[Uncovering rare diseases in medical data-coding]. / Seltene Erkrankungen in den Daten sichtbar machen ­ Kodierung.

The ICD-10-GM coding system used in the German healthcare system only captures a minority of rare disease diagnoses. Therefore, information on the incidence and prevalence of rare diseases as well as necessary (financial) resources for the expert care required for evidence-based decisions by health insurers, care providers, and politicians are lacking. Furthermore, the missing information complicates and sometimes even precludes the generation of scientific knowledge on rare diseases. Therefore, starting in 2023, all in-patient cases in Germany with a rare disease diagnosis must be coded by an ORPHAcode using the Alpha-ID-SE file.The file Alpha-ID-SE links the ICD-10-GM codes to the internationally established ORPHAcodes for rare diseases. Commercially available software tools progressively support the coding of rare diseases. In several centers for rare diseases linked to university hospitals, IT tools and procedures were established to realize a complete coding of rare diseases. These include financial incentives for the institutions providing rare disease codes, systematic queries asking for rare disease codes during the coding process, and a semi-automated coding process for all patients with a rare disease previously seen at the institution. A combination of the different approaches probably results in the most complete coding.To get the complete picture of rare disease epidemiology and care requirements, a specific and unique coding of out-patient cases is also desirable. Furthermore, a structured reporting of phenotype is required, especially for complex rare diseases and for yet undiagnosed cases.

Azospira inquinata sp. nov., a nitrate-reducing bacterium of the family Rhodocyclaceae isolated from contaminated groundwater.

Two novel Gram-stain-negative bacterial strains, Azo-3T and Azo-2, were isolated from a toluene-producing enrichment culture that originated from contaminated groundwater at a site in southeast Louisiana (USA). Cells are non-spore forming straight to curved rods with single polar flagella. Strains Azo-3T and Azo-2 are oxidase-positive, catalase-negative, use nitrate and nitrite as electron acceptors, and are able to fix nitrogen. Poly-ß-hydroxybutyrate storage granules are produced. Dominant fatty acids when grown in R2A medium at 37 °C are C16:0, summed feature 3 (C16:1 ω7c and/or C15:0 iso 2OH), C17:0 cyclo and C18:1 ω7c. 16S rRNA gene sequence based phylogenetic analysis indicated that the strains cluster within the family Rhodocyclaceae, class Betaproteobacteria, most closely related to but distinct from type strains of the species Azospira oryzae (96.94% similarity) and Azospira restricta (95.10% similarity). Complete genome sequences determined for strains Azo-3T and Azo-2 revealed DNA G+C content of 62.70 mol%. Genome-wide comparisons based on average nucleotide identity by orthology and estimated DNA-DNA hybridization values combined with phenotypic and chemotaxonomic traits and phylogenetic analysis indicate that strains Azo-3T and Azo-2 represent a novel species within the genus Azospira for which the name Azospira inquinata sp. nov. is proposed. The type strain of Azospira inquinata is Azo-3T (=NRRL B-65590T=DSM 112046T).

Nursing's Response to the Executive Order to Advance American Kidney Health.

The state of American kidney health is currently under the microscope. In the United States, approximately 20,000 persons advance to end-stage renal disease annually. Trends indicate accelerating increases in cost of care and a high mortality rate among patients with end-stage renal disease, with only 57% of patients surviving after 3 years. An executive order by the White House has placed the transformation of kidney care at the forefront of the country's health care agenda. The order focuses on key issues including improving outcomes, reducing treatment-related expenditures and increasing kidney donations. Mobilization of health care resources directed toward policymaking, workforce growth and development, and research will be critical to effectively achieve this executive order. Nursing's response, as the health care profession with the most members, will be crucial to achieving response implementation and success of the order. This article describes immediate and future actions including policy, leadership, clinical, educational, and research initiatives that the nursing profession should take to advance kidney health. It calls for specific actions by nursing and focuses on nursing organizations, nursing research, quality improvement initiatives, nursing innovation, advanced practice nursing, and the nephrology and transplant nursing workforce in order to improve kidney health nationally. The impact of the SARS-CoV-2 pandemic on kidney health and the implications for the profession of nursing are outlined. Although there are still many unknowns about the pandemic, nursing's voice is necessary to ensure the ongoing delivery of high-quality care.

