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The clinical context of drug interactions detected by automated analysis systems is particularly important in older patients with multimorbidities. We aimed to provide unique, up-to-date data on the prevalence of potentially inappropriate medications (PIMs) and drug–drug interactions (DDIs) in the Polish geriatric population over 80 years old and determine the frequency and the most common PIMs involved in DDIs. We analyzed all non-prescription and prescription drugs in a representative national group of 178 home-dwelling adults over 80 years old with excessive polypharmacy (≥10 drugs). The FORTA List was used to assess PIMs, and the Lexicomp® Drug Interactions database was used for DDIs. DDIs were detected in 66.9% of the study group, whereas PIMs were detected in 94.4%. Verification of clinical indications for the use of substances involved in DDIs resulted in a reduction in the total number of DDIs by more than 1.5 times, as well as in a nearly 3-fold decrease in the number of interactions requiring therapy modification and drug combinations that should be strictly avoided. The most common PIMs involved in DDIs were painkillers, and drugs used in psychiatry and neurology. Special attention should be paid to DDIs with PIMs since they could increase their inappropriate character. The use of automated interaction analysis systems, while maintaining appropriate clinical criticism, can increase both chances for a good therapeutic effect and the safety of the elderly during treatment processes.

The occurrence and mechanisms of developmental adult diseases have gradually attracted attention in recent years. Exposure of gametes and embryos to adverse environments, especially during plastic development, can alter the expression of certain tissue-specific genes, leading to increased susceptibility to certain diseases in adulthood, such as diabetes, cardiovascular disease, neuropsychiatric, and reproductive system diseases, etc. The occurrence of chronic disease in adulthood is partly due to genetic factors, and the remaining risk is partly due to environmental-dependent epigenetic information alteration, including DNA methylation, histone modifications, and noncoding RNAs. Changes in this epigenetic information potentially damage our health, which has also been supported by numerous epidemiological and animal studies in recent years. Environmental factors functionally affect embryo development through epimutation, transmitting diseases to offspring and even later generations. This review mainly elaborated on the concept of developmental origins of adult diseases, and revealed the epigenetic mechanisms underlying these events, discussed the theoretical basis for the prevention and treatment of related diseases.

Abstract Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Objectives The aim of the presented study was to compare the health locus of control (HLC) between employed and unemployed patients after kidney transplantation (KT), and to investigate the relationship between HLC and the quality of life (QoL). Material and Methods The study group consisted of 101 KT patients and the control group of 60 hemodialysis (HD) patients. The applied methods were: the Multidimensional Health Locus of Control Questionnaire (MHLC), the WHO Quality of Life Questionnaire (WHOQoL-BREF), and a survey collecting information on the socio-demographic status and work experience. Results Overall, 57.5% of KT patients were employed and 42.5% were unemployed. In the HD group, 25% were employed and 71% were unemployed, while 4% did not disclose their employment status. The unemployed KT patients, in comparison with the employed ones, presented a higher feeling of the impact of chance on their health (unemployed M±SD 23.68±6.59; employed M±SD 21.02±4.57) and a lower level of QoL on the Somatic Scale (unemployed Me = 14.00, IQR = 3.00; employed Me = 1450, IQR = 3.00) and the Environmental Scale (unemployed M±SD 15.39±2.83; employed M±SD 16.85±3.24). In the employed KT group, the Internal Control Scale (MHLC) correlated with all QoL scales (the Somatic Scale : r = 0.292, p = 0.036; the Psychological Scale : r = 0.455, p = 0.001; the Social Scale : r = 0.304, p = 0.029; and the Environmental Scale : r = 0.307, p = 0.027). In the unemployed KT group, the Internal Control Scale (MHLC) correlated significantly with the Somatic Scale (r = 0.396, p = 0.013) and the Psychological Scale (r = 0.374, p = 0.019). Conclusions The employed KT patients have a higher level of independence, with results indicating a strong internal type. Additionally, the working patients assess their QoL better, both in terms of their health condition and the organization of satisfying environment. The obtained knowledge about the psychological characteristics of KT patients may be useful for the occupational activation programs and psycho-education for those with weaker predispositions. Int J Occup Med Environ Health. 2022;35(1):53–62

A doença de Charcot-Marie-Tooth (CMT) é uma polineuropatia motora, sensitiva, hereditária e de predomínio distal. Os membros inferiores são os mais afetados e, ocasionalmente, há comprometimento dos membros superiores. Este estudo descreve a presença de disfagia orofaríngea e a intervenção fonoaudiológica em uma paciente de 58 anos com diagnóstico de CMT, encaminhada à avaliação fonoaudiológica devido a queixas na deglutição. Na avaliação inicial identificaram-se alterações, tanto de caráter estrutural quanto funcional, que resultaram em uma disfagia orofaríngea leve. Também se utilizou o Questionário de Qualidade de Vida na Disfagia para identificar o impacto na qualidade de vida da paciente. Após um mês de acompanhamento observou-se melhora dos sintomas e aumento do conforto e segurança ao deglutir.

