Wean early leave early: Apt strategy for weaning from non-invasive ventilation.

BACKGROUND: Weaning protocols from Non-invasive ventilation (NIV) are scant. We set out to study a protocol that was different from the British Thoracic Society protocol and lay down a weaning protocol from NIV in patients with Acute acidotic hypercapnic respiratory failure (AAHRF). MATERIALS AND METHODS: Patients admitted with AAHRF and treated with NIV (baseline pH<7.35, PaCO2 >45 mmHg, and not requiring intubation) at a tertiary care teaching hospital, after taking into consideration the inclusion and the exclusion criteria were randomised in to one of the two group of weaning form NIV and serial ABGs were monitored. RESULTS: The primary outcome of the study shows that there was no significant differences in the success rates of weaning from NIV in both the arms. The secondary outcome shows a few factors such as age, gender, SAPS2 score having an effect on the determination of weaning failure. CONCLUSION: Our study showed that both weaning by duration reduction and pressure reduction had equal success rates but a point on noting the SAPS II score on admission and the age of a particular patient will help decide on weaning initiation.CTRI/2019/12/022560 [Registered on: 30/12/2019].

Complete resolution of rectal cancer with liver metastases after palliative chemoradiotherapy and unplanned surgical resection-a case report.

Metastatic colorectal cancer has poor prognosis for many patients at time of diagnosis with <20% 5-year survival rate. Recent advancements in palliative chemotherapy have improved patient outcomes as median survival has increased almost 2-fold. We report a 44-year-old gentleman who initially underwent palliative chemoradiotherapy and subsequently a Hartmann's procedure for ypT3N1M1 upper rectal adenocarcinoma with multiple liver metastases. Fortuitously, he made a remarkable recovery with complete radiological resolution of liver metastasis post-operatively. The patient has remained in remission for the past 10 years.

The Prognostic Value of Eight Immunohistochemical Markers Expressed in the Tumor Microenvironment and on Hodgkin Reed-Sternberg Cells in Pediatric Patients With Classical Hodgkin Lymphoma.

Immunohistochemical markers are associated with treatment outcome in adults with classical Hodgkin Lymphoma (cHL). Studies in children are scarce and inconsistent. We investigated in 67 children with cHL, whether the expression of CD15, CD30, PAX5, PD-1, PD-L1, CD68, CD163 and TARC at diagnosis is associated with disease free survival (DFS) and with interim remission status. Low CD15 and low TARC expression were associated with relapsed disease. Low expression of PD-L1 was associated with complete remission at interim PET-scan. Our data suggest a difference between pediatric and adult cHL. This underlines the importance of future research into specific prognostic factors in pediatric cHL, indispensable for improvement of treatment in this population.

Cross-tissue immune cell analysis reveals tissue-specific features in humans.

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.

Biological and Clinical Implications of Gene-Expression Profiling in Diffuse Large B-Cell Lymphoma: A Proposal for a Targeted BLYM-777 Consortium Panel as Part of a Multilayered Analytical Approach.

Gene-expression profiling (GEP) is used to study the molecular biology of lymphomas. Here, advancing insights from GEP studies in diffuse large B-cell lymphoma (DLBCL) lymphomagenesis are discussed. GEP studies elucidated subtypes based on cell-of-origin principles and profoundly changed the biological understanding of DLBCL with clinical relevance. Studies integrating GEP and next-generation DNA sequencing defined different molecular subtypes of DLBCL entities originating at specific anatomical localizations. With the emergence of high-throughput technologies, the tumor microenvironment (TME) has been recognized as a critical component in DLBCL pathogenesis. TME studies have characterized so-called "lymphoma microenvironments" and "ecotypes". Despite gained insights, unexplained chemo-refractoriness in DLBCL remains. To further elucidate the complex biology of DLBCL, we propose a novel targeted GEP consortium panel, called BLYM-777. This knowledge-based biology-driven panel includes probes for 777 genes, covering many aspects regarding B-cell lymphomagenesis (f.e., MYC signature, TME, immune surveillance and resistance to CAR T-cell therapy). Regarding lymphomagenesis, upcoming DLBCL studies need to incorporate genomic and transcriptomic approaches with proteomic methods and correlate these multi-omics data with patient characteristics of well-defined and homogeneous cohorts. This multilayered methodology potentially enhances diagnostic classification of DLBCL subtypes, prognostication, and the development of novel targeted therapeutic strategies.

