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Rapid identification and management of students with COVID-19 symptoms, exposure, or disease are critical to halting disease spread and protecting public health. We describe the interdisciplinary isolation and quarantine program of a large, public university, the University of Virginia, Charlottesville. The program provided students with wraparound services, including medical, mental health, academic, and other support services during their isolation or quarantine stay. The program successfully accommodated 844 cases during the fall 2020 semester, thereby decreasing exposure to the rest of the university and the local community. (Am J Public Health. 2021;111(10):1772–1775. https://doi.org/10.2105/AJPH.2021.306424 )

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival.

Opposing roles have been proposed for IL-22 in intestinal pathophysiology. We have optimized human small intestinal organoid (hSIO) culturing, constitutively generating all differentiated cell types while maintaining an active stem cell compartment. IL-22 does not promote the expansion of stem cells but rather slows the growth of hSIOs. In hSIOs, IL-22 is required for formation of Paneth cells, the prime producers of intestinal antimicrobial peptides (AMPs). Introduction of inflammatory bowel disease (IBD)-associated loss-of-function mutations in the IL-22 co-receptor gene IL10RB resulted in abolishment of Paneth cells in hSIOs. Moreover, IL-22 induced expression of host defense genes (such as REG1A, REG1B, and DMBT1) in enterocytes, goblet cells, Paneth cells, Tuft cells, and even stem cells. Thus, IL-22 does not directly control the regenerative capacity of crypt stem cells but rather boosts Paneth cell numbers, as well as the expression of AMPs in all cell types.

Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin that is thought to arise as a consequence of derailed myogenic differentiation. Despite intensive treatment regimens, the prognosis for high-risk patients remains dismal. The cellular differentiation states underlying RMS and how these relate to patient outcomes remain largely elusive. Here, we use single-cell mRNA sequencing to generate a transcriptomic atlas of RMS. Analysis of the RMS tumour niche reveals evidence of an immunosuppressive microenvironment. We also identify a putative interaction between NECTIN3 and TIGIT, specific to the more aggressive fusion-positive (FP) RMS subtype, as a potential cause of tumour-induced T-cell dysfunction. In malignant RMS cells, we define transcriptional programs reflective of normal myogenic differentiation and show that these cellular differentiation states are predictive of patient outcomes in both FP RMS and the less aggressive fusion-negative subtype. Our study reveals the potential of therapies targeting the immune microenvironment of RMS and suggests that assessing tumour differentiation states may enable a more refined risk stratification.

Alzheimer’s disease (AD) is heterogenous on the molecular level. Understanding this heterogeneity is critical for AD drug development. We aimed to define AD molecular subtypes by mass spectrometry proteomics in cerebrospinal fluid (CSF). Of the 3863 proteins detected in CSF, 1058 proteins had different levels in individuals with AD (n=419) compared with controls (n=187). Cluster analyses of AD individuals on these 1058 proteins revealed five subtypes: subtype 1 was characterized by neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier dysfunction. Distinct genetic profiles were associated with subtypes, e.g., subtype 1 was enriched withTREM2 R47H. Subtypes also differed in brain atrophy and clinical outcomes. For example, survival was shorter in subtype 3 compared to subtype 1 (5.6 versus 8.9 years). These novel insights into AD molecular heterogeneity highlight the need for personalized medicine.

Background Recovery after surgery intersects the physical, psychological, and social domain. Predicting and early identification of deviations from these multi-domain recovery pathways can facilitate personalized postoperative management and reduce complications. In this study our aims were to assess the feasibility of a mobile health application called PositiveTrends to collect multi-domain data after hip, knee arthroplasty or spine surgery and track procedure-specific, multi-domain recovery trajectories. Methods Prospective, observational study in participants greater than eighteen years of age. Data was collected prior to and up to one hundred and eighty days after completion of surgery within the functional, psycho-social, pain and medication usage domains using PositiveTrends. Generalized linear mixed effects models were used to estimate the change in the outcomes over time. Heat maps and effect plots were used to visualize the recovery trajectories. Participants provided quantitative and qualitative evaluation of the PositiveTrends platform. Results Forty-two participants were enrolled over a four-month recruitment period. Function improved by 8 and 6.4 points per month after hip and knee arthroplasty, respectively. In spine participants, the Oswestry Disability Index decreased by 1.4 units per month. Mood improved in all three cohorts, however stress levels remained elevated in spine participants. Social support remained stable in all groups. Pain decreased by 0.16 (95% Confidence Interval: 0.20, 0.13), 0.25 (0.30, 0.20) and 0.14 (0.15, 0.12) units per month in hip, knee, and spine cohorts respectively. The odds of using no medication increased for each month postoperatively. There was a 10.9-to-40.3-fold increase in the probability of using no medication for each month postoperatively. Mixed-methods analysis demonstrated high app usability scores and acceptability of PositiveTrends by participants. Conclusions In this feasibility study we demonstrate the utility of a mobile health platform to map and track multi-domain recovery trajectories after major arthroplasty or spine surgery.

