Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

Feasibility of a Novel Real-Time Provider Teaching Intervention in Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Background: It is not known whether an intervention using real-time provider teaching in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) improves provider knowledge and/or patient outcomes. Objective: To pilot the combination of a novel, real-time provider teaching intervention delivered by subspecialists to Internal Medicine trainees with a traditional patient education and medication reconciliation (PEMR) intervention and to assess the impact of these interventions on provider knowledge regarding COPD and patient care. Methods: This was a single-center, nonrandomized, quality-improvement study. Patients admitted with AECOPD were prospectively identified between June 19 and November 20, 2019. Patients with asthma, lung cancer, or interstitial lung disease were excluded. The primary care team received a novel intervention featuring in-person, real-time teaching, covering Global Initiative on Chronic Obstructive Lung Disease COPD groups and management, including pulmonary rehabilitation referral. Providers completed a knowledge assessment before and after their real-time teaching session. Provider knowledge scores before and after teaching were compared using McNemar's test. Patients received a traditional PEMR intervention from a nurse practitioner and/or clinical pharmacist. A retrospective chart review was conducted for 50 historical control patients admitted with AECOPD to obtain preintervention rates of discharge on long-acting bronchodilators and referral to pulmonary rehabilitation. The proportions of patients discharged on long-acting bronchodilators and referred to pulmonary rehabilitation in the intervention group were compared with the preintervention historical control patients using chi-square testing. Results: Seventy-one providers caring for patients with AECOPD received real-time teaching. Postintervention, there was significant improvement in knowledge scores pertaining to Global Initiative on Chronic Obstructive Lung Disease groups and exacerbation risk (81% correct vs. 43% on pretest; P < 0.001) and guideline-directed treatment (83% correct vs. 28% on pretest; P < 0.001). Out of 44 eligible patients, 75% (n = 33 patients) received the PEMR intervention. Ninety percent of patients (n = 40 patients) were discharged on any long-acting inhaler, similar to the group of preintervention control subjects. Pulmonary rehabilitation referrals were made for 50% of patients (n = 22 patients) compared with 6% of preintervention control subjects (n = 3 patients; P < 0.001). Conclusion: In this single-center quality-improvement study, the combination of a novel, real-time provider teaching intervention and a traditional PEMR intervention improved provider knowledge and was associated with increased referrals to pulmonary rehabilitation.

Molecular Identification of Bacteria in Intra-abdominal Abscesses Using Deep Sequencing.

BACKGROUND: Intra-abdominal abscesses are localized collections of pus, which generally arise from a breach in the normal mucosal defense barrier that allows bacteria from gastrointestinal tract, and less commonly from the gynecologic or urinary tract, to induce inflammation, resulting in an infection. The microbiology of these abscesses is usually polymicrobial, associated with the primary disease process. However, the microbial identity, diversity and richness in intra-abdominal abscesses have not been well characterized, due in part to the difficulty in cultivating commensal organisms using standard culture-based techniques. METHODS: We used culture-independent 16S rRNA Illumina sequencing to characterize bacterial communities in intra-abdominal abscesses collected by percutaneous drainage. A total of 43 abscess samples, including 19 (44.2%) Gram stain and culture-negative specimens, were analyzed and compared with results from conventional microbiologic cultures. RESULTS: Microbial composition was determined in 8 of 19 culture-negative samples and 18 of 24 culture-positive samples, identifying a total of 221 bacterial taxa or operational taxonomic units (OTUs) and averaging 13.1 OTUs per sample (interquartile range, 8-16.5 OTUs). Microbial richness for monomicrobial and polymicrobial samples was significantly higher than culture-negative samples (17 and 15.2 OTUs vs 8 OTUs, respectively), with a trend toward a higher microbial diversity (Shannon diversity index of 0.87 and 1.18 vs 0.58, respectively). CONCLUSIONS: The bacterial consortia identified by cultures correlated poorly with the microbial composition determined by 16S rRNA sequencing, and in most cases, the cultured isolates were minority constituents of the overall abscess microbiome. Intra-abdominal abscesses were generally polymicrobial with a surprisingly high microbial diversity, but standard culture-based techniques failed to reveal this diversity. These data suggest that molecular-based approaches may be helpful for documenting the presence of bacteria in intra-abdominal abscesses where standard cultures are unrevealing, particularly in the setting of prior antibiotic exposure.