Whether this pattern of hypometabolism is present as early as the prodromal stage of DLB is unknown. We investigated the pattern of hypometabolism in patients with mild cognitive impairment (MCI) who progressed to probable DLB compared to MCI patients who progressed to Alzheimer’s disease (AD) dementia and clinically unimpaired (CU) controls.Patients with dementia with Lewy bodies (DLB) are characterized by hypometabolism in the parieto–occipital cortex and the cingulate island sign (CIS) on Patients with MCI from the Mayo Clinic Alzheimer’s Disease Research Center who underwent FDG PET at baseline and progressed to either probable DLB  or AD dementia  during follow-up, and a comparison cohort of CU controls (n = 100) were included.Patients with MCI-DLB had hypometabolism in the parieto-occipital cortex extending into temporal lobes, substantia nigra and thalamus. When compared to MCI-AD, medial temporal and posterior cingulate metabolism were preserved in patients with MCI-DLB, accompanied by greater hypometabolism in the substantia nigra in MCI-DLB compared to MCI-AD. In distinguishing MCI-DLB from MCI-AD at the maximum value of Youden’s index, CIS ratio was highly specific (90%) but not sensitive (59%), but a higher medial temporal to substantia nigra ratio was both sensitive (94%) and specific (83%).FDG PET is a potential biomarker for the prodromal stage of DLB. A higher medial temporal metabolism and CIS ratio, and lower substantia nigra metabolism have additive value in distinguishing prodromal DLB and AD. Imaging18F-fluorodeoxyglucose (FDG) PET findings in patients with DLB are characterized by a parieto-occipital pattern of hypometabolism and a relatively preserved posterior cingulate metabolism known as the cingulate island sign (CIS) (gn (CIS) . CIS havgn (CIS) . Whethergn (CIS) . MoreoveIn the current study, we investigated the pattern of hypometabolism on FDG PET in patients with MCI who progressed to probable DLB (MCI-DLB) compared to a clinically unimpaired (CU) cohort of controls. We further compared MCI-DLB to MCI patients who progressed to AD dementia (MCI-AD) with the objective of identifying a metabolic signature that distinguishes prodromal DLB from prodromal AD.22.1The subjects of this study were identified from the Mayo Clinic Alzheimer’s Disease Research Center (ADRC). We studied patients diagnosed with MCI who underwent FDG PET imaging along with an MRI examination at baseline from 2006 until 2018 (n = 148) and progressed to either probable DLB (n = 17), or AD dementia (n = 41) during approximately annual follow-ups through 2019. Because this was a study on the FDG PET differences between prodromal DLB and prodromal AD, MCI patients who converted to neurodegenerative diseases other than AD or DLB , who did not return for clinical follow-up (n = 27), or who did not progress to dementia (n = 56) were excluded. Diagnosis of MCI was made according to the criteria by Petersen et al. . DiagnosAssessments for the clinical features of DLB have been detailed in previous reports from the ADRC cohorts . Briefly2.2MRI examinations were performed at 3 Tesla . A 3-D high resolution magnetization prepared rapid gradient echo acquisition with approximately 1 mm cubic resolution was obtained for anatomical segmentation and labeling. PET/computed tomography scanners  operating in 3-dimensional mode were used to acquire PET images. Patients were injected with an average of 296 MBq  FDG. Following a 30 min FDG uptake period, four 3.75 min frames were obtained.2.3FDG PET image analysis was performed using an automated image processing pipeline, which included rigid registration of the PET image volumes to each subject’s own 3-dimensional T1-weighted MRI using SPM12. MR images were segmented using Unified Segmentation in SPM12 with population-optimized priors and settings from the Mayo Clinic Adult Lifespan Template. FDG uptake in each voxel was referenced to the median value of the pons uptake for the standardized uptake value ratio (SUVr) in each voxel. Regional cortical uptake of FDG was determined using the DISTAL atlas  for the 2.4Characteristics of the subjects were described using means and standard deviations for continuous variables, and counts and percentages for categorical variables. Differences in characteristics of the three groups were evaluated using one-way analysis of variance (ANOVA) or Fisher's exact test. Additional pairwise-comparisons were done using contrast statements for continuous variables or pairwise Fisher’s exact tests for categorical variables. FDG SUVr in regions that distinguish MCI-DLB and MCI-AD on voxel-based analysis were included in univariate and then multivariate logistic regression models of two and three variables. Receiver operating characteristic (ROC) curves were generated for the models, and the area under the ROC (AUROC) value was reported for each model as a measure of each model’s ability to distinguish MCI-DLB and MCI-AD. Sensitivity and specificity values were calculated for predicted probability cut-offs across the ROC curves, and the maximum Youden’s index, which maximizes the distance from the ROC curve to the identity line, was calculated as a summary statistic.33.1Characteristics of the cohort classified by the clinical group are listed in 3.2The voxel-based regional differences in FDG SUVr in MCI groups compared to CU  are displayed in .Data from atlas-based analysis with boxplots showing these differences in CIS ratio, medial temporal  and substantia nigra SUVrs are displayed in Fig. 2Univariate logistic regression revealed that each of the three measurements had a greater likelihood of predicting MCI-DLB compared to MCI-AD, and multivariable modeling showed that measurement pairs were predictive of MCI-DLB compared to MCI-AD when adjusting for each other. The AUROCs improved when two and three variables were considered together. Whereas all variables contributed when included in two variable models, only the medial temporal and substantia nigra SUVrs significantly contributed in the three variable model and the CIS ratio did not reach statistical significance .Table 2LGiven the higher medial temporal SUVr and lower substantia nigra SUVr in MCI-DLB compared to MCI-AD, in the univariate and multivariable models, we combined the two measures and investigated the diagnostic accuracy of the ratio of medial temporal SUVr substantia nigra SUVr. 4This study demonstrated that MCI patients who progress to probable DLB (MCI-DLB) have wide-spread hypometabolism on FDG PET compared to the CU controls. The topographic pattern of hypometabolism observed in MCI-DLB, involving posterior cortical regions including the occipital lobes as well as thalamus was consistent with the pattern observed in DLB . FurtherFDG PET has been accurate in distinguishing clinically diagnosed probable DLB and AD dementia patients, as well as distinguishing pathologically confirmed LBD from AD . Based oAD pathology mixed with LBD is common in patients with probable DLB and a subset of patients with probable DLB fulfill the pathologic criteria for the diagnosis of LBD and AD, and also exhibit antemortem AD biomarker positivity . It is pPreservation of medial temporal lobe volume is a supportive biomarker for the diagnosis of probable DLB , and preOne of the main pathways connecting medial temporal lobe and posterior cingulate cortex is the cingulum bundle. Posterior cingulate hypometabolism is associated with hippocampal atrophy through disruption of the cingulum bundle in AD dementia . Hence, Neurodegeneration of the substantia nigra and associated decrease in nigrostriatal dopaminergic input to the basal ganglia is a characteristic feature of Lewy body disease, and is observed on dopamine transporter SPECT imaging in patients with prodromal DLB . CurrentMultivariate logistic regression analysis demonstrated that multiple regional measurements from the FDG PET scans improved the diagnostic accuracy in distinguishing MCI-DLB and MCI-AD. In the three-variable model , only lower substantia nigra and higher medial temporal lobe metabolism contributed to the model and improved the diagnostic accuracy in distinguishing MCI-DLB from MCI-AD. Therefore, we combined the two measurements as the substantia nigra /medial temporal lobe uptake ratio, which had the highest accuracy (AUROC of 93%) with sensitivity of 94% and specificity of 83% at the maximum value of Youden’s Index. Although the ratio of the uptake in these two structures may be quite accurate in distinguishing the two clinical groups cross-sectionally, future research on test–retest reproducibility and longitudinal reliability of these measurements are needed.The clinically classified MCI-DLB and MCI-AD patients all progressed to probable DLB or AD dementia at follow-up by design. In our effort to promote the discovery of new biomarkers for prodromal DLB, we limited the study to this specific subset of ADRC-based MCI who progressed to DLB or AD and did not include the broad range of all MCI patients in a time-to-event analysis . We ackn5Current data demonstrates that FDG PET abnormalities are present as early as the prodromal phase of DLB and regional FDG PET signatures can accurately distinguish prodromal DLB and prodromal AD patients. Because of the profound hypometabolism observed in MCI-DLB patients, it is imperative to determine the longitudinal metabolic change in cohorts that are at-risk for DLB, such as patients with idiopathic RBD and MCI patients with the core clinical features of DLB, to determine the temporal occurrence of regional hypometabolism and clinical progression.6Anonymized data can be provided upon review of the request. Data sharing agreement with the requesting investigator and their institution is required.NIH , Foundation Dr. Corinne Schulerand, the Mangurian Foundation for Lewy Body Research, The Elsie and Marvin Dekelboum Family Foundation, and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program. The funding sources had no role in study design, collection, analysis, interpretation, or decision to submit this paper. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.This study was funded by the The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Nursing homes (NHs) faced an unprecedented crisis during the rapid spread of COVID-19. This pandemic has had a devastating impact on both NH residents and workers who are often on the frontlines providing hands-on care. These workers are vulnerable to the health risks of COVID-19 due to daily exposure to residents with COVID-19, residence in areas with high infection rates, and challenges specific to low-income workers (e.g. reliance on mass transportation). Research has highlighted the experiences of NH workers during the pandemic to learn how to better support them now and during future pandemics. This symposium will add to this research and present new findings from studies conducted in the United States to capture the unique experiences of NH employees. First, Bryant illustrates specific COVID-19-related challenges that NH frontline workers faced and how these workers’ experiences compare to workers in other long-term services and support settings. Reinhardt reports findings from a qualitative study examining the multi-level challenges experienced by nursing assistants during the pandemic. Cimarolli examines if quality of employer communication and workers’ perceived COVID-19-related preparedness mitigate the impact of work-related stress on NH workers’ decision to resign. Franzosa shares recommendations based on priorities identified by nursing assistants and administrators to build future resilience based on lessons learned. Finally, Simpson identifies factors associated with states’ decisions to adopt COVID-19 testing mandates for workers in NHs. Dr. Zimmerman discusses study findings and their contributions for creating supportive NH work environments to ensure most optimal NH worker and resident quality of life.


