The International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting

Abstract

Biopreservation and BiobankingAhead of Print AbstractsFree AccessThe International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting“Come As You Are: Building Biobanking Bridges” In‐Person: May 3–6, 2023 Seattle, Washington Virtual: June 6–7, 2023Published Online:14 Apr 2023https://doi.org/10.1089/bio.2023.29118.abstractsAboutSectionsPDF/EPUB Permissions & CitationsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail The abstracts that follow demonstrate the broad range of timely issues addressed in the contributed Oral and Poster presentations at ISBER's 2023 Annual Meeting & Exhibits.Oral AbstractO‐01 Accelerating Translational Research by Enabling Access to Specimens and DatasetsS. Joshi1, E. Matzke2, D. Galipeau31Fred Hutchinson Cancer Research Center, Seattle, Washington, United States, 2Provincial Health Services Authority, Vancouver, British Columbia, Canada, 3Oregon Health & Science University, Portland, Oregon, United StatesStatement of the Problem: Finding appropriate clinical specimens and associated data often causes bottlenecks in the translational research pipeline. Often investigators procure specimens through only one or a small number of sources which often have limited volume of participants and demographics of the patient population. Seemingly paradoxical, groups with large numbers of banked specimens often struggle to increase awareness and use of their collected specimens, which can lead to limited return on investment for high infrastructure costs.Proposed Solution: To address the above‐mentioned challenges the Specimen & Data Acquisition Network (SAN) was formed in 2019 to increase opportunities for resource exchange in the Pacific Northwest region (Oregon, Washington, and British Columbia). The concept of SAN, a hub and spoke network to speed sharing of resources and ideas, originated in response to sparse specimen resources within our translational research program which was a key bottleneck to research endeavors. Building on existing local connections and those from our research network in other academic institutions, we began collaborations with 7 additional institutions that were aligned with our objectives and goals. SAN serves as a liaison for investigators to leverage collective resources and works to support researchers in their biobanking activities. SAN is a conduit for collaborative science across the regional translational research community.Conclusions: Currently, the SAN consists of 10 member organizations, each with representation on the governance committee. SAN began serving investigators in 2020 and, to date, has received 80 requests and connected more than 40 investigators to critical project resources spanning 12 institutions. SAN works with researchers to provide support across 6 service areas: 1) Access to specimens, 2) Access to datasets, 3) Data Management Support, 4) Research Connections, 5) Regulatory Guidance, and 6) Resource Lifecycle Management. These supportive services are catered to give researchers more time to focus on their next big discovery. Five SAN member institutions are signatory to an umbrella material/data transfer agreement that has expedited resource sharing. We envision that this will be a valuable resource for the translational research community.O‐02 Power of Consortium Shared Resources When External Threats OccurS. Hume4, 1, S. Higgins1, 2, A. J. Mountain1, 3, C. Gilfillan4, W. Ng1, 21Victorian Cancer Biobank Consortium, Melbourne, Victoria, Australia, 2Cancer Council Victoria, Melbourne, Victoria, Australia, 3Austin Health Tissue Bank, Austin Health, Heidelberg, Victoria, Australia, 4Eastern Health Tissue Bank, Eastern Health, Box Hill, Victoria, AustraliaStatement of Problem: The Eastern Health Tissue Bank (EHTB) is a hospital‐integrated cancer biobank and a member of Victorian Cancer Biobank (VCB) Consortium. In 2021, the biobank responded to several external threats that affected daily operations. These included a cyber‐threat incident at the hosting institution and multiple COVID‐19‐related disruptions as the city experienced one of the longest pandemic lockdowns globally.Unplanned events can severely and suddenly restrict biobanking activities, and small biobanks require support to ensure sustainability and business continuity.Proposed Solution: As part of the VCB Consortium, the EHTB has a strong resilience and ability to respond to external threats or incidents. As a hub‐and‐spoke Consortium (comprising a central lead agency with five cancer tissue banks), the VCB utilises shared resources to strengthen business continuity.This presentation depicts two scenarios (cyber threat and pandemic) which demonstrate the combined use of tools across a networked biobank to reduce risks and impacts from large‐scale organisational disruptions.Three Consortium‐wide tools were utilised:1) A robust Business Continuity