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Abstract Background To facilitate safety-net healthcare system partnerships with community social service providers, the Los Angeles County Department of Health Services (LAC DHS) created a new collaboration team to spur cross-agency social and medical referral networks and engage communities affected by health disparities as part of a Sect. 1115 Medicaid waiver in Los Angeles County entitled Whole Person Care-Los Angeles (WPC-LA). Methods This observational research reviews three years of collaboration team implementation (2018–2020) through Medicaid-reportable engagement reports, a collaboration team qualitative survey on challenges, facilitators, and recommendations for community engagement. Member reflections for survey findings were conducted with the collaboration team and LAC DHS WPC-LA leadership. Results Collaboration team Medicaid engagement reports (n = 144) reported > 2,700 events, reaching > 70,000 individuals through cross-agency and community-partnered meetings. The collaboration team survey (n = 9) and member reflection sessions portrayed engagement processes through outreach, service assessments, and facilitation of service partnerships. The collaboration team facilitated community engagement processes through countywide workgroups on justice-system diversion and African American infant and maternal health. Recommendations for future safety net health system engagement processes included assessing health system readiness for community engagement and identifying strategies to build mutually beneficial social service partnerships. Conclusions A dedicated collaboration team allowed for bi-directional knowledge exchange between county services, populations with lived experience, and social services, identifying service gaps and recommendations. Engagement with communities affected by health disparities resulted in health system policy recommendations and changes.

Abstract Background Collaborations between health systems and community-based organizations (CBOs) are increasingly common mechanisms to address the unmet health-related social needs of high-risk populations. However, there is limited evidence on how to develop, manage, and sustain these partnerships, and implementation rarely incorporates perspectives of community social service organizations. To address these gaps, we elicited CBOs’ perspectives on service delivery for clients, the impact of the Whole Person Care-Los Angeles (WPC-LA) initiative to integrate health and social care, and their suggestions for improving health system partnerships. Methods Using stakeholder engaged principles and a qualitative Rapid Assessment Process, we conducted brief surveys and in-depth semi-structured interviews with 65 key informants from 36 CBOs working with WPC-LA. Results Major themes identified by CBOs included: 1) the importance of a holistic, client-centered, continuously engaged approach that is reliant on regional partnerships; 2) benefits of WPC-LA expanding capacity and networks; 3) concerns about communication and redundancy hindering WPC-LA; and 4) a need for more equitable partnerships incorporating their approaches. Conclusions CBOs value opportunities for integration with health systems, bring critical expertise to these partnerships, and seek to strengthen cross-sector collaborations. Early, equitable, and inclusive participation in the development and implementation of these partnerships may enhance their effectiveness, but requires policy that prioritizes and incentivizes sustainable and mutually beneficial partnerships.

BackgroundTo facilitate safety-net healthcare system partnerships with community social service providers, the Los Angeles County Department of Health Services (LAC DHS) created a new collaboration team to spur cross-agency social and medical referral networks and engage communities affected by health disparities as part of a Sect. 1115 Medicaid waiver in Los Angeles County entitled Whole Person Care-Los Angeles (WPC-LA).MethodsThis observational research reviews three years of collaboration team implementation (2018-2020) through Medicaid-reportable engagement reports, a collaboration team qualitative survey on challenges, facilitators, and recommendations for community engagement. Member reflections for survey findings were conducted with the collaboration team and LAC DHS WPC-LA leadership.ResultsCollaboration team Medicaid engagement reports (n = 144) reported > 2,700 events, reaching > 70,000 individuals through cross-agency and community-partnered meetings. The collaboration team survey (n = 9) and member reflection sessions portrayed engagement processes through outreach, service assessments, and facilitation of service partnerships. The collaboration team facilitated community engagement processes through countywide workgroups on justice-system diversion and African American infant and maternal health. Recommendations for future safety net health system engagement processes included assessing health system readiness for community engagement and identifying strategies to build mutually beneficial social service partnerships.ConclusionsA dedicated collaboration team allowed for bi-directional knowledge exchange between county services, populations with lived experience, and social services, identifying service gaps and recommendations. Engagement with communities affected by health disparities resulted in health system policy recommendations and changes.