Low-quality diets contribute to the burden of malnutrition and increase the risk of children not achieving their developmental potential. Nutrition-sensitive agriculture programs address the underlying determinants of malnutrition, though their contributions to improving diets do not factor into current nutrition impact modeling tools.To synthesize the evidence on the effectiveness of nutrition-sensitive agriculture programs in improving dietary diversity in young children (6-23.9 months and 6-60 months).A literature search was conducted for published trials through existing systematic reviews and individual database search of the ISI Web of Science. All dietary diversity measures in the studies selected to be in the analysis were extracted. Estimation of main pooled effects were conducted on outcomes of minimum diet diversity (MDD) and diet diversity score (DDS) using random-effects meta-regression models. We report pooled effect sizes as standardized mean differences (SMDs) or odds ratios (ORs).Nutrition-sensitive agricultural interventions have a significant positive impact on the diet diversity scores of children aged 6-23.9 months  = 0.09-0.36) and on the odds of reaching minimum diet diversity . Similar impacts are found when analyses are expanded to include studies for children aged 6-60 months  .Nutrition-sensitive agriculture interventions consistently have a positive impact on child dietary diversity. Incorporating this evidence in nutrition modeling tools can contribute to decision-making on the relative benefits of nutrition-sensitive interventions as compared with other maternal, newborn, child health and nutrition (MNCHN) interventions. Estimates of the global burden of disease have attributed 20% of deaths to unhealthy diets . PovertyNutrition-sensitive agricultural programs take a variety of forms. The agricultural components include interventions to support the production of diversified or more nutritious crops, livestock rearing and aquaculture. The nutrition components of these interventions often include behavior communication change (BCC) approaches that promote positive health behaviors such as the diversification of diets or improved child feeding and/or sensitization or trainings to improve women’s empowerment through agriculture.Although the evidence is clear that nutrition-sensitive agriculture programs can improve children’s diets, the size of the effect is unknown. However, as evidence on these interventions is growing, there is an opportunity to address the question systematically by using a meta-analysis to determine the overall size of the effect. The objective of this study is to synthesize the evidence on the effectiveness of nutrition-sensitive agriculture programs in improving dietary diversity in young children (6-23.9 months and 6-60 months). The results from this meta-analysis can be incorporated into modeling exercises and can serve to inform program design and policy development.Our search covered a variety of nutrition-sensitive agriculture interventions. Intervention types ranged from biofortification – using conventional plant breeding methods to produce more nutritious crops – paired with behavior communication change (BCC), to school-based or homestead gardening supported by agricultural training and inputs accompanied with nutrition education. We searched for published trials through the existing reviews cited above and also conducted a database search for articles in all languages in Google Scholar and the ISI Web of Science Core Collection – a unifying research tool that aggregates from multiple databases (Web of Science Core Collection: Citation Indexes includes: 1) Science Citation Index Expanded (SCI-EXPANDED)-1974-Present, 2) Social Sciences Citation Index (SSCI)-1974-present, 3) Arts & Humanities Citation Index (A&HCI)-1975-Present, 4) Emerging Sources Citation Index (ESCI)-2015-present)[The database search yielded a total of 972 publications. We reviewed titles and abstracts from this initial group by sub-topic in order to refine which studies would be fully reviewed for inclusion. Publications were excluded during the title and abstract review if they were review studies, observational studies with only one time point, or were conducted in high-income countries, leaving 20 studies. We also included studies published in recent systematic reviews  or in peer-reviewed journals between 2018 (the year of the recent systematic review) and the current year. Seventeen studies were included from , and 39 The data extraction process began with a pilot extraction. One author (CK) created a structured abstraction form. All co-authors reviewed, critiqued and approved the form. Two authors  piloted this form with two studies and made modifications as needed. Then, they assigned all other authors a portion of studies for primary or secondary extraction. Data were extracted in two stages after piloting. First, all co-authors independently extracted general information into the standardized form about study setting, intervention design and inputs, year, country, study type, target population, time period of intervention implementation, study design, treatment arm description, sample size and study population, and outcomes measured. Second, we extracted all dietary diversity measures in these studies. Initially, we included all types of diet diversity measures, from nutrient intake, diet diversity scores (DDS), minimum diet diversity (MDD) and to more narrowly defined indicators such as number of fruits or vegetables consumed or quantity of animal-sourced foods consumed. We also extracted information on the sample size for the outcome measure, effect measure description and value, standard error, 95% CI and statistical significance. Specification of outcomes and effect measures were assessed for comparability across trials. Data were reviewed for accuracy and consistency and all studies were independently dual-coded by the authors. No disagreements for inclusion of studies were encountered between the authors.We estimated the main pooled effects on outcomes of minimum diet diversity (MDD) and diet diversity score (DDS), two indicators based on counts of food groups consumed over a given period that are widely used to assess dietary diversity in low-income countries .The MDD is a score developed by the World Health Organization (WHO) that assesses diet diversity among children aged 6-23 months as part of infant and young child feeding (IYCF) practices . The MDDP values, we calculated the t-statistic and used the t-statistic to calculate Cohen’s d.The diet diversity score (DDS) is a measure of population-level diet diversity that can be measured at household-level to assess household food security status or at the individual level for diet diversity. The DDS specifies the average number of food groups out of seven pre-specified food groups consumed by the target group the prior day. This score has been validated against the micronutrient adequacy of a diet in young children 6-23 months  as well We stratified our findings by treatment comparison in order to clearly distinguish between those studies with a naïve control , and those studies with a control that received some form of agricultural support . This distinction allowed us to better understand the implications of the meta-analysis considering the variation among program and study designs.metafor package [2I proportion. The trim-and-fill method was used to test for publication bias. Effects were pooled across the 6-23.9-month age group in the primary analysis. The 6-23.9-month age group was prioritized as it has been widely validated and because the first 1000 days of a child’s life are the critical period for nutrition interventions [Effect size estimates were pooled using random-effects meta-regression models. Analyses were conducted using the R software   and the  package . We repoThe included articles (n = 9) evaluate a range of nutrition-sensitive agriculture interventions. Most of the programs included in-kind transfers and almost all included other complementary program components such as agriculture trainings or BCC around health and nutrition. The intervention components of the programs included in our analysis are outlined in Olney et al 2015)  evaluate15  evaluAs a final step, we verified the outcomes of interest and CIs with the original study authors and gathered outstanding measures and sample sizes as necessary to complete our analysis.First, we show summaries by outcome of interest: MDD and DDS. We look at comparisons both between and within studies (‘within studies’ in the sense that studies with separate treatment arms were included). Overall, both across and within studies, there were more reported MDD outcomes than DDS outcomes .Overall, we find 4 studies of 9 comparisons suggest a benefit in OR for MDD from a sample of n = 5292 and 3 studies of 6 comparisons suggest a benefit in DDS from a sample of n = 4921 from our pooled analysis of nutrition-sensitive agriculture interventions on child diet diversity (6-23.9 months) (P = 0.48).Nutrition-sensitive agriculture interventions significantly increased the odds of children aged 6-23.9 months reaching minimum diet diversity    (P < 0.001) and the 2I proportion was 63.3%. Among the 14 comparisons within 9 studies included in the DDS meta-analysis, the Cochrane Q test was 68.98 (P < 0.001) and the 2I proportion was 81.7%. Both suggest substantial heterogeneity between studies and support the use of the random effects model. The trim-and-fill method detected no evidence of publication bias, adding no hypothetical studies to the data set  as shown in the 2013 Lancet series . There iThe results of this study can be used to provide parameters for modeling tools that estimate the impact of scaling-up nutrition interventions. This process would be a first step to consider these types of interventions for policy decisions, which currently do not allow policymakers to factor in nutrition-sensitive agriculture programs. These parameters could be updated as the evidence on these interventions grows. One example for potential use of these estimates is in the mathematical modeling of intervention coverage, such as with the Lives Saved Tool (LiST). LiST was developed to generate estimates of the impact of changes in coverage for maternal, newborn, child health and nutrition (MNCHN) interventions on cause-specific mortality in low- and middle-income countries (LMICs). LiST calculates changes in mortality due to intervention coverage change, effectiveness and the percentage of cause-specific mortality that the intervention could affect .One approach would be to model improvements in diet diversity with MDD as a diet quality outcome in LiST, doing so through changes in coverage or through direct entry of changes in MDD. This would allow for policy-relevant comparisons of how nutrition-sensitive agriculture affects a given impact pathway relative to other interventions. This would be a step forward despite the limitations which generally apply to LiST and other modeling software. This approach could also theoretically