Circulating Metabolic Markers Identify Patients at Risk for Tumor Recurrence: A Prospective Cohort Study in Colorectal Cancer Surgery.

OBJECTIVE: To investigate the spermidine pathway capability to predict patients at risk for tumor recurrence following colorectal cancer (CRC) surgery. SUMMARY BACKGROUND DATA: Recurrence rates after CRC surgery remain about 20%, despite an optimal technique and adjuvant therapy when necessary. Identification of risk biomarkers of recurrence is an unmet need. The spermidine pathway is indispensable for cell proliferation and differentiation, and is suggested to accelerate tumor spread. METHODS: Prospective cohort study of patients undergoing CRC surgery from 2015 to 2018. Plasma samples were collected before surgery and on postoperative day 4, and the spermidine pathway was assessed through mass spectrometry. Oncological outcomes were registered. RESULTS: 146 patients were included and 24 (16.4%) developed tumor recurrence. Higher levels of preoperative spermidine pathway components (spermidine, spermine, spermidine synthase enzyme, and spermine/arginine balance) were positively associated with recurrence. Surgery promoted a decrease in these pathway elements. The greater the decline was, the lower the risk of recurrence. Preoperative spermidine over the cut-off 0.198 µM displayed a 4.69-fold higher risk of recurrence. The spermine synthase enzyme behaved in the opposite direction. CONCLUSIONS: The spermidine pathway is associated with tumor recurrence following CRC surgery and, after confirmation in larger cohorts, could be translated as a risk biomarker of recurrence into clinical practice.

Mitochondrial, nuclear and morphological differentiation in the swimming crab Liocarcinus depurator along the Atlantic-Mediterranean transition.

Environmental gradients in the sea may coincide with phenotypic or genetic gradients resulting from an evolutionary balance between selection and dispersal. The population differentiation of the swimming crab, Liocarcinus depurator, an important by-catch species in the Mediterranean Sea and North-East Atlantic, was assessed using both genetic and morphometric approaches. A total of 472 specimens were collected along its distribution area, and 17 morphometric landmarks, one mitochondrial gene (COI) and 11 polymorphic microsatellite markers were scored in 350, 287 and 280 individuals, respectively. Morphometric data lacked significant differences, but genetic analyses showed significant genetic differentiation between Atlantic and Mediterranean populations, with a steeper gradient in COI compared to microsatellite markers. Interestingly, nuclear differentiation was due to an outlier locus with a gradient in the Atlantic-Mediterranean transition area overlapping with the mtDNA gradient. Such overlapping clines are likely to be maintained by natural selection. Our results suggest a scenario of past isolation with local adaptation and secondary contact between the two basins. Local adaptation during the process of vicariance may reinforce genetic differentiation at loci maintained by environmental selection even after secondary contact.

Comparison of two bundles for reducing surgical site infection in colorectal surgery: multicentre cohort study.

BACKGROUND: There is controversy regarding the maximum number of elements that can be included in a surgical site infection prevention bundle. In addition, it is unclear whether a bundle of this type can be implemented at a multicentre level. METHODS: A pragmatic, multicentre cohort study was designed to analyse surgical site infection rates in elective colorectal surgery after the sequential implementation of two preventive bundle protocols. Secondary outcomes were to determine compliance with individual measures and to establish their effectiveness, duration of stay, microbiology and 30-day mortality rate. RESULTS: A total of 32 205 patients were included. A 50% reduction in surgical site infection was achieved after the implementation of two sequential sets of bundles: from 18.16% in the Baseline group to 10.03% with Bundle-1 and 8.19% with Bundle-2. Bundle-2 reduced superficial-surgical site infection (OR 0.74 (95% c.i. 0.58 to 0.95); P = 0.018) and deep-surgical site infection (OR 0.66 (95% c.i. 0.46 to 0.93); P = 0.018) but not organ/space-surgical site infection (OR 0.88 (95% c.i. 0.74 to 1.06); P = 0.172). Compliance increased after the addition of four measures to Bundle-2. In the multivariable analysis, for organ/space-surgical site infection, laparoscopy, oral antibiotic prophylaxis and mechanical bowel preparation were protective factors in colonic procedures, while no protective factors were found in rectal surgery. Duration of stay fell significantly over time, from 7 in the Baseline group to 6 and 5 days for Bundle-1 and Bundle-2 respectively (P < 0.001). The mortality rate fell from 1.4% in the Baseline group to 0.59% and 0.6% for Bundle-1 and Bundle-2 respectively (P < 0.001). There was an increase in Gram-positive bacteria and yeast isolation, and reduction in Gram-negative bacteria and anaerobes in organ/space-surgical site infection. CONCLUSIONS: The addition of measures to create a final 10-measure protocol had a cumulative protective effect on reducing surgical site infection. However, organ/space-surgical site infection did not benefit from the addition. No protective measures were found for organ/space-surgical site infection in rectal surgery. Compliance with preventive measures increased from Bundle-1 to Bundle-2.