ObjectivesIndividuals released from prison have high rates of chronic conditions but minimal engagement in primary care. We compared 2 interventions designed to improve primary care engagement and reduce acute care utilization: Transitions Clinic, a primary care-based care management program with a community health worker, versus expedited primary care.MethodsWe performed a randomized controlled trial from 2007 to 2009 among 200 recently released prisoners who had a chronic medical condition or were older than 50 years. We abstracted 12-month outcomes from an electronic repository available from the safety-net health care system. Main outcomes were (1) primary care utilization (2 or more visits to the assigned primary care clinic) and (2) emergency department (ED) utilization (the proportion of participants making any ED visit).ResultsBoth groups had similar rates of primary care utilization (37.7% vs 47.1%; P = .18). Transitions Clinic participants had lower rates of ED utilization (25.5% vs 39.2%; P = .04).ConclusionsChronically ill patients leaving prison will engage in primary care if provided early access. The addition of a primary care-based care management program tailored for returning prisoners reduces ED utilization over expedited primary care.

Abstract Northern forests are an important carbon sink, but our understanding of the driving factors is limited due to discrepancies between dynamic global vegetation models (DGVMs) and atmospheric inversions. We show that DGVMs simulate a 50% lower sink (1.1 ± 0.5 PgC yr−1 over 2001–2021) across North America, Europe, Russia, and China compared to atmospheric inversions (2.2 ± 0.6 PgC yr−1). We explain why DGVMs underestimate the carbon sink by considering how they represent disturbance processes, specifically the overestimation of fire emissions, and the lack of robust forest demography resulting in lower forest regrowth rates than observed. We reconcile net sink estimates by using alternative disturbance-related fluxes. We estimate carbon uptake through forest regrowth by combining satellite-derived forest age and biomass maps. We calculate a regrowth flux of 1.1 ± 0.1 PgC yr−1, and combine this with satellite-derived estimates of fire emissions (0.4 ± 0.1 PgC yr−1), land-use change emissions from bookkeeping models (0.9 ± 0.2 PgC yr−1), and the DGVM-estimated sink from CO2 fertilisation, nitrogen deposition, and climate change (2.2 ± 0.9 PgC yr−1). The resulting ‘bottom-up’ net flux of 2.1 ± 0.9 PgC yr−1 agrees with atmospheric inversions. The reconciliation holds at regional scales, increasing confidence in our results.

Abstract A promising route towards the deterministic creation and annihilation of single-phonons is to couple a single-photon emitter to a mechanical resonator. The challenge lies in reaching the resolved-sideband regime with a large coupling rate and a high mechanical quality factor. We achieve this by coupling self-assembled InAs quantum dots to a small mode-volume phononic-crystal resonator with mechanical frequency Ωm/2π = 1.466 GHz and quality factor Q m = 2.1 × 103. Thanks to the high coupling rate of g ep/2π = 2.9 MHz, and by exploiting a matching condition between the effective Rabi and mechanical frequencies, we observe the interaction between the two systems via correlations in the emitted photons. Our results represent a major step towards quantum control of the mechanical resonator via a single-photon emitter.