Exposures to the environmental contaminants pentachlorophenol and dichlorodiphenyltrichloroethane increase production of the proinflammatory cytokine, interleukin-1ß, in human immune cells.

Pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) are organochlorine environmental contaminants found in human blood at very significant levels (as high as 5 µm for PCP and 260 nm for DDT). Cancers of the blood (lymphoma and myeloma) and kidney as well as others have been associated with exposure to these contaminants. Interleukin (IL)-1ß is a proinflammatory cytokine and is involved in stimulating cell proliferation. High levels of IL-1ß are associated with inflammatory diseases and tumor progression. Previous studies showed that PCP and DDT at certain concentrations were able to stimulate secretion of IL-1ß. This study shows that the increased secretion of IL-1ß seen with both contaminants is due to compound-induced increases in the production of this cytokine. Increased production began within 6 hours of exposure to PCP and continued to increase up to 24 hours. DDT-induced stimulation of IL-1ß appeared to be maximal after 6 hours of exposure and then diminished by 24 hours. The increases seen in IL-1ß production stimulated by PCP appear to be at least partially due to compound-induced increases in IL-1ß mRNA. Although DDT caused increased production of IL-1ß, it did not appear to cause consistent increases in its mRNA. PCP- and DDT-induced increases in IL-1ß production were dependent primarily on the p38 mitogen-activated protein kinase pathway. These results indicate that both PCP and DDT are able to increase IL-1ß production in a p38 mitogen-activated protein kinase-dependent manner, which may have the potential to influence chronic inflammation.

Acute lung injury by gastric fluid instillation: activation of myofibroblast apoptosis during injury resolution.

BACKGROUND: Gastric contents aspiration in humans has variable consequences depending on the volume of aspirate, ranging from subclinical pneumonitis to respiratory failure with up to 70% mortality. Several experimental approaches have been used to study this condition. In a model of single orotracheal instillation of gastric fluid we have shown that severe acute lung injury evolves from a pattern of diffuse alveolar damage to one of organizing pneumonia (OP), that later resolves leaving normal lung architecture. Little is known about mechanisms of injury resolution after a single aspiration that could be dysregulated with repetitive aspirations. We hypothesized that, in a similar way to cutaneous wound healing, apoptosis may participate in lung injury resolution by reducing the number of myofibroblasts and by affecting the balance between proteases and antiproteases. Our aim was to study activation of apoptosis as well as MMP-2/TIMP-2 balance in the sub-acute phase (4-14 days) of gastric fluid-induced lung injury. METHODS: Anesthesized Sprague-Dawley rats received a single orotracheal instillation of gastric fluid and were euthanized 4, 7 and 14 days later (n = 6/group). In lung tissue we studied caspase-3 activation and its location by double immunofluorescence for cleaved caspase-3 or TUNEL and alpha-SMA. MMP-2/TIMP-2 balance was studied by zymography and Western blot. BALF levels of TGF-ß1 were measured by ELISA. RESULTS: An OP pattern with Masson bodies and granulomas was seen at days 4 and 7 that was no longer present at day 14. Cleaved caspase-3 increased at day 7 and was detected by immunofluorescence in Masson body-alpha-SMA-positive and -negative cells. TUNEL-positive cells at days 4 and 7 were located mainly in Masson bodies. Distribution of cleaved caspase-3 and TUNEL-positive cells at day 14 was similar to that in controls. At the peak of apoptosis (day 7), an imbalance between MMP-2 activity and TIMP-2 expression was produced by reduction in TIMP-2 expression. CONCLUSIONS: Apoptosis is activated in Masson body-alpha-SMA-positive and -negative cells during the sub-acute phase of gastric fluid-induced lung injury. This mechanism likely contributes to OP resolution, by reducing myofibroblast number and new collagen production. In addition, pre-formed collagen degradation is favored by an associated MMP-2/TIMP-2 imbalance.