Drug-related problems (DRP, defined as adverse drug events/reactions and medication errors) are a common threat for patient safety. With the aim to aid improved allocation of specialist resources and to improve detection and prevention of DRP, numerous predictive scoring tools have been proposed. The external validation and evidence for the transferability of these tools still faces limitations. However, the proposed scoring tools include partly overlapping sets of similar factors, which may allow a new approach to estimate the external usability and validity of individual risk factors. Therefore, we conducted this systematic review and analysis. We identified 14 key studies that assessed 844 candidate risk factors for inclusion into predictive scoring tools. After consolidation to account for overlapping terminology and variable definitions, we assessed each risk factor in the number of studies it was assessed, and, if it was found to be a significant predictor of DRP, whether it was included in a final scoring tool. The latter included intake of ≥ 8 drugs, drugs of the Anatomical Therapeutic Chemical (ATC) class N, ≥1 comorbidity, an estimated glomerular filtration rate (eGFR)

Anopheles algeriensis Theobald, 1903, considered a competent vector of Plasmodium parasites, is a mosquito species widely distributed in the Mediterranean area but rare in Northern and Central Europe. The disappearance of its suitable breeding sites in Italy is having a detrimental effect on the occurrence of this species once common along the Southern coasts and on the islands. Recently, molecular investigations have renewed interest in this species, highlighting a genetic heterogeneity among European populations. In this study, An. algeriensis populations from Italy, Germany, Romania, and Sweden were analyzed by molecular typing of the intergenic transcribed spacer 2 (ITS2). The mitochondrial cytochrome c oxidase subunit I (COI) was also analyzed from specimens collected in Southern Italy. With the aim of investigating the population structure of this species, the obtained data were compared to all publicly available ITS2 and COI sequences of An. algeriensis, adding specimens from Spain and Portugal. The analyses of both markers indicate a split between Iberian populations (Spain for ITS2 and Spain/Portugal for COI) and those from the rest of Europe, revealing two cryptic species. The analysis of the COI barcode revealed a third clade representing a cryptic species present in Danube Delta (Romania). The high levels of genetic divergence among the clades of An. algeriensis indicate that this taxon represents a species complex, potentially harboring several distinct cryptic species.

Background: Cleft palate (CP) patients have a higher prevalence of oral and respiratory tract bacterial infections than the general population. Nevertheless, characteristics of bacterial differences induced by CP-related anatomical heterogeneity are unknown. Methods: In this study, we systematically described the characteristics of bacteria in the oral and nasal niches in healthy children, CP children, healthy adolescents, CP adolescents, and postoperative adolescents by 454-pyrosequencing technology (V3–V6) to determine bacterial differences induced by CP. Results: Due to the CP-induced variations in spatial structure, the early establishment of microecology in CP children was different from that in healthy children. Nasal bacterial composition showed greater changes than in the saliva. Moreover, such discrepancy also appeared in CP and postoperative adolescents who had even undergone surgery > 10 years previously. Interestingly, we found by Lefse analysis that part of bacterial biomarkers in the nasal cavity of CP subjects was common oral flora, suggesting bacterial translocation between the oral and nasal niches. Therefore, we defined the oral–nasal translocation bacteria as O-N bac. By comparing multiple groups, we took the intersection sets of O-N bacs selected from CP children, CP adolescents, and postoperative adolescents as TS O-N bacs with time–character, including Streptococcus, Gemella, Alloprevotella, Neisseria, Rothia, Actinomyces, and Veillonella. These bacteria were at the core of the nasal bacterial network in CP subjects, and some were related to infectious diseases. Conclusions: CP would lead to significant and long-term differences in oral and nasal flora. TS O-N bacs migrating from the oral to the nasal might be the key stone causing nasal flora dysbiosis in the CP patients.

Objectives To comprehensively map the existing evidence assessing the impact of travel-related control measures for containment of the SARS-CoV-2/COVID-19 pandemic.Design Rapid evidence map.Data sources MEDLINE, Embase and Web of Science, and COVID-19 specific databases offered by the US Centers for Disease Control and Prevention and the WHO.Eligibility criteria We included studies in human populations susceptible to SARS-CoV-2/COVID-19, SARS-CoV-1/severe acute respiratory syndrome, Middle East respiratory syndrome coronavirus/Middle East respiratory syndrome or influenza. Interventions of interest were travel-related control measures affecting travel across national or subnational borders. Outcomes of interest included infectious disease, screening, other health, economic and social outcomes. We considered all empirical studies that quantitatively evaluate impact available in Armenian, English, French, German, Italian and Russian based on the team’s language capacities.Data extraction and synthesis We extracted data from included studies in a standardised manner and mapped them to a priori and (one) post hoc defined categories.Results We included 122 studies assessing travel-related control measures. These studies were undertaken across the globe, most in the Western Pacific region (n=71). A large proportion of studies focused on COVID-19 (n=59), but a number of studies also examined SARS, MERS and influenza. We identified studies on border closures (n=3), entry/exit screening (n=31), travel-related quarantine (n=6), travel bans (n=8) and travel restrictions (n=25). Many addressed a bundle of travel-related control measures (n=49). Most studies assessed infectious disease (n=98) and/or screening-related (n=25) outcomes; we found only limited evidence on economic and social outcomes. Studies applied numerous methods, both inferential and descriptive in nature, ranging from simple observational methods to complex modelling techniques.Conclusions We identified a heterogeneous and complex evidence base on travel-related control measures. While this map is not sufficient to assess the effectiveness of different measures, it outlines aspects regarding interventions and outcomes, as well as study methodology and reporting that could inform future research and evidence synthesis.