be used to incorporate other outcome measures from nutrition-sensitive interventions. Diet diversity was the easiest outcome to synthesize as most studies measured outcomes consistently and there is a relatively good consensus on the evidence from the impact pathways. However, similar challenges remain in incorporating other outcomes of multisectoral nutrition programs into LiST due to the lack of coherence in design and evaluation and the existence of multiple outcomes or benefits. In particular, the constraints in LiST also entail careful consideration of the overlap of program impact pathways and the risk of double-counting potential effects. For example, an intervention promoting both food supply and demand-side components, such as agricultural and marketing programs with nutrition BCC, would require separation of the impacts of the supply- and demand-side pathways on stunting and/or mortality to avoid double-counting. This accounting of the intermediate effects along the demand and supply pathways is not straightforward.Careful incorporation of the effects of nutrition-sensitive interventions on the diet diversity of young children in this widely-used software could aid policymakers, implementers and donors in understanding the benefits of these interventions. While nutrition-sensitive agriculture programs do not necessarily have a direct effect on nutrition outcomes, this study shows that dietary improvements are very plausible intermediate results. Program designers and evaluators can be more explicit about this conceptual link. Nutrition-related interventions often measure stunting as the key indicator of success. With the ongoing nutrition transition, the focus has also shifted towards diet quality. This entails also viewing a quality diet as an endpoint. Diet diversity is a proxy of adequacy of nutrient intake, and as such, it is an indicator of diet quality with intrinsic value and benefit.Evaluation designs of nutrition-sensitive agriculture interventions are heterogenous, which complicates synthesis. Many of the studies included in the meta-analysis were unadjusted comparisons and several only presented endline measures of diet diversity. Also, there was consistent measurement and homogeneity in the definition of food groups within indicators but the recall periods varied . Nutrition-sensitive interventions by design aim to improve multiple health and nutrition outcomes. Many outcomes affected by nutrition-sensitive interventions were not analyzed in our approach. This raises the question of how to incorporate benefit streams from nutrition-sensitive programs not captured by this methodology. Further impact pathways could be assessed as the evidence base grows and the effect sizes of other outcomes become available. We also did not examine interventions that were nutrition BCC or education only. This is because our focus was specifically on nutrition-sensitive agriculture programs and prior analyses have covered this area with the intention of incorporation into LiST .Nutrition-sensitive agricultural interventions that include BCC have a significant positive effect on the odds of achieving minimum diet diversity and on improving diet diversity scores for children aged 6-23.9 months and 6-60 months. These estimates demonstrate the contributions of nutrition-sensitive agriculture interventions to diets, as well as show the potential of linking to distal outcomes like stunting. Synthesizing evidence on the impacts of nutrition-sensitive agriculture interventions on child dietary diversity can contribute to decision-making on the relative benefits of nutrition-sensitive interventions with other MNCHN interventions including nutrition-specific programs.


The rapidity of SARS-CoV-2 vaccination around the world has substantially reduced the number of new cases of COVID-19 and their severity in highly vaccinated countries. The unanticipated efficacy of SARS-CoV-2 vaccines in older adults has been very encouraging but the longevity of vaccine immunity is currently unknown and protection against emerging variants may be lower. Adoptive immunotherapy with neutralizing mAb may offer an alternative for poor vaccine responders, while the mechanisms underlying failure to respond are still unclear. Further studies of B and T cell responses and their regulation particularly in older populations will provide a more solid foundation to develop suitable approaches to optimize vaccine responses of older adults who fail to mount a durable response. Vaccination is the most effective way of preventing serious consequences of infections . The altEven with the unexpected success of COVID-19 vaccine, some important questions remain to be addressed. The actual longevity of the immune protection induced by vaccination is not yet known, which is especially critical for the old population who are generally less robust immunologically and have lower reserves of resources to deal with challenges. Is an additional vaccine boost necessary for such individuals, and if so when would be the best time? What are the major immune defects of these older adults in terms both of innate immunity and SARS-Cov-2 specific adaptive immunity? What are the available options for these most vulnerable older adults? A better understanding of age-associated changes of immune cells and their regulation is critical for developing specific remedies most needed in older adults.The relatively low efficacy of the seasonal influenza vaccine in older populations has been a constant reminder of the need to develop more effective vaccines for older adults whose immune system is considered less robust than their younger counterparts. However, the initial results from the clinical trials of COVID-19 vaccines with a limited number of older recipients (≥ 65 years of age) were unexpectedly encouraging. The Pfizer–BioNTech BNT162b2 mRNA vaccine induced a good antibody titer 7- and 14-days post-second dose in the group of 65- to 85-year-old compared to the younger age group (18–55 years old) [A recent series of publications that examined the efficacy of these COVID-19 vaccines in the real-world has confirmed these findings from the clinical trials and provided new information. First, analysis of the effectiveness of the BNT162b2 and ChAdOx1-S vaccines for preventing confirmed Covid-19 symptoms, admissions to hospital, and deaths of 156,930 adults aged 70 years and older in the UK showed that the effectiveness of BNT162b2 is 61% (51 to 69%) from 28 to 34 days after vaccination whereas the effectiveness of ChAdOx1-S is 73% (27 to 90%) from day 35 onwards . A singlThe general state of health of older adults is highly variable, and participants in clinical trials are likely healthier than those in the general older population. In this respect, the residents of the long-term care facilities (LTCF) are likely reflecting the less healthy older adults. Two recent reports analyzed BNT162b2 vaccine effectiveness in LTCF residents: one examined 39,040 LTCF residents  in Denmark and found that there was no protective effect after the first dose but 64%  after the second . AnotherThe ultimate solution for treating those older poor vaccine responders relies on a better understanding of the mechanisms underlying the general age-associated dysregulation of immunity as well as any individual-specific defects. The longer-term goal is to design vaccine and immunization schemes specifically for the older populations including increased dose, different adjuvants, and heterologous vaccination. At the moment, passive immunization or serotherapy remains an available option which has been used to combat infectious disease for over a century . Over thThe initial clinical trials of the neutralizing mAb (LY-CoV555) were targeted to mild-to-moderate COVID-19 in adults and pediatric patients 12 years and older and showed a promising ability to accelerate the natural decline in viral load over time . A cockthttps://www.ndm.ox.ac.uk/files/coronavirus/covid-19-infection-survey/finalfinalcombinedve20210816.pdf). Like the measure of influenza vaccine response, the neutralizing antibody titer of COVID-19 vaccine is considered as a major indicator of immune protection from infection and disease. In the case of mild COVID-19 patients, a three-month follow-up study showed that antibodies capable of neutralizing SARS-CoV-2 were present in most people [The success of vaccination in reducing new COVID-19 cases and severe disease is assessed weeks or months post-vaccination. Studies of the adaptive immune response of COVID patients show antigen-specific B and T (both CD4 and CD8) cell responses , 21. Butt people . Anothert people  but it it people . Thus, aCell-mediated immunity plays an essential role in the control of viral replication and eventual viral clearance. Studies of COVID-19 patients have shown a rapid T cell response to different SARS-CoV-2 proteins including S protein  and the COVID-19 vaccination has yielded encouraging results in older populations in the real world following clinical trials, but there may still be a need for supplementary treatments for the older population in general and for others suboptimal responders. Serotherapy is currently an alternative for those older adults that respond poorly to vaccination. The longevity of vaccine immunity and its effectiveness against different variants are uncertain and will need more carefully designed longitudinal studies. The immune response to SARS-CoV-2 is a highly coordinated process and various level of dysregulation could contribute to the failure of effectively combating the disease in older adults [