Chromosome-level genome assembly and annotation of the black sea urchin Arbacia lixula (Linnaeus, 1758).

The black sea urchin (Arbacia lixula) is a keystone species inhabiting the coastal shallow waters of the Mediterranean Sea, which is a key driver of littoral communities' structure. Here, we present the first genome assembly and annotation of this species, standing as the first Arbacioida genome, including both nuclear and mitochondrial genomes. To obtain a chromosome-level assembly, we used a combination of PacBio high fidelity (HiFi) reads and chromatin capture reads (Omni-C). In addition, we generated a high-quality nuclear annotation of both coding and non-coding genes, by using published RNA-Seq data from several individuals of A. lixula and gene models from closely related species. The nuclear genome assembly has a total span of 607.91 Mb, being consistent with its experimentally estimated genome size. The assembly contains 22 chromosome-scale scaffolds (96.52% of the total length), which coincides with its known karyotype. A total of 72,767 transcripts were predicted from the nuclear genome, 24,171 coding, and 48,596 non-coding that included lncRNA, snoRNA, and tRNAs. The circularized mitochondrial genome had 15,740 bp comprising 13 protein-coding genes, 2 rRNA, and 22 tRNA. This reference genome will enhance ongoing A. lixula studies and benefit the wider sea urchin scientific community.

Navigating spatio-temporal microbiome dynamics: Environmental factors and trace elements shape the symbiont community of an invasive marine species.

The proliferation of marine invasive species is a mounting concern. While the role of microbial communities in invasive ascidian species is recognized, the role of seasonal shifts in microbiome composition remains largely unexplored. We sampled five individuals of the invasive ascidian Styela plicata quarterly from January 2020 to October 2021 in two harbours, examining gills, tunics, and surrounding water. By analysing Amplicon Sequence Variants (ASVs) and seawater trace elements, we found that compartment (seawater, tunic, or gills) was the primary differentiating factor, followed by harbour. Clear seasonal patterns were evident in seawater bacteria, less so in gills, and absent in tunics. We identified compartment-specific bacteria, as well as seasonal indicator ASVs and ASVs correlated with trace element concentrations. Among these bacteria, we found that Endozoicomonas, Hepatoplasma and Rhodobacteraceae species had reported functions which might be necessary for overcoming seasonality and trace element shifts. This study contributes to understanding microbiome dynamics in invasive holobiont systems, and the patterns found indicate a potential role in adaptation and invasiveness.

Clinical and neurodevelopmental predictors of psychotic disorders in children and adolescents at clinical high risk for psychosis: the CAPRIS study.

BACKGROUND: The neurodevelopmental hypothesis of schizophrenia represents the disorder as an expression of an alteration during the brain development process early in life. Neurodevelopmental variables could become a trait marker, and the study of these variables in children and adolescents at clinical high risk for psychosis (CHR) could identify a specific cluster of patients who later developed psychosis. The aim of this study is to describe clinical and neurodevelopment predictors of transition to psychosis in child and adolescent participants at CHR. Naturalistic longitudinal two-center study of 101 CHR and 110 healthy controls (HC) aged 10-17. CHR participants were children and adolescents aged 10-17, meeting one or more of the CHR criteria assessed at baseline and at 18 months' follow-up. Neurodevelopmental variables assessed were obstetric complications, delay in principal development milestones, and presence of a neurodevelopment diagnosis. Pairwise comparisons, linear regressions, and binary logistic regression were performed.A transition rate of 23.3% at 1.5 years was observed. Participants who developed psychosis (CHR-P) showed higher rates of grandiosity and higher proportions of antipsychotic medication intake at baseline compared to participants who did not develop a psychotic disorder (CHR-NP). In terms of neurodevelopment alterations, CHR-P group showed a higher proportion of participants reporting delay in language development than the CHR-NP and HC groups. The odds of psychosis increased by 6.238 CI 95% [1.276-30.492] for a one-unit increase in having a positive score in grandiosity; they increased by 4.257 95% CI [1.293-14.023] for a one-unit increase in taking antipsychotic medication, and by 4.522 95% [1.185-64.180] for showing language development delay. However, the p-values did not reach significance after adjusting for multiple comparisons.A combination of clinical and neurodevelopmental alterations could help predict the transition to psychotic disorder in a CHR child and adolescent sample. Our results suggest the potential utility of collecting information about neurodevelopment and using these variable multifactorial models to predict psychosis disorders.

