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Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

Background and objectives The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. Results A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.

Purpose To evaluate the time required to complete a cataract training program for first-year ophthalmology residents using the EyeSi simulator. In addition, evaluate whether the simulator improves virtual performance of cataract surgery during the program. Methods We prospectively included first-year ophthalmology residents who had no experience of cataract surgery. The EyeSi simulator was used, and residents were able to follow the cataract training program, including course A (the easiest) through to course D (the hardest). In course B and above, a “cataract challenge” is proposed to the trainee every hour of simulation. Results A total of 24 participants were included in the study. During the study period, the mean (SD) total time spent on the surgical simulator was 815.6 (174.7) minutes. All the participants completed courses A and B within a mean (SD) of 366.7 (108.0) minutes. A total of 22 residents (91.7%) residents completed course C, and 5 (20.8%) course D. The mean (SD) best score on cataract challenge was 445.6/500 (40.2; range: 330–493) and was obtained in a mean (SD) 7.6 (2.6) attempts. All the residents obtained a score ≥ 60%. The best score in cataract challenge was not correlated to the time spent to achieve courses A and B (r = -0.37, p = 0.0726). Conclusions The time required to complete a basic cataract training program is possible during the first-year residency. The scores obtained in the cataract challenge also increased during the training program and should lead to better surgery skills in these young ophthalmologists.

Purpose: To assess the factors associated with continued cooling duration of core temperature () after prolonged outdoor cold-water swimming. Methods: We designed a cohort study among swimmers participating in an outdoor cold-water swim during qualifying for the English Channel Swim. The day before the event, the participants completed a demographic questionnaire, and body composition was measured using bioelectrical impedance analysis (mBCA 525, Seca). The swimming event consisted of laps over a 1000-m course, for up to 6 hours, in water at 12.5 to 13 °C. was measured using an ingestible temperature sensor (e-Celsius, BodyCap) during and up to 1 hour after the swim. Results: A total of 14 participants (38 [11] y; N = 14, n = 11 males, n = 8 in swimming costume and n = 6 in wetsuit) were included. Before swimming, was 37.54 (0.39) °C. The participants swam for an average of 194.00 (101.94) minutes, and mean when exiting the water was 35.21 (1.30) °C. The duration of continued cooling was 25 (17) minutes with a minimum of 34.66 (1.26) °C. Higher body mass index (r = .595, P = .032) and fat mass (r = .655, P = .015) were associated with longer continued cooling, independent of wetsuit wear. Also, the rate of drop during swimming (−1.22 [1.27] °C/h) was negatively correlated with the rate of gain after swimming (+1.65 [1.23] °C/h, r = −.682, P = .007). Conclusion: Increased body mass index and fat mass were associated with continued cooling duration after prolonged outdoor cold-water swimming at 12.5 to 13 °C. The rate of drop during swimming was negatively correlated with the rate of rewarming.

T-cell redirection therapy using chimeric antigen receptor (CAR) T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), leading to the approval of 2 CAR T-cell products and numerous BiAb trials. Data on the outcomes after relapse following BiAbs are urgently required to develop strategies for sequencing salvage therapies. We identified 58 patients progressing after a BiAb trial at Mount Sinai Hospital. Progression-free survival (PFS) to the first salvage (PFS1), second salvage therapy (PFS2), and overall survival (OS) were estimated using the Kaplan-Meier method. The median age of the patients was 67 years, and 78% had high-risk cytogenetics. They had a median of 6 prior therapy lines, 89% were triple-class refractory, and 44% were penta-drug refractory. After the BiAb trial, patients were followed for a median of 30.5 months and received a median of 2 additional salvage therapies (range, 1-9). The most common first salvage was T-cell redirection in 19 patients (10 BiAb and 9 CAR T cells). Ten patients underwent T-cell redirection as a second salvage treatment. T-cell redirection therapy as first or second salvage was feasible and associated with a median PFS1 of 28.9 months, PFS2 of 30.9 months, and an OS of 62% at 2 years. The sequential use of different T-cell redirection therapies is possible and may lead to deep and durable responses following the relapse after BiAb therapy in RRMM.

