Clinical Validity and Utility of Circulating Tumor DNA (ctDNA) Testing in Advanced Non-small Cell Lung Cancer (aNSCLC): A Systematic Literature Review and Meta-analysis.

PURPOSE: Circulating tumor DNA (ctDNA) testing has become a promising tool to guide first-line (1L) targeted treatment for advanced non-small cell lung cancer (aNSCLC). This study aims to estimate the clinical validity (CV) and clinical utility (CU) of ctDNA-based next-generation sequencing (NGS) for oncogenic driver mutations to inform 1L treatment decisions in aNSCLC through a systematic literature review and meta-analysis. METHODS: A systematic literature search was conducted in PubMed/MEDLINE and Embase to identify randomized control trials or observational studies reporting CV/CU on ctDNA testing in patients with aNSCLC. Meta-analyses were performed using bivariate random-effects models to estimate pooled sensitivity and specificity. Progression-free/overall survival (PFS/OS) was summarized for CU studies. RESULTS: A total of 20 studies were identified: 17 CV only, 2 CU only, and 1 both, and 13 studies were included for the meta-analysis on multi-gene detection. The overall sensitivity and specificity for ctDNA detection of any mutation were 0.69 (95% CI 0.63-0.74) and 0.99 (95% CI 0.97-1.00), respectively. However, sensitivity varied greatly by driver gene, ranging from 0.29 (95% CI 0.13-0.53) for ROS1 to 0.77 (95% CI 0.63-0.86) for KRAS. Two studies that compared PFS with ctDNA versus tissue-based testing followed by 1L targeted therapy found no significant differences. One study reported OS curves on ctDNA-matched and tissue-matched therapies but no hazard ratios were provided. CONCLUSIONS: ctDNA testing demonstrated an overall acceptable diagnostic accuracy in patients with aNSCLC, however, sensitivity varied greatly by driver mutation. Further research is needed, especially for uncommon driver mutations, to better understand the CU of ctDNA testing in guiding targeted treatments for aNSCLC.

Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis.

BACKGROUND: Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated. METHODS: Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and HLA-DRB1*15:01. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined ex vivo by intracellular cytokine staining (ICS) and cross-reactivity of in vitro-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens. RESULTS: EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 p = 0.0079, VCA p = 0.0298) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 p = 0.042 and EBNA3 p = 0.005). In ex vivo assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP. DISCUSSION: Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.

Clinical validity and utility of circulating tumor DNA (ctDNA) testing in advanced non-small cell lung cancer (aNSCLC): a systematic literature review and meta-analysis.

Purpose: Circulating tumor DNA (ctDNA) testing has become a promising tool to guide first-line (1L) targeted treatment for advanced non-small cell lung cancer (aNSCLC). This study aims to estimate the clinical validity (CV) and clinical utility (CU) of ctDNA-based next-generation sequencing (NGS) for oncogenic driver mutations to inform 1L treatment decisions in aNSCLC through a systematic literature review and meta-analysis. Methods: A systematic literature search was conducted in PubMed/MEDLINE and Embase to identify randomized control trials or observational studies reporting CV/CU on ctDNA testing in patients with aNSCLC. Meta-analyses were performed using bivariate random-effects models to estimate pooled sensitivity and specificity. Progression-free/overall survival (PFS/OS) was summarized for CU studies. Results: Eighteen studies were identified: 17 CV only, 2 CU only, and 1 both. Thirteen studies were included for the meta-analysis on multi-gene detection. The overall sensitivity and specificity for ctDNA detection of any mutation were 0.69 (95% CI, 0.63-0.74) and 0.99 (95% CI, 0.97-1.00) respectively. However, sensitivity varied greatly by driver gene, ranging from 0.29 (95% CI, 0.13-0.53) for ROS 1 to 0.77 (95% CI, 0.63-0.86) for KRAS . Two studies compared PFS with ctDNA versus tissue-based testing followed by 1L targeted therapy found no significant differences. One study reported OS curves on ctDNA-matched and tissue-matched therapies but no hazard ratios were provided. Conclusion: ctDNA testing demonstrated an overall acceptable diagnostic accuracy in aNSCLC patients, however, sensitivity varied greatly by driver mutation. Further research is needed, especially for uncommon driver mutations, to better understand the CU of ctDNA testing in guiding targeted treatments for aNSCLC.