There are nine DSB hot spots located in the non-transcribed spacer of human rDNA units. Circular chromosome conformation capture data indicate that the rDNA clusters often shape contact with a specific set of chromosomal regions containing genes controlling differentiation and cancer, and often possessing the DSB hot spots. The data suggest a mechanism for rDNA-mediated translocation, and some of them could lead to tumorigenesis. Here, we searched for translocations in which rDNA clusters are involved. WGS data of normal T cells and NK-cell lymphomas from the same individuals were used. We revealed numerous translocations in which rDNA units are involved. The sites of these translocations in normal T cells and in the lymphomas were mostly different, but occurred at about the same frequency in both cell types. We conclude that oncogenic translocations lead to dysregulation of a specific set of genes controlling development.Endogenous hot spots of DNA double-strand breaks (DSBs) are tightly linked with transcription patterns and cancer. There are nine hot spots of DSBs (denoted Pleiades) in human rDNA units that are located exclusively inside the intergenic spacer (IGS). Profiles of Pleiades coincide with the profiles of γ-H2AX, suggesting a high level of in vivo breakage inside rDNA genes. The data were confirmed by microscopic observation of the largest γ-H2AX foci inside nucleoli in interphase chromosomes. Circular chromosome conformation capture (4C) data indicate that the rDNA units often make contact with a specific set of chromosomal regions containing genes that are involved in differentiation and cancer. Interestingly, these regions also often possess hot spots of DSBs that provide the potential for Robertsonian and oncogenic translocations. In this study, we searched for translocations in which rDNA clusters are involved. The whole genome sequence (WGS) data of normal T cells and NK-cell lymphomas from the same individuals revealed numerous translocations in which Pleiades were involved. The sites of these translocations in normal T cells and in the lymphomas were mostly different, although there were also some common sites. The genes at translocations in normal cells and in lymphomas are associated with predominantly non-overlapping lists of genes that are depleted with silenced genes. Our data indicate that rDNA-mediated translocations occur at about the same frequency in the normal T cells and NK-lymphoma cells but differ at particular sites that correspond to open chromatin. We conclude that oncogenic translocations lead to dysregulation of a specific set of genes controlling development. In normal T cells and in NK cells, there are hot spots of translocations at sites possessing strong H3K27ac marks. The data indicate that Pleiades are involved in rDNA-mediated translocation. Chromosomal translocations are a physiologic mechanism of DNA recombination in germline cells and in lymphocyte development. Although these mechanisms have been studied for several decades, they are still not fully understood. Chromosomal translocations are common in cancers and more frequently occur between neighboring chromosomal regions ,2. As a Natural killer cells play an important role in the innate immune system that controls several types of tumors and infections . NK cellOur data indicate that active rDNA clusters are involved in translocations in both types of cells, particularly in regions with actively transcribed genes, but the spectra of the target genes in these cell types differ. The same rDNA-mediated hot spots of translocations are found in normal and cancer cells corresponding to the hot spots of inter-chromosomal contacts of nucleoli within specific genomic regions.We used the following procedure to find translocations. The data from the European Genome Archive  were anaFor each SAM file, we used Samtools  1.6 to sThe rDNA-mediated translocation-associated amplicons  were mapThe mapping regions were assigned to genes in the following way. Ensembl genome annotation hg19/GRCh37p.13 v.87 was used to obtain the list of genes. The gene names, IDs, and chromosome coordinates were extracted from the annotation file by the R script with the help of refGenome and dplyr libraries. The intersections between the rDNA-mediated translocation mapping file and the gene list were found by intersectBed [EcoRI enzyme and ligation of extensively diluted DNA to favor intramolecular ligations. To shorten the ligation products, digestion with FaeI was performed followed by ligation of diluted DNA samples to favor circularization. The details are described in DNA samples for the 4C experiments were isolated according to procedures described previously ,7. HEK29We performed expression analysis for T and NK cells uniformly. T-cell RNA-Seq data  and NK-cell RNA-Seq data  were used. The Trimmomatic  tool was4C-rDNA genome-wide mappings were performed for human cell line datasets HEK293T (GSM3434713 and GSM3434714), K562 (GSM5351031 and GSM5351032), and hESM01 (GSM5351029 and GSM5351030) uniformly. Adapters were removed according to the appropriate GEO descriptions. The filtered datasets were aligned to the hg19/GRCh37p.13 human genome by the bwa mem algorithm. Samtools was used to remove unaligned reads, sort, and convert alignment files to the BAM format. Then, BAM files were converted to the bedGraph profiles by the genomeCoverageBed  databaseThe following genome-wide fold change compared to the control for hg19 profiles were downloaded from the Encode  project:All the epigenetic charts were created by the SeqPlots  R packagEpigenome chromatin state statistics were calculated for the core 15-state model (five marks) for the data downloaded from NIH Roadmap Epigenomics  for the U-test to verify whether rDNA-mediated translocation gene-subset expression values (expression of genes that intersected with rDNA-mediated translocations by genome-wide mapping) and the full expression dataset values originate from the same distribution. We obtained p = 0.0022 for the paired T-cell full expression set and translocation-associated genes subset, and p = 0.0013 for the paired NK-cell full expression set and translocation-associated genes subset. We obtained p = 0.033 for the Mann–Whitney U-test for the expression values of T-cell and NK-cell subsets, which means that we can reject the null hypothesis and conclude that translocation-associated gene expression value subsets are significantly different between T and NK cells.We applied the non-parametric Mann–Whitney We tested the statistical significance of the difference between epigenome states with the independent samples t-test. All cases that significantly differ are marked by asterisks.To search for rDNA-mediated translocations, we used the dataset with accession EGAD00001003271, which contains the whole genome sequence (WGS) of T cells and NK-cell lymphoma, from the European Genome-phenome Archive. The dataset contains 102 paired samples from tumor (NK cells) and normal (T cells) cells from the same individual. The details of the search are described in the We detected that the Pleiades coincide with translocation sites in rDNA units, which indicates that the hot spots of DSBs are involved in translocation events. The numbers of detected translocations at different hot spots of DSBs in rDNA units significantly vary .The most frequent translocations were formed at R3. The frequencies likely depend not only on the frequencies of DSBs in rDNA but also on the DSB frequencies at a target site. The 3D structure of the rDNA units is also important for establishing the contacts with different genomic regions . The traAs we detected no connection between the translocation frequencies in normal and cancer cells, next, we searched for putative differences in genes that reside at the translocations in T cells and NK-cell lymphomas. We assumed that sites of the translocations in normal T cells and NK-cell lymphomas could differ, depending on the distinct patterns of rDNA contacts and chromatin structures at the target sites in each cell type. These differences in translocation sites may affect different sets of genes in these cells and thus give rise to either normal or cancer phenotypes. For this search, we mapped all detected translocations in the human genome using the non-rDNA halves of the amplicons (see Methods) to obtain lists of the genes located close to the translocation sites (±5 kb) in both cell types . PreviouFHIT  further downstream of the gene. Another large tumor suppressor gene that underwent translocation in NK-cell lymphomas is WWOX (four translocations), which corresponds to another fragile site  with cell projection  search. The target genes in T cells were associated with a number of biological process items relating to cell development and neuron differentiation . In NK-cojection . Among tojection B. Nevertojection D. These Previously, it was shown that there are multiple rDNA-contacting sites that are decorated by the prominent H3K27ac marks within chromosomal regions up to 100 kb in length that probably correspond to super-enhancers ,7. We neThe translocations sites exactly correspond to the regions with very frequent rDNA contacts in three human cell lines  . The funLINC00486, which is a gene of about 100 kb in chr2, possesses 219 translocations in NK-cell lymphomas  are characteristic of translocation sites in both cell types, although there are some differences in the distribution of these marks around the zero point of translocation sites. The active H3K27ac mark is characteristic of the hot spots of both rDNA-contacting sites and rDNA-mediated translocations . The hetp < 0.003). These differences in chromatin states between the two cell types suggest that rDNA contacts during differentiation occur within different genomic regions in different cell lines, which is why the patterns of translocated genes are different in the T cells and NK-cell lymphomas (ymphomas A.DUX4 genes, which are silenced and form frequent contacts with rDNA [Translocations occur between closely located broken chromosomes. The critical distance between chromosomal regions essential for translocation is not known, but the fact that inter-chromosomal rDNA contacts, which were mapped at a resolution of ±2.5 kb . Compartith rDNA ,30, are Recently, an unexpected diversity of NK cells with distinct transcriptomes was described, including a population of NK cells associated with the expression of rDNA . The datThe etiology of NK-cell lymphoma is unknown, although there is a strong association with the Epstein–Barr virus . No specCTCF gene in NK-cell lymphomas (CTCF could disrupt its function. Recently, it was shown that CTCF insulators serve as putative cancer drivers in different tumors, including lymphomas [Translocations inside the big intron in the ymphomas , B mightymphomas .About 100 somatic translocations per genome were detected in both T cells and NK-cell lymphomas . The majAnalysis of genomic features of lung cancer patients revealed mutational signatures in B lymphocytes that are coupled with distant chromosomal rearrangements, some of which correspond to fusions involving genes with important functions . These dWe conclude that in normal cells, rDNA-mediated translocation occurs in somatic cells and reflects the inter-chromosomal contacts of nucleoli with genes that are involved in development and differentiation. We estimate that the frequencies of these translocations are about 100 per genome for the entire population of T or NK cells in an individual. If a translocation is deleterious, a particular cell could be eliminated or give rise to a cancer stem cell. In general, all chromosomal contacts that are connected either with chromosome packaging or with the regulation of gene expression, coupled with DNA breakage, could lead to translocations and cancer. This study aims to uncover the role of rDNA-mediated translocation in tumorigenesis. It was predicted that the DSB hot spots in rDNA repeats that shape frequent inter-chromosomal contact with genes controlling differentiation and development could lead to translocations that give rise to cancer transformation. Analysis of normal T cells and NK-cell lymphomas from the same individuals showed that there are rDNA-mediated translocations in both cell types. However, the translocations in normal cells and tumor cells affect different set of genes that control development. Our data indicate that oncogenic rDNA-mediated translocations lead to dysregulation of a specific set of genes controlling development. The data suggest the role of rDNA units in cancer genesis.