Plan, incorporating key stakeholders' responsibilities in risk management.2) A Consortium Business Plan with local (institution) and networked (consortium) goals.3) Implementation of harmonised Standardised Operating Procedures (SOPs).Scenario Outcomes Included:1) Central Operations “Hub” provided immediate contingency support as part of a framework for rapid response/recovery, including facilitating communications with stakeholders.2) A partner “Spoke” Site allowed EHTB staff access to Biobank shared databases, group business communication platforms, and shared biospecimen storage.3) Harmonised Consortium SOPs allowed large‐scale multisite dispatches to still be completed.Conclusions: In responding to external threat incidents, a robust business continuity plan and immediate access to shared resources enabled the EHTB to retain some functionality. If the EHTB had been a standalone biobank, capacity to operate would have been diminished, resulting in the loss or suspension of activity.The resources described cannot be underestimated in their effectiveness when an external threat occurs.O‐03 The Qualification in Biorepository Science (QBRS) Examination: Progress Report on its Global ReachB. Schacter1, 2, D. Simeon‐Dubach31Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada, 2Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, 3medservice Daniel Simeon Dubach, Walchwil, ZG, SwitzerlandBackground: The importance of quality parameters in biobanking of biological materials like human tissues has been emphasized in the past: Biobanking standards by ISO (ISO 20387), CAP accreditation, Best Practices (ISBER Best Practices 4th ed.), OECD standards, and Standard Operating Practices and Policies by CTRNet were developed to address these challenges.While these procedures are proving invaluable to biobanks to ensure that their processes for accessing, processing, and distributing biobanked materials result in reproducibility and quality performance, they do not address the question of quality performance in the biobanking professionals themselves.Methods: The International Society for Biological and Environmental Repositories (ISBER) and ASCP BOC (American Society for Clinical Pathology Board of Certification) as two leading organisations in their fields joined forces to develop the QBRS (Qualification in Biorepository Science) examination, in order to further enhance reproducible and sustainable quality biobanking in biobanking professionals. The exam is administered online and is unique in its field.Well trained and skilled staff are essential to ensure high quality biospecimens for reproducible results in precision medicine, biomarker development, and biomedical research as a whole, while aiming for sustainable biobanking activities.Results: To date, over 58 individuals in Australia, Hong Kong, Singapore, Ireland, Wales, Nigeria, Saudi Arabia, UAE, Costa Rica, and the USA have taken and passed the exam to qualify for the QBRS, demonstrating its global appeal.Conclusions: The QBRS has become the standard which defines the required level of knowledge and skill in biobanking professionals that will assure sustained quality and reproducibility in biobanking laboratories worldwide. Successful applicants have acknowledged that achieving the QBRS makes them more desirable in hiring competitions and enhances their career trajectory. Conversely, biobanks that hire a QBRS qualified biobanker have acknowledged that they are striving for quality in their biobanking operation. The QBRS qualification establishes that the biobank in which the qualified biobanker works is one that promotes and establishes quality within its biobanking staff. Biobank directors have indicated that the QBRS exam provides further impetus for professional training for their staff.O‐04 A New Tool to Match Organ, Tissue, and Eye Post‐mortem Donors to Research Project CriteriaK. D. Kunkle, G. H. Grossman, T. Cattell, A. AbbottPrecision Ocular Biobank, Advancing Sight Network, Birmingham, Alabama, United StatesBackground: Post‐mortem repositories recover organs, tissues, and eyes for research from authorized donors. However, due to the rapid nature of the donation process conflicting with the laborious task of matching donors to research project criteria, organizations miss opportunities to identify donors for prospective recovery. The ReSync app was developed by the Precision Ocular Biobank to assist in the real‐time identification of research donors at the initial point of the referral call.Methods: ReSync is an app built in Claris FileMaker 19, a low‐code relational database engine. Although ReSync is a closed system, open‐source functionality of Claris FileMaker allows it to universally connect to external donation referral databases. Research project criteria are entered into a table in ReSync prior to activation. Exclusion and inclusion criteria in categories such as donor demographics, medical history, and referral status act as