Abstract Background The pelvic and femoral morphology are associated with the occurrence of early periprosthetic femoral fractures (PFFs) in cementless total hip arthroplasty (THA). Differences exist depending on the performed approach and implanted stem design. Therefore, this study was conducted to analyze the pelvic and femoral morphology in cementless short stem THA via a minimally-invasive (MIS) anterolateral approach. Methods A retrospective, single-center, multi-surgeon, comparative propensity-score matched study of a cohort of 1826 short stem THAs was conducted. A total of 39 PFFs within the first 90 days after surgery was matched on a 2:1 ratio to non-fracture patients. The morphology of the proximal femur was analyzed with canal flare index (CFI), canal-calcar ratio (CCR), canal-bone ratio (CBR), morphological cortical index (MCI), and femoral cortical index (CI). The pelvic morphology was analyzed with ilium–ischial ratio (IR), distance anterior superior iliac spine to the tip of the greater trochanter (AGT). Both groups were analyzed regarding several parameters for femoral and pelvic morphology in non-parametric testing and univariate regression analysis. Results A significantly higher AGT was detected in the fracture group (104.5 mm ± 18 versus 97.4 mm ± 9.8; p = 0.016). All other femoral and pelvic parameters did not differ between both groups, also when compared depending on the Vancouver type of the PFF. Conclusions The morphology of the proximal femur and the pelvis do not differ in several radiological parameters in patients sustaining a PFF in cementless short stem THA via an anterolateral approach compared with matched non-fracture group. The findings are controversial to other studies with different stem types and approaches. Future studies should focus on analyzing the influence of the pelvic geometry and the shape of the proximal femur in the occurrence of PFFs in different approaches with the same stem type and vice versa. Level of Evidence Level III case-controlled study

Abstract Background Wound healing complications are a major challenge following the extended lateral approach in calcaneal fractures. Soft-tissue microcirculation plays an important role via the delivery of oxygen, nutrients, and the regulation of a local milieu. The aim of this clinical study was to examine the effect of intraoperative pneumatic tourniquet application on skin and subcutaneous microcirculation, and its impact on wound healing progression. Methods Patients with calcaneal fractures were randomly assigned to two groups defined by a surgery conducted either with use or without use of a tourniquet. Blood flow (BF [AU]), tissue oxygen saturation (SO 2 [%]) and the relative amount of haemoglobin (rHb[AU]) were intraoperatively measured at two depths (2 and 8 mm) non-invasively by spectrophotometry (Micro-Lightguide O2C ® , LEA Medizintechnik, Giessen, Germany). Time points were before and after inflation of the pneumatic tourniquet and also at the end of surgery before deflation. A linear mixed model (LMM) was fitted for statistical analysis. Results Thirty-four patients (3 women and 31 men) with 37 calcaneal fractures were included. In 22 of them, the surgery was conducted with a tourniquet and in the other 15 without its use. A significant decrease of microcirculation, characterized by decreases in blood flow (p = 0.011) and tissue oxygenation (p = 0.023) was measured in 8 mm depth after inflating the tourniquet. However, these changes did not influence the time of postoperative wound healing. Conclusion The use of a pneumatic tourniquet reduces deep microcirculation without affecting postoperative wound healing. Trial registration The study was registered in www.ClinicalTrials.gov (NCT01264146).

Abstract Butyl octyl magnesium solutions are important raw materials in various chemical processes but suffer from their high reactivity with even traces of water, protic solvents or oxygen and an increased viscosity in hydrocarbon solution due to the formation of polymeric structures. N 1,N 2-diphenylacenaphthylene-1,2-diimines (BIANs) have already been identified as potential candidates to reduce the viscosity of alkyl magnesium solutions and this study provides a systematic insight into the dependence of this ability on the position and structures of substituents on the BIAN. Besides the various BIANs, ZnCl2 complexes and hydrogenated derivatives were characterized and tested for their ability to reduce the viscosity. HPLC-high resolution mass spectrometry, MALDI-ToF mass spectrometry, but most important FTIR and NMR experiments under inert conditions have been used to shine light on the interaction of the different BIAN derivatives with alkyl magnesium solutions. Hydrogenated BIANs, especially those with bulky alkyl groups in the ortho position(s) have been identified as the most promising candidates. An additional benefit of the hydrogenated species is that in contrast to BIANs and BIAN-Zn complexes they do not undergo permanent chemical modification and can be reused after extraction.