Time trends in primary therapy and relative survival of diffuse large B-cell lymphoma by stage: a nationwide, population-based study in the Netherlands, 1989-2018.

It is unclear whether survival in diffuse large B-cell lymphoma (DLBCL) continues to increase in an era where rituximab-containing chemotherapy reigns for almost two decades. Therefore, we evaluated trends in primary therapy and relative survival (RS) among Dutch DLBCL patients diagnosed between 1989 and 2018. Analyses were performed separately according to the stage I (N = 6952) and stage II-IV disease (N = 20,676), stratified by calendar period and age (18-64, 65-74, and ≥75 years). The use of chemotherapy ± radiotherapy increased over time across all age and stage groups. As of the mid-2000s, >95% of chemotherapy-treated patients received chemoimmunotherapy, irrespective of age and stage. Overall, RS increased significantly over time across all age groups, especially after 2003 when rituximab-containing chemotherapy had become the standard of care. However, RS increased less pronounced between 2003-2010 and 2011-2018 than between 1989-2002 and 2003-2010. These findings were congruent across all studied stage groups. Five-year RS across the three age groups during 2011-2018 was 96%, 84%, and 67% for stage I DLBCL and 75%, 60%, and 46% for stage II-IV DLBCL. Collectively, survival in DLBCL increased modestly beyond the initial introduction of rituximab, with apparent survival differences across age and stage that warrant novel treatment approaches.

An Immunological Perspective of Circulating Tumor Cells as Diagnostic Biomarkers and Therapeutic Targets.

Immune modulation is a hallmark of cancer. Cancer-immune interaction shapes the course of disease progression at every step of tumorigenesis, including metastasis, of which circulating tumor cells (CTCs) are regarded as an indicator. These CTCs are a heterogeneous population of tumor cells that have disseminated from the tumor into circulation. They have been increasingly studied in recent years due to their importance in diagnosis, prognosis, and monitoring of treatment response. Ample evidence demonstrates that CTCs interact with immune cells in circulation, where they must evade immune surveillance or modulate immune response. The interaction between CTCs and the immune system is emerging as a critical point by which CTCs facilitate metastatic progression. Understanding the complex crosstalk between the two may provide a basis for devising new diagnostic and treatment strategies. In this review, we will discuss the current understanding of CTCs and the complex immune-CTC interactions. We also present novel options in clinical interventions, targeting the immune-CTC interfaces, and provide some suggestions on future research directions.

Barriers and Facilitators for Implementing a National Guideline to Foster the Responsible Use of Residual Biospecimens and Data in Health Research.

Residual biospecimens that are stored in hospitals' diagnostic specimen archives can be used for scientific research under strict legal and ethical regulations. In the Netherlands, a Code of Conduct governs responsible secondary use of residual biospecimens. However, implementation of this Code seems to be challenging. This study aims to explore the most important factors that facilitate or hinder the implementation of the Code. In addition, it investigates what is needed to further foster the responsible use of residual biospecimens. A mixed-methods design was used. Questionnaires were sent out to pathologists, patient information centers, physicians, researchers, data protection officers (DPOs), members of research ethics committees, and members of the boards of directors of all hospitals in the Netherlands (81 hospitals). To further investigate the barriers and facilitators, interviews were conducted with pathologists, patient information centers, physician-researchers, DPOs, review boards, research coordinators, and quality managers of pathology departments. In total, 246 respondents filled out the questionnaire and 36 interviews were conducted. Major barriers for implementing were a lack of resources (time, money), a lack of attention for responsible use, and a lack of practical knowledge (knowing what to do, where to go with questions). In contrast, the perception that implementing the Code was necessary, either by the respondent or by colleagues, was considered "a driver" for implementation. Practical instruments such as checklists and roadmaps were considered necessary to foster implementation; however, the creation of such instruments was hindered by a lack of clear-cut answers regarding legal aspects. Therefore, more clarity and harmonization on how to interpret both the Code and legislation regarding secondary use were considered necessary.

