Revised timeline and distribution of the earliest diverged human maternal lineages in southern Africa

The oldest extant human maternal lineages include mitochondrial haplogroups L0d and L0k found in the southern African click-speaking forager peoples broadly classified as Khoesan. Profiling these early mitochondrial lineages allows for better understanding of modern human evolution. In this study, we profile 77 new early-diverged complete mitochondrial genomes and sub-classify another 105 L0d/L0k individuals from southern Africa. We use this data to refine basal phylogenetic divergence, coalescence times and Khoesan prehistory. Our results confirm L0d as the earliest diverged lineage (∼172 kya, 95%CI: 149-199 kya), followed by L0k (∼159 kya, 95%CI: 136-183 kya) and a new lineage we name L0g (∼94 kya, 95%CI: 72-116 kya). We identify two new L0d1 subclades we name L0d1d and L0d1c4/L0d1e, and estimate L0d2 and L0d1 divergence at ∼93 kya (95%CI:76-112 kya). We concur the earliest emerging L0d1’2 sublineage L0d1b (∼49 kya, 95%CI:37-58 kya) is widely distributed across southern Africa. Concomitantly, we find the most recent sublineage L0d2a (∼17 kya, 95%CI:10-27 kya) to be equally common. While we agree that lineages L0d1c and L0k1a are restricted to contemporary inland Khoesan populations, our observed predominance of L0d2a and L0d1a in non-Khoesan populations suggests a once independent coastal Khoesan prehistory. The distribution of early-diverged human maternal lineages within contemporary southern Africans suggests a rich history of human existence prior to any archaeological evidence of migration into the region. For the first time, we provide a genetic-based evidence for significant modern human evolution in southern Africa at the time of the Last Glacial Maximum at between ∼21-17 kya, coinciding with the emergence of major lineages L0d1a, L0d2b, L0d2d and L0d2a

Diagnostic Informatics—The Role of Digital Health in Diagnostic Stewardship and the Achievement of Excellence, Safety, and Value

Diagnostic investigations (pathology laboratory and medical imaging) aim to: increase certainty of the presence or absence of disease by supporting the process of differential diagnosis; support clinical management; and monitor a patient's trajectory (e. g., disease progression or response to treatment). Digital health can be defined as the collection, storage, retrieval, transmission, and utilization of data, information, and knowledge to support healthcare. Digital health has become an essential component of the diagnostic process, helping to facilitate the accuracy and timeliness of information transfer and enhance the effectiveness of decision-making processes. Digital health is also important to diagnostic stewardship, which involves coordinated guidance and interventions to ensure the appropriate utilization of diagnostic tests for therapeutic decision-making. Diagnostic stewardship and informatics are thus important in efforts to establish shared decision-making. This is because they contribute to the establishment of shared information platforms (enabling patients to read, comment on, and share in decisions about their care) based on timely and meaningful communication. This paper will outline key diagnostic informatics and stewardship initiatives across three interrelated fields: (1) diagnostic error and the establishment of outcomes-based diagnostic research; (2) the safety and effectiveness of test result management and follow-up; and (3) digitally enhanced decision support systems

Mitochondrial mutations and metabolic adaptation in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited. METHODS: We deployed an integrated approach combining genomics, metabolomics, and phenotypic analysis on a unique cohort of patient-derived pancreatic cancer cell lines (PDCLs). Genome analysis was performed via targeted sequencing of the mitochondrial genome (mtDNA) and nuclear genes encoding mitochondrial components and metabolic genes. Phenotypic characterization of PDCLs included measurement of cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a Seahorse XF extracellular flux analyser, targeted metabolomics and pathway profiling, and radiolabelled glutamine tracing. RESULTS: We identified 24 somatic mutations in the mtDNA of 12 patient-derived pancreatic cancer cell lines (PDCLs). A further 18 mutations were identified in a targeted study of ~1000 nuclear genes important for mitochondrial function and metabolism. Comparison with reference datasets indicated a strong selection bias for non-synonymous mutants with predicted functional effects. Phenotypic analysis showed metabolic changes consistent with mitochondrial dysfunction, including reduced oxygen consumption and increased glycolysis. Metabolomics and radiolabeled substrate tracing indicated the initiation of reductive glutamine metabolism and lipid synthesis in tumours. CONCLUSIONS: The heterogeneous genomic landscape of pancreatic tumours may converge on a common metabolic phenotype, with individual tumours adapting to increased anabolic demands via different genetic mechanisms. Targeting resulting metabolic phenotypes may be a productive therapeutic strategy

Delivering safe and effective test-result communication, management and follow-up : a mixed-methods study protocol

