Citations

Background and motivation: Lung computed tomography (CT) techniques are high-resolution and are well adopted in the intensive care unit (ICU) for COVID-19 disease control classification. Most artificial intelligence (AI) systems do not undergo generalization and are typically overfitted. Such trained AI systems are not practical for clinical settings and therefore do not give accurate results when executed on unseen data sets. We hypothesize that ensemble deep learning (EDL) is superior to deep transfer learning (TL) in both non-augmented and augmented frameworks. Methodology: The system consists of a cascade of quality control, ResNet–UNet-based hybrid deep learning for lung segmentation, and seven models using TL-based classification followed by five types of EDL’s. To prove our hypothesis, five different kinds of data combinations (DC) were designed using a combination of two multicenter cohorts—Croatia (80 COVID) and Italy (72 COVID and 30 controls)—leading to 12,000 CT slices. As part of generalization, the system was tested on unseen data and statistically tested for reliability/stability. Results: Using the K5 (80:20) cross-validation protocol on the balanced and augmented dataset, the five DC datasets improved TL mean accuracy by 3.32%, 6.56%, 12.96%, 47.1%, and 2.78%, respectively. The five EDL systems showed improvements in accuracy of 2.12%, 5.78%, 6.72%, 32.05%, and 2.40%, thus validating our hypothesis. All statistical tests proved positive for reliability and stability. Conclusion: EDL showed superior performance to TL systems for both (a) unbalanced and unaugmented and (b) balanced and augmented datasets for both (i) seen and (ii) unseen paradigms, validating both our hypotheses.

Importance Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent. Objectives To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN. Evidence Review A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement. Findings In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated. Conclusions and Relevance This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.

Background and Aims: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. Approach and Results: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival. Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0–19.3) months; 17 patients (10.7%; 95% CI: 6.4%–16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9–15.7) months; 10 patients (6.3%; 95% CI: 3.1%–11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7–1.8 mo); median overall survival was 7.6 months (95% CI: 5.8–9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). Conclusions: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.

AbstractOur objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Abstract Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09–1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words)

ABSTRACT Purpose Acute exercise redistributes large numbers of memory T cells, which may contribute to enhanced immune surveillance in regular exercisers. It is not known, however, if acute exercise promotes a broad or oligoclonal T-cell receptor (TCR) repertoire or evokes transcriptomic changes in “exercise-responsive” T-cell clones. Methods Healthy volunteers completed a graded bout of cycling exercise up to 80% V̇O 2max . DNA was extracted from peripheral blood mononuclear cells collected at rest, during exercise (EX), and 1 h after (+1H) exercise, and processed for deep TCR-β chain sequencing and tandem single-cell RNA sequencing. Results The number of unique clones and unique rearrangements was decreased at EX compared with rest ( P < 0.01) and +1H ( P < 0.01). Productive clonality was increased compared with rest ( P < 0.05) and +1H ( P < 0.05), whereas Shannon’s Index was decreased compared with rest ( P < 0.05) and +1H ( P < 0.05). The top 10 rearrangements in the repertoire were increased at EX compared with rest ( P < 0.05) and +1H ( P < 0.05). Cross-referencing TCR-β sequences with a public database (VDJdb) revealed that exercise increased the number of clones specific for the most prevalent motifs, including Epstein–Barr virus, cytomegalovirus, and influenza A. We identified 633 unique exercise-responsive T-cell clones that were mobilized and/or egressed in response to exercise. Among these clones, there was an upregulation in genes related to cell death, cytotoxicity, and activation ( P < 0.05). Conclusions Acute exercise promotes an oligoclonal T-cell repertoire by preferentially mobilizing the most dominant clones, several of which are specific to known viral antigens and display differentially expressed genes indicative of cytotoxicity, activation, and apoptosis.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

AbstractBackgroundWhite matter (WM) injury visible on MRI is a common finding in Alzheimer’s disease (AD) and is often attributed to small vessel ischemic changes secondary to increased systemic vascular risk. Increased WM injury has been associated with the progression of Autosomal Dominant AD (ADAD), though ADAD pathogenic variant carriers are relatively young and may not have elevated vascular risk factors. We hypothesized that WM injury in ADAD may reflect worsening of cerebral amyloid angiopathy (CAA) and neurodegeneration. Here we examine this hypothesis using cross‐sectional and longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN).MethodMRI data from ADAD pathogenic variant carriers (n=223) and non‐carriers (n=136) were used in the present study (Table 1). We extracted FreeSurfer‐based WM lesion (WML) volume from T1‐weighted images (hypointensities). Cortical microbleed (CMB) burden was assessed visually on susceptibility weighted/T2*‐weighted gradient echo images by experienced radiologists (blineded to the mutation status) at the Mayo Clinic in Rochester. Linear regression models compared WML volume at baseline in people with and without CMB. Linear mixed effect models assessed the relationships between longitudinal WML and both CMBs and FreeSurfer‐based total gray matter (GM) volume. Models were corrected for age and estimated years to symptom onset (EYO).ResultGreater baseline WML volume was seen in ADAD carriers vs. non‐carriers, particularly close to the age of estimated symptom onset. Baseline WML volume was greater in carriers with CMBs compared to those without (t=2.9, p=0.003, Figure 1). Longitudinal increase in WML amongst ADAD pathogenic variant carriers with CMBs was estimated to be 214 mm3/year greater than that amongst carriers without CMBs (t=4.1, p<0.001, Figure 2). Independent of this CMB effect, decreasing GM volume was strongly associated with increasing longitudinal WML volume (t=‐6.2, p<0.001, Figure 3). Similar analyses in the non‐carrier group yielded no significant findings.ConclusionConsistent with prior reports, WML volume was increased in ADAD pathogenic variant carriers. However, the results here suggest WML in ADAD may not solely be due to small vessel ischemic changes, but rather may be a result of worsening CAA and more rapid neurodegeneration.