Hormogastrid earthworms are found in the diversity hotspot of the Franco-Iberian domain, together with the better-known family Lumbricidae. Integrative systematics (the combination of morphological, molecular and ecological data) have increased our knowledge of the diversity and evolutionary history of these earthworms, highlighting unresolved taxonomic conflicts. One example of a species group in need of integrative taxonomic revision is the genus Boucheona in France. In this work, we analyzed their diversity using previously published data together with additional data obtained from recently sampled localities. Molecular data including DNA barcodes and additional markers enabled us to reconstruct Bayesian and time-calibrated phylogenies to discuss the evolutionary relationships among the different taxa, and to propose hypotheses regarding their biogeographical history. Based on our results, four species of Boucheona are present in Southern France, including two new taxa. Morphological distinctness and molecular phylogenetics results supported the status of four populations as the newly described Boucheona corbierensis sp. nov., as well as the status of “Hormogaster pretiosa var. nigra” as an independent species, redescribed as Boucheona tenebrae sp. nov. These results provide a new perspective of the importance of the genus Boucheona in southern France, as the possible evolutionary origin of a clade of giant anecic earthworms with unknown (but probably remarkable) impact on ecosystem functioning across their range.

Abstract. Immunotherapy is becoming increasingly important in the management of urological, gynecological, and gastrointestinal cancers. Immune checkpoint inhibitor-based combinations have become a standard of care for patients with metastatic renal and liver cancers, as well as for many patients with bladder, cervical, gastric, and esophageal cancers, based on various biomarkers. Some tumor types are less responsive to immunotherapy, such as prostate and colon cancer. In these tumors, however, a subgroup of patients with a microsatellite-instability-high/DNA-mismatch repair deficient molecular phenotype significantly benefits from immunotherapy. Molecular characterization is therefore essential to identify patients who may benefit from these treatments. One of the major challenges is the search for new predictive biomarkers and novel combinations or strategies to further improve patient outcome.

Abstract. Gastrointestinal toxicities secondary to immune checkpoint inhibitors are very frequent. Because in some instances this can be severe or fatal, it is essential to be able to identify immune-related adverse events rapidly. Prompt initiation of systemic immunosuppression can improve outcomes. A biopsy is often necessary to confirm the diagnosis of immune-related adverse events. Moderate or severe irAEs need an interruption of ICI. After the resolution of the toxicities, the rechallenge of immune checkpoint inhibitors must be discussed case by case.

Background and Aims The most species-rich and ecologically diverse plant radiation on the Canary Islands is the Aeonium alliance (Crassulaceae). In island radiations like this, speciation can take place either within islands or following dispersal between islands. Aiming at quantifying intra- and inter-island speciation events in the evolution of Aeonium, and exploring their consequences, we hypothesized that (1) intra-island diversification resulted in stronger ecological divergence of sister lineages, and that (2) taxa on islands with a longer history of habitation by Aeonium show stronger ecological differentiation and produce fewer natural hybrids. Methods We studied the biogeographical and ecological setting of diversification processes in Aeonium with a fully sampled and dated phylogeny inferred using a ddRADseq approach. Ancestral areas and biogeographical events were reconstructed in BioGeoBEARS. Eleven morphological characters and three habitat characteristics were taken into account to quantify the morphological and ecological divergence between sister lineages. A co-occurrence matrix of all Aeonium taxa is presented to assess the spatial separation of taxa on each island. Key Results We found intra- and inter-island diversification events in almost equal numbers. In lineages that diversified within single islands, morphological and ecological divergence was more pronounced than in lineages derived from inter-island diversification, but only the difference in morphological divergence was significant. Those islands with the longest history of habitation by Aeonium had the lowest percentages of co-occurring and hybridizing taxon pairs compared with islands where Aeonium arrived later. Conclusions Our findings illustrate the importance of both inter- and intra-island speciation, the latter of which is potentially sympatric speciation. Speciation on the same island entailed significantly higher levels of morphological divergence compared with inter-island speciation, but ecological divergence was not significantly different. Longer periods of shared island habitation resulted in the evolution of a higher degree of spatial separation and stronger reproductive barriers.