Self-testing for the detection of SARS-CoV-2 infection with rapid antigen tests.

IntroductionSelf-testing for COVID-19 infection with lateral flow assay SARS-CoV-2 rapid antigen detection tests (RDT), provides rapid results and could enable frequent and extensive testing in the community, thereby improving the control of SARS-CoV-2. The objective of this study is to evaluate the performance of self-testing using RDT without assistance. MethodsParticipants visiting a municipal SARS-CoV-2 testing centre, received self-testing kits containing either the BD Veritor System (BD RDT) or Roche SARS-CoV-2 antigen detection test (Roche RDT). Oro-nasopharyngeal swabs were collected from the participants for qRT-PCR testing. As a proxy for contagiousness, viral culture was performed on a selection of qRT-PCR positive samples to determine the Ct-value at which the chance of a positive culture was dropping below 0.5 (Ct-value cut-off). Sensitivity and specificity of self-testing were compared to qRT-PCR with a Ct-value below the Ct value cut-off. Determinants independently associated with a false-negative self-test result were determined. ResultsA total of 3,215 participants were included (BD RDT n=1604; Roche RDT n=1611). Sensitivity and specificity of self-testing compared to the qRT-PCR results with Ct-value below the Ct-value cut-off was 78.0% (95% CI:72.5-82.8) and 99.4% (95%CI: 99.0-99.6) respectively. Determinants independently associated with a false-negative self-testing results were: higher age, low viral load and finding self-testing difficult. DiscussionSelf-testing using currently available RDTs has a high specificity and relatively high sensitivity to identify individuals with a high probability of contagiousness. The performance of two tests were comparable. This application has the potential for frequent and extensive testing which may be an aid to lift restrictions to society while controlling the spread of SARS-CoV-2.

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation.

Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage-, dendritic cell-, or monocyte-differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist-assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis-affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim-Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell-of-origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long-term follow-up of all histiocytosis patients.

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.

Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.

Stage-specific trends in primary therapy and survival in follicular lymphoma: a nationwide population-based analysis in the Netherlands, 1989-2016.

We assessed stage-specific trends in primary therapy and relative survival among adult follicular lymphoma (FL) patients diagnosed in the Netherlands between 1989-2016 (N = 12,372; median age, 62 years; and 21% stage I disease). Patients were stratified by disease stage and subsequently categorized into four calendar periods (1989-1995, 1996-2002, 2003-2008, and 2009-2016) and three age groups (18-60, 61-70, and >70 years). The use of radiotherapy in stage I FL remained relatively stable over time and across the three age groups (i.e., 66%, 54%, and 49% in 2009-2016, respectively). In stage II-IV FL, the start of chemotherapy within 12 months post-diagnosis decreased over time, indicating a broader application of a watch-and-wait approach. Relative survival improved considerably over time, especially since 2003 when rituximab was introduced in the Netherlands, and for stage III-IV FL patients and older age groups. Five-year relative survival for patients with stage I-II versus stage III-IV FL in the period 2009-2016 was 96% versus 90%, 93% versus 83%, and 92% versus 68% across the three age groups, respectively. Collectively, the improvement in survival since 2003 is accounted for by advances in FL management, particularly the implementation of rituximab. There remains, however, room for improvement among elderly stage III-IV FL patients.