The emergence of a highly transmissible and a more pathogenic B.1.617.2 (delta) variant of SARS-CoV-2 has brought concern over COVID-19 vaccine efficacy and the increased risk of severe breakthrough infections. The objective of this study was to assess the frequency and the clinical characteristics of severe breakthrough COVID-19 cases recorded in 10 Polish healthcare units between 1 June and 31 December 2021, a period during which a rapid surge in the share of B.1.617.2 infections was seen, while a significant number of populations were already fully vaccinated. Overall, 723 individuals who completed the initial vaccination regime (fully vaccinated group) and an additional 18 who received a booster dose were identified—together, they represented 20.8% of all the COVID-19 patients hospitalized during the same period in the same healthcare institutions (0.5% in the case of a group that received a booster dose). Although laboratory and clinical parameters did not differ between both groups, patients who received a booster tended to have lower CRP, IL-6, PCT, and d-dimer levels and they required oxygen therapy less frequently. The most common early COVID-19 symptoms in the studied group were fatigue, cough, fever (>38 °C), and dyspnea. Individuals with no detectable anti-spike IgG antibodies constituted 13%; the odds of being a humoral non-responder to the vaccine were increased in patients aged >70 years. Fully vaccinated patients hospitalized after more than 180 days from the last vaccine dose were significantly older and they were predominantly represented by individuals over 70 years and with comorbidities, particularly cardiovascular disease. Contrary to mRNA vaccines, most patients vaccinated with adenoviral vector vaccines were infected within six months. A total of 102 fatal cases (14% of all deaths among vaccinated individuals; 0.7% in the case of a group that received a booster dose) were recorded, representing 17.6% of all the COVID-19 fatalities recorded in June–December 2021 in the considered healthcare units. The odds of death were significantly increased in men, individuals aged >70 years, patients with comorbidities, and those identified as humoral non-responders to vaccination; in fully vaccinated patients the odds were also increased when the second vaccine dose was given >180 days before the first COVID-19 symptoms. The mortality rate in immunocompromised subjects was 19%. The results indicate that compared to vaccinated individuals, severe COVID-19 and deaths in the unvaccinated group were significantly more prevalent during the B.1.617.2-dominated wave in Poland; and, it highlight the protective role of a booster dose, particularly for more vulnerable individuals.

BackgroundCirculating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively.MethodsWe related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study who attended a routine examination.ResultsAdjusting for age, sex, smoking, and eGFR, we observed significant associations of ADMA (direct) and ARG/ADMA (inverse) with odds of MetS (N = 1461 prevalent cases; Odds Ratio [OR] per SD increment 1.13, 95%CI 1.04-1.22; and 0.89, 95%CI 0.82-0.97 for ADMA and ARG/ADMA, respectively). Upon further adjustment for waist circumference, systolic and diastolic blood pressure, glucose, high-density lipoprotein cholesterol, and triglycerides, we observed a positive relation between SDMA and MetS (OR per SD increment 1.15, 95% CI 1.01-1.30) but the other associations were rendered statistically non-significant. We did not observe statistically significant associations between any of the methylarginines and the risk of new-onset MetS (752 incident events) over a median follow-up of 11 years.ConclusionIt is unclear whether dimethylarginines play an important role in the incidence of cardiometabolic risk in the community, notwithstanding cross-sectional associations. Further studies of larger samples are needed to replicate our findings.

Liver disease is a common condition worldwide that can cause alterations in drug disposition and susceptibility to drug toxicities, with increased risk of adverse drug reactions. European Summaries of Product Characteristics (SmPCs) and United States Prescribing Information (US PI) should therefore be comprehensible to prescribers regarding their liver-associated contraindications to ensure safe prescribing. This study aimed to evaluate the ambiguity of terminology used in communicating liver-associated absolute contraindications in SmPCs/PI of commonly prescribed drugs in four major drug markets (Germany, Switzerland, the United Kingdom, and the United States) by assigning wordings to different categories and analyzing their clinical comprehensibility. For US PI, 79% did not contain liver-related contraindications, compared to 2, 13, and 6% of German, Swiss, and British SmPCs, respectively. Study findings indicate that out of 228 examined SmPCs/PI containing liver-related contraindications, 77, 79, 76, and 52% contained unclear wording in the German, Swiss, British, and American drug market, respectively. Only 40% (German), 52% (Swiss), 39% (British), and 29% (American) of SmPCs/PI included terms with explicit wording. Including more precise statements in SmPCs/PI based on laboratory parameters (such as albumin) or scores (e.g., the Child–Pugh score) to objectify the severity of liver disease may improve the clarity of SmPCs/PI and the safety of drug prescription.

The aim of this study was to analyze the waning of anti-spike (S) antibodies after mRNA vaccination against COVID-19 in maintenance dialysis patients, and to assess the safety and effectiveness of the complementary third dose. This was a prospective, longitudinal study in which we analyzed the kinetics of antibodies up to six months after a two-dose vaccination (first protocol) in infection-naïve dialysis patients (IN-Ds), previously infected dialysis patients (PI-Ds) and subjects without chronic kidney disease (the controls), as well as their humoral response to the third dose of the same mRNA vaccine (second protocol). The respective reduction in antibody titer after 3 and 6 months by 82.9% and 93.03% in IN-Ds (n = 109), 73.4% and 93.36% in PI-Ds (n = 32) and 75.5% and 88.8% in the controls (n = 20) was demonstrated. Consequently, a protective antibody titer above 141 BAU/mL was found in only 47.7% and 23.8% of IN-Ds after 3 and 6 months, respectively. After the third vaccine dose, a significant increase in antibody titer was observed in all groups, with increases by a factor of ×51.6 in IN-Ds, ×30.1 in the controls and ×8.4 in PI-Ds. The median antibody titer after the third dose differed significantly between groups, and was the highest in PI-Ds: PI-Ds, 9090 (3300–15,000) BAU/mL; the controls, 6945 (2130–11,800); IN-Ds, 3715 (1470–7325) (p < 0.001). In conclusion, we observed similar degrees of antibody waning in all patients. After 3 months, over half of the infection-naïve dialysis patients had a very low antibody titer, and almost twenty percent of them had no antibodies at all. The humoral response to the third dose was very good, raising their titer of antibodies to a higher level than those in the general population who have received the primary two-dose scheme. The results support the administration of a complementary third dose of the mRNA vaccine for dialysis patients as soon as possible.