When using the unit cell average of first moment data from four-dimensional scanning transmission electron microscopy (4D-STEM) to characterize ferroelectric materials, a variety of sources of systematic errors needs to be taken into account. In particular, these are the magnitude of the acceleration voltage, STEM probe semi-convergence angle, sample thickness, and sample tilt out of zone axis. Simulations show that a systematic error of calculated electric fields using the unit cell averaged momentum transfer originates from violation of point symmetry within the unit cells. Thus, values can easily exceed those of potential polarization-induced electric fields in ferroelectrics. Importantly, this systematic error produces deflection gradients between different domains seemingly representing measured fields. However, it could be shown that for PbZr0.2Ti0.8O3, many adjacent domains exhibit a relative crystallographic mistilt and in-plane rotation. The experimental results show that the method gives qualitative domain contrast. Comparison of the calculated electric field with the systematic error showed that the domain contrast of the unit cell averaged electric fields is mainly caused by dynamical scattering effects and the electric field plays only a minor role, if present at all.

B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration–approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post–CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell–engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell–engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell–engaging therapies appear to maintain pronounced clinical activity in this setting.

The degree distributions of complex networks are usually considered to be power law. However, it is not the case for a large number of them. We thus propose a new model able to build random growing networks with (almost) any wanted degree distribution. The degree distribution can either be theoretical or extracted from a real-world network. The main idea is to invert the recurrence equation commonly used to compute the degree distribution in order to find a convenient attachment function for node connections - commonly chosen as linear. We compute this attachment function for some classical distributions, as the power-law, broken power-law, geometric and Poisson distributions. We also use the model on an undirected version of the Twitter network, for which the degree distribution has an unusual shape. We finally show that the divergence of chosen attachment functions is heavily links to the heavy-tailed property of the obtained degree distributions., Comment: 23 pages, 3 figures

Background: We report the creation and evaluation of a de novo assembly of the genome of the spontaneously hypertensive rat, the most widely used model of human cardiovascular disease. Methods: The genome is assembled from long read sequencing (PacBio HiFi and continuous long read data [CLR]) and scaffolded with long-range structural information obtained from Bionano optical maps and proximity ligation sequencing proximity analysis of the genome. The genome assembly was polished with Illumina short reads. Completeness of the assembly was investigated using Benchmarking Universal Single Copy Orthologs analysis. The genome assembly was also evaluated with the rat reference gene set, using NCBI automated protocols. We also generated orthogonal single molecule transcript sequence reads (Iso-Seq) from 8 tissues and used them to validate the coding assembly, to annotate the assembly with RNA transcripts representing unique full length transcript isoforms for each gene and to determine whether divergences between RefSeq sequences and the assembly were attributable to assembly errors or polymorphisms. Results: The assembly analysis indicates that this assembly is comparable in contiguity and completeness to the current rat reference assembly, while the use of HiFi sequencing yields an assembly that is more correct at the single base level. Synteny analysis was performed to uncover the extent of synteny and the presence and distribution of chromosomal rearrangements between the reference and this assembly. Conclusion: The resulting genome assembly is reference quality and captures significant structural variation.

In this paper, we study a paratransit application in which children are transported every day from their homes to their special schools or medical-social establishments. To optimize this transportation system, the establishments collaborate to propose a joint transportation plan. We propose a new algorithm to jointly build vehicle routes that visit several establishments and simultaneously set the establishments’ opening hours. This algorithm combines a large neighborhood search, the resolution of a route-based model, and the progressive shrinkage of the planning window. It is applied to a real case from the area of Lyon in France, including 34 schools and 575 heterogeneous users served by a heterogeneous fleet of reconfigurable vehicles. On average, we show that in addition to the 10% of saving that can be expected by sharing vehicle routes between schools, 7% of additional savings can be achieved by school bell adjustment. This cost saving also decreases average user ride times and the number of vehicles required, creating longer routes that are more attractive for driver services. Funding: This work was supported by the European Union through the European Regional Development Fund [Grant RA0012500] and by the French Région Auvergne-Rhône-Alpes through the NOMAd project. Supplemental Material: The online appendices are available at https://doi.org/10.1287/trsc.2022.1160 .