Exposures to the environmental toxicants pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) modify secretion of interleukin 1-beta (IL-1ß) from human immune cells.

Pentachlorophenol (PCP) and Dichlorodiphenyltrichloroethane (DDT) are environmental contaminants found in human blood. Previous studies have shown that PCP and DDT inhibit the lytic function of highly purified human natural killer (NK) lymphocytes and decrease the expression of several surface proteins on NK cells. Interleukin-1 ßeta (IL-1ß) is a cytokine produced by lymphocytes and monocytes, and anything that elevates its levels inappropriately can lead to chronic inflammation, which among other consequences can increase tumor development and invasiveness. Here, PCP and DDT were examined for their ability to alter secretion of IL-1ß from immune cell preparations of various complexity: NK cells; monocyte-depleted (MD) peripheral blood mononuclear cells (PBMCS); and PBMCs. Cells were exposed to concentrations of PCP ranging from 5 to 0.05 µM and DDT concentrations of 2.5-0.025 µM for 24, 48 h, and 6 days. Results showed that both PCP and DDT increased IL-1ß secretion from all of the immune cell preparations. The specific concentrations of PCP and DDT that increased IL-1ß secretion varied by donor. Immune cells from all donors showed compound-induced increases in IL-1ß secretion at one or more concentration at one or more length of exposure. The mechanism of PCP stimulation of IL1-ß secretion was also addressed, and it appears that the MAPKs, ERK1/2 and p38, may be utilized by PCP to stimulate secretion of IL-1ß.

Supplemental Breast Cancer Screening With Molecular Breast Imaging for Women With Dense Breast Tissue.

OBJECTIVE: Molecular breast imaging was implemented in routine clinical practice at a large community-based breast imaging center. The aim of this study was to retrospectively assess the clinical performance of molecular breast imaging as a supplementary screening tool for women with dense breast tissue. MATERIALS AND METHODS: Women with dense breasts and negative mammography results who subsequently underwent screening with 300 MBq (8 mCi) (99m)Tc-sestamibi molecular breast imaging were retrospectively analyzed. Outcome measures included cancer detection rate, recall rate, biopsy rate, and positive predictive values (PPVs). RESULTS: Molecular breast imaging screening of 1696 women in this study resulted in the detection of 13 mammographically occult malignancies, of which 11 were invasive, one was node positive, and one had unknown node positivity. The lesion size ranged from 0.6 to 2.4 cm, with a mean of 1.1 cm. The incremental cancer detection rate was 7.7‰ (95% CI, 4.5-13.1‰), the recall rate was 8.4% (95% CI, 7.2-9.8%), and the biopsy rate was 3.7% (95% CI, 2.9%-4.7%). The PPV for recall (PPV 1) was 9.1% (95% CI, 5.4-15.0%), and the PPV for biopsy (PPV 3) was 19.4% (95% CI, 11.4-30.9%). CONCLUSION: When incorporated into a community-based clinical practice environment, molecular breast imaging yielded a high incremental cancer detection rate of 7.7‰ at an acceptable radiation dose. These results show the utility of molecular breast imaging as a supplementary screening tool to mammography for women with dense breasts.

Small heat shock protein 20 (Hsp20) facilitates nuclear import of protein kinase D 1 (PKD1) during cardiac hypertrophy.