Background: The efficacy of SARS-CoV-2 vaccination among kidney transplant recipients (KTR) is low. The main goal of this study was to analyze factors that may influence the humoral response to vaccination. Methods: We analyzed the titer magnitude of IgG antibodies directed against spike (S)-SARS-CoV-2 antigen after the second dose of the mRNA vaccine in 142 infection naïve KTR (83 men, i.e., 58.4%) with a median age (IQR) of 54 (41–63), and 36 respective controls without chronic kidney disease. mRNA-1273 or BNT162b2 were applied in 26% and 74% of KTR, respectively. Results: S-specific immune response (seroconversion) was seen in 73 (51.41%) of KTR, and in all controls 36 (100%). Independent predictors of no response were elder age, shorter transplantation vintage, and a more than two-drug immunosuppressive protocol. In subgroup analyses, the seroconversion rate was highest among KTR without MMF/MPS treatment (70%), treated with no more than two immunosuppressants (69.2%), treated without corticosteroid (66.7%), younger patients aged

Usutu virus (USUV) is an emerging mosquitoborne flavivirus with an increasing number of reports from several countries in Europe, where USUV infection has caused high avian mortality rates. However, 20 years after the first observed outbreak of USUV in Europe, there is still no reliable assessment of the large-scale impact of USUV outbreaks on bird populations. In this study, we identified the areas suitable for USUV circulation in Germany and analyzed the effects of USUV on breeding bird populations. We calculated the USUV-associated additional decline of common blackbird (Turdus merula) populations as 15.7% inside USUV-suitable areas but found no significant effect for the other 14 common bird species investigated. Our results show that the emergence of USUV is a further threat for birds in Europe and that the large-scale impact on population levels, at least for common blackbirds, must be considered.

Abstract Low plasma concentration of L-homoarginine is an independent predictor of cardiovascular events and total mortality. Experimental data indicate that supplementation of L-homoarginine may have protective effects. We aimed to elucidate the mechanisms involved in the cellular uptake of L-homoarginine, which are little understood, so far. Using human embryonic kidney (HEK293) cell lines stably overexpressing the human cationic amino acid transporters CAT1 [solute carrier family 7 (SLC7A1)], CAT2A (SLC7A2A) or CAT2B (SLC7A2B) we assessed the transport kinetics of L-homoarginine and interactions with the CAT substrates L-arginine and asymmetric dimethylarginine (ADMA). Significant uptake of L-homoarginine was observed for all three CATs with apparent KM-values of 175 ± 7 µM for CAT1 and 523 ± 35 µM for CAT2B. Saturation of CAT2A-mediated L-homoarginine uptake could not be reached. Uptake of L-homoarginine by any of the three CATs could be inhibited by L-arginine and ADMA. Significant inhibition of CAT1-mediated uptake of L-homoarginine by L-arginine already occurred in the physiological concentration range. Taken together these data demonstrate that L-homoarginine is a substrate of CAT1, CAT2A and CAT2B and that CAT1 is a key site with regard to physiological relevance and interactions with related substrates such as L-arginine.

Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoarginine [L-arginine:glycine amidinotransferase (AGAT)] are expressed in human proximal tubule cells. So far, it is not known which transport protein in the basolateral membrane of proximal tubule cells is mediating the uptake of ADMA into the cells for subsequent degradation or the export of intracellularly synthesized L-homoarginine. One study suggested that the uptake transporter OATP4C1 (gene symbol SLCO4C1) may be involved in the transport of ADMA and other uremic toxins. OATP4C1 is a member of the SLCO/SLC21 family of solute carriers, localized in the basolateral membrane of human proximal tubule cells. By using stably-transfected HEK cells overexpressing human OATP4C1, we demonstrate that ADMA and L-homoarginine are substrates of OATP4C1 with Km values of 232.1 μM and 49.9 μM, respectively. ADMA and the structurally related uremic toxin SDMA (100 μM) inhibited OATP4C1-mediated L-homoarginine uptake (P < 0.01), whereas other tested uremic toxins such as urea and p-cresyl sulfate have no effect on OATP4C1-mediated transport. Preloading experiments (300 μM for 60 min) with subsequent efflux studies revealed that OATP4C1 also facilitates efflux e.g. of L-homoarginine. Both ADMA and L-homoarginine are substrates of human OATP4C1. Because proximal tubule cells are one site of ADMA metabolism and L-homoarginine synthesis, we postulate a protective role of OATP4C1 by mediating uptake of ADMA from and export of L-homoarginine into the systemic circulation.

L-arginine and its derivatives, asymmetric and symmetric dimethylarginine (ADMA and SDMA) and L-homoarginine, have emerged as cardiovascular biomarkers linked to cardiovascular outcomes and various metabolic and functional pathways such as NO-mediated endothelial function. Cellular uptake and efflux of L-arginine and its derivatives are facilitated by transport proteins. In this respect the cationic amino acid transporters CAT1 and CAT2 (SLC7A1 and SLC7A2) and the system y+L amino acid transporters (SLC7A6 and SLC7A7) have been most extensively investigated, so far, but the number of transporters shown to mediate the transport of L-arginine and its derivatives is constantly increasing. In the present review we assess the growing body of evidence regarding the function, expression, and clinical relevance of these transporters and their possible relation to cardiovascular diseases.