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that frequently infiltrates the peri-kidney space ("hairy kidney" appearance), kidney pelvis and proximal ureters, leading to obstructive uropathy. Here, we analyzed the clinical characteristics, imaging findings and long-term kidney outcome of a large multicenter cohort comprising 195 consecutive patients with ECD. Retroperitoneal peri-kidney or peri-ureteral involvement was detected at diagnosis in 147 patients. Of them, 70 had hydronephrosis (bilateral in 47), and 16 with kidney atrophy (unilateral in 14). Kidney vascular peduncle infiltration was found in 60 patients, and kidney artery stenosis in 31. The estimated glomerular filtration rate (eGFR) at diagnosis was significantly lower in patients with than in those without peri-kidney involvement (median 74 vs. 98 mL/min/1.73 m

Nous avons étudié le retentissement psychologique des confinements à partir des réponses d’une étude réalisée en deux phases sur une année dans une population de patients douloureux chroniques. Ce travail montre l’impact en termes de majoration importante des douleurs, des troubles de l’humeur et des conduites instinctuelles dans les populations de patients douloureux chroniques. Pour la moitié des répondants, l’expérience de confinement a produit angoisse, troubles de l’humeur et du sommeil, fatigue. Les liens entre durée prolongée du confinement et risque accru de troubles anxio-dépressifs témoignent également de la nécessité d’être vigilant à cette symptomatologie dans les cas de re-confinement, même lorsqu’ils sont partiels. Dans ces espaces de restriction, les psychologues auront sans doute à mettre en travail le rapport au corps, à mobiliser la résistance vitale individuelle chez les patients et dans les équipes de soins – puisque nous partageons cette même expérience – et chercher à mobiliser les capacités d’imagination et de rêverie individuelle et collective.

Diabetic macular edema (DME) is now a well-known condition for which a number of treatments have been shown to be effective. Intraocular corticosteroids are part of this therapeutic arsenal but are sometimes responsible for ocular hypertension. We describe here the case of a 60-year-old man with a history of bilateral DME who received an intravitreal injection of 190 µg fluocinolone acetonide (FAc) (ILUVIEN®, Alimera Sciences, Alpharetta, GA, USA) who presented a persistent ocular hypertension in one eye despite FAc removal by pars plana vitrectomy and was successfully managed by Preserflo® microshunt surgery.

Market gardening in Yamoussoukro, Côte d'Ivoire, is characterized by monoculture dominated by Solanum lycopersicum and Solanum macrocarpon. Yields are generally low despite a large amount of chemical inputs which deteriorates the sanitary quality of the products. A consortium included a training organization, a research center and an agricultural cooperative, worked with 20 pilot farmers to test and evaluate agroecological innovations to improve and diversify their production. At the same time, IECD created a social enterprise to sell a part of these agroecologically grown agricultural products. Surveys and biological indicators were used to evaluate the impacts of these agroecological innovations and the results showed that local organic fertilisers and plant extracts allowed farmers to significantly reduce chemical inputs. These innovations combined with the diversification of cropping systems, have contributed to improving the quality and safety of vegetables, but also the health of farmers and biodiversity. Bio-aggressors were no higher in agroecological systems than when using conventional practices, on the contrary. According to producers, the risks of losses due to pests and marketing have decreased and farmers are starting to sell on local markets. Despite the increased workload, some of the pilot farmers have adopted and extended the agroecological innovations to their entire cropping system. However, the use of agroecological innovations takes time and requires more interaction with other farmers and local actors. The cooperative and circular economy could help farmers to make this transition.

International audience; The mesoporous iron polycarboxylate MIL-100(Fe) was synthesized in the presence of Pseudomonas putida bacteria. The synthesis was performed under green conditions, i.e., pure aqueous media at 30 °C that were compatible with the preservation of the cell membrane integrity. Interestingly, the resulting biohybrid exhibited a very different microstructure than a physical mixture of the two components, as it led to the formation of a novel living material featuring an exoskeleton encapsulating individual bacteria cell. Remarkably, TEM and STEM observations on cross sections revealed that this shell was not directly in contact with the cell wall, suggesting the exopolysaccharides network promotes strong interactions with the MOF precursors, leading to high proximity between the two components.