Superagers Resist Typical Age-Related White Matter Structural Changes.

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age, 81.9; 59% women) and 55 typical older adults (mean age, 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed the better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibers and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus, and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional aging pattern is in line with the last-in-first-out hypothesis.

Genome composition and GC content influence loci distribution in reduced representation genomic studies.

BACKGROUND: Genomic architecture is a key evolutionary trait for living organisms. Due to multiple complex adaptive and neutral forces which impose evolutionary pressures on genomes, there is a huge variability of genomic features. However, their variability and the extent to which genomic content determines the distribution of recovered loci in reduced representation sequencing studies is largely unexplored. RESULTS: Here, by using 80 genome assemblies, we observed that whereas plants primarily increase their genome size by expanding their intergenic regions, animals expand both intergenic and intronic regions, although the expansion patterns differ between deuterostomes and protostomes. Loci mapping in introns, exons, and intergenic categories obtained by in silico digestion using 2b-enzymes are positively correlated with the percentage of these regions in the corresponding genomes, suggesting that loci distribution mostly mirrors genomic architecture of the selected taxon. However, exonic regions showed a significant enrichment of loci in all groups regardless of the used enzyme. Moreover, when using selective adaptors to obtain a secondarily reduced loci dataset, the percentage and distribution of retained loci also varied. Adaptors with G/C terminals recovered a lower percentage of selected loci, with a further enrichment of exonic regions, while adaptors with A/T terminals retained a higher percentage of loci and slightly selected more intronic regions than expected. CONCLUSIONS: Our results highlight how genome composition, genome GC content, RAD enzyme choice and use of base-selective adaptors influence reduced genome representation techniques. This is important to acknowledge in population and conservation genomic studies, as it determines the abundance and distribution of loci.

New colonisers drive the increase of the emerging loggerhead turtle nesting in Western Mediterranean.

The loggerhead sea turtle (Caretta caretta) is sensitive to climate change and is responding by colonising the Western Mediterranean. To understand the rapid nesting increase in recent years in Spain, we sampled 45 hatchlings from 8 nests between 2016 and 2019. We sequenced a mtDNA D-loop region, genotyped 2291 SNPs using 2bRAD and collected data on clutch size, hatching success, and incubation duration. We confirmed that the colonisation has a Mediterranean and Atlantic mixed origin and we detected that these nests were laid by different females, except for two nests within the same season. Our results suggest that the recent increase in nesting is due to an increase in the number of colonising individuals rather than females born in the same area returning to breed. We hypothesize that this increase in the number of colonisers results from successful conservation efforts, feminisation of the populations of origin and earlier sexual maturation. However, the percentage of offspring females produced in Spain suggests that future returning individuals will aid to the settlement of the new population. These results allow defining the current status of this colonisation although future efforts are needed to detect remigrants to confirm the establishment of a resident population.

Going beyond a reference genome in conservation genomics.

The current biodiversity crisis demands scientifically based management. The generation of reference genomes is crucial in conservation, but is not enough to capture species diversity. By incorporating whole-genome sequencing (WGS) at the population level, Nigenda-Morales et al. provide key genomic information for the conservation of fin whale populations in the Pacific.

Circulating metabolic markers after surgery identify patients at risk for severe postoperative complications: a prospective cohort study in colorectal cancer.