The Health Inequality Impact of Liquid Biopsy to Inform First-Line Treatment of Advanced Non-Small Cell Lung Cancer: A Distributional Cost-Effectiveness Analysis.

OBJECTIVES: To perform a distributional cost-effectiveness analysis of liquid biopsy (LB) followed by, if needed, tissue biopsy (TB) (LB-first strategy) relative to a TB-only strategy to inform first-line treatment of advanced non-small cell lung cancer (aNSCLC) from a US payer perspective by which we quantify the impact of LB-first on population health inequality according to race and ethnicity. METHODS: With a health economic model, quality-adjusted life-years (QALYs) and costs per patient were estimated for each subgroup. Given the lifetime risk of aNSCLC, and assuming equally distributed opportunity costs, the incremental net health benefits of LB-first were calculated, which were used to estimate general population quality-adjusted life expectancy at birth (QALE) by race and ethnicity with and without LB-first. The degree of QALYs and QALE differences with the strategies was expressed with inequality indices. Their differences were defined as the inequality impact of LB-first. RESULTS: LB-first resulted in an additional 0.21 (95% uncertainty interval: 0.07-0.39) QALYs among treated patients, with the greatest gain observed among Asian patients (0.31 QALYs [0.09-0.61]). LB-first resulted in an increase in relative inequality in QALYs among patients, but a minor decrease in relative inequality in QALE. CONCLUSIONS: LB-first to inform first-line aNSCLC therapy can improve health outcomes. With current diagnostic performance, the benefit is the greatest among Asian patients, thereby potentially widening racial and ethnic differences in survival among patients with aNSCLC. Assuming equally distributed opportunity costs and access, LB-first does not worsen and, in fact, may reduce inequality in general population health according to race and ethnicity.

Regulation of epithelial transitional states in murine and human pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from impaired regeneration of the alveolar epithelium after injury. During regeneration, type 2 alveolar epithelial cells (AEC2s) assume a transitional state that upregulates multiple keratins and ultimately differentiate into AEC1s. In IPF, transitional AECs accumulate with ineffectual AEC1 differentiation. However, whether and how transitional cells cause fibrosis, whether keratins regulate transitional cell accumulation and fibrosis, and why transitional AECs and fibrosis resolve in mouse models but accumulate in IPF are unclear. Here, we show that human keratin 8 (KRT8) genetic variants were associated with IPF. Krt8-/- mice were protected from fibrosis and accumulation of the transitional state. Keratin 8 (K8) regulated the expression of macrophage chemokines and macrophage recruitment. Profibrotic macrophages and myofibroblasts promoted the accumulation of transitional AECs, establishing a K8-dependent positive feedback loop driving fibrogenesis. Finally, rare murine transitional AECs were highly senescent and basaloid and may not differentiate into AEC1s, recapitulating the aberrant basaloid state in human IPF. We conclude that transitional AECs induced and were maintained by fibrosis in a K8-dependent manner; in mice, most transitional cells and fibrosis resolved, whereas in human IPF, transitional AECs evolved into an aberrant basaloid state that persisted with progressive fibrosis.

Using Spinal Anesthesia and a Fracture Table for Closed Reduction of an Obturator Foramen Hip Dislocation: A Case Report.

CASE: A 37-year-old man with a right obturator foramen hip dislocation underwent closed reduction under spinal anesthesia with the use of a fracture traction table. CONCLUSION: This novel technique provides surgeons and anesthesiologists an alternative method of treating obturator foramen hip dislocations that provides a more controlled reduction and less need for assistants.

Multimodal Pain Control Utilizing Buprenorphine for Robotic-assisted Laparoscopic Prostatectomy: A Quality Improvement Comparison to Conventional Opioid Management.