Case report: a fatal combination of hemophagocytic lymphohistiocytosis with extensive pulmonary microvascular damage in COVID-19 pneumonia.

The clinical features of COVID-19 have a considerable range from a mild illness to severe disease. Underlying pathophysiological mechanisms of the rapidly progressive, and often fatal, pulmonary disease frequently observed in COVID-19 need to be elucidated, in order to develop new treatment strategies for different disease endotypes. Fatal cases can display features of a cytokine storm, which may be related to hemophagocytic lymphohistiocytosis. Also, a spectrum of vascular changes, including microvascular damage, is known to accompany severe COVID-19. In this paper, we describe the co-occurrence of hemophagocytic lymphohistiocytosis and extensive pulmonary microvascular damage with thrombosis and its sequelae in a patient with fatal COVID-19. We believe these response patterns may be linked by common mechanisms involving hypercytokinemia and require further investigation as a fatal constellation in COVID-19, to generate appropriate treatment in patients who display these combined features.

Chemical Modification of Linkers Provides Stable Linker-Payloads for the Generation of Antibody-Drug Conjugates.

Stability of antibody-drug conjugates (ADCs) in mouse serum is one of the critical requirements for the evaluation of ADCs in mouse tumor models. Described herein is a strategy to address the mouse serum instability of uncialamycin linker-payloads through various chemical approaches that involve modification of different parts of the linker and payload. This effort ultimately led to the identification of a m-amide p-aminobenzyl carbamate (MA-PABC) group that resulted in linkers with dramatic improvement of mouse serum stability without affecting the desired proteolytic cleavage.

Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84).

PURPOSE: Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP. PATIENTS AND METHODS: A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat. RESULTS: CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections. CONCLUSION: Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.

Profiling cytotoxic microRNAs in pediatric and adult glioblastoma cells by high-content screening, identification, and validation of miR-1300.

MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 transfected cells due to cytokinesis failure followed by apoptosis. This was also observed in two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In GBM cells, where miR-1300 is normally not expressed, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target. ECT2 siRNA phenocopied the effects of miR-1300, and ECT2 overexpression led to rescue of miR-1300 induced binucleation. We showed that ectopic expression of miR-1300 led to decreased tumor growth in an orthotopic GBM model. Our screen provides a resource for the neuro-oncology community and identified miR-1300 as a novel regulator of endomitosis with translatable potential for therapeutic application.

Surface morphology enhances deposition efficiency in biomimetic, wind-driven fog collection.

Passive interception of fog from the wind is an effective solution for accessing water in regions where fog is frequent and other sources scarce. A Namib Desert beetle is often cited as bioinspiration for further advancement, in a narrative which focuses on patterned wettability of its bumpy elytra as a means of transporting accumulated water from its back to its mouth. However, surface transport in fog collection is secondary to the role of the fluid dynamics of droplet deposition, in which inertial droplets migrate across diverging streamlines approaching an obstruction. 3D geometry of biological surface features inevitably affect this process, but its specific role in flow physics of fog collection has not previously been explored. Here, we report experimental measurements of deposition efficiency of targets with identical surface chemistry but varying surface morphology. We find a nearly threefold increase in collection upon addition of millimetric bumps to a spherical target, and provide insight into the micromechanics underlying the performance. Modifying surface morphology can be easier than overall geometry for both manufactured structures and evolved organisms and should therefore be both considered in the design of separation devices and expected in other biological systems for which extraction of particles from flow is important.

Molecular basis defining the selectivity of substituted isoquinolinones for the melatonin MT2 receptor.