Abstract Preoperative identification of intracranial meningiomas with aggressive behaviour may help in choosing the optimal treatment strategy. Radiomics is emerging as a powerful diagnostic tool with potential applications in patient risk stratification. In this study, we aimed to compare the predictive value of conventional, semantic based and radiomic analyses to determine CNS WHO grade and early tumour relapse in intracranial meningiomas. We performed a single-centre retrospective analysis of intracranial meningiomas operated between 2007 and 2018. Recurrence within 5 years after Simpson Grade I-III resection was considered as early. Preoperative T1 CE MRI sequences were analysed conventionally by two radiologists. Additionally a semantic feature score based on systematic analysis of morphological characteristics was developed and a radiomic analysis were performed. For the radiomic model, tumour volume was extracted manually, 791 radiomic features were extracted. Eight feature selection algorithms and eight machine learning methods were used. Models were analysed using test and training datasets. In total, 226 patients were included. There were 21% CNS WHO grade 2 tumours, no CNS WHO grade 3 tumour, and 25 (11%) tumour recurrences were detected in total. In ROC analysis the best radiomic models demonstrated superior performance for determination of CNS WHO grade (AUC 0.930) and early recurrence (AUC 0.892) in comparison to the semantic feature score (AUC 0.74 and AUC 0.65) and conventional radiological analysis (AUC 0.65 and 0.54). The combination of human classifiers, semantic score and radiomic analysis did not markedly increase the model performance. Radiomic analysis is a promising tool for preoperative identification of aggressive and atypical intracranial meningiomas and could become a useful tool in the future.

Abstract Accurate estimates of CO2 emissions from anthropogenic land-use change (E LUC) and of the natural terrestrial CO2 sink (S LAND) are crucial to precisely know how much CO2 can still be emitted to meet the goals of the Paris Agreement. In current carbon budgets, E LUC and S LAND stem from two model families that differ in how CO2 fluxes are attributed to environmental and land-use changes, making their estimates conceptually inconsistent. Here we provide consistent estimates of E LUC and S LAND by integrating environmental effects on land carbon into a spatially explicit bookkeeping model. We find that state-of-the-art process-based models overestimate S LAND by 23% (min: 8%, max: 33%) in 2012–2021, as they include hypothetical sinks that in reality are lost through historical ecosystem degradation. Additionally, E LUC increases by 14% (8%, 23%) in 2012–2021 when considering environmental effects. Altogether, we find a weaker net land sink, which makes reaching carbon neutrality even more ambitious. These results highlight that a consistent estimation of terrestrial carbon fluxes is essential to assess the progress of net-zero emission commitments and the remaining carbon budget.

Abstract Eocene hyperthermal events reflect profound perturbations of the global carbon cycle. Most of our knowledge about their onset, timing, and rates originates from marine records. Hence, the pacing and magnitude of hyperthermal continental warming remains largely unaccounted for due to a lack of high-resolution climate records. Here we use terrestrial biomarkers and carbon isotopes retrieved from varved lake deposits of the UNESCO World Heritage site ‘Messel Fossil Pit’ (Germany) to quantify sub-millennial to millennial-scale temperature and carbon isotope changes across hyperthermal event C21n-H1 (47.2 million years ago). Our results show maximum warming of ca. 3.5 °C during C21n-H1. We propose that two components are responsible for the warming pattern across the hyperthermal: (1) the massive release of greenhouse gases into the atmosphere-ocean system and (2) half-precession orbital forcing indicated by ~12.000-year temperature cycles. The carbon isotope record of bulk organic matter indicates a sharp, 7‰ decrease at the peak of the hyperthermal, corresponding to increased organic carbon content and a shift in the lake algal community. Collectively, our proxy data reveal the structure of continental temperature response during the hyperthermal event that is characterized by overall warming with a superimposed pattern of sub-orbital scale temperature fluctuations.