PURPOSE:Previous studies suggest an association between use of anticholinergic drugs in elderly patients and cognitive impairment. However, there are still limited data on the association of anticholinergic drug use and cognitive impairment as well as contribution of individual drugs to anticholinergic load using large, well-documented patient cohorts treated in geriatric units from Europe. METHODS:We investigated 797,440 prescriptions to 89,579 hospitalized patients treated in geriatric units within the GiB-DAT database. Data of all patients discharged between 1 January 2013 and 30 June 2015 was included. The Anticholinergic Cognitive Burden (ACB) scale was used to classify anticholinergic drugs as definite (score 2 or 3) and possible anticholinergics (score 1). Cognitive function was determined using Mini-Mental State Examination (MMSE) and the standardized scale for dementia (4D+S). RESULTS:In two multivariable logistic regression models age, sex, number of drugs and ACB total scores were identified as variables independently associated with cognitive impairment as measured by MMSE (odds ratio per ACB unit 1.114, 95% CI 1.099-1.130) or the diagnosis dementia (odds ratio 1.159 per ACB unit, 95% CI 1.144-1.173, both p < 0.0001). High anticholinergic load was associated with patients with severe cognitive impairment (p < 0.05 for all pairwise comparisons). ACB score 3 anticholinergic drugs contributed 77.9% to the cumulative amount of ACB points in patients with an anticholinergic load of 3 and higher. CONCLUSIONS:Using a cross-sectional study design, a significant positive association between anticholinergic drug load and cognitive impairment in European patients treated in specialised geriatric units was found. The most frequently used definitve anticholinergic drugs were quetiapine, amitriptyline and carbamazepine.

BACKGROUND:Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited. OBJECTIVE:This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs. METHODS:In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria-Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs). RESULTS:Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions. CONCLUSION:In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT-drugs with higher risk only could be detected by using more than one classification-system. Local adaption of international classifications can improve identification of patients at risk.

A growing number of studies linked elevated concentrations of circulating asymmetric (ADMA) and symmetric (SDMA) dimethylarginine to mortality and cardiovascular disease (CVD) events. To summarize the evidence, we conducted a systematic review and quantified associations of ADMA and SDMA with the risks of all-cause mortality and incident CVD in meta-analyses accounting for different populations and methodological approaches of the studies.Relevant studies were identified in PubMed until February 2015. We used random effect models to obtain summary relative risks (RR) and 95% confidence intervals (95%CIs), comparing top versus bottom tertiles. Dose-response relations were assessed by restricted cubic spline regression models and potential non-linearity was evaluated using a likelihood ratio test. Heterogeneity between subgroups was assessed by meta-regression analysis.For ADMA, 34 studies (total n = 32,428) investigating associations with all-cause mortality (events = 5,035) and 30 studies (total n = 30,624) investigating the association with incident CVD (events = 3,396) were included. The summary RRs (95%CI) for all-cause mortality were 1.52 (1.37-1.68) and for CVD 1.33 (1.22-1.45), comparing high versus low ADMA concentrations. Slight differences were observed across study populations and methodological approaches, with the strongest association of ADMA being reported with all-cause mortality in critically ill patients. For SDMA, 17 studies (total n = 18,163) were included for all-cause mortality (events = 2,903), and 13 studies (total n = 16,807) for CVD (events = 1,534). High vs. low levels of SDMA, were associated with increased risk of all-cause mortality [summary RR (95%CI): 1.31 (1.18-1.46)] and CVD [summary RR (95%CI): 1.36 (1.10-1.68) Strongest associations were observed in general population samples.The dimethylarginines ADMA and SDMA are independent risk markers for all-cause mortality and CVD across different populations and methodological approaches.

The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP+) or 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP+ or ASP+ might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP+ and ASP+. We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP+ uptake. Data on inhibition of OCT2-mediated ASP+ uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP+, ASP+, and metformin uptake was observed (pairwise rs between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP+ and ASP+ (Tanimoto similarity T = 0.28) was even lower (rs = 0.27) than the correlation between structurally distinct substrates, such as ASP+ and metformin (T = 0.01; rs = 0.48) or MPP+ and metformin (T = 0.01; rs = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited.

Radiation caries have been reported to be correlated with radiotherapy-induced destruction of salivary function and changes in oral microbiota. There have been no published reports detailing patients who have remained radiation caries-free following radiotherapy for nasopharyngeal carcinoma. The aim of this study was to investigate the relationship between salivary function, oral microbiota and the absence of radiation caries. Twelve radiation caries-free patients and nine patients exhibiting radiation caries following irradiated nasopharyngeal carcinoma were selected. V40, the dose at which the volume of the contralateral parotid gland receives more than 40 Gy, was recorded. Stimulated saliva flow rate, pH values and buffering capacity were examined to assess salivary function. Stimulated saliva was used for molecular profiling by Denaturing Gradient Gel Electrophoresis. Mutans streptococci and Lactobacilli in saliva were also cultivated. There were no significant differences in V40 between radiation caries-free individuals and those with radiation caries. Compared with normal values, the radiation caries-free group had significantly decreased simulated saliva flow rate, while there were no significant differences in the saliva pH value and buffering capacity. Similar results were observed in the radiation caries group. There was no statistical difference in microbial diversity, composition and log CFU counts in cultivation from the radiation caries-free group and the radiation caries group. Eleven genera were detected in these two groups, among which Streptococcus spp. and Neisseria spp. had the highest distribution. Our results suggest that changes in salivary function and in salivary microbiota do not explain the absence of radiation caries in radiation caries-free individuals.