Background The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells. Methods We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination. Results In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. Conclusion The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.

BackgroundLiquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors.Materials and methodsRegions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed.ResultsTLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse.ConclusionWe demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols.

Foxo1, Foxo3 and Foxo4 expression levels and depletion in mILC1.

FOXOs mediated gene expression influences a plethora of cellular processes.

Supplementary tables S1,S2 and S3 in separate tabs of an Excel file.

FOXOs control PI3K signaling feedback in human cancer cells.

Purpose: Hereditary breast cancer is partly explained by germline mutations in BRCA1 and BRCA2. Although patients carry heterozygous mutations, their tumors have typically lost the remaining wild-type allele. Selectively targeting BRCA deficiency may therefore constitute an important therapeutic approach. Clinical trials applying this principle are underway, but it is unknown whether the compounds tested are optimal. It is therefore important to identify alternative compounds that specifically target BRCA deficiency and to test new combination therapies to establish optimal treatment strategies.Experimental Design: We did a high-throughput pharmaceutical screen on BRCA2-deficient mouse mammary tumor cells and isogenic controls with restored BRCA2 function. Subsequently, we validated positive hits in vitro and in vivo using mice carrying BRCA2-deficient mammary tumors.Results: Three alkylators—chlorambucil, melphalan, and nimustine—displayed strong and specific toxicity against BRCA2-deficient cells. In vivo, these showed heterogeneous but generally strong BRCA2-deficient antitumor activity, with melphalan and nimustine doing better than cisplatin and the poly-(ADP-ribose)-polymerase inhibitor olaparib (AZD2281) in this small study. In vitro drug combination experiments showed synergistic interactions between the alkylators and olaparib. Tumor intervention studies combining nimustine and olaparib resulted in recurrence-free survival exceeding 330 days in 3 of 5 animals tested.Conclusions: We generated and validated a platform for identification of compounds with specific activity against BRCA2-deficient cells that translates well to the preclinical setting. Our data call for the re-evaluation of alkylators, especially melphalan and nimustine, alone or in combination with the poly-(ADP-ribose)-polymerase inhibitors, for the treatment of breast cancers with a defective BRCA pathway. Clin Cancer Res; 16(1); 99–108

Restoring GFR-signaling in mILC1-shFOXOs cells is insufficient to rescue cell proliferation and stress kinase induction.

FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K signaling, all of which must be carefully balanced for tumor cells to thrive.Significance: FOXO proteins are not solely tumor suppressors, but also support tumor growth and metastasis by regulating a multitude of cellular processes essential for tumorigenesis. Cancer Res; 78(9); 2356–69. ©2018 AACR.

3D Spheroid formation of human breast cancer cells / Expression of catalase and Sod2 in mILC1

Immunohistochemistry analysis of mILC1-iFOXO3.A3 tumors & primary tumor size upon detection of metastasis.

Immunohistochemistry analysis of mILC1-shFOXOs tumors & primary tumor size upon detection of metastasis.

Figure S1. Immunohistochemistry analysis of mILC1-iFOXO3.A3 tumors & primary tumor size upon detection of metastasis. Figure S2. Foxo1, Foxo3 and Foxo4 expression levels and depletion in mILC1. Figure S3. Immunohistochemistry analysis of mILC1-shFOXOs tumors & primary tumor size upon detection of metastasis. S4-5 3D Spheroid formation of human breast cancer cells / Expression of catalase and Sod2 in mILC1. Figure S6. FOXOs control PI3K signaling feedback in human cancer cells. Figure S7. Restoring GFR-signaling in mILC1-shFOXOs cells is insufficient to rescue cell proliferation and stress kinase induction. Figure S8. FOXOs mediated gene expression influences a plethora of cellular processes.