BACKGROUND: Nuclear import of protein kinase D1 (PKD1) is an important event in the transcriptional regulation of cardiac gene reprogramming leading to the hypertrophic growth response, however, little is known about the molecular events that govern this event. We have identified a novel complex between PKD1 and a heat shock protein (Hsp), Hsp20, which has been implicated as cardioprotective. This study aims to characterize the role of the complex in PKD1-mediated myocardial regulatory mechanisms that depend on PKD1 nuclear translocation. RESULTS: In mapping the Hsp20 binding sites on PKD1 within its catalytic unit using peptide array analysis, we were able to develop a cell-permeable peptide that disrupts the Hsp20-PKD1 complex. We use this peptide to show that formation of the Hsp20-PKD1 complex is essential for PKD1 nuclear translocation, signaling mechanisms leading to hypertrophy, activation of the fetal gene programme and pathological cardiac remodeling leading to cardiac fibrosis. CONCLUSIONS: These results identify a new signaling complex that is pivotal to pathological remodelling of the heart that could be targeted therapeutically.

Adult cardiac fibroblast proliferation is modulated by calcium/calmodulin-dependent protein kinase II in normal and hypertrophied hearts.

Increased adult cardiac fibroblast proliferation results in an increased collagen deposition responsible for the fibrosis accompanying pathological remodelling of the heart. The mechanisms regulating cardiac fibroblast proliferation remain poorly understood. Using a minimally invasive transverse aortic banding (MTAB) mouse model of cardiac hypertrophy, we have assessed fibrosis and cardiac fibroblast proliferation. We have investigated whether calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) regulates proliferation in fibroblasts isolated from normal and hypertrophied hearts. It is known that CaMKIIδ plays a central role in cardiac myocyte contractility, but nothing is known of its role in adult cardiac fibroblast function. The MTAB model used here produces extensive hypertrophy and fibrosis. CaMKIIδ protein expression and activity is upregulated in MTAB hearts and, specifically, in cardiac fibroblasts isolated from hypertrophied hearts. In response to angiotensin II, cardiac fibroblasts isolated from MTAB hearts show increased proliferation rates. Inhibition of CaMKII with autocamtide inhibitory peptide inhibits proliferation in cells isolated from both sham and MTAB hearts, with a significantly greater effect evident in MTAB cells. These results are the first to show selective upregulation of CaMKIIδ in adult cardiac fibroblasts following cardiac hypertrophy and to assign a previously unrecognised role to CaMKII in regulating adult cardiac fibroblast function in normal and diseased hearts.

The cardioprotective role of small heat-shock protein 20.

The small HSP (heat-shock protein) HSP20 is a molecular chaperone that is transiently up-regulated in response to cellular stress/damage. Although ubiquitously expressed in various tissues, it is most highly expressed in skeletal, cardiac and smooth muscle. Phosphorylation at Ser16 by PKA (cAMP-dependent protein kinase) is essential for HSP20 to confer its protective qualities. HSP20 and its phosphorylation have been implicated in a variety of pathophysiological processes, but most prominently cardiovascular disease. A wealth of knowledge of the importance of HSP20 in contractile function and cardioprotection has been gained over the last decade. The present mini-review highlights more recent findings illustrating the cardioprotective properties of HSP20 and its potential as a therapeutic agent.

Enhanced Donor Antigen Presentation by B Cells Predicts Acute Cellular Rejection and Late Outcomes After Transplantation.

Background: Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients. Methods: To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05-23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors. Results: We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ±â€…0.2 versus 0.6 ±â€…0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients (P = 0.011) and graft loss in IT recipients (P = 0.008), compared with recipients with API <1.1, respectively. Conclusions: Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation.

A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Effects of DDT and triclosan on tumor-cell binding capacity and cell-surface protein expression of human natural killer cells.