Elevated plasma concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine have repeatedly been linked to adverse clinical outcomes. Both methylarginines are substrates of alanine-glyoxylate aminotransferase 2 (AGXT2). It was the aim of the present study to simultaneously investigate the functional relevance and relative contributions of common AGXT2 single nucleotide polymorphisms (SNPs) to plasma and urinary concentrations of methylarginines as well as β-aminoisobutyrate (BAIB), a prototypic substrate of AGXT2. In a cohort of 400 healthy volunteers ADMA, SDMA and BAIB concentrations were determined in plasma and urine using HPLC-MS/MS and were related to the coding AGXT2 SNPs rs37369 (p.Val140Ile) and rs16899974 (p.Val498Leu). Volunteers heterozygous or homozygous for the AGXT2 SNP rs37369 had higher SDMA plasma concentrations by 5% and 20% (p = 0.002) as well as higher BAIB concentrations by 54% and 146%, respectively, in plasma and 237% and 1661%, respectively, in urine (both p

The online resource Wikipedia is increasingly used by students for knowledge acquisition and learning. However, the lack of a formal editorial review and the heterogeneous expertise of contributors often results in skepticism by educators whether Wikipedia should be recommended to students as an information source. In this study we systematically analyzed the accuracy and completeness of drug information in the German and English language versions of Wikipedia in comparison to standard textbooks of pharmacology. In addition, references, revision history and readability were evaluated. Analysis of readability was performed using the Amstad readability index and the Erste Wiener Sachtextformel. The data on indication, mechanism of action, pharmacokinetics, adverse effects and contraindications for 100 curricular drugs were retrieved from standard German textbooks of general pharmacology and compared with the corresponding articles in the German language version of Wikipedia. Quantitative analysis revealed that accuracy of drug information in Wikipedia was 99.7% ± 0.2% when compared to the textbook data. The overall completeness of drug information in Wikipedia was 83.8 ± 1.5% (p < 0.001). Completeness varied in-between categories, and was lowest in the category "pharmacokinetics" (68.0% ± 4.2%; p < 0.001) and highest in the category "indication" (91.3% ± 2.0%) when compared to the textbook data overlap. Similar results were obtained for the English language version of Wikipedia. Of the drug information missing in Wikipedia, 62.5% was rated as didactically non-relevant in a qualitative re-evaluation study. Drug articles in Wikipedia had an average of 14.6 ± 1.6 references and 262.8 ± 37.4 edits performed by 142.7 ± 17.6 editors. Both Wikipedia and textbooks samples had comparable, low readability. Our study suggests that Wikipedia is an accurate and comprehensive source of drug-related information for undergraduate medical education.

BACKGROUND AND AIMS: Homoarginine, a precursor of nitric oxide, is an inverse predictor of death in dialysis patients and in subjects with cardiovascular disease and normal kidney function but its relationship with clinical outcomes in chronic kidney disease (CKD) patients not yet on dialysis is unknown. DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: We enrolled 168 consecutive predialysis CKD patients (Age: 70 ± 11 yrs; 26% Diabetics; eGFR 34 ± 18 ml/min/1.73 m(2)) referred to a tertiary care centre and measured laboratory data on kidney function and cardiovascular risk factors. We modeled progression to dialysis or death as a function of homoarginine, using Cox's regression, accounting for clinical characteristics, baseline levels of kidney function, and markers of inflammation. RESULTS: On crude and adjusted analyses homoarginine was directly associated with the eGFR and patients with more compromised renal function exhibited lower homoarginine levels. Furthermore homoarginine was also independently related to L-arginine, serum albumin and body mass index, and inversely related to proteinuria, C-reactive protein and age. During the study (follow up median time 4 years, inter-quartile range 1.7 to 7.0 years) 56 patients started dialysis and 103 died and homoarginine was a strong inverse predictor of the incidence rate of both outcomes (P=0.002 and P=0.017). CONCLUSIONS: Homoarginine declines with advancing renal disease and is inversely related to progression to dialysis and mortality. The nature of the link between homoarginine and clinical outcomes is amenable to testing in clinical trials.

In bacterial biofilms, high molecular weight, secreted exopolysaccharides can serve as a scaffold to which additional carbohydrates, proteins, lipids, and nucleic acids adhere, forming the matrix of the developing biofilm. Here we report methods to extract and purify high molecular weight (>15 kDa) exopolysaccharides from biofilms of eight human pathogens, including species of Staphylcococcus, Klebsiella, Acinetobacter, Pseudomonas, and a toxigenic strain of Escherichia coli O157:H7. Glycosyl composition analysis indicated a high total mannose content across all strains with P. aeruginosa and A. baumannii exopolysaccharides comprised of 80-90% mannose, K. pneumoniae and S. epidermidis strains containing 40-50% mannose, and E. coli with ∼10% mannose. Galactose and glucose were also present in all eight strains, usually as the second and third most abundant carbohydrates. N-acetyl-glucosamine and galacturonic acid were found in 6 of 8 strains, while arabinose, fucose, rhamnose, and xylose were found in 5 of 8 strains. For linkage analysis, 33 distinct residue-linkage combinations were detected with the most abundant being mannose-linked moieties, in line with the composition analysis. The exopolysaccharides of two P. aeruginosa strains analyzed were consistent with the Psl carbohydrate, but not Pel or alginate. The S. epidermidis strain had a composition rich in mannose and glucose, which is consistent with the previously described slime associated antigen (SAA) and the extracellular slime substance (ESS), respectively, but no polysaccharide intracellular adhesion (PIA) was detected. The high molecular weight exopolysaccharides from E. coli, K. pneumoniae, and A. baumannii appear to be novel, based on composition and/or ratio analysis of carbohydrates.