Data collected from a moving lidar sensor can produce an accurate digital representation of the physical environment that is scanned, provided the time-dependent positions and orientations of the lidar sensor can be determined. The most widely used approach to determining these positions and orientations is to collect data with a GNSS/INS sensor. The use of dual-antenna GNSS/INS sensors within commercial UAS-lidar systems is uncommon due to the higher cost and more complex installation of the GNSS antennas. This study investigates the impacts of using a single-antenna and dual-antenna GNSS/INS MEMS-based sensor on the positional precision of a UAS-lidar generated point cloud, with an emphasis on the different heading determination techniques employed by each type of GNSS/INS sensor. Specifically, the impacts that sensor velocity and acceleration (single-antenna), and a GNSS compass  have on heading precision are investigated. Results indicate that at the slower flying speeds often used by UAS (≤5 m/s), a dual-antenna GNSS/INS sensor can improve heading precision by up to a factor of five relative to a single-antenna GNSS/INS sensor, and that a point of diminishing returns for the improvement of heading precision exists at a flying speed of approximately 15 m/s for single-antenna GNSS/INS sensors. Additionally, a simple estimator for the expected heading precision of a single-antenna GNSS/INS sensor based on flying speed is presented. Utilizing UAS-lidar mapping systems with dual-antenna GNSS/INS sensors provides reliable, robust, and higher precision heading estimates, resulting in point clouds with higher accuracy and precision. Three-dimensional mapping of natural or built environments using high-resolution light detection and ranging (lidar) sensors onboard unoccupied aerial systems (UAS) is now a common practice. Recent advancements in robotics and real-time computing have led to the possibility of autonomous UAS-lidar mapping operations in global navigation satellite system (GNSS)-denied environments  . HoweverA GNSS receiver can estimate position, velocity, and time (PVT) by observing encoded radio frequency (RF) signals from a constellation of medium Earth-orbit satellites. The encoded RF signal from each satellite allows a GNSS receiver to estimate the signal’s travel (transit) time, the satellite’s clock error, and the position of the satellite when the signal was transmitted within a global reference frame. The transit time estimates are multiplied by the speed of light to produce range estimates between the GNSS receiver and the satellites. However, the transit time estimates are all biased by a common systematic error known as the receiver’s clock offset. By observing encoded RF signals from a minimum of four satellites, a GNSS receiver can simultaneously estimate its clock offset to a precision of less than 30 nanoseconds  and its An INS consists of triads of orthogonally mounted accelerometers and gyroscopes, collectively called an IMU, in addition to mechanization algorithms, a gravity model, and a computer . The accCapitalizing on the complementary characteristics of GNSS and INS, their synergistic integration overcomes their individual drawbacks and provides a more accurate and robust navigation solution than either could achieve on its own . EstimatThe navigation solution—commonly referred to as a trajectory—contains the time-tagged position estimates , angular orientation estimates , and velocity estimates for the GNSS/INS sensor. These estimates are commonly reported at rates of 200 Hz or higher. The highest accuracy position estimates are achieved when differential GNSS techniques based on the carrier phase observable are used, provided the carrier phase ambiguity terms are resolved to their correct integer values. High accuracy roll and pitch orientation estimates are achieved when the direction of gravity is precisely determined by the accelerometers, which is improved when GNSS measurements are used to account for the impact of dynamic motion on the accelerometer readings . Unlike For single-antenna GNSS/INS sensors, a combination of a triaxial magnetometer and dynamic alignment is widely employed for heading determination. This type of GNSS/INS sensor loses the observability of heading during low-dynamic or static situations in which dynamic alignment becomes impossible and commonly falls back on the lower accuracy magnetometers’ observations to continue stabilizing heading . For duaprovide the theoretical foundations behind different heading determination techniques used by GNSS/INS sensors;detail the practical considerations for implementing these heading determination techniques during UAS-lidar field operations ;compare the precisions of heading orientation estimates reported by a single-antenna and a dual-antenna GNSS/INS sensor at different UAS flying speeds; andassess the positional precisions of UAS-lidar point clouds generated from a single-antenna and a dual-antenna GNSS/INS sensor.Only a few studies have been published that partially address the impact of GNSS/INS heading estimates on the positional precision of UAS-lidar point clouds. In , a theorAn Applanix APX-18 UAV sensor  was used to collect the GNSS/INS data for this study . The APXThe use of a magnetometer for heading determination is the simplest method as the magnetic field of the Earth can be directly measured and used to infer the direction of true north. However, the magnetic vector at the position of the magnetometer will likely have contributions from other sources  . TherefoMost GNSS/INS sensors used in commercial UAS-lidar systems including the Applanix APX-18 UAV utilize MEMS-based IMUs. These types of IMUs often experience gyroscope bias and noise errors that exceed the Earth’s rotation rate ; therefore, the stationary gyro-compassing method for determining heading is not feasible . The preThe primary benefit of a dual-antenna GNSS/INS sensor is the capability of using the GNSS compass method for heading determination. A GNSS compass is able to compute the heading angle estimate, measured as the clockwise angle from true North, and the elevation (tilt) angle estimate of the compass vector within a local level (east–north–up) frame . The prehσ is the precision of the relative displacement between the GNSS antennas in the local horizontal plane. The GNSS compass method employs differential GNSS positioning using carrier phase measurements to precisely determine the relative displacements of the GNSS compass vector within a local frame. For carrier phase measurements to produce precise results, the unknown ambiguity terms must be correctly resolved to their integer values. Once this has been done successfully, the carrier phase measurements will act as very precise pseudo-range data, which makes very precise orientation determination possible . Using tBoth single-antenna and dual-antenna GNSS/INS sensors utilize the dynamic alignment method for heading determination during UAS-lidar mapping operations. Dynamic heading alignment works by comparing the accelerometer measurements from the INS solution and the position and velocity measurements from the GNSS solution to estimate the internal dynamics of the system ,13. The A simpler concept that illustrates how sensor dynamics can be used to determine heading is the GNSS velocity method, which is sometimes used to initialize heading within the dynamic alignment method . The GNSInitializing the heading from a GNSS-derived velocity is only applicable if the forward axis of the navigation reference frame is parallel to the velocity vector, which is a reasonable assumption for most land vehicle navigation applications , or if tEquation (7) illustrates one of the conceptual relationships between heading precision and GNSS/INS sensor dynamics: as velocity increases, heading precision improves c. HoweveUAS-lidar mapping systems that directly georeference lidar observations require high-accuracy trajectory data to produce high-accuracy point clouds. Understanding how trajectory errors propagate to the positional accuracy of a UAS-lidar point cloud is an important consideration for hardware selection and mission planning. Most GNSS/INS sensor manufacturers report the performance specifications of their products in terms of trajectory errors as shown in Several published works have rigorously analyzed the effects of trajectory errors on point cloud coordinate accuracies for both UAS-based  and occp) observed by a UAS-lidar system within a north–east–down local level reference frame (superscript l). The lidar sensor reference frame is denoted by the superscript s and the GNSS/INS sensor reference frame is denoted by the superscript n.Equation (8) expresses the 3D coordinates of a point  and the navigation reference frame (n) are perfectly aligned  illustrates that heading precision has no effect on the precision of the Z  coordinate of an observed point. If it is assumed that the UAS-lidar system is operated while nominally level  and (13) illustrate that the X and Y coordinate standard deviations [To represent the horizontal precision of an observed point, the distance root mean square measure (viations . The dRMEquation (15) illustrates the relationship between lidar observations, GNSS/INS heading precision, and the horizontal precision of an observed point under level operating conditions . The heaα6000 RGB camera  (The UAS-lidar mapping system used in this study was an implementation of the open-source Open Mobile Mapping System (OpenMMS)   and cons, Japan) a. The ma, Japan) b that opThe experiment involved collecting UAS-lidar mapping data during four separate flights (mission) as shown in A local GNSS reference station was established at a location within the project area and consisted of a Trimble R10 GNSS receiver/antenna installed on a calibrated tribrach and was secured to a standard wooden-legged tripod. The position of the reference station as shown in Applanix POSPac UAV software  was used to post-process the APX-18 GNSS/INS data with the static reference station GNSS data to produce two separate smoothed best estimate trajectories (SBETs) for each of the four missions. The horizontal and vertical datum parameters and reference station coordinates were input into POSPac. The first processing run had the GAMS functionality enabled. GAMS utilizes the GNSS observations from both antennas in order to leverage the GNSS compass observations within the resulting trajectory estimates. The second processing run had the GAMS functionality disabled with GNSS observations used from only the primary antenna. The SBET position and orientation estimates including the associated precisions were exported to an ASCII file after each processing run. The ASCII trajectory files and the collected lidar data were then processed with OpenMMS software  to generate two true-color georeferenced point clouds for each mission. The same localized transverse Mercator projection applied to the GCPs was used to produce ground-referenced coordinates for the point clouds. A vertical accuracy assessment was performed on each georeferenced point cloud by comparing the RTK-surveyed GCPs with the nearest lidar point within the point cloud. The assessment followed the American Society for Photogrammetry and Remote Sensing (ASPRS) Positional Accuracy Standards for Digital Geospatial Data . No obviThe