Citations

Abstract Genome-wide association studies (GWAS) have linked more than a hundred non-coding genomic loci to Parkinson’s disease (PD) risk. Deciphering their functional impact on gene regulation requires cell type-aware modeling approaches to assess the effects of sequence variation on enhancer function and target gene expression. To address this challenge, we generated a comprehensive matched dataset from 190 human donors (115 controls and 75 PD), comprising long-read whole-genome sequencing alongside single nucleus multiome atlases (snATAC-seq and snRNA-seq for 3.1 and 1.1 million nuclei respectively) of the anterior cingulate cortex and substantia nigra. By integrating chromatin accessibility quantitative trait loci (caQTL), DNA methylation QTL (meQTL), and allele-specific chromatin accessibility (ASCA), we identified 53,841 high-confidence cis -acting genetic variants that modulate cell type-specific enhancer accessibility in one or both brain regions. We further demonstrate that sequence-to-function models can accurately predict the impact of these variants directly from the genomic sequence. Novel explainability approaches allowed stratifying these variants according to their regulatory function, with the majority disrupting specific transcription factor binding sites in a cell type specific manner. Integrating these “enhancer variants” (EV) with eQTL mapping and gene locus modeling linked a subset of EVs to their target genes. Finally, we applied these models to prioritize regulatory variants at known PD GWAS loci, bypassing statistical limitations in rare disease-relevant populations like dopaminergic neurons. All together, we establish a unique resource and new sequence modeling strategies to interpret functional non-coding variation in the human brain.

Background: ASCO recommends extended venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs) following cancer surgery. However, these recommendations were based on trials using routine venography, which detects asymptomatic VTEs, and real-life efficacy is not well studied. We aimed to assess the association of extended VTE prophylaxis with the incidence of clinically significant VTE after elective cancer surgery. Patients and Methods: In this retrospective, population-based cohort study, we identified patients who underwent surgical resection for lung, breast, esophageal, gastric, pancreas, and colon cancer from 2010 to 2017 using the SEER–Medicare linked dataset. Patients were divided into 1 of 2 main groups for comparative analyses: those who received extended VTE prophylaxis after cancer surgery and those who did not. Patients who received extended VTE prophylaxis after cancer surgery were identified as those prescribed prophylactic doses of LMWH or a DOAC within 7 days of discharge, as captured in Medicare Part D files. Results: A total of 113,739 Medicare beneficiaries were identified, of whom 1,570 (1.4%) received extended VTE prophylaxis. There was a year-over-year increase in the use of extended VTE prophylaxis during the study period, rising from 0.6% in 2010 to 3.3% in 2017. The overall incidence of VTE was 1.6% at 1 month, 4.3% at 6 months, 5.7% at 12 months, with significant differences observed across cancer types ( P <.001). However, patients who received extended VTE prophylaxis had a higher 1-year cumulative incidence of postoperative VTE compared with those who did not (11.4% vs 5.3%; P <.001), an association that was consistent across cancer sites. In adjusted analyses, extended VTE prophylaxis was independently associated with an increased risk of VTE (hazard ratio, 1.6; 95% CI, 1.3–2.0; P <.001). Extended prophylaxis was also associated with a higher 1-year incidence of bleeding events compared with patients who did not receive prophylaxis (12.0% vs 8.5%; P <.001). Conclusions: The utilization of extended VTE prophylaxis after cancer surgery remains low, although it has increased every year. Paradoxically, patients who received extended VTE prophylaxis had higher incidences of clinically significant VTE and bleeding compared with those who did not, likely reflecting patient selection and surveillance bias after surgery. In light of these findings, national guidelines recommending postoperative extended VTE prophylaxis, and its use as a surrogate for quality of care, should continue to be re-examined.

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

The intersection between radiomics, the computational analysis of imaging data, and machine learning (ML) may lead to new developments in the diagnosis, prognosis, and management of diseases. For spinal tumors specifically, applications of these fields appear promising. In this educational narrative review, we provide a summary of the current advancements in radiomics and artificial intelligence (AI), as well as applications of both fields in the diagnosis and management of spinal tumors. We also provide a suggested workflow of radiomics and machine learning analysis of spinal tumors for researchers, including a list and description of commonly used radiomic features. Future directions in the field of radiomics and machine learning applications to spinal tumors may involve validating already proposed algorithms with larger datasets, ensuring that all computational applications to patient care maintain high ethical standards, and continuing work in developing novel and highly accurate computational techniques to enhance patient outcomes.

Recurrent bowel obstruction secondary to angioedema is uncommon, particularly when due to C1 esterase inhibitor (C1-INH) deficiency. We present a case of a 56 year old, male patient with recurrent abdominal pain, nausea and vomiting secondary to bowel angioedema resulting in multiple hospitalisations and surgical interventions. This case underscores the importance of considering hereditary and acquired C1-INH deficiency in the differential diagnosis of recurrent abdominal pain and bowel oedema despite late onset and lack of concomitant facial or peripheral angioedema. We review the clinical presentation, laboratory evaluation and management of C1-INH deficiency, including the hereditary and acquired forms.

Abstract There is a growing number of cancer survivors given improvement in early cancer diagnosis, therapeutics, and supportive care strategies. Cognitive impairment is among the most common and clinically significant symptoms managed by cancer survivors, which negatively impacts quality of life, functional and occupational status for patients and their care partners. Cancer-related cognitive impairment is often multifactorial—impacted by patient and cancer-specific factors. For systemic (non-CNS) malignancies, cognitive impairment has been identified in up to 75%, depending on cohort, which persists in up to 35% of patients in the years following initial treatment. The most common areas of impairment include memory and processing speed, and executive function. These adverse effects of cancer treatment have been reported after chemotherapy, hormone therapy, targeted therapy, and immunotherapy. This review will summarize existing knowledge regarding the nature and pattern of cognitive changes, mechanisms and risk factors underlying these changes, and biomarkers to support identification of this adverse consequence of cancer therapies.