Introduction: The failure to follow-up pathology and medical imaging test results poses patient-safety risks which threaten the effectiveness, quality and safety of patient care. The objective of this project is to: (1) improve the effectiveness and safety of test-result management through the establishment of clear governance processes of communication, responsibility and accountability; (2) harness health information technology (IT) to inform and monitor test-result management; (3) enhance the contribution of consumers to the establishment of safe and effective test-result management systems. Methods and analysis: This convergent mixed-methods project triangulates three multistage studies at seven adult hospitals and one paediatric hospital in Australia. Study 1 adopts qualitative research approaches including semistructured interviews, focus groups and ethnographic observations to gain a better understanding of test-result communication and management practices in hospitals, and to identify patient-safety risks which require quality-improvement interventions. Study 2 analyses linked sets of routinely collected healthcare data to examine critical test-result thresholds and test-result notification processes. A controlled before-and-after study across three emergency departments will measure the impact of interventions (including the use of IT) developed to improve the safety and quality of test-result communication and management processes. Study 3 adopts a consumer-driven approach, including semistructured interviews, and the convening of consumer-reference groups and community forums. The qualitative data will identify mechanisms to enhance the role of consumers in test-management governance processes, and inform the direction of the research and the interpretation of findings. Ethics and dissemination: Ethical approval has been granted by the South Eastern Sydney Local Health District Human Research Ethics Committee and Macquarie University. Findings will be disseminated in academic, industry and consumer journals, newsletters and conferences

Delivering safe and effective test-result communication, management and follow-up: A mixed-methods study protocol

IntroductionThe failure to follow-up pathology and medical imaging test results poses patient-safety risks which threaten the effectiveness, quality and safety of patient care. The objective of this project is to: (1) improve the effectiveness and safety of test-result management through the establishment of clear governance processes of communication, responsibility and accountability; (2) harness health information technology (IT) to inform and monitor test-result management; (3) enhance the contribution of consumers to the establishment of safe and effective test-result management systems.Methods and analysisThis convergent mixed-methods project triangulates three multistage studies at seven adult hospitals and one paediatric hospital in Australia.Study 1 adopts qualitative research approaches including semistructured interviews, focus groups and ethnographic observations to gain a better understanding of test-result communication and management practices in hospitals, and to identify patient-safety risks which require quality-improvement interventions.Study 2 analyses linked sets of routinely collected healthcare data to examine critical test-result thresholds and test-result notification processes. A controlled before-and-after study across three emergency departments will measure the impact of interventions (including the use of IT) developed to improve the safety and quality of test-result communication and management processes.Study 3 adopts a consumer-driven approach, including semistructured interviews, and the convening of consumer-reference groups and community forums. The qualitative data will identify mechanisms to enhance the role of consumers in test-management governance processes, and inform the direction of the research and the interpretation of findings

Informatics External Quality Assurance (IEQA) Down Under: evaluation of a pilot implementation

External quality assurance (EQA) provides ongoing evaluation to verify that laboratory medicine results conform to quality standards expected for patient care. While attention has focused predominantly on test accuracy, the diagnostic phases, consisting of pre- and post-laboratory phases of testing, have thus far lagged in the development of an appropriate diagnostic-phase EQA program. One of the challenges faced by Australian EQA has been a lack of standardisation or harmonisation resulting from variations in reporting between different laboratory medicine providers. This may introduce interpretation errors and misunderstanding of results by clinicians, resulting in a threat to patient safety. While initiatives such as the Australian Pathology Information, Terminology and Units Standardisation (PITUS) program have produced Standards for Pathology Informatics in Australia (SPIA), conformity to these requires regular monitoring to maintain integrity of data between sending (laboratory medicine providers) and receiving (physicians, MyHealth Record, registries) organisations\u27 systems. The PITUS 16 Informatics EQA (IEQA) Project together with the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) has created a system to perform quality assurance on the electronic laboratory message when the laboratory sends a result back to the EQA provider. The purpose of this study was to perform a small scale pilot implementation of an IEQA protocol, which was performed to test the suitability of the system to check compliance of existing Health Level-7 (HL7 v2.4) reporting standards localised and constrained by the RCPA SPIA. Here, we present key milestones from the implementation, including: (1) software development, (2) installation, and verification of the system and communication services, (3) implementation of the IEQA program and compliance testing of the received HL7 v2.4 report messages, (4) compilation of a draft Informatics Program Survey Report for each laboratory and (5) review consisting of presentation of a report showing the compliance checking tool to each participating laboratory

Mitochondrial genetic variation in the evolution of humans and metabolism of cancer