Numerous works have been proposed to generate random graphs preserving the same properties as real-life large-scale networks. However, many real networks are better represented by hypergraphs. Few models for generating random hypergraphs exist, and also, just a few models allow to both preserve a power-law degree distribution and a high modularity indicating the presence of communities. We present a dynamic preferential attachment hypergraph model which features partition into communities. We prove that its degree distribution follows a power-law, and we give theoretical lower bounds for its modularity. We compare its characteristics with a real-life co-authorship network and show that our model achieves good performances. We believe that our hypergraph model will be an interesting tool that may be used in many research domains in order to reflect better real-life phenomena.

Background: UCART191 is an “off-the-shelf” genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells. Methods: UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology. Results: Responder patients (12/25) had higher UCART19 expansion (Cmax) and exposure (AUCTlast) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28. Conclusions: UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection. Significance: First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.

Chimeric antigen receptor (CAR)-T cell therapies have shown tremendous results against various hematologic cancers. Prior to cell infusion, a host preconditioning regimen is required to achieve lymphodepletion and improve CAR-T cell pharmacokinetic exposure, leading to greater chances of therapeutic success. To better understand and quantify the impact of the preconditioning regimen, we built a population-based mechanistic pharmacokinetic-pharmacodynamic model describing the complex interplay between lymphodepletion, host immune system, homeostatic cytokines, and pharmacokinetics of UCART19, an allogeneic product developed against CD19+ B cells. Data were collected from a phase I clinical trial in adult relapsed/refractory B-cell acute lymphoblastic leukemia and revealed three different UCART19 temporal patterns: (i) expansion and persistence, (ii) transient expansion with subsequent rapid decline, and (iii) absence of observed expansion. On the basis of translational assumptions, the final model was able to capture this variability through the incorporation of IL-7 kinetics, which are thought to be increased owing to lymphodepletion, and through an elimination of UCART19 by host T cells, which is specific to the allogeneic context. Simulations from the final model recapitulated UCART19 expansion rates in the clinical trial, confirmed the need for alemtuzumab to observe UCART19 expansion (along with fludarabine cyclophosphamide), quantified the importance of allogeneic elimination, and suggested a high impact of multipotent memory T-cell subpopulations on UCART19 expansion and persistence. In addition to supporting the role of host cytokines and lymphocytes in CAR-T cell therapy, such a model could help optimizing the preconditioning regimens in future clinical trials. Significance: A mathematical mechanistic pharmacokinetic/pharmacodynamic model supports and captures quantitatively the beneficial impact of lymphodepleting patients before the infusion of an allogeneic CAR-T cell product. Mediation through IL-7 increase and host T lymphocytes decrease is underlined, and the model can be further used to optimize CAR-T cell therapies lymphodepletion regimen.

Background Rectal cancers represent 35% of colorectal cancers; 90% are adenocarcinomas, while squamous cell carcinoma accounts for 0.3% of them. Given its rarity, little is known concerning its pathogenesis, molecular profile and therapeutic management. The current treatment trend is to treat rectal squamous cell carcinoma by analogy to anal squamous cell carcinoma with definitive chemo-radiotherapy, setting aside surgery in case of local recurrence. Methods We performed an in-depth genomic analysis (next-generation sequencing, copy number variation, and human papilloma virus characterization) on 10 rectal squamous cell carcinoma samples and compared them in silico to those of anal squamous cell carcinoma and rectal adenocarcinoma. Results Rectal squamous cell carcinoma shows 100% HPV positivity. It has a mutational (PIK3CA, PTEN, TP53, ATM, BCL6, SOX2) and copy number variation profile (3p, 10p, 10q, 16q deletion and 1q, 3q, 5p, 8q, 20p gain) similar to anal squamous cell carcinoma. PI3K/Akt/mTOR is the most commonly affected signaling pathway similarly to anal squamous cell carcinoma. Most commonly gained or lost genes seen in rectal adenocarcinoma (FLT3, CDX2, GNAS, BCL2, SMAD4, MALT1) are not found in rectal squamous cell carcinoma. Conclusion This study presents the first comprehensive genomic characterization of rectal squamous cell carcinoma. We confirm the existence of this rare histology and its molecular similarity with anal squamous cell carcinoma. This molecular proximity confirms the adequacy of therapeutic management based on histology and not localization, suggesting that rectal squamous cell carcinoma should be treated like anal squamous cell carcinoma and not as a rectal adenocarcinoma.