1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) and triclosan (TCS) are organochlorine (OC) compounds that contaminate the environment, are found in human blood and have been shown to decrease the tumor-cell killing (lytic) function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. They bind to these targets, utilizing a variety of cell surface proteins. The present study examined concentrations of DDT and TCS that decrease lytic function for alteration of NK binding to tumor targets. Levels of either compound that caused loss of binding function were then examined for effects on expression of cell-surface proteins needed for binding. NK cells exposed to 2.5 µM DDT for 24 h (which caused a greater than 55% loss of lytic function) showed a decrease in NK binding function of about 22%, and a decrease in CD16 cell-surface protein of 20%. NK cells exposed to 5 µM TCS for 24 h showed a decrease in ability to bind tumor cells of 37% and a decrease in expression of CD56 of about 34%. This same treatment caused a decrease in lytic function of greater than 87%. These results indicated that only a portion of the loss of NK lytic function seen with exposures to these compounds could be accounted for by loss of binding function. They also showed that loss of binding function is accompanied by a loss of cell-surface proteins important in binding function.

Rare Diseases in Hospital Information Systems-An Interoperable Methodology for Distributed Data Quality Assessments.

BACKGROUND: Multisite research networks such as the project "Collaboration on Rare Diseases" connect various hospitals to obtain sufficient data for clinical research. However, data quality (DQ) remains a challenge for the secondary use of data recorded in different health information systems. High levels of DQ as well as appropriate quality assessment methods are needed to support the reuse of such distributed data. OBJECTIVES: The aim of this work is the development of an interoperable methodology for assessing the quality of data recorded in heterogeneous sources to improve the quality of rare disease (RD) documentation and support clinical research. METHODS: We first developed a conceptual framework for DQ assessment. Using this theoretical guidance, we implemented a software framework that provides appropriate tools for calculating DQ metrics and for generating local as well as cross-institutional reports. We further applied our methodology on synthetic data distributed across multiple hospitals using Personal Health Train. Finally, we used precision and recall as metrics to validate our implementation. RESULTS: Four DQ dimensions were defined and represented as disjunct ontological categories. Based on these top dimensions, 9 DQ concepts, 10 DQ indicators, and 25 DQ parameters were developed and applied to different data sets. Randomly introduced DQ issues were all identified and reported automatically. The generated reports show the resulting DQ indicators and detected DQ issues. CONCLUSION: We have shown that our approach yields promising results, which can be used for local and cross-institutional DQ assessments. The developed frameworks provide useful methods for interoperable and privacy-preserving assessments of DQ that meet the specified requirements. This study has demonstrated that our methodology is capable of detecting DQ issues such as ambiguity or implausibility of coded diagnoses. It can be used for DQ benchmarking to improve the quality of RD documentation and to support clinical research on distributed data.

Local Data Quality Assessments on EHR-Based Real-World Data for Rare Diseases.

The project "Collaboration on Rare Diseases" CORD-MI connects various university hospitals in Germany to collect sufficient harmonized electronic health record (EHR) data for supporting clinical research in the field of rare diseases (RDs). However, the integration and transformation of heterogeneous data into an interoperable standard through Extract-Transform-Load (ETL) processes is a complex task that may influence the data quality (DQ). Local DQ assessments and control processes are needed to ensure and improve the quality of RD data. We therefore aim to investigate the impact of ETL processes on the quality of transformed RD data. Seven DQ indicators for three independent DQ dimensions were evaluated. The resulting reports show the correctness of calculated DQ metrics and detected DQ issues. Our study provides the first comparison results between the DQ of RD data before and after ETL processes. We found that ETL processes are challenging tasks that influence the quality of RD data. We have demonstrated that our methodology is useful and capable of evaluating the quality of real-world data stored in different formats and structures. Our methodology can therefore be used to improve the quality of RD documentation and to support clinical research.

Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction.

AIMS: Myocardial infarction (MI) is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following MI, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility. Expression of the transcription factor RUNX1 is increased in the border zone 1-day after MI, suggesting potential for targeted therapeutic intervention. OBJECTIVE: This study sought to investigate whether an increase in RUNX1 in the border zone can be therapeutically targeted to preserve contractility following MI. METHODS AND RESULTS: In this work we demonstrate that Runx1 drives reductions in cardiomyocyte contractility, calcium handling, mitochondrial density, and expression of genes important for oxidative phosphorylation. Both tamoxifen-inducible Runx1-deficient and essential co-factor common ß subunit (Cbfß)-deficient cardiomyocyte-specific mouse models demonstrated that antagonizing RUNX1 function preserves the expression of genes important for oxidative phosphorylation following MI. Antagonizing RUNX1 expression via short-hairpin RNA interference preserved contractile function following MI. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with CBFß. CONCLUSIONS: Our results confirm the translational potential of RUNX1 as a novel therapeutic target in MI, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.