triggers to match with donor information. Once active, referral coordinators enter donor information into the host database during the initial call from the hospital with a recent or impending death. Filtering occurs through connecting pairs of fields in tables in ReSync and the host database to validate or invalidate a donor candidate against each project. When a match between a project and donor occurs, a flag alerts the coordinator in real‐time. Matching projects appear in a pop‐up window, and referral coordinators can then consult with research specialists or directly assign the case to one of the projects and initiate recovery dispatch.Results: Since its employment, ReSync has allowed the Precision Ocular Biobank to expand its open research requests from 3 to 18 at any given point, representing a six‐fold increase in concomitant projects. This also led to a dramatically decrease in the time a donor was matched to a project, from twenty minutes to five (400% decrease). Even with more projects open simultaneously, request fulfillment time decreased by 25%.Conclusions: Low‐code, automated donor matching solutions allow post‐mortem repositories with limited software developing capability to better fulfil prospective research requests. While simultaneously reducing missed opportunities and eligibility times, programs like ReSync allow for the expansion of enrolled projects.O‐05 Determining Pre‐analytical Variables and Molecular Determinants to Ensure High Quality of Luxor BiobankN. Kordy, S. Ezzat, S. Mahmoud, R. Mohamed, A. Hagag, A. M. Gamal, M. M. Saady, A. SalehResearch Department, Shefa Al Orman Hospital, Luxor, EgyptBackground: Biobank sample preparation methods must ensure long‐term functionality of the products obtained. Preanalytical variables affect the integrity of the biospecimens, and results of analyses. The quality of nucleic acids has a major importance for molecular biology techniques used in genetic analysis. Quality indicators are the tool to measure these parameters; purity and integrity are the determinants for DNA quality. This study aims to determine the quality of SOH Biobank (SOHB) by independently evaluating the preanalytical variables in terms of measurement of processing time, aliquots position audit, and the quality of DNA samples.Methodology: SOHB biospecimen collection is performed after SOH‐IRB approval. Standard operating procedures (SOPs) were written with strict adherence by the team. Blood samples are collected after participant recruitment in the biobank program and obtaining informed consent. After blood collection, the blood is processed within one‐hour and stored in ‐80 degree Celsius freezers. Quality control was determined first, through recording sample withdrawal, receiving, and processing time. Second, aliquots position audits were performed manually on recruited patients for the last 6 months of 2021 to ensure 100% accurate aliquots position, Finally, DNA extracted from buffy coat samples was stored in the duration of 01‐2017 to 02‐2022 using QIAamp DNA kit (Qiagen). Concentration and purity are measured by spectrophotometer (Multisky scan, Thermofisher). Pure DNA ratio should be between 1.8 to 2.0; a higher ratio reveals DNA degradation, while a lower ratio indicates protein contamination.Results: Mean value of processing time for 6600 samples is calculated to ensure that samples are processed and stored in ‐80 degree Celsius freezers within 1 hour of sample withdrawal. Results showed the mean value is 23 ± 0.08 minutes. Manual aliquots position audit was performed for samples stored from July to December 2021; 1087 cases showed 96% accuracy, while 4% aliquot misassigned position inside box. Purity detection for 980 samples out of 6600 samples were analyzed and showed a mean of A260/A280ratio of 1.8 ± 0.025.Conclusion: SOHB quality control results are satisfactory ensuring that SOHB can provide high‐quality samples for genomic studies. Quality control should be performed in a regular manner to ensure the appropriate management of the samples, avoiding low confidence in results, high costs, and sample wasting.O‐06 MIRRI‐ERIC: A Pan‐European Research Infrastructure for Making Microbial Science and Innovation HappenR. Aznar1, M. Bosschaerts2, N. Lima3, L. Soares41Departamento de Microbiología y Ecología and Colección Española de Cultivos Tipo (CECT), Universitat de València, Valencia, Spain, 2BCCM Coordination Cell, Belgian Science Policy, Brussels, Belgium, 3CEB‐Universidade do Minho, Micoteca da Universidade do Minho, Braga, Portugal, 4MIRRI‐ERIC Central Coordinating Unit, MIRRI‐ERIC, Braga, PortugalStatement of the Problem: Several hurdles hamper microbial research and cause inefficient, ineffective, and costly science and innovation: difficulty to access strains cited in papers and databases; sharing of unverified strains; gaps in the current offer; fragmentation of resources, data, services, and expertise; and deficient support to individual