Patients with out-of-hospital cardiac arrest (OHCA) due to acute coronary syndromes (ACS) who undergo percutaneous coronary intervention (PCI) are at high risk of bleeding and thrombosis. While predictive bleeding and stent thrombosis risk scores have been established, their performance in patients with OHCA has not been evaluated.All consecutive patients admitted for OHCA due to ACS who underwent PCI between January 2007 and December 2019 were included. The ACTION and CRUSADE bleeding risk scores and the Dangas score for early stent thrombosis risk were calculated for each patient. A C-statistic analysis was performed to assess the performance of these scores.Among 386 included patients, 82 patients (21.2%) experienced severe bleeding and 30 patients (7.8%) experienced stent thrombosis. The predictive performance of the ACTION and CRUSADE bleeding risk scores for major bleeding was poor, with areas under the curve (AUCs) of 0.596 and 0.548, respectively. Likewise, the predictive performance of the Dangas stent thrombosis risk score was poor (AUC 0.513). Using multivariable analysis, prolonged low-flow (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00-1.05; P=0.025), reduced haematocrit or fibrinogen at admission (OR 0.93, 95% CI 0.88-0.98; P=0.010 and OR 0.61; 95% CI 0.41-0.89; P=0.012, respectively) and the use of glycoprotein IIb/IIIa inhibitors (OR 2.10, 95% CI 1.18-3.73; P=0.011) were independent risk factors for major bleeding.The classic bleeding and stent thrombosis risk scores have poor performance in a population of patients with ACS complicated by OHCA. Other predictive factors might be more pertinent to determine major bleeding and stent thrombosis risks in this specific population.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers.The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms.Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers.A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82;After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.

Funder: CIBERNED, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative Schorling Foundation, Funder: Swedish Alzheimer Foundation, Funder: Karolinska Institutet; doi: http://dx.doi.org/10.13039/501100004047, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Miriam Marks Brain Research UK, BACKGROUND: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. METHODS: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. RESULTS: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. CONCLUSIONS: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

The generation of plausible virtual patients (VPs) is an important step in most quantitative systems pharmacology (QSP) workflows, which requires time-intensive solving of ordinary differential equations (ODEs). However, non-physiological profiles of outputs of interest (OoI) are frequently produced, and additional acceptance/rejection steps are needed for comparing and removing VPs with predicted values outside a pre-defined range. Here, a new approach is developed to accelerate the acceptance/rejection steps by leveraging patterns of parameter associations with OoI. In most models, some parameters are monotonic with respect to OoI, such that an increase in a parameter value always induces an increase or decrease in the OoI. This monotonic property can be used to replace some ODE-solving steps with appropriate monotonic parameter value comparisons to extrapolate the rejection or interpolate the acceptance of some VPs (after simulation) to others. Two algorithms were built that directly extract plausible VPs from a pre-defined initial cohort. These algorithms were first tested using a simple tumor growth inhibition model. Analyzing 200,000 VPs took 50 s with a reference method and 3 to 41 s (depending on the initial set-up) with the first algorithm. The method was then applied to an apoptosis QSP model, in which the clinical phenotypes (i.e., treatment sensitive or resistant) of 200,000 VPs were fully characterized for four different drug regimens in 12 min as compared to over 80 min with the reference approach. Extraction of each phenotype can also be performed individually in 34 s to 8 min, demonstrating the time benefit and flexibility of this approach.

The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society1,2. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals3,4. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome5. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity6. Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent–child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements.