BACKGROUND: Early detection of postoperative complications after colorectal cancer (CRC) surgery is associated with improved outcomes. The aim was to investigate early metabolomics signatures capable to detect patients at risk for severe postoperative complications after CRC surgery. MATERIALS AND METHODS: Prospective cohort study of patients undergoing CRC surgery from 2015 to 2018. Plasma samples were collected before and after surgery, and analyzed by mass spectrometry obtaining 188 metabolites and 21 ratios. Postoperative complications were registered with Clavien-Dindo Classification and Comprehensive Complication Index. RESULTS: One hundred forty-six patients were included. Surgery substantially modified metabolome and metabolic changes after surgery were quantitatively associated with the severity of postoperative complications. The strongest positive relationship with both Clavien-Dindo and Comprehensive Complication Index (ß=4.09 and 63.05, P <0.001) corresponded to kynurenine/tryptophan, against an inverse relationship with lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs). Patients with LPC18:2/PCa36:2 below the cut-off 0.084 µM/µM resulted in a sevenfold higher risk of major complications (OR=7.38, 95% CI: 2.82-21.25, P <0.001), while kynurenine/tryptophan above 0.067 µM/µM a ninefold (OR=9.35, 95% CI: 3.03-32.66, P <0.001). Hexadecanoylcarnitine below 0.093 µM displayed a 12-fold higher risk of anastomotic leakage-related complications (OR=11.99, 95% CI: 2.62-80.79, P =0.004). CONCLUSION: Surgery-induced phospholipids and amino acid dysregulation is associated with the severity of postoperative complications after CRC surgery, including anastomotic leakage-related outcomes. The authors provide quantitative insight on metabolic markers, measuring vulnerability to postoperative morbidity that might help guide early decision-making and improve surgical outcomes.

How chromosomal inversions reorient the evolutionary process.

Inversions are structural mutations that reverse the sequence of a chromosome segment and reduce the effective rate of recombination in the heterozygous state. They play a major role in adaptation, as well as in other evolutionary processes such as speciation. Although inversions have been studied since the 1920s, they remain difficult to investigate because the reduced recombination conferred by them strengthens the effects of drift and hitchhiking, which in turn can obscure signatures of selection. Nonetheless, numerous inversions have been found to be under selection. Given recent advances in population genetic theory and empirical study, here we review how different mechanisms of selection affect the evolution of inversions. A key difference between inversions and other mutations, such as single nucleotide variants, is that the fitness of an inversion may be affected by a larger number of frequently interacting processes. This considerably complicates the analysis of the causes underlying the evolution of inversions. We discuss the extent to which these mechanisms can be disentangled, and by which approach.

Obsessive-Compulsive Spectrum Symptoms Are Associated With Functional Impairment in Children and Adolescents With Psychosis Risk Syndrome: The CAPRIS Study.

Objective: To compare clinical and functional variables among 3 groups of children and adolescents: subjects at clinical high risk for psychosis (CHR-P) who also have obsessive-compulsive symptoms (OCS), CHR-P patients without OCS, and healthy controls (HC).Methods: A total of 128 CHR-P patients and 98 HC between the ages of 10 and 17 years were recruited as part of a multicenter prospective longitudinal study conducted in Spain between January 1, 2011, and December 31, 2018, with diagnoses made for CHR-P using the Scale of Prodromal Symptoms (SOPS). Two groups were obtained based on Leyton Obsessional Inventory-Child Version (LOI-CV) scores: 64 CHR-P patients with OCS (OCS+) and 64 CHR-P patients without OCS (OCS-). Clinical variables were analyzed with a generalized linear model.Results: Overall, 128 CHR-P patients, 64 (50%) with OCS (mean ± SD age = 15.5 ± 1.4 years, 34.4% male), 64 CHR-P patients without OCS (mean ± SD age = 15.1 ± 1.9 years, 34.4% male), and 98 HC (mean ± SD age = 15.5 ± 1.5 years, 42.9% male), of whom 19 (19.5%) had OCS, were included. Generalized linear model analysis revealed significant differences between the groups. The OCS+ group showed more severe prodromal symptoms (P = .007), worse functioning at baseline (P = .044) and during the previous year (P = .004), and more dysmorphophobic symptoms (P < .001) compared to the OCS- group. OCS+ patients were also more frequently treated with antidepressants (P = .004) than were OCS- patients.Conclusions: In our sample, among children and adolescents with CHR-P, the prevalence of OCS was high (50%). OCS+ subjects had a more severe clinical and functional profile than OCS- subjects. Early detection and treatment of these symptoms can lead to better outcomes for these patients.

Syntaxin-1 is necessary for UNC5A-C/Netrin-1-dependent macropinocytosis and chemorepulsion.

Introduction: Brain connectivity requires correct axonal guidance to drive axons to their appropriate targets. This process is orchestrated by guidance cues that exert attraction or repulsion to developing axons. However, the intricacies of the cellular machinery responsible for the correct response of growth cones are just being unveiled. Netrin-1 is a bifunctional molecule involved in axon pathfinding and cell migration that induces repulsion during postnatal cerebellar development. This process is mediated by UNC5 homolog receptors located on external granule layer (EGL) tracts. Methods: Biochemical, imaging and cell biology techniques, as well as syntaxin-1A/B (Stx1A/B) knock-out mice were used in primary cultures and brain explants. Results and discussion: Here, we demonstrate that this response is characterized by enhanced membrane internalization through macropinocytosis, but not clathrin-mediated endocytosis. We show that UNC5A, UNC5B, and UNC5C receptors form a protein complex with the t-SNARE syntaxin-1. By combining botulinum neurotoxins, an shRNA knock-down strategy and Stx1 knock-out mice, we demonstrate that this SNARE protein is required for Netrin1-induced macropinocytosis and chemorepulsion, suggesting that Stx1 is crucial in regulating Netrin-1-mediated axonal guidance.