culture collections (CCs).Proposed Solution: The Microbial Resource Research Infrastructure ‐ European Research Infrastructure Consortium (MIRRI‐ERIC) has been created as a pan‐European distributed research infrastructure, with the goal of solving/mitigating these bottlenecks, promoting complementarity, reducing redundancy, and continuously improving the capacity of its Partner Microbial domain Biological Resource Centres (mBRCs). MIRRI brings together ∼50 mBRCs, CCs, and research institutes from ten European countries working for the preservation, systematic investigation, provision, and valorisation of microbial resources and biodiversity, with a special focus on the domains of Health & Food, Agro‐Food, and Environment & Energy.MIRRI serves the bioscience and the bioindustry communities by facilitating the access, through a single point, to a catalogue of 400,000+ high‐quality microbial resources, such as bacteria, cyanobacteria, archaea, yeasts, filamentous fungi, micro‐algae, bacteriophages, viruses, and other microbiological material, such as microbiomes, plasmids, and genomic DNA. The MIRRI Information System will also provide users with resources' associated data, as available – e.g., taxonomy, ecology, pathogenicity, morphology, physiology, chemical characterization, DNA barcoding, or genomics.Based on its partner organisations' state‐of‐the‐art facilities/equipment and top‐level expertise, MIRRI also offers its users a diverse catalogue of high‐quality services, including pipelines of integrated, product‐oriented services made available as tailor‐made, turnkey solutions.Conclusions: The resources, services, and expertise provided by MIRRI and its partners can help researchers and bioindustries deliver the maximum value and impacts from their projects, technologies, and products.MIRRI is continuously engaged in enlarging its coverage in Europe and beyond. EU Member States, associated countries, third countries other than associated countries, and intergovernmental organisations may become a Member or an Observer of MIRRI‐ERIC. Individual organisations may become Partners of MIRRI‐ERIC.O‐07 Developing Genomic and Biomaterials Resources for Establishing Nonhuman Primate Models of Human DiseaseE. J. Vallender1, 2, S. M. Peterson3, A. Lewis3, A. J. Ericsen4, 5, K. G. Ray3, B. N. Bimber3, B. Ferguson31The University of Mississippi Medical Center, Jackson, Mississippi, United States, 2Tulane National Primate Research Center, Covington, Louisiana, United States, 3Oregon Health & Science University Oregon National Primate Research Center, Beaverton, Oregon, United States, 4Emory University, Atlanta, Georgia, United States, 5Emory National Primate Research Center, Atlanta, Georgia, United StatesBackground: Animal models of human disease play a vital role in biomedical research and therapeutic development. Nonhuman primates, in particular rhesus macaques, share behavioral, anatomical, physiological, and genetic similarities with humans that make them excellent translational models. The wealth of information developed on these animals through diverse research efforts can be leveraged through interconnected repositories of phenotypic data, biomaterials, and genomic information. Through the development of a centralized framework it is possible to accelerate the generation of nonhuman primate models of human disease and effect vital synergies that go beyond individual laboratories or research programs.Methods: The macaque Genotype and Phenotype (mGAP) resource serves as a repository for genomic data derived from rhesus macaques, largely those found at NIH‐funded Primate Research Centers. A standardized bioinformatic pipeline is used to call single nucleotide variation (SNV) and to cross reference human data on regulatory elements, disease‐associated variation, and evolutionary conservation. SNVs are also annotated using variant effect prediction tools. Data are made openly available to the research community both in aggregate as well as at the individual animal level. This information can then be tied back to specific animal health records, phenotypic information, and biomaterials through the contributing centers.Results: mGAP currently houses genomic information from 2,985 rhesus macaques including nearly 52 million variants. Of these, 11.5 thousand overlap with human ClinVar annotations and 33.2 thousand overlap with GWAS associations housed in GRASP. Many more, 125 thousand, are predicted deleterious by Polyphen2 or high impact by SnpEff. Coupled with phenotypic information derived from animal health records and pathology reports, spontaneously occurring genetic models of multiple rare human diseases have been identified and are being used for novel therapeutic development and biomarker discovery.Conclusions: Through the integration of genomic and phenotypic information, rhesus macaques are being developed and harnessed for translationally important nonhuman primate animal models. These