To evaluate choriocapillaris alterations following proton beam therapy irradiation using swept-source optical coherence tomography-angiography, and to assess their correlation with the grade of radiation retinopathy (RR).Eyes with uveal melanoma evaluated before and after irradiation with proton beam therapy were included, as well as the healthy fellow eye. The gradation of RR was based on a previously published classification. Choriocapillaris flow voids area was analyzed using Phansalkar thresholding. Retinal vascularization was described by foveal avascular zone (FAZ) perimeter, FAZ area, FAZ circularity index, and percentage of nonperfusion area (PAN) in the superficial capillary plexus (SCP) or deep capillary plexus.A total of 157 eyes of 83 patients were analyzed. Overall, there was a significant difference between the control group, the uveal melanoma before proton beam therapy group, and the grades of RR in the uveal melanoma after proton beam therapy group for FAZ perimeter ( P0.001), FAZ area ( P0.001), FAZ-circularity index ( P0.001), PAN-SCP ( P0.001), PAN-deep capillary plexus ( P0.001), and choriocapillaris flow voids area ( P0.001). Moreover, choriocapillaris flow voids area was significantly increased in the early stages of RR ( P = 0.003) and was further significantly correlated with FAZ perimeter ( P0.001), FAZ area ( P0.001), FAZ-circularity index ( P = 0.010), PAN-SCP ( P0.001), and PAN-deep capillary plexus ( P0.001).Quantitative optical coherence tomography-angiography alterations in the choriocapillaris microvascularization are an early biomarker of RR and are correlated to the severity of the disease.

Data availability: The datasets analyzed for the current study reflect collaborative efforts of two research consortia: ALLFTD and GENFI. Each consortium provides clinical data access based on established policies for data use: processes for request are available for review at allftd.org/data for ALLFTD data and by emailing genfi@ucl.ac.uk. Certain data elements from both consortia (for example raw MRI images) may be restricted due to the potential for identifiability in the context of the sensitive nature of the genetic data. The deidentified combined dataset will be available for request through the FTD Prevention Initiative in 2023 (https://www.thefpi.org/). Code availability: Custom R code is available at https://doi.org/10.5281/zenodo.6687486. Copyright © The Author(s). Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects. Data collection and dissemination of the data presented in this paper were supported by the ALLFTD Consortium (U19: AG063911, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) and the former ARTFL and LEFFTDS Consortia (ARTFL: U54 NS092089, funded by the National Institute of Neurological Diseases and Stroke and National Center for Advancing Translational Sciences; LEFFTDS: U01 AG045390, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke). The manuscript was reviewed by the ALLFTD Executive Committee for scientific content. The authors acknowledge the invaluable contributions of the study participants and families as well as the assistance of the support staffs at each of the participating sites. This work is also supported by the Association for Frontotemporal Degeneration (including the FTD Biomarkers Initiative), the Bluefield Project to Cure FTD, Larry L. Hillblom Foundation (2018-A-025-FEL (A.M.S.)), the National Institutes of Health (AG038791 (A.L.B.), AG032306 (H.J.R.), AG016976 (W.K.), AG062677 (Ron C. Peterson), AG019724 (B.L.M.), AG058233 (Suzee E. Lee), AG072122 (Walter Kukull), P30 AG062422 (B.L.M.), K12 HD001459 (N.G.), K23AG061253 (A.M.S.), AG062422 (RCP), K24AG045333 (H.J.R.)) and the Rainwater Charitable Foundation. Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886 (T.F.)) awarded by the National Institute on Aging (NIA), were used in this study. This work was also supported by Medical Research Council UK GENFI grant MR/M023664/1 (J.D.R.), the Bluefield Project, the National Institute for Health Research including awards to Cambridge and UCL Biomedical Research Centres and a JPND GENFI-PROX grant (2019–02248). Several authors of this publication are members of the European Reference Network for Rare Neurologic Diseases, project 739510. J.D.R. and L.L.R. are also supported by the National Institute for Health and Care Research (NIHR) UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is also supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). RC and C.G. are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). J.B.R. is supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care), the Wellcome Trust (220258), the Cambridge Centre for Parkinson-plus and the Medical Research Council (SUAG/092 G116768); I.L.B. is supported by ANR-PRTS PREV-DemAls, PHRC PREDICT-PGRN, and several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project 739510). J.L. is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). R.S.-V. was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundació Marató TV3, Spain (grant code 20143810 to R.S.-V.). M.M. was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, by Canadian Institutes of Health Research operating grants (MOP- 371851 and PJT-175242) and by funding from the Weston Brain Institute. R.L. is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Schörling Foundation, Swedish Research Council, JPND Prefrontals, 2015–02926,2018–02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Stockholm County Council ALF/Region Stockholm. J.L. is supported by Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (German Research Foundation, EXC 2145 Synergy 390857198). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK.

ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause-specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF).ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office-based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non-S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment.At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non-S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non-S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient-years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient-years in the non-S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non-S/V, S/V, and rS/V groups, respectively.This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real-world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment.

To conduct the direct comparison of abiraterone acetate and docetaxel for first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) in real-life settings. Data were extracted from the French nationwide claims database (SNDS) on all men aged ≥40 years starting first-line treatment with abiraterone acetate or docetaxel for mCRPC in 2014. A high-dimensional propensity score including 100 baseline characteristics was used to match patients of both groups and form two comparative cohorts. Three-year overall survival and treatment discontinuation-free survival were determined using Kaplan–Meier analysis. In 2014, 2,444 patients started abiraterone for treatment of mCRPC and 1,214 started docetaxel. After trimming and matching, 716 patients were available in each group. Median overall survival tended to be longer in the abiraterone acetate cohort (23.8 months, 95% confidence interval = [21.5; 26.0]) than in the docetaxel cohort (20.3 [18.4; 21.6] months). Survival at 36 months was 34.6% for abiraterone acetate and 27.9% for docetaxel (p = 0.0027). Treatment discontinuation-free median was longer in the abiraterone acetate cohort compared to the docetaxel cohort (10.8 [10.1; 11.7] versus 7.4 [7.0; 8.0] months). The findings underline the interest of oral abiraterone acetate over intravenous docetaxel as the first-line treatment option in mCRPC.

Hemophagocytic lymphohistiocytosis (HLH) may be secondary to cancer or other conditions in adults. We aimed to compare characteristics and outcomes of secondary HLH depending on cancer status among adults. Weight loss over 10 %, headache and enlarged lymph nodes were more frequent in malignant- HLH (M-HLH). Higher phosphatase alkaline level and CRP level were present in M-HLH. Mortality rate tended to be higher in M-HLH group in the first month and during the two years follow-up. Some clinical features and biological abnormalities are associated with an increased probability of malignancy in secondary HLH among adults.

Acne is one of the most common skin concerns of unknown etiology, often connected to the menstrual cycle in women, and possibly to the microbial profile and function.We aimed to investigate how hormonal fluctuation affects hormonal acne-prone skin in different populations in relation to skin clinical parameters and microbial profiles.We evaluated skin features by using biophysical and topographical tools. For microbial profiling, we sequenced facial skin microbiota and associated the findings with the skin clinical parameters during the different phases of the menstrual cycle.We identified differences between and within hormonal phases in women of Chinese and Caucasian origin. Changes were discovered in transepidermal water loss (TEWL), sebum level, hydration level, and pore volume. The most abundant identifiable genera in both ethnicities were Cutibacterium, Staphylococcus, and Streptococcus, without any significant abundant differences within the menstrual cycle. Interestingly, 11 bacterial metabolic pathways were downregulated in Chinese compared to Caucasian skin during the follicular phase. The majority of these pathways were associated with skin redox balance, perhaps indicating a weaker oxidative stress response in Chinese versus Caucasian skin. Novosphingobium taxa were increased in the Chinese skin microbiome, which has been reported to protect skin from pollution-mediated oxidative stress.Thus, this pilot study explored some of the clinical and metagenomic changes in acne-prone skin, and provide guidance to tailor-personalized skin care regimes during the menstrual cycle. Also, the skin redox status in acne-prone skin, provides more opportunity to tailor-personalized skin care regimes.