Legends for Supplemental Figures 1-8

Supplementary Figure S2 from Multiple Robust Signatures for Detecting Lymph Node Metastasis in Head and Neck Cancer

Genome-wide mRNA expression measurements can identify molecular signatures of cancer and are anticipated to improve patient management. Such expression profiles are currently being critically evaluated based on an apparent instability in gene composition and the limited overlap between signatures from different studies. We have recently identified a primary tumor signature for detection of lymph node metastasis in head and neck squamous cell carcinomas. Before starting a large multicenter prospective validation, we have thoroughly evaluated the composition of this signature. A multiple training approach was used for validating the original set of predictive genes. Based on different combinations of training samples, multiple signatures were assessed for predictive accuracy and gene composition. The initial set of predictive genes is a subset of a larger group of 825 genes with predictive power. Many of the predictive genes are interchangeable because of a similar expression pattern across the tumor samples. The head and neck metastasis signature has a more stable gene composition than previous predictors. Exclusion of the strongest predictive genes could be compensated by raising the number of genes included in the signature. Multiple accurate predictive signatures can be designed using various subsets of predictive genes. The absence of genes with strong predictive power can be compensated by including more genes with lower predictive power. Lack of overlap between predictive signatures from different studies with the same goal may be explained by the fact that there are more predictive genes than required to design an accurate predictor. (Cancer Res 2006; 66(4): 2361-6)

Approximately half of all hereditary breast cancers are compromised in their DNA repair mechanisms due to loss of BRCA1 or BRCA2 function. Previous research has found a strong correlation between BRCA mutation and TP53 mutation. However, TP53 mutation status is often indirectly assessed by immunohistochemical staining of accumulated p53 protein. We sequenced TP53 exons 2 to 9 in 21 BRCA1-related breast cancers and 37 sporadic breast tumors. Strikingly, all BRCA1-related breast tumors contained TP53 mutations, whereas only half of these tumors stained positive for p53 accumulation. Positive p53 staining correlates with the presence of TP53 hotspot mutations in both BRCA1-related and sporadic breast tumors. However, whereas the majority of sporadic breast tumors that stained negative for p53 accumulation had wild-type TP53, the majority of BRCA1-associated breast tumors that stained negative for p53 accumulation had protein-truncating TP53 mutations (nonsense, frameshift, and splice mutations). Therefore, the strong selection for p53 loss in BRCA1-related tumors is achieved by an increase of protein-truncating TP53 mutations rather than hotspot mutations. Hence, immunohistochemical detection of TP53 mutation could lead to misdiagnosis in approximately half of all BRCA1-related tumors. The presence of deleterious TP53 mutations in most, if not all, BRCA1-related breast cancers suggests that p53 loss of function is essential for BRCA1-associated tumorigenesis. BRCA1-related tumors may therefore be treated not only with drugs that target BRCA1 deficiency [e.g., poly(ADP-ribose) polymerase inhibitors] but also with drugs that selectively target p53-deficient cells. This raises interesting possibilities for combination therapies against BRCA1-deficient breast cancers and BRCA1-like tumors with homologous recombination deficiency. [Cancer Res 2009;69(8):3625–33]

Supplementary Results from High Incidence of Protein-Truncating TP53 Mutations in BRCA1-Related Breast Cancer

Supplementary Figure 6 from High Incidence of Protein-Truncating TP53 Mutations in BRCA1-Related Breast Cancer

Supplementary Table S1 from Multiple Robust Signatures for Detecting Lymph Node Metastasis in Head and Neck Cancer

This article reviews the background, metabolism, clinical effects, and treatment of toxic alcohols, specifically ethylene glycol, methanol, diethylene glycol, propylene glycol, and isopropyl alcohol. This article also reviews the importance of an anion gap metabolic acidosis in relation to toxic alcohols and explores both the utility and the limitations of the osmol gap in patient management.

SORL1encodes the retromer-associated receptor SORLA that functions in endosomal recycling. Rare variants inSORL1have been associated with Alzheimer’s disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified inSORL1, are pathogenic. Here we address this question by relying on SORLA’s distinct molecular architecture. First, we completed a structure-guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases. We identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impairSORL1, and lead to AD. Together, our findings represent a comprehensive compendium on SORLA protein variation and functional effects, which allowed us to prioritizeSORL1genetic variants into high or moderate priority mutations. We envision that this compendium will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Utimately, this compendium will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies forSORL1variant-carrying patients.