INTRODUCTION: This study investigated the effectiveness of buprenorphine as an alternative to the use of conventional opioids perioperatively in an effort to help mitigate the impact of the use of perioperative conventional opioids for patients undergoing robotic-assisted laparoscopic prostatectomy. METHODS: Outcomes of patients with localized prostate cancer undergoing robotic-assisted laparoscopic prostatectomy were examined before and after implementation of novel quality improvement study that included receiving buprenorphine compared to conventional opioids for pain control intraoperatively and postoperatively. The primary end point was adequate pain control with secondary end points being analgesic consumption at home, opioid-related side effects, and patient satisfaction. RESULTS: When analyzing the secondary end point of oral morphine milligram equivalents, the buprenorphine group received significantly less morphine milligram equivalent compared to the conventional opioid group (15.19 vs 47.91, P = .006). The buprenorphine group also had lower reported pain scores at discharge (4.3; scale 1-10) compared to the conventional opioid group (5.4), though this did not reach significance (P = .069). In the buprenorphine group, 76.9% strongly agreed that their pain was adequately controlled in the hospital compared to 57.5% of the conventional opioid group (P = .223). There was no difference in overall satisfaction at postoperative day 5 (P = .358). CONCLUSIONS: Our study demonstrates buprenorphine's analgesic capabilities to maintain adequate pain control and patient satisfaction compared to conventional opioids during robotic-assisted laparoscopic prostatectomy, while decreasing perioperative opioid use.

Private Payer and Medicare Coverage Policies for Use of Circulating Tumor DNA Tests in Cancer Diagnostics and Treatment.

BACKGROUND: Circulating tumor DNA (ctDNA) is used to select initial targeted therapy, identify mechanisms of therapeutic resistance, and measure minimal residual disease (MRD) after treatment. Our objective was to review private and Medicare coverage policies for ctDNA testing. METHODS: Policy Reporter was used to identify coverage policies (as of February 2022) from private payers and Medicare Local Coverage Determinations (LCDs) for ctDNA tests. We abstracted data regarding policy existence, ctDNA test coverage, cancer types covered, and clinical indications. Descriptive analyses were performed by payer, clinical indication, and cancer type. RESULTS: A total of 71 of 1,066 total policies met study inclusion criteria, of which 57 were private policies and 14 were Medicare LCDs; 70% of private policies and 100% of Medicare LCDs covered at least one indication. Among 57 private policies, 89% specified a policy for at least 1 clinical indication, with coverage for ctDNA for initial treatment selection most common (69%). Of 40 policies addressing progression, coverage was provided 28% of the time, and of 20 policies addressing MRD, coverage was provided 65% of the time. Non-small cell lung cancer (NSCLC) was the cancer type most frequently covered for initial treatment (47%) and progression (60%). Among policies with ctDNA coverage, coverage was restricted to patients without available tissue or in whom biopsy was contraindicated in 91% of policies. MRD was commonly covered for hematologic malignancies (30%) and NSCLC (25%). Of the 14 Medicare LCD policies, 64% provided coverage for initial treatment selection and progression, and 36% for MRD. CONCLUSIONS: Some private payers and Medicare LCDs provide coverage for ctDNA testing. Private payers frequently cover testing for initial treatment, especially for NSCLC, when tissue is insufficient or biopsy is contraindicated. Coverage remains variable across payers, clinical indications, and cancer types despite inclusion in clinical guidelines, which could impact delivery of effective cancer care.

Perspectives of private payers on multicancer early-detection tests: informing research, implementation, and policy.

Emerging blood-based multicancer early-detection (MCED) tests may redefine cancer screening, reduce mortality, and address health disparities if their benefit is demonstrated. U.S. payers' coverage policies will impact MCED test adoption and access; thus, their perspectives must be understood. We examined views, coverage barriers, and evidentiary needs for MCED from 19 private payers collectively covering 150 000 000 enrollees. Most saw an MCED test's potential merit for cancers without current screening (84%), but fewer saw its merit for cancers with existing screening (37%). The largest coverage barriers were inclusion of cancers without demonstrated benefits of early diagnosis (73%), a high false-negative rate (53%), and lack of care protocols for MCED-detected but unconfirmed cancers (53%). The majority (58%) would not require mortality evidence and would accept surrogate endpoints. Most payers (64%) would accept rigorous real-world evidence in the absence of a large randomized controlled trial. The majority (74%) did not expect MCED to reduce disparities due to potential harm from overtreatment resulting from an MCED and barriers to downstream care. Payers' perspectives and evidentiary needs may inform MCED test developers, researchers producing evidence, and health systems framing MCED screening programs. Private payers should be stakeholders of a national MCED policy and equity agenda.