lever-arm offsets between the origin of the lidar sensor and the center of the GNSS/INS sensor were taken from the hardware dimensions within the OpenMMS documentation with a measurement precision of 0.1–0.2 cm . The levThe boresight rotations for both the lidar sensor and the camera with respect to the GNSS/INS sensor’s navigation reference frame were estimated as part of the first mission . Specifically, the flight A trajectory file with GAMS enabled was used within the boresight calibration procedures. The estimated boresight rotations were then held constant and applied within the processing of the remaining flights. The lidar sensor boresight calibration utilized a parametric least-squares (PLS) optimization of the RMS errors for planar surfaces found in areas of the point cloud that were observed within overlapping flight lines. Similarly, the camera boresight calibration utilized a PLS optimization of the residuals between the camera’s GNSS/INS-derived exterior orientation parameters (EOPs) and the EOPs resulting from a photogrammetric bundle adjustment. The details of the boresight calibration methods are beyond the scope of this study; see  for furtA primary objective of this study was the assessment of the heading estimates produced by the Applanix APX-18 UAV with and without the use of GAMS. As a commercially available sensor designed for use on multiple UAS platforms, the results of this APX-18 analysis are intended to serve as a representative performance of typical single-antenna and dual-antenna GNSS/INS MEMS-based sensors used within UAS-lidar mapping systems. The methods used to achieve this objective included both theoretical and practical analyses. First, an investigation was conducted into the theoretical concepts underlying the different heading determination techniques employed by GNSS/INS sensors including analytical formulas for the expected precisions. Then, a theoretical analysis was performed examining the impact of heading precision on the positional precision of a UAS-lidar point cloud when utilizing direct georeferencing. Lastly, a field experiment was conducted that collected multiple UAS-lidar mapping datasets over a single project area. Each dataset was collected at a different horizontal speed to ensure the APX-18 experienced a variety of sensor dynamics. The trajectories and point clouds from each dataset were analyzed, compared to expected values and trends, and used to support the conclusions of this study.The slow horizontal velocity experienced by the APX-18 sensor during flight A allowed for the best analysis of the impact of using a single versus dual-antenna GNSS/INS sensor to estimate heading. As the horizontal velocity of the UAS was the slowest of all the flights, the differences between the single-antenna and dual-antenna heading precisions would be maximized. As illustrated in An inspection of The heading precisions for the single-antenna GNSS/INS trajectory varied between 0.28° and 0.45° with a mean of 0.369°, and the heading precisions for the dual-antenna GNSS/INS trajectory varied between 0.07° and 0.11° with a mean of 0.082°. These results align with the manufacturer’s heading error performance specifications for the APX-18 sensor shown in The different horizontal velocities experienced within the flights allowed for an analysis of the impact of increasing velocity on estimating heading using a single-antenna and dual-antenna GNSS/INS sensor. An inspection of vhσ) and heading precision achievable limit (cσ) parameters via a general least-squares adjustment. The resulting estimates were 0.015 m/s for vhσ, which agrees with the manufacturer’s velocity error performance specification for the APX-18 sensor shown in cσ. These results suggest that the GNSS velocity model may be a reasonable estimator of the expected heading precision for a single-antenna GNSS/INS sensor based on horizontal velocity. They also suggest that a point of diminishing returns for the improvement of heading precisions exists at a horizontal velocity of approximately 15 m/s for single-antenna GNSS/INS sensors. For each flight, the mean horizontal velocity of the APX-18 during the longer north–south flight lines was calculated. The shorter east–west flight lines were excluded as the APX-18 was moving at a considerably lower velocity during these flight lines, which introduced a bias within the mean velocity measures. The mean horizontal velocities and associated mean single-antenna heading precisions were then considered as observations produced by a theoretical GNSS velocity model  in The slow horizontal velocity experienced by the APX-18 sensor during flight A allowed for the best analysis of the impact of heading precision on the positional precision of a UAS-lidar point cloud. As the horizontal velocity of the UAS was the slowest of all flights, the APX-18 sensor was closest to being in a level orientation during this mission. The total tilt angle of the sensor, calculated with respect to the nadir direction, was typically less than 10° during each N–S flight line.θ) and vertical angle (α) for a point at the edge of a circular FoV are related by cos(θ)cos(α) = cos(W/2), where W is the total FoV angle . As a result, the two georeferenced point clouds produced from the single-antenna and dual-antenna trajectories for flight A were filtered to only include points that were observed within one of four narrow edge regions of the Mid-40′s FoV. For comparison, an additional narrow region of points least affected by the precision of the heading estimate, located at the middle of the FoV, were also included for analysis (A point observed near the edge of the circular field of view (FoV) of the Mid-40 lidar sensor is most affected by the precision of the trajectory heading estimate. The observable horizontal angle  and east (X) coordinate differences of the horizontal position differences within the four edge regions suggested the presence of a bias within the heading estimates for the single-antenna GNSS/INS trajectory, relative to the dual-antenna GNSS/INS trajectory. Computing the differences between the heading estimates from the single and dual-antenna GNSS/INS trajectories produced a mean difference of 0.27°. To investigate if this heading bias contributed to the horizontal position differences being considerably different for the north and south flow flight lines, it was used to adjust the single-antenna GNSS/INS heading estimates. Then, the horizontal position differences between the matched points of the single-antenna and dual-antenna point clouds were recomputed. An inspection of Using the theoretical point cloud horizontal precision model presented in Equation (15) also indicates that the horizontal position of a point at the middle of the FoV is not affected by the precision of the heading estimate. Therefore, the expected horizontal position difference between the two point cloud regions would be zero. However, Equation (11) indicates that heading precision has no effect on the vertical coordinate of an observed lidar point. Therefore, the vertical position differences between the single and dual-antenna point clouds within any of the five regions would be zero. An inspection of Due to the wide adoption of smaller, lower-cost MEMS-based IMUs within GNSS/INS solutions, hardware sensors that are suitable for UAS applications now exist. However, the ability to accurately determine heading with such sensors is often challenging, especially at the lower velocities often experienced during UAS operations. By utilizing two GNSS antennas, a real-time differential GNSS solution leveraging the millimeter precise carrier phase observable to determine heading is possible. Though widely employed in ground-based and sea-based applications, dual-antenna GNSS/INS sensors are not commonly used onboard UAS due to the increased cost, weight, and complexity of installing the dual GNSS antennas with an adequate separation onboard the airframe of the UAS. The principal objective of this study was to assess and understand the impacts of using either a single-antenna or a dual-antenna GNSS/INS sensor for UAS-lidar applications by collecting and analyzing field-collected data from a typical UAS-lidar mapping system.The positioning and navigation principles involved within GNSS and inertial-based systems were presented with a specific focus on heading determination. The theoretical relationship between a GNSS compass and heading precision was discussed, for which the results of this study supported the theory and provided compelling arguments that heading precision can be improved by up to a factor of five when a dual-antenna GNSS/INS sensor is used. Additionally, the theoretical relationship between the horizontal velocity of a GNSS/INS sensor and the heading precision was discussed and validated through the results of the four UAS-lidar flights conducted within this study. At higher horizontal velocities, a single-antenna GNSS/INS sensor can estimate heading to a level of precision that approaches that of a dual-antenna GNSS/INS sensor, but even at 15 m/s, the single-antenna heading estimates are still less precise than the dual-antenna estimates by a factor of 1.5. Additionally, a downside of collecting lidar observations while flying at higher horizontal velocities concerns a decrease in the point density of the generated point cloud. Interpolating between the experimental results of the test flights, an argument can be made that a balance between improving heading precision and maintaining point cloud density exists at a horizontal velocity between 5 m/s and 10 m/s for single-antenna GNSS/INS sensors. Dual-antenna GNSS/INS sensors are practically unaffected by horizontal velocity and maintain the ability to provide higher-precision heading estimates given adequate satellite visibility and a low multipath environment. The results of this study also indicated that the precisions of the remaining roll, pitch, and positional GNSS/INS trajectory estimates were negligibly impacted by using a single-antenna versus a dual-antenna or by changes in the horizontal velocity. Lastly, the theoretical relationship between the experienced heading precision of a GNSS/INS sensor and the positional precision of a resulting point cloud was discussed, for which the results of this study supported the theory and provided compelling arguments that a dual-antenna GNSS/INS sensor consistently produces a point cloud with improved 3D positional precision.In addition to the precision assessments performed in this study, discussions were presented that aim to provide useful information to UAS-lidar mapping practitioners with respect to sensor placement and alignment, the importance of sensor dynamics , and mission planning considerations . As reported in existing literature and confirmed by this study, the precision of the heading estimates of a GNSS/INS sensor directly impacts the 3D positional precision of a point cloud produced from a UAS-lidar mapping system, notably more so than any other trajectory estimate. Although the use of dual-antenna GNSS/INS sensors can increase the cost and complexity of a UAS-lidar mapping system, investing in a system with a dual-antenna GNSS/INS sensor is recommended, as it provides a simple solution to realizing higher-precision heading estimates and as a result, more accurate and precise point clouds.