Multidimensional variability of the microbiome of an invasive ascidian species.

Animals, including invasive species, are complex entities consisting of a host and its associated symbionts (holobiont). The interaction between the holobiont components is crucial for the host's survival. However, our understanding of how microbiomes of invasive species change across different tissues, localities, and ontogenetic stages, is limited. In the introduced ascidian Styela plicata, we found that its microbiome is highly distinct and specialized among compartments (tunic, gill, and gut). Smaller but significant differences were also found across harbors, suggesting local adaptation, and between juveniles and adults. Furthermore, we found a correlation between the microbiome and environmental trace element concentrations, especially in adults. Functional analyses showed that adult microbiomes possess specific metabolic pathways that may enhance fitness during the introduction process. These findings highlight the importance of integrated approaches in studying the interplay between animals and microbiomes, as a first step toward understanding how it can affect the species' invasive success.

Evaluating restriction enzyme selection for reduced representation sequencing in conservation genomics.

Conservation genomic studies in non-model organisms generally rely on reduced representation sequencing techniques based on restriction enzymes to identify population structure as well as candidate loci for local adaptation. While the expectation is that the reduced representation of the genome is randomly distributed, the proportion of the genome sampled might depend on the GC content of the recognition site of the restriction enzyme used. Here, we evaluated the distribution and functional composition of loci obtained after a reduced representation approach using Genotyping-by-Sequencing (GBS). To do so, we compared experimental data from two endemic fish species (Symphodus ocellatus and Symphodus tinca, EcoT22I enzyme) and two ecosystem engineer sea urchins (Paracentrotus lividus and Arbacia lixula, ApeKI enzyme). In brief, we mapped the sequenced loci to the phylogenetically closest reference genome available (Labrus bergylta in the fish and Strongylocentrotus purpuratus in the sea urchin datasets), classified them as exonic, intronic and intergenic, and studied their function by using Gene Ontology (GO) terms. We also simulated the effect of using both enzymes in the two reference genomes. In both simulated and experimental data, we detected an enrichment towards exonic or intergenic regions depending on the restriction enzyme used and failed to detect differences between total loci and candidate loci for adaptation in the empirical dataset. Most of the functions assigned to the mapped loci were shared between the four species and involved a myriad of general functions. Our results highlight the importance of restriction enzyme selection and the need for high-quality annotated genomes in conservation genomic studies.

Brain structure and phenotypic profile of superagers compared with age-matched older adults: a longitudinal analysis from the Vallecas Project.

BACKGROUND: Cognitive abilities, particularly memory, normally decline with age. However, some individuals, often designated as superagers, can reach late life with the memory function of individuals 30 years younger. We aimed to characterise the brain structure of superagers and identify demographic, lifestyle, and clinical factors associated with this phenotype. METHODS: We selected cognitively healthy participants from the Vallecas Project longitudinal cohort recruited between Oct 10, 2011, and Jan 14, 2014, aged 79·5 years or older, on the basis of their delayed verbal episodic memory score. Participants were assessed with the Free and Cued Selective Reminding Test and with three non-memory tests (the 15-item version of the Boston Naming Test, the Digit Symbol Substitution Test, and the Animal Fluency Test). Participants were classified as superagers if they scored at or above the mean values for a 50-56-year-old in the Free and Cued Selective Reminding Test and within one standard deviation of the mean or above for their age and education level in the three non-memory tests, or as typical older adults if they scored within one standard deviation of the mean for their age and education level in the Free and Cued Selective Reminding Test. Data acquired as per protocol from up to six yearly follow-ups were used for longitudinal analyses. FINDINGS: We included 64 superagers (mean age 81·9 years; 38 [59%] women and 26 [41%] men) and 55 typical older adults (82·4 years; 35 [64%] women and 20 [36%] men). The median number of follow-up visits was 5·0 (IQR 5·0-6·0) for superagers and 5·0 (4·5-6·0) for typical older adults. Superagers exhibited higher grey matter volume cross-sectionally in the medial temporal lobe, cholinergic forebrain, and motor thalamus. Longitudinally, superagers also showed slower total grey matter atrophy, particularly within the medial temporal lobe, than did typical older adults. A machine learning classification including 89 demographic, lifestyle, and clinical predictors showed that faster movement speed (despite no group differences in exercise frequency) and better mental health were the most differentiating factors for superagers. Similar concentrations of dementia blood biomarkers in superager and typical older adult groups suggest that group differences reflect inherent superager resistance to typical age-related memory loss. INTERPRETATION: Factors associated with dementia prevention are also relevant for resistance to age-related memory decline and brain atrophy, and the association between superageing and movement speed could provide potential novel insights into how to preserve memory function into the ninth decade. FUNDING: Queen Sofia Foundation, CIEN Foundation, Spanish Ministry of Science and Innovation, Alzheimer's Association, European Research Council, MAPFRE Foundation, Carl Zeiss Foundation, and the EU Comission for Horizon 2020. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Time Interval Between the End of Neoadjuvant Therapy and Elective Resection of Locally Advanced Rectal Cancer in the CRONOS Study.