Genetic counselors' experience with reimbursement and patient out-of-pocket cost for multi-cancer gene panel testing for hereditary cancer syndromes.

Multi-cancer gene panels for hereditary cancer syndromes (hereditary cancer panels, HCPs) are widely available, and some laboratories have programs that limit patients' out-of-pocket (OOP) cost share. However, little is known about practices by cancer genetic counselors for discussing and ordering an HCP and how insurance reimbursement and patient out-of-pocket share impact these practices. We conducted a survey of cancer genetic counselors based in the United States through the National Society of Genetic Counselors to assess the impact of reimbursement and patient OOP share on ordering of an HCP and hereditary cancer genetic counseling. Data analyses were conducted using chi-square and t tests. We received 135 responses (16% response rate). We found that the vast majority of respondents (94%, 127/135) ordered an HCP for patients rather than single-gene tests to assess hereditary cancer predisposition. Two-thirds of respondents reported that their institution had no protocol related to discussing HCPs with patients. Most respondents (84%, 114/135) indicated clinical indications and patients' requests as important in selecting and ordering HCPs, while 42%, 57/135, considered reimbursement and patient OOP share factors important. We found statistically significant differences in reporting of insurance as a frequently used payment method for HCPs and in-person genetic counseling (84% versus 59%, respectively, p < 0.0001). Perceived patient willingness to pay more than $100 was significantly higher for HCPs than for genetic counseling(41% versus 22%, respectively, p < 0.01). In sum, genetic counselors' widespread selection and ordering of HCPs is driven more by clinical indications and patient preferences than payment considerations. Respondents perceived that testing is more often reimbursed by insurance than genetic counseling, and patients are more willing to pay for an HCP than for genetic counseling. Policy efforts should address this incongruence in reimbursement and patient OOP share. Patient-centered communication should educate patients on the benefit of genetic counseling.

Analyzing Precision Medicine Utilization with Real-World Data: A Scoping Review.

Precision medicine (PM), specifically genetic-based testing, is currently used in over 140,000 individual tests to inform the clinical management of disease. Though several databases (e.g., the NIH Genetic Testing Registry) demonstrate the availability of these sequencing-based tests, we do not currently understand the extent to which these tests are used. There exists a need to synthesize the body of real-world data (RWD) describing the use of sequencing-based tests to inform their appropriate use. To accomplish this, we performed a scoping review to examine what RWD sources have been used in studies of PM utilization between January 2015 and August 2021 to characterize the use of genome sequencing (GS), exome sequencing (ES), tumor sequencing (TS), next-generation sequencing-based panels (NGS), gene expression profiling (GEP), and pharmacogenomics (PGx) panels. We abstracted variables describing the use of these types of tests and performed a descriptive statistical analysis. We identified 440 articles in our search and included 72 articles in our study. Publications based on registry databases were the most common, followed by studies based on private insurer administrative claims. Slightly more than one-third (38%) used integrated datasets. Two thirds (67%) of the studies focused on the use of tests for oncological clinical applications. We summarize the RWD sources used in peer-reviewed literature on the use of PM. Our findings will help improve future study design by encouraging the use of centralized databases and registries to track the implementation and use of PM.

Multicancer Screening Tests: Anticipating And Addressing Considerations For Payer Coverage And Patient Access.