Depression and anxiety are among the most common mental health conditions treated in primary care. They frequently co-occur and involve recommended treatments that overlap. Evidence from randomised controlled trials (RCTs) shows specific stepped care interventions to be cost-effective in improving symptom remission. However, most RCTs have focused on either depression or anxiety, which limits their generalisability to routine primary care settings. This study aimed to evaluate the cost-effectiveness of a collaborative stepped care (CSC) intervention to treat depression and/or anxiety among adults in Australian primary care settings.n = 158) from 30 primary care clinics in the Netherlands. The CSC intervention involved two steps: (1) guided self-help with a nurse at a primary care clinic; and (2) referral to specialised mental healthcare. The cost-effectiveness model adopted a health sector perspective and synthesised data from two main sources: RCT data on intervention pathways, remission probabilities and healthcare service utilisation; and Australia-specific data on demography, epidemiology and unit costs from external sources. Incremental costs and incremental health outcomes were estimated across a 1-year time horizon. Health outcomes were measured as disability-adjusted life years (DALYs) due to remitted cases of depression and/or anxiety. Incremental cost-effectiveness ratios (ICERs) were measured in 2019 Australian dollars (A$) per DALY averted. Uncertainty and sensitivity analyses were performed to test the robustness of cost-effectiveness findings.A quasi-decision tree model was developed to evaluate the cost-effectiveness of a CSC intervention relative to care-as-usual (CAU). The model adapted a CSC intervention described in a previous Dutch RCT to the Australian context. This 8-month, cluster RCT recruited patients with depression and/or anxiety (dominant to 25 345) fell below the willingness-to-pay threshold of A$50 000/DALY. ICERs were robust to changes in model parameters and assumptions.The CSC intervention had a high probability (99.6%) of being cost-effective relative to CAU. The resulting ICER (A$5207/DALY; 95% uncertainty interval: This study found that a Dutch CSC intervention, with nurse-delivered guided self-help treatment as a first step, could potentially be cost-effective in treating depression and/or anxiety if transferred to the Australian primary care context. However, adaptations may be required to ensure feasibility and acceptability in the Australian healthcare context. In addition, further evidence is needed to verify the real-world cost-effectiveness of the CSC intervention when implemented in routine practice and to evaluate its effectiveness/cost-effectiveness when compared to other viable stepped care interventions for the treatment of depression and/or anxiety. Previous systematic reviews were used to identify RCTs of stepped care models for the treatment of depression/anxiety that had evidence of effectiveness and could be feasibly implemented in Australia. In-scope RCTs informed the design of a cost-effectiveness model based on the Assessing Cost-Effectiveness (ACE) approach – i.e. a framework previously developed to evaluate healthcare interventions in the Australian context  metric and costs in 2019 Australian dollars (A$). The model calculated incremental cost-effectiveness ratios (ICERs) which were evaluated with respect to an Australian willingness-to-pay (WTP) threshold of A$50 000 per DALY averted  were measured as 4-month probabilities and reported separately for depression and anxiety at 4-, 8- and 12-month intervals  comprised the difference in total DALYs averted between the intervention and comparator. ICERs were estimated by dividing net incremental costs by incremental DALYs averted.http://www.epigear.com/) was used to perform Monte Carlo simulation with 3000 iterations and produce 95% uncertainty intervals (95% UI) around all model outputs. Uncertainty parameters are presented in online Supplementary Table S4 for health outcome modelling inputs and online Supplementary Table S7 for cost analysis inputs. Uncertainty analysis results were presented on a cost-effectiveness plane, where incremental DALYs averted are plotted on the x-axis; net incremental costs are plotted on the y-axis; and the origin  represents the comparator. The cost-effectiveness plane is divided into four quadrants that each indicates how costly and effective the intervention is relative to the comparator. Cost-effectiveness acceptability curves were used to gauge the probability of the CSC intervention being cost-effective relative to different WTP thresholds.An uncertainty analysis was conducted to quantify the impact of input parameter uncertainty on the results of the cost-effectiveness model. The Ersatz program ; and including patient time and travel costs (SA2). Time and travel cost parameters are presented in online Supplementary Table S8.dominant to $25 345) which fell below the WTP threshold of A$50 000/DALY (see dominant to $23 570). When analysing anxiety only, wide uncertainty intervals were observed around the ICER . The CSC intervention had a 5.4% probability of being dominated, such that the cost of the CSC intervention exceeded the CAU comparator while simultaneously leading to poorer health outcomes. The cost-effectiveness plane for the analysis of depression/anxiety is presented in The CSC intervention was found to be cost-effective in treating depression/anxiety when compared with the CAU comparator. It produced an ICER of A$5207/DALY . Scenario analysis results are shown in online Supplementary Table S12. Despite higher ICERs being observed across every scenario, all ICERs remained below the WTP threshold of A$50 000/DALY.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., This exploratory analysis found that the Dutch CSC intervention had the potential to be cost-effective in treating depression/anxiety compared to the CAU comparator if adapted to the Australian context. These results were robust to changes implemented across scenario analyses. Even so, the univariate sensitivity analysis demonstrated that cost-effectiveness results were highly sensitive to changes to remission outcomes. Several international studies have examined the cost-effectiveness of alternative stepped care models incorporating low-intensity treatment as a first step for the treatment of depression only  for patients with mild-to-moderate depression/anxiety. Other lower intensity interventions may be as appropriate for mild-to-moderate cases – e.g. unguided self-help, guided self-help delivered online and watchful waiting. Moreover, any prospective adaptation of the CSC intervention may encounter issues around the availability of appropriately trained mental health nurses and the acceptability to stakeholders of a nurse-led treatment model within GP clinics. Limited access to specialised mental healthcare may also be an issue for people living in rural/remote regions of Australia.et al., et al., In Australia, government guidance on the wide-scale implementation of stepped care across the primary care setting has predominantly focussed on defining the types of care to be provided across different levels of mental illness severity .et al., et al., This study sourced best-available evidence to inform the cost-effectiveness model and underlying input parameters; and to apply conservative assumptions in the absence of data. Several limitations may impact on the validity of study findings. First, the cost-effectiveness model was based on an RCT conducted in the Netherlands (Oosterbaan This study found that a Dutch CSC intervention, with nurse-delivered guided self-help treatment as a first step, has the potential to be cost-effective in treating depression/anxiety if transferred to the Australian context. The CSC intervention would be a good candidate for adaptation and further testing as part of a broader stepped care approach implemented in the Australian primary care setting. However, further evidence is needed to verify the real-world cost-effectiveness of the CSC intervention when implemented in practice and to evaluate its effectiveness/cost-effectiveness when compared to other viable stepped care models for the treatment of depression/anxiety.


