the extraction platforms and qPCR assay/platform.

• MeSH
• Molecular Diagnostic Techniques standards   methods   MeSH
• DNA, Fungal * blood   genetics   MeSH
• Real-Time Polymerase Chain Reaction * standards   methods   MeSH
• Humans MeSH
• Mucorales * genetics   isolation & purification   MeSH
• Mucormycosis * diagnosis   microbiology   blood   MeSH
• Sensitivity and Specificity * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH

BACKGROUND: Widespread use of pneumococcal conjugate vaccines (PCVs) has reduced vaccine-type invasive pneumococcal disease (IPD). We describe the serotype distribution of IPD after extensive use of ten-valent PCV (PCV10; Synflorix, GSK) and 13-valent PCV (PCV13; Prevenar 13, Pfizer) globally. METHODS: IPD data were obtained from surveillance sites participating in the WHO-commissioned Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project that exclusively used PCV10 or PCV13 (hereafter PCV10 and PCV13 sites, respectively) in their national immunisation programmes and had primary series uptake of at least 70%. Serotype distribution was estimated for IPD cases occurring 5 years or more after PCV10 or PCV13 introduction (ie, the mature period when the serotype distribution had stabilised) using multinomial Dirichlet regression, stratified by PCV product and age group (<5 years, 5-17 years, 18-49 years, and ≥50 years). FINDINGS: The analysis included cases occurring primarily between 2015 and 2018 from 42 PCV13 sites (63 362 cases) and 12 PCV10 sites (6806 cases) in 41 countries. Sites were mostly high income (36 [67%] of 54) and used three-dose or four-dose booster schedules (44 [81%]). At PCV10 sites, PCV10 serotypes caused 10·0% (95% CI 6·3-12·9) of IPD cases in children younger than 5 years and 15·5% (13·4-19·3) of cases in adults aged 50 years or older, while PCV13 serotypes caused 52·1% (49·2-65·4) and 45·6% (40·0-50·0), respectively. At PCV13 sites, PCV13 serotypes caused 26·4% (21·3-30·0) of IPD cases in children younger than 5 years and 29·5% (27·5-33·0) of cases in adults aged 50 years or older. The leading serotype at PCV10 sites was 19A in children younger than 5 years (30·6% [95% CI 18·2-43·1]) and adults aged 50 years or older (14·8% [11·9-17·8]). Serotype 3 was a top-ranked serotype, causing about 9% of cases in children younger than 5 years and 14% in adults aged 50 years or older at both PCV10 and PCV13 sites. Across all age and PCV10 or PCV13 strata, the proportion of IPD targeted by higher-valency PCVs beyond PCV13 was 4·1-9·7% for PCV15, 13·5-36·0% for PCV20, 29·9-53·8% for PCV21, 15·6-42·0% for PCV24, and 31·5-50·1% for PCV25. All top-ten ranked non-PCV13 serotypes are included in at least one higher-valency PCV. INTERPRETATION: The proportion of IPD due to serotypes included in PCVs in use was low in mature PCV10 and PCV13 settings. Serotype distribution differed between PCV10 and PCV13 sites and age groups. Higher-valency PCVs target most remaining IPD and are expected to extend impact. FUNDING: Bill & Melinda Gates Foundation as part of the WHO Pneumococcal Vaccines Technical Coordination Project.