Abstract Background Tucatinib (TUC), a HER2-directed tyrosine kinase inhibitor, is the first targeted drug demonstrating intracranial efficacy and significantly prolonged survival in metastatic HER2-positive breast cancer (BC) patients with brain metastases. Current treatments for brain metastases often include radiotherapy, but little is known about the effects of combination treatment with TUC. Therefore, we examined the combined effects of irradiation and TUC in human HER2-overexpressing BC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) cell lines. For the latter two, a standard therapy successfully targeting HER2 is yet to be established. Methods Nine HER2-overexpressing (BC: BT474, ZR7530, HCC1954; CRC: LS411N, DLD1, COLO201; NSCLC: DV90, NCI-H1781) and three control cell lines (BC: MCF7, HCC38; NSCLC: NCI-H2030) were examined. WST-1 assay (metabolic activity), BrdU ELISA (proliferation), γH2AX assay (DNA double-strand breaks (DSB), Annexin V assay (apoptosis), and clonogenic assay (clonogenicity) were performed after treatment with TUC and/or irradiation (IR). The relevance of the treatment sequence was analyzed exemplarily. Results In BC, combinatorial treatment with TUC and IR significantly decreased metabolic activity, cell proliferation, clonogenicity and enhanced apoptotis compared to IR alone, whereby cell line-specific differences occurred. In the PI3KCA-mutated HCC1954 cell line, addition of alpelisib (ALP) further decreased clonogenicity. TUC delayed the repair of IR-induced DNA damage but did not induce DSB itself. Investigation of treatment sequence indicated a benefit of IR before TUC versus IR after TUC. Also in CRC and NSCLC, the combination led to a stronger inhibition of metabolic activity, proliferation, and clonogenic survival (only in NSCLC) than IR alone, whereby about 10-fold higher concentrations of TUC had to be applied than in BC to induce significant changes. Conclusion Our data indicate that combination of TUC and IR could be more effective than single treatment strategies for BC. Thereby, treatment sequence seems to be an important factor. The lower sensitivity to TUC in NSCLC and particularly in CRC (compared to BC) implicates, that tumor promotion there might be less HER2-related. Combination with inhibitors of other driver mutations may aid in overcoming partial TUC resistance. These findings are of high relevance to improve long-time prognosis especially in brain-metastasized situations given the intracranial activity of TUC.

Abstract To determine the diagnostic yield of cone beam computed tomography (CBCT) compared with 3 T magnetic resonance imaging (MRI) for the evaluation of subchondral insufficiency fractures of the knee. Consecutive patients with subchondral insufficiency fractures of the knee examined by 3 T MRI and CBCT of the femoral condyles were reviewed. Two experienced raters graded the lesion severity on 3 T MRI and CBCT images: grade 1: no signs of a subchondral bone lesion; grade 2: subchondral trabecular fracture or cystic changes, but without infraction of the subchondral bone plate; grade 3: collapse of the subchondral bone plate. Ratings were repeated after six weeks to determine reliability. In addition, the bone lesion size was measured as elliptical area (mm2) and compared between CBCT and T1-weighted MRI sequences. Among 30 patients included (43.3% women; mean age: 60.9 ± 12.8 years; body mass index (BMI) 29.0 ± 12.8 kg/m2), the medial femoral condyle was affected in 21/30 patients (70%). The grading of subchondral lesions between MRI and CBCT did not match in 12 cases (40%). Based on MRI images, an underestimation (i.e., undergrading) compared with CBCT was observed in nine cases (30%), whereas overgrading occurred in three cases (10%). Compared to CBCT, routine T1-weighted 3 T sequences significantly overestimated osseus defect zones in sagittal (84.7 ± 68.9 mm2 vs. 35.9 ± 38.2 mm2, p

Abstract Understanding the impact of induction and maintenance therapy on patients’ quality of life (QoL) is important for treatment selection. This study aims to compare patient‐reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL‐C 30 and QOL‐MY20 questionnaires in the AGMT‐02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health‐related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross‐sectional comparisons indicated a “slight” superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross‐sectional comparisons revealed a “slight” improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with “slight” or “moderate” impairments in several QoL scales compared with the observation group.