Abstract Accurate species identification is crucial to assess the medical relevance of a mosquito specimen, but requires intensive experience of the observers and well-equipped laboratories. In this proof-of-concept study, we developed a convolutional neural network (CNN) to identify seven Aedes species by wing images, only. While previous studies used images of the whole mosquito body, the nearly two-dimensional wings may facilitate standardized image capture and reduce the complexity of the CNN implementation. Mosquitoes were sampled from different sites in Germany. Their wings were mounted and photographed with a professional stereomicroscope. The data set consisted of 1155 wing images from seven Aedes species as well as 554 wings from different non-Aedes mosquitoes. A CNN was trained to differentiate between Aedes and non-Aedes mosquitoes and to classify the seven Aedes species based on grayscale and RGB images. Image processing, data augmentation, training, validation and testing were conducted in python using deep-learning framework PyTorch. Our best-performing CNN configuration achieved a macro F1 score of 99% to discriminate Aedes from non-Aedes mosquito species. The mean macro F1 score to predict the Aedes species was 90% for grayscale images and 91% for RGB images. In conclusion, wing images are sufficient to identify mosquito species by CNNs.

Introduction Diffuse intrinsic pontine glioma (DIPG) and paediatric high-grade glioma (pHGG) are aggressive glial tumours, for which conventional treatment modalities fall short. Dendritic cell (DC)-based immunotherapy is being investigated as a promising and safe adjuvant therapy. The Wilms’ tumour protein (WT1) is a potent target for this type of antigen-specific immunotherapy and is overexpressed in DIPG and pHGG. Based on this, we designed a non-randomised phase I/II trial, assessing the feasibility and safety of WT1 mRNA-loaded DC (WT1/DC) immunotherapy in combination with conventional treatment in pHGG and DIPG.Methods and analysis 10 paediatric patients with newly diagnosed or pretreated HGG or DIPG were treated according to the trial protocol. The trial protocol consists of leukapheresis of mononuclear cells, the manufacturing of autologous WT1/DC vaccines and the combination of WT1/DC-vaccine immunotherapy with conventional antiglioma treatment. In newly diagnosed patients, this comprises chemoradiation (oral temozolomide 90 mg/m2 daily+radiotherapy 54 Gy in 1.8 Gy fractions) followed by three induction WT1/DC vaccines (8–10×106 cells/vaccine) given on a weekly basis and a chemoimmunotherapy booster phase consisting of six 28-day cycles of oral temozolomide (150–200 mg/m2 on days 1–5) and a WT1/DC vaccine on day 21. In pretreated patients, the induction and booster phase are combined with best possible antiglioma treatment at hand. Primary objectives are to assess the feasibility of the production of mRNA-electroporated WT1/DC vaccines in this patient population and to assess the safety and feasibility of combining conventional antiglioma treatment with the proposed immunotherapy. Secondary objectives are to investigate in vivo immunogenicity of WT1/DC vaccination and to assess disease-specific and general quality of life.Ethics and dissemination The ethics committee of the Antwerp University Hospital and the University of Antwerp granted ethics approval. Results of the clinical trial will be shared through publication in a peer-reviewed journal and presentations at conferences.Trial registration number NCT04911621

Abstract The increasing trend of mosquito-borne pathogens demands more accurate global estimations of infection and transmission risks between mosquitoes. Here, we systematically review field and laboratory studies to assess the natural field infection and experimental laboratory transmission risk in Culex mosquitoes. We studied four worldwide flaviviruses: West Nile, Usutu, Japanese encephalitis, and St. Louis encephalitis, belonging to the Japanese encephalitis Serocomplex (JES). The PRISMA statement was carried out for both approaches. The Transmission-Infection Risk of the diverse mosquito species for the different viruses was estimated through seven variables. We considered 130 and 95 articles for field and experimental approach, respectively. We identified 30 species naturally infected, and 23 species capable to transmit some of the four flaviviruses. For the JES, the highest Transmission-Infection Risk estimate was recorded in Culex quinquefasciatus (North America). The maximum Infection-Transmission Risk values for West Nile was Culex restuans, for Usutu it was Culex pipiens (Europe), for St. Louis encephalitis Culex quinquefasciatus (North America), and for Japanese encephalitis Culex gelidus (Oceania). We conclude that on a worldwide scale, a combination of field and experimental data offers a better way of understanding natural infection and transmission risks between mosquito populations.

Rectal examination through proctoscopy or rigid sigmoidoscopy is a common investigation in clinical practice. It is an important diagnostic tool for the workup and management of anorectal pathologies. Performing the examination can be daunting not only for patients but also for junior doctors. There are associated risks with the procedure, such as pain, diagnostic failure, and perforation of the bowel. Simulation-based training is recognised as an important adjunct in clinical education. It allows students and doctors to practice skills and techniques at their own pace in a risk-free environment. These skills can then be transferred to and developed further in clinical practice. There is extensive research published regarding the role of simulation-based training in endoscopy, however, we identified no published study regarding simulation-based training in rigid sigmoidoscopy or proctoscopy. This study aims to establish the initial face, content, and construct validity of a tool-based visual anorectal examination advanced simulator model for proctoscopy and rigid sigmoidoscopy. This innovative, highly realistic simulated environment aims to enhance the training of healthcare professionals and improve the efficiency of detecting and diagnosing distal colorectal disease.

