Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.

BACKGROUND: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. CONCLUSIONS: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

The Netherlands Heart Tissue Bank : Strengthening the cardiovascular research infrastructure with an open access Cardiac Tissue Repository.

AIM: Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank. METHODS: The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged ≥ 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers. CONCLUSION: To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies.

[Development of a cooperative autopsy network of pathology, neuropathology and forensic medicine]. / Entwicklung eines kooperativen Obduktionsnetzwerks aus Pathologie, Neuropathologie und Rechtsmedizin.

BACKGROUND: Autopsies are an important tool for understanding novel diseases, including COVID-19. MATERIALS AND METHODS: The German Registry of COVID-19 Autopsies (DeRegCOVID) was established and launched in April 2020. DeRegCOVID acts as the electronic backbone of the German Network for Autopsies in Pandemics (DEFEAT PANDEMIcs), which started in September 2020. RESULTS: The results of DeRegCOVID and DEFEAT PANDEMIcs are characterized by an unprecedented collaboration of more than 35 university and non-university autopsy centers linking pathological, neuropathological, and forensic medicine institutes. DeRegCOVID has evolved, adapted to new challenges, and currently contains the largest international autopsy dataset. After only a short period of operation, more than 80 publications have been produced, which have contributed to the understanding of the pathogenesis of COVID-19, e.g., through the discovery of thromboembolic events, multiorgan tropism, and NeuroCovid-19. The autopsy centers have carried out extensive educational work and, beyond the scientific gain in knowledge, have explained to politicians and the general public the essential role of autopsies in pandemic management. To further develop autopsy-driven research, a continuation of DEFEAT PANDEMIcs was conceived, the National Autopsy Network (NATON). CONCLUSIONS: The registry and network, in which all interested centers can participate, have demonstrated the value of networked medical research and the high value of autopsy for medicine.

A Biobank of Stem Cells of Human Exfoliated Deciduous Teeth: Overview of Applications and Developments in Brazil.

A biobank is an organized collection of biological human material and its associated information stored for research according to regulations under institutional responsibility, without commercial purposes, being a mandatory and strategical activity for research, regenerative medicine, and innovation. Stem cells have largely been employed in research and frequently stored in biobanks, which have been used as an essential source of biological materials. Stem cells of human exfoliated deciduous teeth (SHED) are stem cells which have a high multipotency and can be easily obtained. Besides, this extremely accessible tissue has advantages with respect to storage, as the SHED obtained in childhood can be used in later life, which implies the necessity for the creation and regulation of biobanks. The proper planning for the creation of a biobank includes knowledge of the material types to be stored, requirements regarding handling and storage conditions, storage time, and room for the number of samples. Thus, this study aimed to establish an overview of the development of a SHED biobank. Ethical and legal standardization, current applications, specific orientations, and challenges for the implementation of a SHED biobank were discussed. Through this overview, we hope to encourage further studies to use SHED biobanks.

A Federated Online Search Tool for Biospecimens (Sample Locator): Usability Study.

BACKGROUND: The German Biobank Alliance (GBA) aims to establish a cross-site biobank network. For this endeavor, the so-called Sample Locator, a federated search tool for biospecimens and related data, has been developed, forming the heart of its information technology (IT) infrastructure. OBJECTIVE: To ensure the sustainable use of such a tool, we included researchers as participants in an end user-based usability evaluation. METHODS: To develop a prototype ready for evaluation, we needed input from GBA IT experts. Thus, we conducted a 2-day workshop with 8 GBA IT team members. The focus was on the respective steps of a user-centered design process. With the acquired knowledge, the participants designed low-fidelity mock-ups. The main ideas of these mock-ups were discussed, extracted, and summarized into a comprehensive prototype using Microsoft PowerPoint. Furthermore, we created a questionnaire concerning the usability of the prototype, including the System Usability Scale (SUS), questions on negative and positive aspects, and typical tasks to be fulfilled with the tool. Subsequently, the prototype was pretested on the basis of this questionnaire with researchers who have a biobank background. Based on this preliminary work, the usability analysis was ultimately carried out with researchers and the results were evaluated. RESULTS: Altogether, 27 researchers familiar with sample requests evaluated the prototype. The analysis of the feedback certified a good usability, given that the Sample Locator prototype was seen as intuitive and user-friendly by 74% (20/27) of the participants. The total SUS score by the 25 persons that completed the questionnaire was 80.4, indicating good system usability. Still, the evaluation provided useful advice on optimization potential (eg, offering a help function). CONCLUSIONS: The findings of this usability analysis indicate that the considerations regarding a user-friendly application that have been made in the development process so far strongly coincide with the perception of the study participants. Nevertheless, it was important to engage prospective end users to ensure that the previous development is going in the desired direction and that the Sample Locator will be used in the future. The user comments and suggestions for improvement will be considered in upcoming iterations for refinement.