• MeSH
• Global Health MeSH
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Immunization Programs MeSH
• Pneumococcal Infections * prevention & control   epidemiology   microbiology   MeSH
• Pneumococcal Vaccines * administration & dosage   MeSH
• Child, Preschool MeSH
• Aged MeSH
• Serogroup * MeSH
• Streptococcus pneumoniae * classification   immunology   MeSH
• Vaccines, Conjugate administration & dosage   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) that are ten-valent (PCV10) and 13-valent (PCV13) became available in 2010. We evaluated their global impact on invasive pneumococcal disease (IPD) incidence in all ages. METHODS: Serotype-specific IPD cases and population denominators were obtained directly from surveillance sites using PCV10 or PCV13 in their national immunisation programmes and with a primary series uptake of at least 50%. Annual incidence rate ratios (IRRs) were estimated comparing the incidence before any PCV with each year post-PCV10 or post-PCV13 introduction using Bayesian multi-level, mixed-effects Poisson regressions, by site and age group. All site-weighted average IRRs were estimated using linear mixed-effects regression, stratified by product and previous seven-valent PCV (PCV7) effect (none, moderate, or substantial). FINDINGS: Analyses included 32 PCV13 sites (488 758 cases) and 15 PCV10 sites (46 386 cases) in 30 countries, primarily high income (39 sites), using booster dose schedules (41 sites). By 6 years after PCV10 or PCV13 introduction, IPD due to PCV10-type serotypes and PCV10-related serotype 6A declined substantially for both products (age <5 years: 83-99% decline; ≥65 years: 54-96% decline). PCV7-related serotype 19A increases before PCV10 or PCV13 introduction were reversed at PCV13 sites (age <5 years: 61-79% decline relative to before any PCV; age ≥65 years: 7-26% decline) but increased at PCV10 sites (age <5 years: 1·6-2·3-fold; age ≥65 years: 3·6-4·9-fold). Serotype 3 IRRs had no consistent trends for either product or age group. Non-PCV13-type IPD increased similarly for both products (age <5 years: 2·3-3·3-fold; age ≥65 years: 1·7-2·3-fold). Despite different serotype 19A trends, all-serotype IPD declined similarly between products among children younger than 5 years (58-74%); among adults aged 65 years or older, declines were greater at PCV13 (25-29%) than PCV10 (4-14%) sites, but other differences between sites precluded attribution to product. INTERPRETATION: Long-term use of PCV10 or PCV13 reduced IPD substantially in young children and more moderately in older ages. Non-vaccine-type serotypes increased approximately two-fold to three-fold by 6 years after introduction of PCV10 or PCV13. Continuing serotype 19A increases at PCV10 sites and declines at PCV13 sites suggest that PCV13 use would further reduce IPD at PCV10 sites. FUNDING: Bill & Melinda Gates Foundation as part of the WHO Pneumococcal Vaccines Technical Coordination Project.

• MeSH
• Global Health * MeSH
• Child MeSH
• Adult MeSH
• Incidence MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Infant, Newborn MeSH
• Pneumococcal Infections * prevention & control   epidemiology   MeSH
• Pneumococcal Vaccines * administration & dosage   MeSH
• Child, Preschool MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Serogroup MeSH
• Streptococcus pneumoniae * classification   immunology   MeSH
• Vaccines, Conjugate administration & dosage   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.

• MeSH
• Anti-Inflammatory Agents pharmacology   chemistry   MeSH
• Dexamethasone * pharmacology   chemistry   analogs & derivatives   MeSH
• Liver * drug effects   metabolism   MeSH
• Polylactic Acid-Polyglycolic Acid Copolymer * chemistry   MeSH
• Macrophages * drug effects   metabolism   MeSH
• Mice MeSH
• Nanospheres * chemistry   MeSH
• Drug Carriers chemistry   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Humans MeSH
• Pneumococcal Infections * prevention & control   MeSH
• Pneumococcal Vaccines * economics   MeSH
• Primary Health Care MeSH
• Risk Factors MeSH
• Vaccination MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