efforts can occur at scale only through resources that bring together diverse data and research expertise while still allowing for the connection to individual animals and samples.O‐08 AI in Medicine Based on Biobank Data ‐ New Opportunities and (Not) Known RisksK. SargsyanInternational Biobanking and Education, Medical University of Graz, Graz, STMK, AustriaThe possibilities for improving effectiveness and interoperability clearly show the directions in which BBs will develop soon. Today, virtual links between different DAs allow an exchange of data and samples, which previously could only occur with great effort and long waiting times or even rejections of queries, have decreased. Furthermore, the notion of a biological “sample” is extended to imaging samples, which multiplies the amount and dimensionality of the data obtained and thus provides biobanks with a more complete picture of individual patients and entire disease patterns. With the integration of digitalization into biobanks, a steady flow of data is ensured that, in the best case, does not cease for the duration of a patient's lifetime. This steady flow of data updates and exchange enables better tracking of the health status of individual patients and populations and can provide far‐reaching and as yet unknown information for the epidemiology of certain diseases in terms of course, treatment response, and prognosis. Particularly concerning genotype‐phenotype predictions, there is the potential to use genetic traits to develop new personalized therapies or targeted therapies and to identify subgroups that, for example, have an increased risk of developing certain diseases based on their genetic features or to facilitate the early detection of the respective diseases and, among other things, to single out non‐responders and to focus more specifically on their specific needs. The consent forms that patients and donors have to fill out and accept with their signature and consent when providing samples to clinical institutes or biobanks, or similar repositories will also evolve into more flexible, dynamic, digitally accessible forms that enable patients/donors to track their own samples and their informative value or usefulness in research whenever and wherever they are. They can withdraw their consent at any time and thus exercise complete control over their genetic material processing. Thus, they will be better treated, jet better informed, and educated.O‐09 Biobanking during War: Experience of Audubon BioscienceM. Yanovytska, B. Shkurupii, H. Chytaieva, E. Serdyukova, A. Shekhovtsov, I. Voievoda, A. Yudchenko, N. Sobetska‐Koloda, T. Nguyen, A. Giardina, A. Popova, R. SemikovAudubon Bioscience, Kyiv, UkraineOn February 24, 2022, the large‐scale Russian army invasion severely interrupted the operations of our biobank in Ukraine. Our team globally and especially in Ukraine faced and is still facing many challenges. Before the events occurred (when risks of the war escalation increased), we prepared our contingency and business continuity plans. They were partially executed. We have since been able to resume operations in Ukraine.On the first day of the large‐scale war, the Operations team, together with Revenue and HR teams, organized the evacuation of the staff with all documentation and laptops, as well as laboratory equipment and ambient storage specimens to the Western region of Ukraine. We were able to eventually move the ambient specimens to the US. Once in our US operations facility, we reorganized and cataloged every specimen and reestablished our biobank there. For frozen specimens, since we can't relocate them due to the lack of proper transportation at that time, we decided to seal all freezers with specimens and installed surveillance cameras to keep them safe. Together with our temperature monitoring system, we were able to keep track of our freezers' temperature and ensured that the specimens were properly stored during the 2‐month period when only a few members of our team remained at the biobank.Ongoing Ukrainian projects were immediately transferred to other countries of operations such as Turkey, USA, Armenia, etc. In three months (May 2022) we achieved financial break‐even (monthly) confirming the fact that global organization was stabilized. After two months, when active warfare was stopped in the Kyiv region, new logistic chains were organized and we started to rebuild our workflow. By August 2022, the Ukrainian operations reached the level of pre‐war collection rates. However, we continue to distribute projects among all of our affiliates in other countries to minimize risks for our partners.In conclusion, the operations of Ukrainian biobanking have been faced with severe difficulties due to the Russian‐Ukrainian war. Although we were not able to execute our contingency and business continuity plans in full, right planning together with good execution and improvisation helped minimize the negative