Helminths (parasitic worms) are a diverse group of organisms that utilize a wide range of species as their intermediate and definitive hosts. The nematodes consist of the whipworms, roundworms, hookworms and filarial worms, and these sit alongside the platyhelminth flatworms (or blood flukes) and tapeworms - all of which have species that cause serious disease in humans. Some species have free living stages, others rely on insect vectors for transmission, while some can reproduce to release live larval stages within their mammalian host. The diversity of infection route, larval migration within the host and the location of the adult parasite have major implications for the pathology and immune responses elicited by each species.Recent Advances in the Immunology of Helminth Infection – Protection, Pathogenesis and Panaceas.Here, we briefly outline the contributions to the Research Topic Zawawi and Else outline the challenges involved in helminth vaccine development, and review recent findings on the identification of suitable vaccine candidates as well as the results of recent pre-clinical and clinical trials in the context of soil-transmitted helminths. Silvane et al. investigate the protective immune responses induced by vaccination of mice with a peptide from a well-characterized protease inhibitor molecule made by the liver fluke Fasciola hepatica. Using a novel adjuvant formulation, FhKTM/CpG-ODN/Coa-ASC16 induced enhanced type 1 and type 17 responses and reduced liver pathology after F. hepatica infection.Many millions of people are infected with helminths world-wide , and thevia mucosal immune cross-talk  have been of particular interest to helminth immunologists in recent years , and theColombo and Grencis outline the models traditionally used to investigate soil-transmitted helminth infections in laboratory animals and highlight the major differences between these and natural infections of humans and wild rodents. They go on to discuss the potential benefits of using the ‘trickle-infection’ method for modelling more natural infections in the laboratory.Of course, much of what we know regarding host immune responses to helminth infections has been gained from laboratory infection models. In their extensive review, Bobardt et al., Wiedemann and Voehringer and Ryan et al. take an in-depth look at the molecules made by a range of helminth species to impact the immune response against them, thus allowing them to successfully invade and persist in their hosts for long periods of time.An area of great interest in the field has been the immunomodulatory effects of helminths on their hosts, and their potential use as therapeutic agents in inflammatory diseases . Recent Chauche et al. explain mechanistically how a truncated form of Alarmin Release Inhibitor from H. polygyrus (HpARI) binds to the cytokine interleukin (IL)-33 to prevent its degradation and enhance its actions in vivo. In contrast to the full-length form of HpARI which binds IL-33 and suppresses its actions, the truncated form HpARI_CCP1/2 amplifies IL-33-dependent responses to N. brasiliensis infection and fungal allergen administration. In a study by Jin et al. a protein from the excretory-secretory (ES) products of Trichinella spiralis - thioredoxin peroxidase-2 (TsTPX2) – is found to potently activate macrophages to a protective M2 phenotype, with the adoptive transfer of these antigen-activated macrophages limiting adult worm numbers significantly.Two original research papers examined individual helminth-derived immunomodulatory molecules in precise detail. Firstly, Ricafrente et al. use an innovative data-mining approach to identify potential gene targets for F. hepatica miRNAs within innate immune cells, thus providing information for the development of novel strategies for controlling liver fluke infection.Most of the helminth-derived immunomodulatory molecules characterized to-date are proteins. However, recently the potential importance of micro(mi)RNAs released in extracellular vesicles secreted by helminths has been investigated  . Importantly, this protection was ablated in mice lacking the interleukin-4/13 receptor alpha chain (IL-4Rα) and protection was not linked with regulatory T cell activity. Additionally, Filbey et al. show that infection significantly reduces skin inflammation in a model of contact hypersensitivity, likely via suppression of innate cell recruitment to the skin after allergen sensitization. Neutrophil-attracting chemokine levels, and neutrophil numbers in the skin of mice treated with the contact sensitizer dibutyl phthalate fluorescein isothiocynate (DBP-FITC), were significantly decreased by helminth infection.Two papers used the well-characterized gastrointestinal helminth Rajamanickam et al. focused on parameters associated with non-diabetic obesity and assessed outcomes in a human cohort before and 6 months after anthelminthic treatment. The predominant helminth species endemic to the Tamil Nadu region of southern India is the soil-transmitted GI helminth Strongyloides stercoralis which appeared to protect people from the inflammatory immune signature of non-diabetic obesity, a phenomenon that was reversed after worm clearance. An important review by Chetty et al. looks at the often overlooked field of female reproductive health, focusing on the impact of helminth infection on sexually-transmitted infections, female reproductive tract pathology and reproduction. Finally, Fonte et al. take a timely look at the possible impacts of concomitant infection with helminths and SARS-CoV-2.Three reviews in this Research Topic expertly outline the impact of helminth infection on a diverse range of human health concerns. Firstly, Recent Advances in the Immunology of Helminth Infection – Protection, Pathogenesis and Panaceas has offered an up-to-date insight into the diverse and collaborative field of helminth immunology. We would like to thank all of the contributing authors, editors, and especially all of the reviewers who dedicated their precious time in what has proved to be a most challenging year.An estimated quarter of the world’s population is infected with helminths, which clearly have wide-ranging and potent effects on the immune systems of their hosts. Much is yet to be discovered regarding the responses elicited by and the exciting potential uses of helminths. As guest Topic Editors we hope that the Research Topic All authors contributed equally to this manuscript. All authors contributed to the article and approved the submitted version.KF is funded by The Kennedy Trust for Rheumatology Research (via the Senior Research Fellowship of Dr John Grainger). CF is funded by the Canadian Foundation for Innovation (CFI - JELF 33617) and the Natural Sciences & Engineering Research Council of Canada (NSERC - RGPIN/04305-2014). PG is funded by the Australian National Health and Medical Research Council (NHMRC - 1105300). MS is funded by the National Institutes of Health .PG is a co-founder of Paragen Bio, a biotech company that aims to translate and commercialise hookworm-derived proteins for inflammatory diseases. This has previously involved investment from pharma (Abbvie Inc) and venture capitalist firms .MS is founder and president of the biotech company NemaGen Discoveries.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Chondroid tenosynovial giant cell tumour (TGCT) is an extremely rare disease affecting the temporomandibular joint (TMJ). This report details the peri-operative findings and treatment with custom TMJ replacement of an initially misdiagnosed chondroid TGCT involving the TMJ. Tenosynovial giant cell tumour (TGCT) is a remarkably rare benign proliferative disorder of the synovium and can be categorized into localized-TGCT and diffuse-TGCT (D-TGCT) types . The occA 33-year-old woman complained of a 3-month history of left-sided TMJ morning stiffness. She had never been treated nor undergone any previous TMJ procedures and reported an unremarkable medical history. Examination findings showed a small left-sided preauricular swelling with tenderness worse at the joint level. Mouth opening restricted by pain was 35 mm. Normal excursive movements and no malocclusion or lateral deviation was observed. Computed tomography (CT) and magnetic resonance imaging (MRI) of the TMJs showed: superior joint space effusion, multiple small low-signal intensity foci within the fluid and extensive erosions within the glenoid fossa, articular eminence and root of the zygoma  and 2. TArthroplasty (capsulectomy and discectomy) of the left TMJ with abdominal fat graft was performed. Capsule and soft tissue lesions extending into the bone were curetted and sent for histopathological analysis, which showed multinucleated giant cells and nodular immature chondroid metaplasia deemed to be a form of synovial chondromatosis.The patient was regularly reviewed reporting no improvement to stiffness on mouth opening. At her 3-month post-operative review, she complained of worsening stiffness to mouth opening. A follow-up CT of the TMJs portrayed extensive progressive bony erosion to the mandibular condylar head. This provoked a discussion with the pathologist to reconsider the diagnosis of the previously sent specimen. A histopathological revision reported a chondroid fibrohistioctyic lesion with overall features more in keeping with PVNS with chondroid metaplasia .The patient was subsequently planned for a second operation for resection of the affected tissue. To achieve clear surgical margins, this included the total resection of the left TMJ and the entire root of the zygoma along with the glenoid fossa. The TMJ was planned to be reconstructed with a custom TMJ prosthesis. Consequently, a three-component custom TMJ prosthesis (Zimmer Biomet) was fabricated. This included: (i) a titanium zygomatic root component to be fixated to the zygomatic arch and temporal bone, (ii) an ultra-high molecular weight polyethylene (UHMWPE) fossa component to be fixated into the zygomatic root component and (iii) a titanium (Ti-6Al-4V) alloy with titanium alloy coating mandibular component to replace the articular surface of the mandibular condyle . OrderinD-TGCT is an articular pathology originating from a tendon sheath, joint capsule or bursae. The aetiology of this locally aggressive and proliferative tumour involves both inflammatory and neoplastic processes. This rare disease has an annual incidence of 1.8:1000 000 and predominantly affects the knees and hips of patients in their second to fourth decade of life with female predominance . D-TGCT Chondroid TGCT can mimic other cartilage-forming pathologies such as chondrosarcoma and synovial chondromatosis rendering its diagnostic challenge even greater , 6. BetwNevertheless, chondroid TGCT is a rare disease of the TMJ, which poses diagnostic delays and uncertainty. Our case demonstrated a definitive diagnosis and treatment were reached 8 and 18 months, respectively, following the patient’s initial presentation, in keeping with the delays described in the literature. The authors believe it is advisable to consider D-TGCT of the TMJ on the differential list of preauricular swellings, and treatment with complete resection, and close follow-up is paramount. The authors have demonstrated a custom TMJ prosthesis extending to local extra-articular surfaces is a viable solution for TMJ reconstruction in instances with extra-articular disease spread.