Citations

AbstractWe aimed to evaluate the value of ATN biomarker classification system (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) for predicting conversion from mild cognitive impairment (MCI) to dementia. In a sample of people with MCI (n = 415) we assessed predictive performance of ATN classification using empirical knowledge‐based cut‐offs for each component of ATN and compared it to two data‐driven approaches, logistic regression and RUSBoost machine learning classifiers, which used continuous clinical or biomarker scores. In data‐driven approaches, we identified ATN features that distinguish normals from individuals with dementia and used them to classify persons with MCI into dementia‐like and normal groups. Both data‐driven classification methods performed better than the empirical cut‐offs for ATN biomarkers in predicting conversion to dementia. Classifiers that used clinical features performed as well as classifiers that used ATN biomarkers for prediction of progression to dementia. We discuss that data‐driven modeling approaches can improve our ability to predict disease progression and might have implications in future clinical trials.

AbstractAs pharmacogenomic (PGx) testing increases in popularity, lay concepts of drug‐gene interactions set the stage for shared decision making in precision medicine. Few studies explore what recipients of PGx results think is happening in their bodies when a drug‐gene interaction is discovered. To characterize biobank participants’ understanding of PGx research results, we conducted a focus group study, which took place after PGx variants conferring increased risk of dihydropyrimidine dehydrogenase (DPD) deficiency were disclosed to biobank contributors. DPD deficiency confers an increased risk of adverse reaction to commonly used cancer chemotherapeutics. Ten focus groups were conducted, ranging from two to eight participants. Fifty‐four individuals participated in focus groups. A framework approach was used for descriptive and explanatory analysis. Descriptive themes included participants’ efforts to make sense of PGx findings as they related to: (1) health implications, (2) drugs, and (3) genetics. Explanatory analysis supplied a functional framework of how participant word choices can perform different purposes in PGx communication. Results bear three main implications for PGx research‐related disclosure. First, participants’ use of various terms suggest participants generally understanding their PGx results, including how positive PGx results differ from positive disease susceptibility genetic results. Second, PGx disclosure in biobanking can involve participant conflation of drug‐gene interactions with allergies or other types of medical reactions. Third, the functional framework suggests a need to move beyond a deficit model of genetic literacy in PGx communication. Together, findings provide an initial evidence base for supporting bidirectional expert‐recipient PGx results communication.

We present the case of a cognitively unimpaired 77-year-old man with elevated, asymmetric, and longitudinally increasing Flortaucipir tau PET despite normal (visually negative) amyloid PET. His atypical tau PET signal persisted and globally increased in a follow-up scan five years later. Across eight years of observations, temporoparietal atrophy was observed consistent with tau PET patterns, but he retained the cognitively unimpaired classification. Altogether, his atypical tau PET signal is not explained by any known risk factors or alternative pathologies, and other imaging findings were not remarkable. He remains enrolled for further observation.

Purpose To analyze recent trends in orthopaedic surgery consolidation and quantify these changes temporally and geographically from 2012 to 2020. Methods We performed a retrospective cross‐sectional analysis of orthopaedic surgeon practice size in the United States using 2012 and 2020 data obtained from the Physician Compare database. Results Although we observed an increase from 21,216 unique orthopaedic surgeons in 2012 to 21,553 in 2020 (1.6% increase), the number of practices experienced a large decrease from 7,299 practices in 2012 to 5,829 in 2020 (20.1% decrease). The proportion of orthopaedic surgeons working in solo practices decreased from 13.2% (2,790) in 2012 to 7.4% (1,595) in 2020, and the proportion of orthopaedic surgeons working in groups sized 2 to 24 decreased from 35.3% (7,482) in 2012 to 22.2% (4,775) in 2020. In contrast, groups sized 25 to 99 have grown from 20.7% (4,387) of all orthopaedic surgeons to 23.4% (5,048) in 2020. Groups sized 100 to 499 have increased from 16.9% (3,593) in 2012 to 24.1% (5,190) in 2020, whereas groups sized 500 or greater have grown from 14% (2,964) in 2012 to 22.9% (4,945) in 2020. The number of unique group practices showed a significant decrease in the number of solo groups, which comprised 43.8% (3,200) of the total number of individual practices in 2012, decreasing to 32% (1,886) in 2020. All other groups increased in number and proportionally from 2012 to 2020. Conclusions This study shows that over the period from 2012 to 2020, there has been a substantial trend of orthopaedic surgeons shifting to increasing practice sizes, potentially indicating that more orthopaedic surgeons are working for large health care organizations rather than small independent practices. Clinical Relevance The impact of these changes should be examined to determine large‐scale effects on patient care, payment models, access, and outcomes, along with physician compensation, lifestyle, and satisfaction.