Comorbidity of pain and depression is a common health problem that seriously affects the physical and psychological health of patients. However, the pathogenesis of these symptoms remains unclear. To comprehensively understand the mechanisms and treatments of pain and depression comorbidity, this review summarizes the establishment of related animal models and behavioral evaluation methods of pain and depression comorbidity at home and abroad.

We discuss the CV safety and efficacy data for subcutaneous testosterone therapy (STT) in postmenopausal women. We also highlight new directions and applications of correct dosages performed in a specialized center. To recommend STT, we propose innovative criteria (IDEALSTT) according to total testosterone (T) level, carotid artery intima-media thickness, and calculated SCORE for a 10-year risk of fatal cardiovascular disease (CVD). Despite all the controversies, hormone replacement therapy (HRT) with T has gained prominence in treating pre and postmenopausal women in the last decades. HRT with silastic and bioabsorbable testosterone hormone implants has gained prominence recently due to its practicality and effectiveness in treating menopausal symptoms and hypoactive sexual desire disorder. A recent publication on the complications of STT, looking at a large cohort of patients over seven years, demonstrated its long-term safety. However, the cardiovascular (CV) risk and safety of STT in women are still controversial.

Drug-related problems (DRPs), i.e., adverse drug reactions (ADRs) and medication errors (MEs), constitute a serious threat to the patient’s safety. DRPs are often insufficiently captured by clinical routine documentation, and thus, they frequently remain unaddressed. The aim of this study was to assess the coverage and usability of the new 11th revision of the WHO International Classification of Diseases (ICD-11) to document DRPs. We refined the ‘Quality and Safety Algorithm’ from the ICD-11 Reference Guide and used it for DRP reporting to code 100 different anonymized DRPs (50 ADRs and 50 MEs) in a German hospital. The ICD-11 three-part model consisting of harm, cause, and mode was used whenever they were applicable. Of 50 ADRs, 15 (30.0%), such as drug-induced osteoporosis, were fully classifiable and codable by the ICD-11, whereas 35 (70.0%), such as drug-induced hypokalaemia, could not be fully classified due to sanctioning rules preventing the postcoordination (i.e., a combination of specific codes, such as drug and diagnosis). However, coding without the loss of information was possible in the 35 of these 35 (100.0%) ADR cases when we were deviating from the cluster code order of the Reference Guide. In all 50 MEs, the mode could be encoded, but for none of the MEs, postcoordination, i.e., the assignment of the ME to a specific drug, was allowed. In conclusion, the ICD-11 three-part model enables us to acquire more detailed documentation of DRPs than the previous ICD versions did. However, the codability, documentation, and reporting of DRPs could be significantly improved by simple modifications of the current ICD-11 sanctioning rules and by the addition of new ICD-11 codes.

In the routine pharmacist’s medication review in ambulatory care and nursing homes in Germany, clinical diagnoses are often insufficiently considered as they are frequently not accessible to pharmacists and their electronic support tools. This may leave a significant proportion of medication-related problems (MRP) undetected and unresolved. Moreover, limited and incomplete data may promote spurious alerts of low clinical relevance. In order to assess the impact of improved data availability, we conducted a study (German Clinical Trials Register DRKS00025346) to evaluate the impact of an extended pharmacist’s medication review, made possible by diagnosis data being routinely available to the pharmacist. At six nursing homes in the Nuremberg metropolitan area, 338 patients treated by 32 physicians were enrolled. A pharmacist’s medication review, considering only the medication data, identified 114 potential MRPs, and additional consideration of diagnoses further identified 69 potential MRPs. The physicians adapted the therapy in response to 69.9% of alerts. The observed gain in MRP identified indicates that efforts should be intensified to facilitate and improve consideration of drug–diagnosis-related MRP by improving data sharing and communication between pharmacists and physicians caring for nursing home residents.

Contraindications (CIs) in Summaries of Product Characteristics (SmPCs)/Prescribing Information (PI) that lack clarity may pose a risk to medication safety and increase the risk for adverse drug reactions. We assessed and compared SmPCs/PI from three major drug markets regarding comprehensibility from the prescriber perspective, as well as usability in clinical decision support systems. 158 drugs met the following inclusion criteria: marketed in Germany (DE), United Kingdom (UK) and United States (US) and belonged to the 100 most recently FDA approved and/or 100 most frequently prescribed drugs in either country. In the 474 (3 × 158) SmPCs/PI all expressions for absolute CIs were identified, divided into 3999 stand-alone terms and evaluated according to ‘clarity’ and ‘codability’. The average number of absolute CIs per drug differed drastically between the three markets (DE: 11.7, UK: 9.0, US: 4.6). Expressions were frequently unclear (DE: 27.2% (95% CI 25.2–29.2%), UK: 28.5% (26.2–30.9%), US: 22.6% (19.7–25.8%)). Moreover, 60.9% (58.6–63.1%), 63.6% (61.0–66.0%), and 64.7% (61.2–68.1%) of the expressions were not codable in DE, UK, and US, respectively. Taken together, in three major drug markets, statements regarding CIs in SmPCs/PI substantially differ in frequency and frequently lack clarity and codability which poses an unnecessary obstacle to medication safety.