Lessons from HeLa Cells: The Ethics and Policy of Biospecimens.

Human biospecimens have played a crucial role in scientific and medical advances. Although the ethical and policy issues associated with biospecimen research have long been the subject of scholarly debate, the story of Henrietta Lacks, her family, and the creation of HeLa cells captured the attention of a much broader audience. The story has been a catalyst for policy change, including major regulatory changes proposed in the United States surrounding informed consent. These proposals are premised in part on public opinion data, necessitating a closer look at what such data tell us. The development of biospecimen policy should be informed by many considerations-one of which is public input, robustly gathered, on acceptable approaches that optimize shared interests, including access for all to the benefits of research. There is a need for consent approaches that are guided by realistic aspirations and a balanced view of autonomy within an expanded ethical framework.

"As Long as You Ask": A Qualitative Study of Biobanking Consent-Oncology Patients' and Health Care Professionals' Attitudes, Motivations, and Experiences-the B-PPAE Study.

INTRODUCTION: Consent to biobanking remains controversial, with little empirical data to guide policy and practice. This study aimed to explore the attitudes, motivations, and concerns of both oncology patients and health care professionals (HCPs) regarding biobanking. MATERIALS AND METHODS: Qualitative interviews were conducted with oncology patients and HCPs purposively selected from five Australian hospitals. Patients were invited to give biobanking consent as part of a clinical trial and/or for future research were eligible. HCPs were eligible if involved in consenting patients to biobanking or to donate specimens to clinical trials. RESULTS: Twenty-two patients participated, with head and neck (36%) and prostate (18%) the most common cancer diagnoses; all had consented to biobanking. Twenty-two HCPs participated, from across eight cancer streams and five disciplines. Themes identified were (a) biobanking is a "no brainer"; (b) altruism or scientific enquiry; (c) trust in clinicians, science, and institutions; (d) no consent-just do it; (e) respecting patient choice ("opt-out"); (f) respectful timing of the request; (g) need for emotional/family support; (h) context of the biobanking request matters; and (i) factors for biobanking success. DISCUSSION: These findings reinforced previous findings regarding high public trust in, and support for, biobanking. An initial opt-in consent approach with the option of later opt-out was favored by patients to respect and recognize donor generosity, whereas HCPs preferred an upfront opt-out model. Factors impacting biobanking success included the context of the request for use in a trial or specific research question, pre-existing patient and HCP rapport, a local institution champion, and infrastructure. IMPLICATIONS FOR PRACTICE: Patients and health care professionals (HCPs) who experienced cancer biobanking consent were overwhelmingly supportive of biobanking. The motivations and approaches to seeking consent were largely mirrored between the groups. The findings of this study support the opt-in model of biobanking favored by patients; however, HCPs preferred an opt-out model. Both groups recognize the importance of making the request for biobanking at an appropriate time, preferably with emotional or family support, and respecting the timing of the request and privacy of the patient. Biobanking success can be promoted by hospital departments with a research focus by identifying an institutional biobanking champion and ensuring local infrastructure is available.

Faecal microbiota transplantation for treatment of recurrent or refractory Clostridioides difficile infection in Hong Kong.

INTRODUCTION: Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated infection globally, causing significant morbidity and mortality. Faecal microbiota transplantation (FMT) has emerged as a promising option for recurrent and refractory CDI. This study aimed to assess the safety, efficacy, and feasibility of FMT for CDI in Hong Kong. METHODS: We conducted a single-centre, retrospective study for all consecutive cases of recurrent or refractory CDI who underwent FMT from 2013 to 2018. Clinical demographics, outcome, and safety parameters were collected. RESULTS: A total of 24 patients with recurrent or refractory CDI (median age 70 years, interquartile range=45.0-78.3 years; 67% male) were included. Over 80% had been recently hospitalised or were long-term care facility residents. Faecal microbiota transplantation was delivered by feeding tube in 11 (45.8%), oesophagogastroduodenoscopy in eight (33.3%), and colonoscopy in six (25%) of the patients. Resolution of diarrhoea without relapse within 8 weeks was achieved in 21 out of 24 patients (87.5%) after FMT. No deaths occurred within 30 days. The FMT was well tolerated and no serious adverse events attributable to FMT were reported. CONCLUSION: Our results confirm that FMT is a safe, efficacious, and feasible intervention for patients with refractory or recurrent CDI in Hong Kong. Given the increasing disease burden and the lack of effective alternatives in Hong Kong for difficult-to-treat cases of CDI, we recommend that a territory-wide FMT service be established to address increasing demand for this treatment.