effect. Solutions that we put in place to ensure proper specimen storage were implemented and proved to be effective. Our ability to redistribute projects globally enabled us to continue supporting precision medicine researchers.O‐10 Survey of Adolescents Regarding Their Opinion of Research and Vaccination During the COVID‐19 PandemicQ. Aujla1, I. Kayda1, A. Ellis1, D. Goldfarb1, 2, J. Bettinger2, 3, L. Mâsse2, 3, J. Bush1, 2, S. Vercauteren1, 21Pathology and Lab Medicine, BC Children's Hospital, Vancouver, British Columbia, Canada, 2Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada, 3BC Children's Hospital Research Institute, Vancouver, British Columbia, CanadaBackground: The COVID‐19 pandemic has emphasized the importance of research into disease biology, prevention, and treatment of emerging diseases and pathogens. Currently, there is limited understanding on adolescent perceptions towards biobanking, research participation, vaccinations, and how the pandemic has altered these perceptions. The BC Children's Hospital BioBank (BCCHB) surveyed Grade 8‐12 students in British Columbia (BC) to determine perceptions before and after the pandemic about topics such as research, pediatric biobanking, vaccinations, and public health policies.Methods: A voluntary, anonymous, 15‐question online survey was distributed through student emails, online school portals, and parent newsletters. Phase 1 of the survey was conducted from May to June 2021 and Phase 2 was conducted from Sept 2021 to June 2022. Questions were edited between Phases 1 and 2 to reflect vaccine availability for adolescents, and the emergence of new variants of COVID‐19.Results: We received a total of 1,022 completed survey responses, from participants aged 12‐19 years in 13 BC school districts and compared the findings to a previous completed school survey [1]. The majority of participants (94%) agreed that COVID‐19 is a serious disease and 95% stated that the pandemic has shown them how important medical research is. While many (95%) agreed on the importance of research before the COVID‐19 pandemic, this increased to 97% after pandemic onset. This desire to contribute to research was reflected by the 80% of participants willing to donate an extra blood sample for biobanking purposes during the COVID‐19 pandemic, compared to 64% from a 2016 school survey conducted among the same age group [1]. Participants (97%) also agreed that research participation would allow them to help others. Of the adolescents surveyed, the majority (85%) were comfortable with making the decision on their own to donate a sample specifically to research. Considering the current public health climate, 92% of participants stated that they will be vaccinated, for reasons such as knowing vaccines are safe, allowing them to engage in social activities, and protecting them from COVID‐19.Conclusion: Adolescents across BC were found to be more willing to participate in research after living through the COVID‐19 pandemic. They also were found to be more willing to donate leftover samples towards biobanking after knowing the importance of research in disease diagnosis and treatment.Reference: [1] Kong CC, Tarling TE, Strahlendorf C, Dittrick M, Vercauteren SM. Opinions of Adolescents and Parents About Pediatric Biobanking. J Adolesc Health, 2016; 58(4):474‐480. doi: 10.1016/j.jadohealth.2015.12.015. PMID: 27013273.O‐11 Tissue Microarrays: Turning Hidden Resources in Research GemsA. Yuksel1, M. Krivanek2, D. R. Catchpoole11Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, SCHN, Westmead, New South Wales, Australia, 2Anatomical Pathology, The Children's Hospital at Westmead, Westmead, New South Wales, AustraliaIt is expected that biobanks provide critical tissue resources to researchers to conduct fundamental investigation into disease states and to ensure the best research use of all tissue biospecimens by linking them to key questions being asked in research. Recognizing the rarity of childhood cancers, small tumour specimen volumes, and the burgeoning need for tissue‐directed research, we describe here the impact of a research‐focussed biospecimen resource. The Tumour Bank at The Children's Hospital at Westmead (TB‐CHW) has initiated alongside the main source of all such tissue, our histopathology department. In 2012 we leveraged the hospital's formalin‐fixed paraffin‐embedded (FFPE) tissue block archive to commence a tissue microarray (TMA) construction program. Our purpose was to provide rationalised access to FFPE tissue whilst not impacting on the availability of blocks for future diagnostic or medico‐legal review. Construction of the TMAs that represented a single childhood cancer subtypes required a deep dive into the block archives with blocks selected covering sample collected over a couple of decade‐long periods or more. This resulted in a tissue resource where enough rare paediatric tumours representing all patients seen at a single centre are dr