Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962

Infections Due to Carbapenem-Resistant Bacteria in Patients With Hematologic Malignancies

In developed countries, hematological malignancies (HM) account for 8 to 10% of cancers diagnosed annually and one-third of patients with HM (HMP) are expected to die from their disease. The former wide spectrum ``magic bullet,'' imipenem, has been ousted by the emergence of carbapenem resistant (CR) pathogens. In endemic areas, infections with CR-bacteria occur in vulnerable patients, notably in HMP, who suffer from high mortality related to infectious complications. In this work, we reviewed epidemiologic and clinical factors associated with CR-infections in adult HMP and data on CR-related mortality and antibiotic treatments in this population. We found that resistance profile of strains involved in HMP infections, mainly bacteremia, reflect local epidemiology. Significant risk factors for infections with CR-bacteria include sex male, age around 50 years old, acute leukemia, selvage chemotherapy, neutropenia, and digestive colonization by CR-bacteria. Mortality rate is high in HMP infected with CR-Enterobacteriaceae, more particularly in case of acute myeloid leukemia and unresolved neutropenia, due to inappropriate empiric management and delayed administration of targeted antibiotics, such as tigecycline, colistin, or new associations of active drugs. Thus, we developed an algorithm for clinicians, assessing the incremental risk for CR-bacterial infection occurrence and mortality in febrile HMP, to guide decisions related to empirical therapeutic strategies

Temperature affects growth allometry and development patterns in brown trout (Salmo trutta) fry: a multitrait approach

To study the influence of temperature (4, 6, and 12 °C) on the development of brown trout (Salmo trutta) from hatching to the end of metamorphosis, an analysis of allometric growth patterns was conducted to identify two different groups of individuals, namely developmental phases at total lengths (TL) ranging from 2.72 cm at 4 °C to 2.22 cm at 12 °C. Then, a multitrait approach considering different variables like the survival rate, development time, morphometric characteristics, energetic value, and skeletal mineralization was conducted on these two groups. Results indicated that the first growth phase was slower at 4 °C, whereas the second was also slower at this temperature, even though swimming behavior was already present. However, at 12 °C, fry showed a delay in their development (i.e., lower levels of skeletal mineralization and energetic content) during the first growth phase, but they compensated during the second growth phase, reaching the same size in TL when compared with the other temperatures (4 and 6 °C); fry at 12 C° showed low energy reserves. Our study demonstrated that the use of an allometric analysis to identify different developmental stages coupled with a multitrait approach was more efficient than a classical distinction between biological stages (hatching, emergence, first food intake, and exogenous feeding), and this procedure is of interest when evaluating the impact of rearing conditions on early development in fish.info:eu-repo/semantics/acceptedVersio

Using Win-Win Strategies to Implement Health in All Policies: A Cross-Case Analysis.

BACKGROUND:In spite of increasing research into intersections of public policy and health, little evidence shows how policy processes impact the implementation of Health in All Policies (HiAP) initiatives. Our research sought to understand how and why strategies for engaging partners from diverse policy sectors in the implementation of HiAP succeed or fail in order to uncover the underlying social mechanisms contributing to sustainable implementation of HiAP. METHODS:In this explanatory multiple case study, we analyzed grey and peer-review literature and key informant interviews to identify mechanisms leading to implementation successes and failures in relation to different strategies for engagement across three case studies (Sweden, Quebec and South Australia), after accounting for the role of different contextual conditions. FINDINGS:Our results yielded no support for the use of awareness-raising or directive strategies as standalone approaches for engaging partners to implement HiAP. However, we found strong evidence that mechanisms related to "win-win" strategies facilitated implementation by increasing perceived acceptability (or buy-in) and feasibility of HiAP implementation across sectors. Win-win strategies were facilitated by mechanisms related to several activities, including: the development of a shared language to facilitate communication between actors from different sectors; integrating health into other policy agendas (eg., sustainability) and use of dual outcomes to appeal to the interests of diverse policy sectors; use of scientific evidence to demonstrate the effectiveness of HiAP; and using health impact assessment to make policy coordination for public health outcomes more feasible and to give credibility to policies being developed by diverse policy sectors. CONCLUSION:Our findings enrich theoretical understanding in an under-unexplored area of intersectoral action. They also provide policy makers with examples of HiAP across wealthy welfare regimes, and improve understanding of successful HiAP implementation practices, including the win-win approach

Energetic properties of rocket propellants evaluated through the computational determination of heats of formation of nitrogen-rich compounds

International audienceThe use of ab initio and DFT methods to calculate the enthalpies of formation of solid ionic compounds is described. The results obtained from the calculations are then compared with those from experimental measurements on nitrogen-rich salts of the 2,2-dimethyltriazanium cation (DMTZ) synthesized in our laboratory and on other nitrogen-rich ionic compounds. The importance of calculating accurate volumes and lattice enthalpies for the determination of heats of formation is also discussed. Furthermore, the crystal structure and hydrogen-bonding networks of the nitroformate salt of the DMTZ cation is described in detail. Lastly, the theoretical heats of formation were used to calculate the specific impulses (I-sp) of the salts of the DMTZ cation in view of a prospective application in propellant formulations

Frequency-following responses in sensorineural hearing loss : a systematic review

Abstract: Purpose This systematic review aims to assess the impact of sensorineural hearing loss (SNHL) on various frequency following response (FFR) parameters. Methods Following PRISMA guidelines, a systematic review was conducted using PubMed, Web of Science, and Scopus databases up to January 2023. Studies evaluating FFRs in patients with SNHL and normal hearing controls were included. Results Sixteen case\u2013control studies were included, revealing variability in acquisition parameters. In the time domain, patients with SNHL exhibited prolonged latencies. The specific waves that were prolonged differed across studies. There was no consensus regarding wave amplitude in the time domain. In the frequency domain, focusing on studies that elicited FFRs with stimuli of 170 ms or longer, participants with SNHL displayed a significantly smaller fundamental frequency (F0). Results regarding changes in the temporal fine structure (TFS) were inconsistent. Conclusion Patients with SNHL may require more time for processing (speech) stimuli, reflected in prolonged latencies. However, the exact timing of this delay remains unclear. Additionally, when presenting longer stimuli ( 65 170 ms), patients with SNHL show difficulties tracking the F0 of (speech) stimuli. No definite conclusions could be drawn on changes in wave amplitude in the time domain and the TFS in the frequency domain. Patient characteristics, acquisition parameters, and FFR outcome parameters differed greatly across studies. Future studies should be performed in larger and carefully matched subject groups, using longer stimuli presented at the same intensity in dB HL for both groups, or at a carefully determined maximum comfortable loudness level

Availability of evidence by jurisdiction for each case on win-win mechanisms and the strength of support for each mechanism area.

<p>Availability of evidence by jurisdiction for each case on win-win mechanisms and the strength of support for each mechanism area.</p