[Requirements for a cross-location biobank IT infrastructure : Survey of stakeholder input on the establishment of a biobank network of the German Biobank Alliance (GBA)]. / Anforderungen an eine standortübergreifende Biobanken-IT-Infrastruktur : Erhebung des Stakeholderinputs zum Aufbau eines Biobankennetzwerks der German Biobank Alliance (GBA).

BACKGROUND: The large number of biobanks within Germany results in a high degree of heterogeneity with regard to the IT components used at the respective locations. Within the German Biobank Alliance (GBA), 13 biobanks implement harmonized processes for the provision of biomaterial and accompanying data. OBJECTIVES: The networking of the individual biobanks and the associated harmonisation of the IT infrastructure should facilitate access to biomaterial and related clinical data. METHODS: For this purpose, the relevant target groups were first identified in order to determine their requirements for IT solutions to be developed in a workshop. RESULTS: Of the seven identified interest groups, three were initially invited to a first round of discussions. The stakeholder input expressed resulted in a catalogue of requirements with regard to IT support for (i) a sample and data request, (ii) the handling of patient consent and inclusion, and (iii) the subsequent evaluation of the sample and data request. CONCLUSIONS: The next step is to design the IT solutions as prototypes based on these requirements. In parallel, further user groups are being surveyed in order to be able to further concretise the specifications for development.

[Merging different biobanks under one roof : Benefits and constraints on the way to a centralized biobank using the example of the BMBH]. / Alle unter einem Dach : Erfolge und Herausforderungen auf dem Weg zu einer zentralisierten Biobank am Beispiel der BMBH.

Founded in 1386, Heidelberg University is Germany's oldest and one of Europe's most reputable universities. As a scientific hub in Germany, Heidelberg is home to several internationally renowned medical research facilities that have an enormous demand for biomaterial samples and data-especially in the field of translational and cancer research.The main objective of the BMBF-funded project "BioMaterialBank Heidelberg" (BMBH) was the harmonization of local biobanking under the same administrative roof through the implementation of common and standardized project, data, and quality management procedures.In the very beginning, existing structures and processes of the participating biobanks in Heidelberg were identified and a common administrative structure with central representatives for IT and quality management (QM) was established to coordinate all BMBH activities.Over time, implementation of consented structures and processes took place, also revealing organizational challenges that had to be solved concerning, for example, differences in sample handling and the definition of consistent access regulations.We will discuss below these challenges as well as the opportunities of building a centralized biobank and show how issues can be resolved using the example of the BMBH.

[Biobanking requirements from the perspective of the clinician : Experiences in hematology and oncology]. / Biobankinganforderungen aus Sicht des Klinikers : Erfahrungen aus der Hämatologie und Onkologie.

The requirements for optimal biobanking from the point of view of the clinical partner can be highly variable. Depending on the material, processing, storage conditions, clinical data, and involvement of external partners, there will be special requirements for the participating clinician and specialist areas. What they all have in common is that the goal of any biobanking must be to improve clinical, translational, and basic research. While in the past biomaterials often had to be individually stored for each research project, modern biobanking offers decisive advantages: a comprehensive ethics vote fulfilling state-of-the-art data safety requirements, standardized processing and storage protocols, specialized biobank software for pseudonymization and localization, protection against power failures and defects of the equipment, centralized and sustainable storage, easy localization and return of samples, and their destruction or anonymization after completion of an individual project. In addition to this important pure storage function, central biobanking can provide a link to clinical data as well as the anonymous use of samples for project-independent research. Both biobank functions serve different purposes, are associated with specific requirements, and should be pursued in parallel. If successful, central biomaterial management can achieve a sustainable improvement of academic and non-academic biomedical research and the optimal use of resources. The close collaboration between clinicians and non-clinicians is a crucial prerequisite for this.

[Biobanking and the further development of precision medicine]. / Biobanking und die Weiterentwicklung der Präzisionsmedizin.