The original version of this Article omitted from the author list the 212th author Patrizia Mecocci, who is from the Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Consequently, the “Sample Contribution” section of Author Contributions was updated to add “P.M” between “P.D.” and “R.C.”. Additionally, the original version of this Article contained the incorrect affiliation for author Patrick Gavin Kehoe, which incorrectly read “German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany”. The correct version replaces this affiliation with “Bristol Medical School (THS), University of Bristol, Southmead Hospital, Bristol, UK”. This has been corrected in both the PDF and HTML versions of the Article. CA extern

Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact effect of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that androgen, ether lipid, glucocorticoid, tryptophan, and xenobiotic metabolism have more activity in the male liver, and serotonin, melatonin, pentose, glucuronate, and vitamin A metabolism have more activity in the female liver. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we see little response in those sex-altered subsystems, and the largest differences are in subsystems related to lipid metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the import of bile acids and salts. This result suggests that the sexually dimorphic behavior of the liver may be caused by differences in enterohepatic recirculation, and we suggest an investigation into sex-specific microbiome composition as an avenue of further research.Author SummaryMale-bias in clinical testing of drugs has led to a disproportionate number of hepatotoxic events in women. Previous works use gene-by-gene differences in biological sex to explain this discrepancy, but there is little focus on the systematic interactions of these differences. To this end, we use a combination of gene expression data and metabolic modeling to compare metabolic activity between the male and female liver and treated and untreated hepatocytes. We find several subsystems with differential activity in each sex; however, when comparing these subsystems with those pathways altered by hepatotoxic agents, we find little overlap. To explore these differences on a reaction-by-reaction basis, we use the same sex-specific transcriptomic data to contextualize the previously published Human1 human cell metabolic model. In these models we find a difference in flux for the import of bile acids and salts, suggesting a potential difference in enterohepatic circulation. These findings can help guide future drug design, toxicological testing, and sex-specific research to better account for the entire human population.

Additional file 1: Supplementary material. Supplementary Methods. Supplementary Results. Figure S1. Gene fusions supported by one or more SV tools. Figure S2. Allele fraction of distinct fusions per SV type. Figure S3. Filtering predicted gene fusions to a high confidence subset. Figure S4. High gene fusion burden is associated with copy number instability. Figure S5. Osteosarcomas with TP53 gene fusion. Figure S6. Potentially pathogenic gene fusion candidates in individual patients. Figure S7. HOXA9 gene expression and gene fusion status. Figure S8. Association between ZBTB20 gene expression and survival. Figure S9. Co-occurring fusions and SNVs indicative of TSG disruption. Figure S10. MTAP--CDKN2B-AS1 fusions and associated expression changes of CDKNB-AS1 and CDKN2A. References for supplementary methods and results.

Gepubliceerd interview in ICT&health: Zorgaanbieder Omring heeft samen met Hogeschool InHolland een bijzonder lectoraat in het leven geroepen om inzichtelijk te maken welke kansrijke innovaties op het gebied van zorg en behandeling en technologie toepasbaar en uiteindelijk bewezen effectief zijn voor geriatrische revalidatie. Ook heeft Omring samen met onderwijsorganisatie Vonk het practoraat zorgtechnologie ingesteld. Het doel is praktijkgericht onderzoek te koppelen aan toekomstbestendige ouderenzorg, aan innovatie en aan professionalisering in het onderwijs en de beroepspraktijk.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Purpose To describe a guidance on the management of post-acute COVID 19 patients in geriatric rehabilitation. Methods The guidance is based on guidelines for post-acute COVID-19 geriatric rehabilitation developed in the Netherlands, updated with recent insights from literature, related guidance from other countries and disciplines, and combined with experiences from experts in countries participating in the Geriatric Rehabilitation Special Interest Group of the European Geriatric Medicine Society. Results This guidance for post-acute COVID-19 rehabilitation is divided into a section addressing general recommendations for geriatric rehabilitation and a section addressing specific processes and procedures. The Sect. "General recommendations for geriatric rehabilitation" addresses: (1) general requirements for post-acute COVID-19 rehabilitation and (2) critical aspects for quality assurance during COVID-19 pandemic. The Sect. "Specific processes and procedures", addresses the following topics: (1) patient selection; (2) admission; (3) treatment; (4) discharge; and (5) follow-up and monitoring. Conclusion Providing tailored geriatric rehabilitation treatment to post-acute COVID-19 patients is a challenge for which the guidance is designed to provide support. There is a strong need for additional evidence on COVID-19 geriatric rehabilitation including developing an understanding of risk profiles of older patients living with frailty to develop individualised treatment regimes. The present guidance will be regularly updated based on additional evidence from practice and research. Key summary pointsAim To describe a guidance on the management of post-acute COVID 19 patients in geriatric rehabilitation. Findings This guidance addresses general requirements for post-acute COVID-19 geriatric rehabilitation and critical aspects for quality assurance during the COVID-19 pandemic. Furthermore, the guidance describes relevant care processes and procedures divided in five topics: patient selection; admission; treatment; discharge; and follow-up and monitoring. Message This guidance is designed to provide support to care professionals involved in the geriatric rehabilitation treatment of post-acute COVID-19 patients.