There is a tremendous public health need to identify potentially lethal cancers at earlier stages, when there is a greater chance for improved survival. Although in the US there are currently screening recommendations for only five cancers (breast, colorectal, cervical, lung, and prostate), new tests can screen for up to fifty cancers simultaneously based on a simple blood draw. However, these multicancer screening tests (also called "liquid biopsy" tests) will also present challenges to payers because of intrinsic features of the tests and the complexity of payer coverage assessments for screening tests. We describe these considerations while also offering potential solutions that can inform payers' decision making if these tests prove to be beneficial.

Hereditary cancer panel testing challenges and solutions for the latinx community: costs, access, and variants.

Hereditary breast and ovarian cancers (HBOCs) are common among the Latinx population, and risk testing is recommended using multi-gene hereditary cancer panels (HCPs). However, little is known about how payer reimbursement and out-of-pocket expenses impact provider ordering of HCP in the Latinx population. Our objective is to describe key challenges and possible solutions for HCP testing in the Latinx population. As part of a larger study, we conducted semi-structured interviews with key provider informants (genetic counselors, oncologist, nurse practitioner) from safety-net institutions in the San Francisco Bay Area. We used a deductive thematic analysis approach to summarize themes around challenges and possible solutions to facilitating HCP testing in Latinx patients. We found few financial barriers for HCP testing for the Latinx population due to laboratory patient assistance programs that cover testing at low or no cost to patients. However, we found potential challenges related to the sustainability of low-cost testing and out-of-pocket expenses for patients, access to cascade testing for family members, and pathogenic variants specific to Latinx. Providers questioned whether current laboratory payment programs that decrease barriers to testing are sustainable and suggested solutions for accessing cascade testing and ensuring variants specific to the Latinx population were included in testing. The use of laboratories with payment assistance programs reduces barriers to HCP testing among the US population; however, other barriers are present that may impact testing use in the Latinx population and must be addressed to ensure equitable access to HCP testing for this population.

Influence of payer coverage and out-of-pocket costs on ordering of NGS panel tests for hereditary cancer in diverse settings.

The landscape of payment for genetic testing has been changing, with an increase in the number of laboratories offering testing, larger panel offerings, and lower prices. To determine the influence of payer coverage and out-of-pocket costs on the ordering of NGS panel tests for hereditary cancer in diverse settings, we conducted semi-structured interviews with providers who conduct genetic counseling and order next-generation sequencing (NGS) panels purposefully recruited from 11 safety-net clinics and academic medical centers (AMCs) in California and North Carolina, states with diverse populations and divergent Medicaid expansion policies. Thematic analysis was done to identify themes related to the impact of reimbursement and out-of-pocket expenses on test ordering. Specific focus was put on differences between settings. Respondents from both safety-net clinics and AMCs reported that they are increasingly ordering panels instead of single-gene tests, and tests were ordered primarily from a few commercial laboratories. Surprisingly, safety-net clinics reported few barriers to testing related to cost, largely due to laboratory assistance with prior authorization requests and patient payment assistance programs that result in little to no patient out-of-pocket expenses. AMCs reported greater challenges navigating insurance issues, particularly prior authorization. Both groups cited non-coverage of genetic counseling as a major barrier to testing. Difficulty of access to cascade testing, particularly for family members that do not live in the United States, was also of concern. Long-term sustainability of laboratory payment assistance programs was a major concern; safety-net clinics were particularly concerned about access to testing without such programs. There were few differences between states. In conclusion, the use of laboratories with payment assistance programs reduces barriers to NGS panel testing among diverse populations. Such programs represent a major change to the financing and affordability of genetic testing. However, access to genetic counseling is a barrier and must be addressed to ensure equity in testing.

Parallel introgression, not recurrent emergence, explains apparent elevational ecotypes of polyploid Himalayan snowtrout.