BACKGROUND: Over the last 15 years, an estimated 3000 large centralized biobanks have been established worldwide, making important contributions to the further development of precision medicine. In many cases, these biobanks are affiliated with pathological institutes or work closely with them. OBJECTIVE: In which translational research projects, and during which phases in the development of new drugs are human bioprobes being used and can their use be easily traced in the literature? METHODS: PubMed, Internet research, and information from the German Biobank Alliance and the European initiative BBMRI-ERIC. RESULTS: High-quality biosamples from centralized biobanks are increasingly used in clinical research and development projects. Success stories, where bioprobes have contributed to the further development of precision medicine, are shown in this paper using among others the example of RET gene fusion discovery in lung cancer. Interestingly enough, many key publications in the field of precision medicine do not contain exact references to the biobanks involved. CONCLUSIONS: The importance of centralized biobanks in translational research and clinical development is constantly increasing. However, in order to ensure the acceptance and visibility of biobanks, their participation in success stories of biomedical progress must be systematically documented and published.

A qualitative study of adolescents' understanding of biobanks and their attitudes toward participation, re-contact, and data sharing.

While biobanks have become more prevalent, little is known about adolescents' views of key governance issues. We conducted semi-structured interviews with adolescents between 15 and 17 years old to solicit their views. All interviews were audiotaped and transcribed. Two investigators coded the transcripts and resolved any discrepancies through consensus. We conducted 18 interviews before reaching data saturation. Four participants (22%) had previously heard of a biobank. Many participants had misunderstandings about biobanks, some of which persisted after education. Participants believed that enrolling in a biobank would benefit others through scientific research. Many study participants were unable to identify risks of biobank participation. Thirteen participants (72%) were willing to enroll in a biobank and only one (6%) initially was not. Participants believed that if they were unable to provide assent when enrolled, then they should be re-contacted at the age of majority and their data should not be shared until that time. Participants emphasized the importance of being aware of their enrollment and the possibility of disagreeing with their parents. Participants' misunderstanding of biobanks suggests that assent may not be adequately informed without additional education. While adolescents had positive attitudes toward biobanks, they emphasized the importance of awareness of and involvement in the decision to enroll.

Women Epidemiology Lung Cancer (WELCA) study: reproductive, hormonal, occupational risk factors and biobank.

BACKGROUND: Lung cancer aetiology and clinical aspects have been mainly studied in men, although specific risk factors probably exist in women. Here we present the rationale, design and organization of the WELCA study (Women Epidemiology Lung CAncer) that has been launched to investigate lung cancer in women, focusing particularly on hormonal and occupational factors. METHODS/DESIGN: WELCA is a population based case-control study and planned to recruit 1000 cases and 1000 controls in three years, based on study power calculation. Eligible cases are female patients newly diagnosed with lung cancer, living in Paris and the Ile de France area and aged up to 75 years. Almost all Parisian pneumology and oncology clinical departments are involved. The control group is a random sample of the population living in the same area, frequency-matched on age and additionally stratified on the distribution of socio-professional categories of women residing there. After acquisition of written consent, research nurses administer standardized computer assisted questionnaires to all the subjects in face-to-face interviews and acquire anthropometric measures. Besides usual socio-demographic characteristics, information is gathered about menstrual and reproductive factors, hormonal treatments, lifestyle and leisure characteristics, occupational history, personal and familial medical history. Biological samples are also collected, in order to establish a biobank for molecular epidemiology studies. Molecular characteristics of the tumours will be obtained and patients will be followed up for five years. DISCUSSION: The WELCA study aims to answer key questions in lung cancer aetiology and clinical characteristics specifically in women. The role of hormonal impregnation is investigated, and the interactions with cigarette smoking or body mass index (BMI) will be analyzed in detail. The occupational history of the subjects is carefully reconstructed, focusing in particular on the service sector. The creation of a biobank for collection of serum, plasma, DNA and tumour tissue will allow the genetic and biochemical characterization of both the subjets and the tumours. The follow-up of the patients will help in disentangling the role of hormonal factors and tumour molecular characteristics in survival.

RePORT International: Advancing Tuberculosis Biomarker Research Through Global Collaboration.

Progress in tuberculosis clinical research is hampered by a lack of reliable biomarkers that predict progression from latent to active tuberculosis, and subsequent cure, relapse, or failure. Regional Prospective Observational Research in Tuberculosis (RePORT) International represents a consortium of regional cohorts (RePORT India, RePORT Brazil, and RePORT Indonesia) that are linked through the implementation of a Common Protocol for data and specimen collection, and are poised to address this critical research need. Each RePORT network is designed to support local, in-country tuberculosis-specific data and specimen biorepositories, and associated research. Taken together, the expected results include greater global clinical research capacity in high-burden settings, and increased local access to quality data and specimens for members of each network and their domestic and international collaborators. Additional networks are expected to be added, helping to spur tuberculosis treatment and prevention research around the world.