To determine risk factors associated with concussion among the general collegiate population using a unique data linkage methodology.Student health medical, counseling, and disability access service data were linked with university enrollment data to provide a comprehensive, deidentified dataset of students who sought care at the student health center for concussion from 2016-2020. Using chi-squared tests and logistic regression, characteristics of students with and without concussion were evaluated.During the study period, 506 concussions from 474 students were identified (cumulative incidence rate of 51.7 per 10,000 students). Significant predictors of concussion included: younger age (21 years): odds ratio (OR) = 3.52 (95% confidence intervals [CI], 2.78, 4.50), Greek affiliation: OR = 1.89 (95% CI, 1.56, 2.30), and utilization of counseling and psychological services: OR = 1.92 (95% CI 1.59, 2.32). Of the students with concussion, 47% had at least one other concussion within the preceding year. History of prior hospitalization or medical imaging for head injury increased subsequent concussion risk by 4.5 fold.Linking unique datasets provides a richer understanding of the characteristics and risk factors associated with student concussions than analysis of a single data source. This comprehensive dataset will enable future targeted interventions to prevent and treat college student concussions.

Background:Phospholipase C gamma 2 (PLCγ2) is encoded by thePLCG2gene. A single-nucleotide polymorphism (p.P522R) associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human peripheral immune cells.Methods:We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid-cell assays, andin vivoSARS-CoV-2 vaccination.Results:As expected, effects of p.P522R on immune cell function were small. Immune cell numbers in p.P522R carriers better resembled a younger reference cohort than those of non-carriers. Moreover, carriers expressed lower levels of FcεRI on several immune cell subsets and elevated CD33 levels on classical monocytes. Upon B-cell stimulation, PLCγ2 phosphorylation and calcium release were increased in carriers compared to non-carriers. Normalized ROS production in myeloid cells was higher upon PLCγ2-dependent stimulation, but lower upon PLCγ2-independent stimulation. Carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination.Conclusion:Compared to non-carriers, immune profiles from carriers more closely resembled those from younger individuals, suggesting that p.P522R associates with resilience against immunological aging.

Metadata is generally viewed from a third-party perspective, standing aside from both the creator and the audience of a work. This paper looks at the problem from the creator's standpoint: metadata that is deeply intertwined with the process of creation. Two important classes of metadata stand out: signature metadata, which is for the creator of a work to claim authorship and communicate with their audience, and process metadata, which is to help the creator recover key details of the creation process for themselves to drive further creation. Some key techniques for capturing and embedding signature and process metadata are detailed for a particular use case are described, along with some lessons learned.

Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin which is thought to arise as a consequence of derailed myogenic differentiation. Despite intensive treatment regimens, the prognosis for high-risk patients remains dismal. The cellular differentiation states underlying RMS and how these relate to patient outcomes remain largely elusive. Here, we used single-cell mRNA-sequencing to generate a transcriptomic atlas of RMS. Analysis of the RMS tumour niche revealed evidence of an immunosuppressive microenvironment. We also identified an interaction between NECTIN3 and TIGIT, specific to the more aggressive fusion-positive (FP) RMS subtype, as a putative cause of tumour-induced T-cell dysfunction. In malignant RMS cells we defined transcriptional programs reflective of normal myogenic differentiation. Furthermore, we showed that these cellular differentiation states are predictive of patient outcomes in both FP RMS and the more clinically homogenous fusion-negative subtype. Our study reveals the potential of therapies targeting the immune microenvironment of RMS and suggests that assessing tumour differentiation states may enable a more refined risk stratification.