The recurrence of similar evolutionary patterns within different habitats often reflects parallel selective pressures acting upon either standing or independently occurring genetic variation to produce a convergence of phenotypes. This interpretation (i.e. parallel divergences within adjacent streams) has been hypothesized for drainage-specific morphological 'ecotypes' observed in polyploid snowtrout (Cyprinidae: Schizothorax). However, parallel patterns of differential introgression during secondary contact are a viable alternative hypothesis. Here, we used ddRADseq (N = 35 319 de novo and N = 10 884 transcriptome-aligned SNPs), as derived from Nepali/Bhutanese samples (N = 48 each), to test these competing hypotheses. We first employed genome-wide allelic depths to derive appropriate ploidy models, then a Bayesian approach to yield genotypes statistically consistent under the inferred expectations. Elevational 'ecotypes' were consistent in geometric morphometric space, but with phylogenetic relationships at the drainage level, sustaining a hypothesis of independent emergence. However, partitioned analyses of phylogeny and admixture identified subsets of loci under selection that retained genealogical concordance with morphology, suggesting instead that apparent patterns of morphological/phylogenetic discordance are driven by widespread genomic homogenization. Here, admixture occurring in secondary contact effectively 'masks' previous isolation. Our results underscore two salient factors: (i) morphological adaptations are retained despite hybridization and (ii) the degree of admixture varies across tributaries, presumably concomitant with underlying environmental or anthropogenic factors.

Taxonomic Uncertainty and the Anomaly Zone: Phylogenomics Disentangle a Rapid Radiation to Resolve Contentious Species (Gila robusta Complex) in the Colorado River.

Species are indisputable units for biodiversity conservation, yet their delimitation is fraught with both conceptual and methodological difficulties. A classic example is the taxonomic controversy surrounding the Gila robusta complex in the lower Colorado River of southwestern North America. Nominal species designations were originally defined according to weakly diagnostic morphological differences, but these conflicted with subsequent genetic analyses. Given this ambiguity, the complex was re-defined as a single polytypic unit, with the proposed "threatened" status under the U.S. Endangered Species Act of two elements being withdrawn. Here we re-evaluated the status of the complex by utilizing dense spatial and genomic sampling (n = 387 and >22 k loci), coupled with SNP-based coalescent and polymorphism-aware phylogenetic models. In doing so, we found that all three species were indeed supported as evolutionarily independent lineages, despite widespread phylogenetic discordance. To juxtapose this discrepancy with previous studies, we first categorized those evolutionary mechanisms driving discordance, then tested (and subsequently rejected) prior hypotheses which argued phylogenetic discord in the complex was driven by the hybrid origin of Gila nigra. The inconsistent patterns of diversity we found within G. robusta were instead associated with rapid Plio-Pleistocene drainage evolution, with subsequent divergence within the "anomaly zone" of tree space producing ambiguities that served to confound prior studies. Our results not only support the resurrection of the three species as distinct entities but also offer an empirical example of how phylogenetic discordance can be categorized within other recalcitrant taxa, particularly when variation is primarily partitioned at the species level.

Born to move: a review on the impact of physical exercise on brain health and the evidence from human controlled trials / Nascidos para o movimento: uma revisão sobre o impacto do exercício físico na saúde do cérebro e as evidências de estudos controlados em humanos

Abstract Background: Physical exercise has been found to impact neurophysiological and structural aspects of the human brain. However, most research has used animal models, which yields much confusion regarding the real effects of exercise on the human brain, as well as the underlying mechanisms. Objective: To present an update on the impact of physical exercise on brain health; and to review and analyze the evidence exclusively from human randomized controlled studies from the last six years. Methods: A search of the literature search was conducted using the MEDLINE (via PubMed), EMBASE, Web of Science and PsycINFO databases for all randomized controlled trials published between January 2014 and January 2020. Results: Twenty-four human controlled trials that observed the relationship between exercise and structural or neurochemical changes were reviewed. Conclusions: Even though this review found that physical exercise improves brain plasticity in humans, particularly through changes in brain-derived neurotrophic factor (BDNF), functional connectivity, basal ganglia and the hippocampus, many unanswered questions remain. Given the recent advances on this subject and its therapeutic potential for the general population, it is hoped that this review and future research correlating molecular, psychological and image data may help elucidate the mechanisms through which physical exercise improves brain health.