Kinetics of the use of cryopreserved autologous stem cell grafts: a GITMO-SIDEM survey.

BACKGROUND AIMS: Hematopoietic stem cell cryopreservation significantly contributed to autologous stem cell transplantation (ASCT). Cryopreserved stem cell units (SCU) are expected to be used soon after harvesting for most purposes, but, in a number of cases, they remain stored for some time, creating an increasing load for SCU depositories. Disposal policies vary widely in each center, and the existing guidelines are insufficient. METHODS: We conducted a survey of seven Gruppo Italiano Trapianto di Midollo Osseo centers to investigate the outcome of SCU harvested from January 2005 to December 2009 for ASCT. The data from 1603 collections were gathered, for a total of 5822 SCU. RESULTS: In our cohort, 79% of patients collected >5 × 106 CD34+ cells/kg, and 3.4% collected <2 × 106 CD34+ cells/kg. Up to 21% of all the patients and 42% of those with acute leukemia did not undergo reinfusion, and 37% of the cryopreserved SCU were excess, resulting from patients not reinfusing or partially reinfusing. Less than one-third of the excess SCU was disposed, and the major causes of disposal were death and, in a minority of cases, withdrawal of the indication for ASCT. In our analysis, very few first reinfusions occurred after 2 years, and those after 5 years were exceptional. Through the use of a multivariate analysis, we sought to identify the risk factors for collection non-use, independent of the centers' policies. Non-use of SCU was significantly associated with patients with acute leukemia, collections of <2 × 106 CD34/kg and lower age groups. CONCLUSIONS: These data serve as a valid basis to support rational recommendations for cost-effective storage and disposal of SCU.

Dimensional clinical phenotyping using post-mortem brain donor medical records: post-mortem RDoC profiling is associated with Alzheimer's disease neuropathology.

Introduction: Transdiagnostic dimensional phenotypes are essential to investigate the relationship between continuous symptom dimensions and pathological changes. This is a fundamental challenge to post-mortem work, as assessments of phenotypic concepts need to rely on existing records. Methods: We adapted well-validated methodologies to compute National Institute of Mental Health Research Domain Criteria (RDoC) scores using natural language processing (NLP) from electronic health records (EHRs) obtained from post-mortem brain donors and tested whether cognitive domain scores were associated with Alzheimer's disease neuropathological measures. Results: Our results confirm an association of EHR-derived cognitive scores with neuropathological findings. Notably, higher neuropathological load, particularly neuritic plaques, was associated with higher cognitive burden scores in the frontal (ß = 0.38, P = 0.0004), parietal (ß = 0.35, P = 0.0008), temporal (ß = 0.37, P = 0.0004) and occipital (ß = 0.37, P = 0.0003) lobes. Discussion: This proof-of-concept study supports the validity of NLP-based methodologies to obtain quantitative measures of RDoC clinical domains from post-mortem EHR. The associations may accelerate post-mortem brain research beyond classical case-control designs.

Clinical Epidemiological Studies of Colorectal Cancer by Record Linkage of Cancer Registries and Biospecimen Data: A Systematic Review.

BACKGROUND: The incidence and prognosis of colorectal cancer are associated with lifestyle, family history, and genetic predisposition. Record linkage between cancer registries and biospecimen data would enable us to conduct clinical epidemiological studies on incidence or prognosis including genome information. In this study, we conducted a systematic review of clinical epidemiological studies of colorectal cancer using record linkage between cancer registries and biospecimen data and examined the possibilities for future use of this linkage. METHODS: We searched PubMed and Google Scholar for articles regarding cancer registries and biospecimen data use published before December 2021. Selected articles were summarized by cancer registry use, biospecimen use, exposure, outcome, informed consent, and participant numbers by study design and type of cancer registry. RESULTS: Of the 2,793 identified articles, 81 studies were included in this review. The most frequently used cancer registries and study design were site specific cancer registries and cohort studies. Most use of cancer registries was for patient selection in cohort studies and case selection in case-control studies. Most use of biospecimen data was for prognostic factors in cohort studies and risk factors in case-control studies. In site specific cancer registries for the examination of familial colorectal cancer, most use of biospecimen data is to examine genome mutation, expression, or deficiency. CONCLUSION: We suggest that record linkage between cancer registries and biospecimen data would enable the accurate capture of outcomes and detailed genome-environmental factors, and to conduct clinical epidemiological studies according to specific research questions and tailored study designs.