Mitochondria act as the cell’s powerhouse for aerobic energy production. Mitochondria carry their own genetic material (mtDNA), which is maternally inherited and has a high mutation rate. Hence the mtDNA is an ideal genetic tool to trace human evolution and migrations, and a candidate for somatic mutation studies in cancer. These aspects of mitochondrial genetics form the two main foci of this thesis. Southern Africa is known to encompass the world’s greatest genomic diversity, and genetic, anthropological, and archaeological studies support the region as a candidate for the origin of modern humans. In summary, this study used mitochondrial genomes to identify great maternal diversity in the Southern Bantu. Haplogroup distributions in each population suggest a migration route from the Bantu homeland in Western Africa, across Central Africa to the Eastern Great Lakes region, and down the Eastern side of Southern Africa, absorbing indigenous Khoesan lineages to their present day home resulting in the Southern Bantu of today. This study also identified new mtDNA haplogroups, many of which are among the earliest diverging lineages. This study contributes to the global mitochondrial haplogroup diversity knowledge bank. The role of mitochondrial genetic mutations was studied in the context of altered metabolism in cancer, where biosynthesis and maintenance of redox capacity is favoured over energy production via oxidative phosphorylation in tumour cells. 24 somatic mutations were identified in the mitochondrial genomes of 12 patient-derived pancreatic cancer tumour cell lines, most of which were nonsynonymous and located in coding regions for electron transport chain (ETC) subunits or important control regions, in addition to another 18 mutations in nuclear genes predicted to have important mitochondrial or metabolic function. Additionally, significant variation was observed in metabolic phenotype between normal pancreatic cells and tumour cells, including decreased oxygen consumption in tumours, altered metabolomic profiles with an upregulation in biosynthetic pathways such as fatty acid synthesis in tumour cells, and reduced expression of various mitochondrial electron transport chain subunits in tumours. These findings may inform development of new therapeutic strategies targeting these pathways

Identification of four novel KIR2DL2 alleles and two novel KIR2DL3 alleles in an East African population

We report four novel KIR2DL2 alleles and two novel KIR2DL3 alleles identified from an East African population using sequence-based typing. Sequencing and molecular cloning of exon 4 confirmed that the new 2DL2 alleles were identical to 2DL2*003, except for the following nucleotide differences: 2DL2*00601 had a difference at codon 16 (CGC→CCC), resulting in a coding change from arginine to proline; 2DL2*00602 also had this difference at codon 16, as well as a synonymous difference (GAT→GAC) at codon 31; 2DL2*00303 had a synonymous difference (AAA→AAG) at codon 61; and 2DL2*00304 had a synonymous difference (GGG→GGA) at codon 75. 2DL3*017 was identical to 2DL3*005 except at codon 11 (CGG→CTG, arginine→leucine) and exon 9, codons 297 (CAC→CGC, histidine→arginine) and 321 (TGA→AGA, stop codon→arginine). 2DL3*00104 was identical to KIR2DL3*001 except for a synonymous difference (GAG→GAA) at codon 54. Identification of novel killer cell immunoglobulin-like receptor (KIR) alleles is a testament to the genetic diversity in this population.4 page(s

Interaction and innovation: practical strategies for inclusive consumer-driven research in health services

Introduction Despite advances in the co-creation of clinical research involving consumers in the last few decades, consumer engagement in health services research generally remains inconsistent and is too often treated as a perfunctory exercise. Objective Drawing on a health services study on diagnostic test result management, communication and follow-up, we: (1) outline practical strategies used to enhance the contribution of health consumer representatives across all stages of health services research, including active involvement in prioritising objectives for data analysis and participating in data analysis and the dissemination of findings; and (2) describe the impact of continued engagement of consumers on the programme of research, the interpretation of findings and their translational potential. Key innovations Key enabling innovations for engagement included: (1) planned opportunities for long-term consumer involvement across all stages of the research process from conception to dissemination; (2) enhanced consumer engagement capacity; (3) purposeful recruitment of appropriately trained consumers; (4) provision of support structures for active consumer involvement in research design, analysis and write-up; and (5) financial support for consumer involvement. Impact/Conclusion Enhancing consumer contribution and establishing inclusive research design requires a negotiated, interactive, meaningful and transparent process. As a collaborative approach, consumer-driven research involvement offers opportunities for new, often unexpected or unexplored perspectives to feature across the whole research process. In a move away from tokenistic consumer involvement, consumers and researchers who participated in this novel and immersive research project identified inclusive research as a powerful tool to enhance health services research and its translation into effective policy.This work was supported by a National Health and Medical Research Council Partnership Project Grant 111192