Background and objective: The primary cilium is a small protrusion found on most mammalian cells. It acts as a cellular antenna, being involved in various cell signaling pathways. The length of the primary cilium affects its function. To study the impact of physical or chemical stimuli on cilia, their lengths must be determined easily and reproducibly. Methods: We have developed and evaluated an open-source R package called detectCilia to detect and measure primary cilia automatically. As a case study to demonstrate the capability of our tool, we compared the influence of 4 different cell culture media compositions on the lengths of primary cilia in human chondrocytes. These media compositions include (1) insulin-transferrin-selenium (ITS); (2) ITS and dexamethasone (Dexa); (3) ITS, Dexa, insulin-like growth factor 1 (IGF-1), and transforming growth factor beta 1 (TGF-β1); and (4) fetal bovine serum (FBS). Results: The assessment of detectCilia included a comparison with 2 similar tools: ACDC (Automated Cilia Detection in Cells) and CiliaQ. Several differences and advantages of our package make it a valuable addition to these tools. In the case study, we have observed variations in the ciliary lengths associated with using different media compositions. Conclusions: We conclude that detectCilia can automatically and reproducibly detect and measure primary cilia in confocal microscopy images with low false-positive rates without requiring extensive user interaction.

Al-Mg-Si alloys are an important class of Al wrought alloys. Further increasing their strength has significant economic potential. Previous approaches were focusing on increasing the amount of the main hardening elements Mg and Si, adding Cu and Zn for additional hardening potential, and adding dispersoid-forming elements such as Cr and Zr. In terms of processing, multi-step heat treatments and interrupted quenching have been pursued. Despite recent advances in the field, data points from the literature are difficult to compare due to widely varying alloy compositions and processing conditions. Here we present a comprehensive through-process rolling and extrusion study on four experimental high-strength Al-Mg-Si alloys (named A1–A4) with a particular focus on comparability of the results between our alloys and with the literature. Mechanical testing after artificial aging and in-depth microstructural investigations at various steps of the processing chain were employed, including scanning and transmission electron microscopy. We found that Cr addition leads to a strong increase in dispersoids and thus has a strong influence on hot workability, whereas the effect of increasing Mg and Si levels was negligible within the studied composition range. Al3Zr dispersoids were found to coexist with Al(Fe,Mn,Cr)Si dispersoids. Overall, the strength of the rolled sheets was slightly higher than that of the profiles. After 8 h of artificial aging at 180 °C, 2 mm thick sheet made of alloy A4, falling within the specification of AA6086, showed a notable yield strength of 393 MPa, due to nanoscale hardening phases that were smaller and appeared more numerous than in a commercial alloy (AA6082-T6).

Abstract The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.

Abstract In this work we introduce a method for calculating holographic duals of BCFTs with more than two boundaries. We apply it to calculating the dynamics of entanglement entropy in a 1+1d CFT that is instantaneously split into multiple segments and calculate the entanglement entropy as a function of time for the case of two splits, showing that our approach reproduces earlier results for the double split case. Our manuscript lays the groundwork for future calculations of the entanglement entropy for more than two splits and systems at nonzero temperature.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Abstract The evolution of the northern hemispheric climate during the last glacial period was beset by quasi-episodic iceberg discharge events from the Laurentide ice sheet, known as Heinrich events (HEs). The paleo record places most HEs into the cold stadial of the Dansgaard-Oeschger cycle. However, not every Dansgaard-Oeschger cycle is associated with a HE, revealing a complex interplay between the two modes of glacial variability. Here, using a coupled ice sheet-solid earth model, we introduce a mechanism that explains the synchronicity of HEs and Dansgaard-Oeschger cycles. Unlike earlier studies, our mechanism does not require a trigger during the stadial. Instead, the atmospheric warming signal during the interstadial of the Dansgaard-Oeschger cycle causes enhanced ice stream thickening that leads to the HE during the late interstadial. We demonstrate that this mechanism reproduces the key HE characteristics and provides an explanation for synchronous HEs from different regions of the Laurentide ice sheet.