RESUMO Introdução: Evidências das últimas décadas têm mostrado que o exercício físico impacta de forma significativa aspectos neurofisiológicos e estruturais do cérebro humano. No entanto, a maioria das pesquisas emprega modelos animais, o que gera confusão no que diz respeito aos efeitos reais do exercício no cérebro humano, assim como os mecanismos adjacentes. Objetivo: Apresentar uma atualização sobre o impacto do exercício no cérebro; revisar e analisar sistematicamente as evidências provenientes exclusivamente de estudos randomizados controlados em humanos, dos últimos seis anos. Métodos: Foi conduzida uma busca na literatura usando as bases de dados MEDLINE (via PubMed), EMBASE, Web of Science e PsycINFO, para todos os estudos randomizados e controlados publicados entre janeiro de 2014 e janeiro de 2020. Resultados: Foram revisados 24 estudos randomizados controlados em humanos, que observavam a relação entre exercício físico e alterações neuroquímicas e estruturais no cérebro. Conclusões: Ainda que esta revisão tenha observado que o exercício físico melhora a plasticidade cerebral em humanos, particularmente por meio de alterações no fator neurotrófico derivado do cérebro (BDNF), conectividade funcional, núcleos da base e hipocampo, muitas questões ainda precisam ser respondidas. Dados os avanços recentes nessa temática e seu potencial terapêutico para a população em geral, espera-se que este manuscrito e pesquisas futuras que correlacionem estudos moleculares e variáveis psicológicas e de imagem possam ajudar na elucidação dos mecanismos pelos quais o exercício físico melhora a saúde cerebral.

Availability and funding of clinical genomic sequencing globally.

The emergence of next-generation genomic sequencing (NGS) tests for use in clinical care has generated widespread interest around the globe, but little is known about the availability and funding of these tests worldwide. We examined NGS availability across world regions and countries, with a particular focus on availability of three key NGS tests-Whole-Exome Sequencing or Whole-Genome Sequencing for diagnosis of suspected genetic diseases such as intellectual disability disorders or rare diseases, non-invasive prenatal testing for common genetic abnormalities in fetuses and tumor sequencing for therapy selection and monitoring of cancer treatment. We found that these NGS tests are available or becoming available in every major region of the world. This includes both high-income countries with robust genomic programmes such as the USA and the UK, and growing availability in countries with upper-middle-income economies. We used exploratory case studies across three diverse health care systems (publicly funded/national (UK), publicly funded/provincial (Canada) and mixed private/public system (USA)) to illustrate the funding challenges and approaches used to address those challenges that might be adopted by other countries. We conclude by assessing what type of data and initiatives will be needed to better track and understand the use of NGS around the world as such testing continues to expand.

Vigilance for Medical Products of Human Origin-Progress on the Notify Library's Global Effort to Share Information and Learning.

BACKGROUND: World Health Assembly Resolution 63.22 mandated World Health Organization to facilitate Member State access to appropriate information on medical products of human origin (MPHO), including collecting data on serious adverse events and reactions. To meet this challenge, the Italian National Transplant Center, with a mandate from World Health Organization, has built and maintained an open-access searchable database of instructive records on disease transmission and other MPHO adverse occurrences. METHODS: One record in the Notify Library describes a specific type of adverse occurrence in 1 type of MPHO and might be linked with 1 or multiple different references. The record inclusion criteria are that it has been reliably documented in a published article or official vigilance reporting system and that it has instructive value for the fields of transfusion, transplantation, or assisted reproduction. The selection and review of references for publication is performed by international experts who collaborate in 5 topic-specific editorial groups: infection transmission, malignancy transmission, living-donor reactions, process-related incidents, and clinical complications. New relevant references are identified through systematic searches and proactive communication by the experts. RESULTS: The Library contains 1733 records, quoting 2632 references. Of the records, 41.8% are related to organs, 20.8% to blood and blood components, 16.5% to hematopoietic progenitor cells, 15.2% to tissues, 4.2% to reproductive tissues and cells, and 1.5% to other MPHO. CONCLUSIONS: Notify Library is the first open-access, searchable database of systematically identified reports of disease transmission and other adverse occurrences arising from the donation and clinical application of MPHO.