Importance: The treatment for extraperitoneal locally advanced rectal cancer (LARC) is neoadjuvant therapy (NAT) followed by total mesorectal excision (TME). Robust evidence on the optimal time interval between NAT completion and surgery is lacking. Objective: To assess the association of time interval between NAT completion and TME with short- and long-term outcomes. It was hypothesized that longer intervals increase the pathologic complete response (pCR) rate without increasing perioperative morbidity. Design, Setting, and Participants: This cohort study included patients with LARC from 6 referral centers who completed NAT and underwent TME between January 2005 and December 2020. The cohort was divided into 3 groups depending on the time interval between NAT completion and surgery: short (≤8 weeks), intermediate (>8 and ≤12 weeks), and long (>12 weeks). The median follow-up duration was 33 months. Data analyses were conducted from May 1, 2021, to May 31, 2022. The inverse probability of treatment weighting method was used to homogenize the analysis groups. Exposure: Long-course chemoradiotherapy or short-course radiotherapy with delayed surgery. Main outcome and Measures: The primary outcome was pCR. Other histopathologic results, perioperative events, and survival outcomes constituted the secondary outcomes. Results: Among the 1506 patients, 908 were male (60.3%), and the median (IQR) age was 68.8 (59.4-76.5) years. The short-, intermediate-, and long-interval groups included 511 patients (33.9%), 797 patients (52.9%), and 198 patients (13.1%), respectively. The overall pCR was 17.2% (259 of 1506 patients; 95% CI, 15.4%-19.2%). When compared with the intermediate-interval group, no association was observed between time intervals and pCR in short-interval (odds ratio [OR], 0.74; 95% CI, 0.55-1.01) and long-interval (OR, 1.07; 95% CI, 0.73-1.61) groups. The long-interval group was significantly associated with lower risk of bad response (tumor regression grade [TRG] 2-3; OR, 0.47; 95% CI, 0.24-0.91), systemic recurrence (hazard ratio, 0.59; 95% CI, 0.36-0.96), higher conversion risk (OR, 3.14; 95% CI, 1.62-6.07), minor postoperative complications (OR, 1.43; 95% CI, 1.04-1.97), and incomplete mesorectum (OR, 1.89; 95% CI, 1.02-3.50) when compared with the intermediate-interval group. Conclusions and Relevance: Time intervals longer than 12 weeks were associated with improved TRG and systemic recurrence but may increase surgical complexity and minor morbidity.

Analysis of the P. lividus sea urchin genome highlights contrasting trends of genomic and regulatory evolution in deuterostomes.

Sea urchins are emblematic models in developmental biology and display several characteristics that set them apart from other deuterostomes. To uncover the genomic cues that may underlie these specificities, we generated a chromosome-scale genome assembly for the sea urchin Paracentrotus lividus and an extensive gene expression and epigenetic profiles of its embryonic development. We found that, unlike vertebrates, sea urchins retained ancestral chromosomal linkages but underwent very fast intrachromosomal gene order mixing. We identified a burst of gene duplication in the echinoid lineage and showed that some of these expanded genes have been recruited in novel structures (water vascular system, Aristotle's lantern, and skeletogenic micromere lineage). Finally, we identified gene-regulatory modules conserved between sea urchins and chordates. Our results suggest that gene-regulatory networks controlling development can be conserved despite extensive gene order rearrangement.