The prevalence of left-sided valvular heart disease (VHD) increases with age, but data on the impact of pre-existing VHD in patients with acute myocardial infarction (AMI) are limited. We aimed to define the clinical characteristics and outcomes of AMI patients with pre-existing left VHD. The analysis is based on data from three merged national registries. The dataset included 47,436 patients admitted with AMI over a 5year period at all Cath Labs nationwide. Pre-existing VHD was diagnosed in 1,445 patients (3.0%), moderate-to-severe mitral regurgitation (MR) in 510 patients (35.3%), and moderate-to-severe aortic stenosis (AS) in 869 patients (60.1%). Patients with VHD had worse baseline characteristics, pre-existing coronary artery disease, more complicated in-hospital course with higher Killip class, lower left ventricular ejection fraction, and more comorbidities. Angiographically more frequent left main stenosis, TIMI flow 3 before PCI, less frequent stent implantation. Patients with pre-existing VHD had significantly higher 7-day (10.1% vs. 4.5%, p < 0.001), 30-day (16.0% vs. 7.0%, p < 0.001) and 1-year mortality (28.7 vs. 12.7%, p < 0.001) compared to patients without. Conclusions. Patients with pre-existing VHD and AMI are characterized by complicated in-hospital course with higher Killip class, lower ejection fraction, angiographically less severe stenosis, TIMI flow 3 prior to PCI, and less frequent stent implantation. This is a high-risk group with higher short - and long-term mortality and earlier intervention should be considered.

• MeSH
• Aortic Valve Stenosis * complications   epidemiology   MeSH
• Myocardial Infarction * complications   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mitral Valve Insufficiency * complications   epidemiology   MeSH
• Registries MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Many ulcerative colitis (UC) patients require the use of second-line agents after the failure of anti-TNF therapy. RESEARCH DESIGN AND METHODS: We conducted a multicenter, retrospective study including 683 chronically active, moderate-to-severe UC patients who failed first-line anti-TNFs. The rate of treatment persistence and colectomy-free survival was assessed up to 3 years after the initiation of second-line therapy. Predictors for colectomy and persistence were investigated. RESULTS: After the failure of the first-line anti-TNF, ustekinumab had superior persistence and colectomy-free survival rates compared to tofacitinib (p = 0.05; p = 0.001) and vedolizumab (p = 0.02; p = 0.05), but significant difference was only found in persistence rates in comparison with anti-TNFs (p < 0.001). Regardless of the number of prior anti-TNFs, significantly higher persistence (p = 0.05) and colectomy-free survival rates (p = 0.01) were observed over 2 years with ustekinumab than with vedolizumab or tofacitinib, whereas ustekinumab's superiority over tofacitinib seemed to disappear by the third year. Hypoalbuminaemia (p = 0.002) and shorter disease duration at second-line initiation (p = 0.03) increased, while concomitant immunomodulators (p = 0.05) reduced the risk for colectomy. Shorter disease duration (p = 0.01) and primary non-response to the previously used anti-TNF (p < 0.001) negatively influenced persistence with second-line non-TNF-targeted agents. CONCLUSION: After first-line anti-TNF failure, switching to a non-anti-TNF agent is worth considering in moderate-to-severe UC.

• MeSH
• Chronic Disease MeSH
• Adult MeSH
• Gastrointestinal Agents * therapeutic use   administration & dosage   MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   administration & dosage   MeSH
• Cohort Studies MeSH
• Colectomy MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Treatment Failure MeSH
• Piperidines therapeutic use   administration & dosage   MeSH
• Pyrimidines therapeutic use   administration & dosage   MeSH
• Pyrrolidines therapeutic use   administration & dosage   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Severity of Illness Index MeSH
• Tumor Necrosis Factor-alpha * antagonists & inhibitors   MeSH
• Colitis, Ulcerative * drug therapy   surgery   MeSH
• Ustekinumab therapeutic use   administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH

This study aimed to determine the effects of different defensive styles (i.e., man-to-man vs. zone) and court sizes (full vs. half) on physical [PlayerLoadTM (PL), total jumps and jumps in low (<20 cm), medium (21-40 cm), and high (>41 cm) bands, the number of and distance covered during accelerations and decelerations divided in high (>2 m∙s-2) and low intensity (<2 m∙s-2) bands], perceived [rating of perceived exertion (RPE)] and technical (total, scored, missed and % of made shots, rebounds, steals, assists, turnovers, and blocks) demands during basketball small-sided games (SSGs). Ten semi-professional male basketball players (age: 20.4 ± 2.1 years; stature: 189.4 ± 8.1 cm; body mass: 77.4 ± 8.4 kg) from the same basketball team participated in this study. Players were asked to play four 5 vs. 5 SSG typologies in randomized order: 1) half-court man-to-man defense, 2) half-court zone defense, 3) full-court man-to-man defense, and 4) full-court zone defense. No significant interaction (p > 0.05) between two independent variables was observed for physical demands. An effect of court size was found for most of the physical demand measures (except jumps) with higher values (p < 0.05) found in full court SSGs. The defensive style had an effect (p < 0.05, trivial-to-small) on total distance and low-intensity accelerations and decelerations. No effects were evident for the independent variables on the RPE and technical demands. Coaches should design full court SSGs when aiming at increasing players' physical demands. Differently, similar physical, perceived and technical demands should be expected when playing man-to-man or zone defense during SSGs.

• Publication type
• Journal Article MeSH

Digital transformation is widely understood as a process where technology is used to modify an organization's products and services and to create new ones. It is rapidly advancing in all sectors of society. Researchers have shown that it is a multidimensional process determined by human decisions based on ideologies, ideas, beliefs, goals, and the ways in which technology is used. In health care and health, the end result of digital transformation is digital health. In this study, a detailed literature review covering 560 research articles published in major journals was performed, followed by an analysis of ideas, beliefs, and goals guiding digital transformation and their possible consequences for privacy, human rights, dignity, and autonomy in health care and health. Results of literature analyses demonstrated that from the point of view of privacy, dignity, and human rights, the current laws, regulations, and system architectures have major weaknesses. One possible model of digital health is based on the dominant ideas and goals of the business world related to the digital economy and neoliberalism, including privatization of health care services, monetization and commodification of health data, and personal responsibility for health. These ideas represent meaningful risks to human rights, privacy, dignity, and autonomy. In this paper, we present an alternative solution for digital health called human-centric digital health (HCDH). Using system thinking and system modeling methods, we developed a system model for HCDH. It uses 5 views (ideas, health data, principles, regulation, and organizational and technical innovations) to align with human rights and values and support dignity, privacy, and autonomy. To make HCDH future proof, extensions to human rights, the adoption of the principle of restricted informational ownership of health data, and the development of new duties, responsibilities, and laws are needed. Finally, we developed a system-oriented, architecture-centric, ontology-based, and policy-driven approach to represent and manage HCDH ecosystems.

• MeSH
• Digital Technology MeSH
• Digital Health * MeSH
• Humans MeSH
• Human Rights MeSH
• Patient-Centered Care * MeSH
• Privacy MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Although existing studies have acknowledged the impacts of Hofstede's cultural dimensions on the proactive behaviors of employees or innovations in various contexts, they have not examined the mediating role of proactive behavior between Hofstede's cultural dimensions and entrepreneurial innovativeness. Thus, this study aimed to investigate the mediating impact of proactive behavior between six of Hofstede's cultural dimensions and entrepreneurial innovativeness. Data were collected through standardized surveys from 150 retail entrepreneurs running businesses in China. SPSS and Wrap PLS SEM were used to analyze the data. The findings revealed a positive and significant impact of all six of Hofstede's cultural dimensions, including low power distance, low uncertainty avoidance, long-term orientation, indulgence, collectivism, and masculinity, on proactive behavior among entrepreneurs. Additionally, the mediating influence of proactive behavior was positive and significant for all studied Hofstede cultural dimensions and entrepreneurial innovativeness among entrepreneurs. This study provides important implications for entrepreneurs by emphasizing the importance of proactive behaviors for entrepreneurial innovativeness. Consequently, this study contributes to the existing literature by providing empirical evidence regarding the mediating role of proactive behavior among cultural dimensions and entrepreneurial innovativeness. It suggests that entrepreneurs should exhibit proactive behaviors to implement various innovative practices within their firms.

• MeSH
• Adult MeSH
• Creativity * MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Entrepreneurship * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• China MeSH