Oncolytic viruses (OVs) can have utility for direct killing of cancer cells, but may also serve to activate the immune system against cancer cells. While viruses alone can serve as immune stimulators, there is great interest in arming OVs with genes encoding immune stimulatory proteins to amplify their effects. In this work, we have tested the efficacy of conditionally-replicating adenoviruses (CRAds) with and without selected immunostimulatory payloads, murine CD40L (mCD40L) or 4-1BBL (m4-1BBL), in an immune competent mouse model of melanoma. When CRAd657-m4-1BBL and CRAd657-mCD40L were injected into B16-hCAR murine melanoma tumors, both single vectors delayed tumor growth and prolong survival compared to empty CRAd657. However, combined injection of both CRAd-m4-1BBL and CRAd-mCD40L mediated significantly better control of tumor growth. All of the payloads increased immune cell infiltration into tumors and notably reduced expression of PD-1 exhaustion marker on T cells. Tumor volumes were negatively associated with total infiltrating T cell population. We found that the payloads increased immune cell infiltration into tumors with some specificities: recruitment of CD8 + T cells was higher with m4-1BBL expression, while mCD40L expression induced more CD4 + T cell infiltration. Importantly, the combination of CRAd657-m4-1BBL and CRAd657-mCD40L induced the highest immune cells/T cell infiltration and the highest anti-TRP-2 tumor-associated antigen T cell responses than empty or single gene vector. This combination also caused depigmentation in areas adjacent to the tumor sites in more animals. These data indicate that driving two axes of the immune system with combined immune stimulatory payloads can lead to improved anticancer immune responses and better tumor control in an immune competent model of cancer.

PURPOSETo determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.MATERIALS AND METHODSThe study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).RESULTSThe frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.CONCLUSIONThe study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

Background: Blastomycosis can cause severe disease with progressive respiratory failure and dissemination even in immunocompetent individuals. We sought to evaluate risk factors for severe disease and mortality using clinical and laboratory data within a large health system in an endemic area. Methods: We performed a retrospective cohort study of patients diagnosed with blastomycosis at all Mayo Clinic sites from 1 January 2004 through 31 March 2020. Diagnosis was established by culture, histopathology/cytopathology, serology, antigen testing, or PCR. Disease was categorized as mild for patients treated in the outpatient setting, moderate for hospitalized patients who did not require intensive care, and severe for patients admitted to the intensive care unit. Logistic regression was used to evaluate risk factors for severe disease. A Cox proportional hazards model was constructed to evaluate mortality. Findings: We identified 210 patients diagnosed with blastomycosis. Mean age was 51 years (range, 6–84). Most subjects were male (71.0%). Extrapulmonary disease was confirmed in 24.8%. In this cohort, 40.5% of patients had mild disease, 37.6% had moderate disease, and 21.9% had severe disease. Independent risk factors for severe disease were neutrophilia (odds ratio (OR) 3.35 (95% CI 1.53–7.35), p = 0.002) and lymphopenia (OR 3.34 (95% CI 1.59–7.03), p = 0.001). Mortality at 90 days was 11.9%. Median time from diagnosis to death was 23 days (interquartile range 8–31 days). Independent risk factors for mortality were age (OR 1.04 (95% CI 1.01–1.08), p = 0.009), neutrophilia (OR 2.84 (95% CI 1.04–7.76), p = 0.041), and lymphopenia (OR 4.50 (95% CI 1.67–12.11), p = 0.003). Blastomyces immunodiffusion had an overall sensitivity of 39.6% (95% CI 30.1–49.8). Sensitivity was higher among those who were tested 4 weeks or longer after the onset of symptoms. Urine Blastomyces antigen had a significantly higher sensitivity of 80.8% (95% CI 68.1–89.2) compared to serology. There was a trend towards higher antigen concentration in patients with severe disease. The sensitivity of PCR from respiratory specimens was 67.6% (95% CI 50.1–85.5). Conclusion: In this cohort, we did not find an association between pharmacologic immunosuppression and disease severity. Lymphopenia at diagnosis was an independent risk factor for mortality. This simple marker may aid clinicians in determining disease prognosis.