Melatonin MT1 and MT2 receptors represent attractive drug targets for the treatment of various disorders. However, the high conservation of the melatonin binding pocket has hindered the development of subtype-selective compounds. By leveraging on the recently resolved crystal structures of MT1 and MT2 receptors, this study aims to elucidate the structural basis of MT2-selectivity of a panel of isoquinolinone derivatives. Molecular modelling and ligand docking approaches were employed to predict residues involved in forming interactions with the MT2-selective isoquinolinones. Seven conserved residues (Asn175, His208, Trp264, Asn268, Gly271, Tyr294 and Tyr298) were selected as targets for site-directed mutagenesis. Ca2+ mobilization, cAMP inhibition, phosphorylation of extracellular signal-regulated kinase, and ligand binding assays were performed to functionally characterize the receptor mutants in transfected CHO cells. Unlike melatonin, isoquinolinones bearing a 3-methoxybenzyloxyl substituent were unaffected by alanine substitution at His208 of MT2. Although alanine substitutions at Tyr294 or Tyr298 reduced the potency of melatonin and some isoquinolinones on MT2, similar mutations on MT1 allowed five hitherto ineffective isoquinolinones to act as agonists. An isoquinolinone antagonist bearing a 4-methoxybenzyloxyl moiety turned into an agonist at MT2 mutants with alanine substitutions at His208, Tyr294 or Tyr298. A subset of residues is apparently involved in forming a hydrophobic binding cavity to confer selectivity upon the aromatic substituent of isoquinolinone compounds. Two conserved tyrosine residues on transmembrane helix 7 may confer ligand selectivity at MT1 and MT2 receptors, while a conserved histidine on transmembrane helix 5 is apparently involved in receptor activation.

Occupant kinematics and biomechanics during frontal collision in autonomous vehicles-can rotatable seat provides additional protection?

In a highly autonomous vehicle (HAV), the rotatable seat is likely to be designed to facilitate ease of communication between the occupants. We hypothesize that the protective effects of current restraint systems vary among different seating configurations and that by using the rotational seat to alter the occupant's orientation in accordance with the direction of impact, occupants will be better protected. Moreover, in HAVs, it's likely that an imminent impact could be detected at a time of 200 ms, or even longer, prior to the initial contact. The availability of this additional time could be used strategically to actively position the occupants into a safer position for impact.Finite element simulations were performed using the THUMS model to test the hypothesis. The simulation results indicated that during a frontal impact, the backward-facing occupant is safer than occupants in other seating orientations. Moreover, 200 ms is sufficient to rotate the occupant by ±45° and ±90° without introducing additional injuries. Finally, the timing of the post-rotation impact also plays a role in injury risk of the rear-facing impact. Further studies are needed to optimize the rotating seat parameters in order to maintain occupant posture and improve crash safety in HAVs.

Development of a finite element biomechanical whole spine model for analyzing lumbar spine loads under caudocephalad acceleration.

Background:Spine injury risk due to military conflict is an ongoing concern among defense organizations throughout the world. A better understanding of spine biomechanics could assist in developing protection devices to reduce injuries caused by caudocephalad acceleration (+Gz) in under-body blasts (UBB). Although some finite element (FE) human models have demonstrated reasonable lumbar spine biofidelity, they were either partial spine models or not validated for UBB-type loading modes at the lumbar functional spinal unit (FSU) level, thus limiting their ability to analyze UBB-associated occupant kinematics.Methods:An FE functional representation of the human spine with simplified geometry was developed to study the lumbar spine responses under +Gz loading. Fifty-seven load curves obtained from post mortem human subject experiments were used to optimize the model.Results:The model was cumulatively validated for compression, flexion, extension, and anterior-, posterior-, and lateral-shears of the lumbar spine and flexion and extension of the cervical spine. The thoracic spine was optimized for flexion and compression. The cumulative CORrelation and Analysis (CORA) rating for the lumbar spine was 0.766 and the cervical spine was 0.818; both surpassed the 0.7 objective goal. The model's element size was confirmed as converged.Conclusions:An FE functional representation of the human spine was developed for +Gz lumbar load analysis. The lumbar and cervical spines were demonstrated to be quantitatively biofidelic to the FSU level for multi-directional loading and bending typically experienced in +Gz loading, filling the capability gap in current models.