Surgical optimization and characterization of a minimally invasive aortic banding procedure to induce cardiac hypertrophy in mice.

Left ventricular pressure overload in response to aortic banding is an invaluable model for studying progression of cardiac hypertrophy and transition to heart failure. Traditional aortic banding has recently been superceded by minimally invasive transverse aortic banding (MTAB), which does not require ventilation so is less technically challenging. Although the MTAB approach is superior, few laboratories have documented success, and minimal information on the model is available. The aim of this study was to optimize conditions for MTAB and to characterize the development and progression of cardiac hypertrophy. Isofluorane proved the most suitable anaesthetic for MTAB surgery in mice, and 1 week after surgery the MTAB animals showed significant increases in systolic blood pressure (MTAB 110 ± 6 mmHg versus sham 78 ± 3 mmHg, n = 7, P < 0.0001) and heart weight to body weight ratio (MTAB 6.2 ± 0.2 versus sham 5.1 ± 0.1, n = 12, P < 0.001), together with systolic (e.g. fractional shortening, MTAB 31.7 ± 1% versus sham 36.6 ± 1.4%, P = 0.01) and diastolic dysfunction (e.g. left ventricular end-diastolic pressure, MTAB 12.7 ± 1.0 mmHg versus sham 6.7 ± 0.8 mmHg, P < 0.001). Leucocyte infiltration to the heart was evident after 1 week in MTAB hearts, signifying an inflammatory response. More pronounced remodelling was observed 4 weeks postsurgery (heart weight to body weight ratio, MTAB 9.1 ± 0.6 versus sham 4.6 ± 0.04, n = 10, P < 0.0001) and fractional shortening was further decreased (MTAB 24.3 ± 2.5% versus sham 43.6 ± 1.7%, n = 10, P = 0.003), together with a significant increase in cardiac fibrosis and further cardiac inflammation. Our findings demonstrate that MTAB is a relevant experimental model for studying development and progression of cardiac hypertrophy, which will be highly valuable for future studies examining potential novel therapeutic interventions in this setting.

Secondary task engagement, risk-taking, and safety-related equipment use in German bicycle and e-scooter riders - An observation.

The behavioral safety of e-bike and e-scooter riders is a significant concern in traffic safety. In an observational study in Braunschweig, Germany, 4,514 bicycle and e-scooter riders were observed concerning their used vehicles type, secondary task engagement, use of additional safety equipment, and traffic rule violation. Overall, 13.4% of all riders were engaged in any secondary task, wearing headphones or earphones being the most frequent behavior (6.7%), followed by conversations with other cyclists (3.7%). Banned mobile phone use was low (0.8%). Secondary task engagement was positively correlated with traffic rule violations and at-fault conflicts and negatively with the use of additional safety equipment. Cluster analysis on vehicle types and behaviors revealed five groups of riders, two with relatively high numbers of risky behaviors: young and middle-aged, predominantly male riders of conventional bicycles, and a group of demographically similar users of electric bikes and e-scooters. Campaigns targeted at these specific groups may help reduce risky behaviors.

Preclinical models of myocardial infarction: from mechanism to translation.

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models. Despite this, preclinical models are limited in their ability to fully reproduce the complexity of MI in humans. The preclinical model must be carefully selected to maximise the translational potential of experimental findings. This review describes current experimental models of MI and considers how they have been used to understand drug mechanisms of action and support translational medicine development. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size.

AIMS: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. METHODS AND RESULTS: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. CONCLUSION: Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.