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2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Raphael Roger ◽  
Melissa A. Hilmes ◽  
Jonathan M. Williams ◽  
Daniel J. Moore ◽  
Alvin C. Powers ◽  
...  

AbstractPancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals at high risk for developing type 1 diabetes (T1D). Studies investigating pancreas volume are underway to assess pancreas volume in large clinical databases and studies, but manual pancreas annotation is time-consuming and subjective, preventing extension to large studies and databases. This study develops deep learning for automated pancreas volume measurement in individuals with diabetes. A convolutional neural network was trained using manual pancreas annotation on 160 abdominal magnetic resonance imaging (MRI) scans from individuals with T1D, controls, or a combination thereof. Models trained using each cohort were then tested on scans of 25 individuals with T1D. Deep learning and manual segmentations of the pancreas displayed high overlap (Dice coefficient = 0.81) and excellent correlation of pancreas volume measurements (R2 = 0.94). Correlation was highest when training data included individuals both with and without T1D. The pancreas of individuals with T1D can be automatically segmented to measure pancreas volume. This algorithm can be applied to large imaging datasets to quantify the spectrum of human pancreas volume.


2022 ◽  
Vol 104-B (1) ◽  
pp. 168-176
Author(s):  
◽  
Stephanie Spence ◽  
James Doonan ◽  
Omer M. Farhan-Alanie ◽  
Corey D. Chan ◽  
...  

Aims The modified Glasgow Prognostic Score (mGPS) uses preoperative CRP and albumin to calculate a score from 0 to 2 (2 being associated with poor outcomes). mGPS is validated in multiple carcinomas. To date, its use in soft-tissue sarcoma (STS) is limited, with only small cohorts reporting that increased mGPS scores correlates with decreased survival in STS patients. Methods This retrospective multicentre cohort study identified 493 STS patients using clinical databases from six collaborating hospitals in three countries. Centres performed a retrospective data collection for patient demographics, preoperative blood results (CRP and albumin levels and neutrophil, leucocyte, and platelets counts), and oncological outcomes (disease-free survival, local, or metastatic recurrence) with a minimum of two years' follow-up. Results We found that increased mGPS, tumour size, grade, neutrophil/lymphocyte ratio, and disease recurrence were associated with reduced survival. Importantly, mGPS was the best at stratifying prognosis and could be used in conjunction with tumour grade to sub-stratify patient survival. Conclusion This study demonstrated that prognosis of localized STS strongly correlates with mGPS, as an increasing score is associated with a poorer outcome. We note that 203 patients (41%) with an STS have evidence of systemic inflammation. We recommend the mGPS and other biochemical blood indicators be introduced into the routine diagnostic assessment in STS patients to stratify patient prognosis. Its use will support clinical decision-making, especially when morbid treatment options such as amputation are being considered. Cite this article: Bone Joint J 2022;104-B(1):168–176.


2021 ◽  
Vol 11 (1) ◽  
pp. 70
Author(s):  
Steven H. Rauchman ◽  
Sherri G. Mendelson ◽  
Courtney Rauchman ◽  
Lora J. Kasselman ◽  
Aaron Pinkhasov ◽  
...  

SARS-CoV-2 continues to have devastating consequences worldwide. Though vaccinations have helped reduce spread, new strains still pose a threat. Therefore, it is imperative to identify treatments that prevent severe COVID-19 infection. Recently, acute use of SSRI antidepressants in COVID+ patients was shown to reduce symptom severity. The aim of this retrospective observational study was to determine whether COVID+ patients already on SSRIs upon hospital admission had reduced mortality compared to COVID+ patients not on chronic SSRI treatment. Electronic medical records of 9044 patients with laboratory-confirmed COVID-19 from six hospitals were queried for demographic and clinical information. Using R, a logistic regression model was run with mortality as the outcome and SSRI status as the exposure. In this sample, no patients admitted on SSRIs had them discontinued. There was no significant difference in the odds of dying between COVID+ patients on chronic SSRIs vs. those not taking SSRIs, after controlling for age category, gender, and race. This study shows the utility of large clinical databases in determining what commonly prescribed drugs might be useful in treating COVID-19. During pandemics due to novel infectious agents, it is critical to evaluate safety and efficacy of drugs that might be repurposed for treatment.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zhili Dou ◽  
Ye Xia ◽  
Jiawei Zhang ◽  
Yizhen Li ◽  
Yunan Zhang ◽  
...  

ObjectiveThe goal of this study was to systematically summarize and categorize the syndrome differentiation, medication rules, and acupoint therapy in the domestic traditional Chinese medicine (TCM) literature on type 2 diabetes mellitus (T2DM), such that guidelines and new insights can be provided for future practitioners and researchers.MethodsTaking randomized controlled trials (RCTs) on the treatment of T2DM in TCM as the research theme, we searched for full-text literature in three major clinical databases, including CNKI, Wan Fang, and VIP, published between 1990 and 2020. We then conducted frequency statistics, cluster analysis, association rules extraction, and topic modeling based on a corpus of medical academic words extracted from 3,654 research articles.ResultsThe TCM syndrome types, subjective symptoms, objective indicators, Chinese herbal medicine, acupuncture points, and TCM prescriptions for T2DM were compiled based on invigorating the kidney and Qi, nourishing Yin, and strengthening the spleen. Most TCM syndrome differentiation for T2DM was identified as “Zhongxiao” (the lesion in the spleen and stomach) and “Xiaxiao” (the lesion in the kidney) deficiency syndromes, and most medications and acupoint therapies were focused on the “Spleen Channel” and “Kidney Channel.” However, stagnation of liver Qi was mentioned less when compared with other syndromes, which did not have symptomatic medicines.ConclusionThis study provides an in-depth perspective for the TCM syndrome differentiation, medication rules, and acupoint therapy for T2DM and provides practitioners and researchers with valuable information about the current status and frontier trends of TCM research on T2DM in terms of both diagnosis and treatment.


2021 ◽  
Author(s):  
Lei Duan ◽  
Sarah J Calhoun ◽  
Ricardo E Perez ◽  
Virgilia Macias ◽  
Fatima Mir ◽  
...  

Abstract Background Prolylcarboxypeptidase (PRCP) is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. Previous studies have linked PRCP to blood-pressure and appetite control through its ability to cleave peptide substrates such as angiotensin II and a-MSH. A potential role for PRCP in cancer has to date not been widely appreciated. Endocrine therapy resistance in breast cancer is an enduring clinical problem mediated in part by aberrant receptor tyrosine kinase (RTK) signaling. We previously found PRCP overexpression promoted tamoxifen (TAM) resistance in estrogen receptor-positive (ER+) breast cancer cells. Currently we tested the potential association between PRCP with breast cancer patient outcome and RTK signaling, and tumor responsiveness to endocrine therapy. Methods We analyzed PRCP protein expression by IHC staining of ER+ breast cancer samples and PRCP gene expression in clinical databases and used Kaplan-Meier survival curves to determine the significance of PRCP expression correlation with recurrence free survival and overall survival. We analyzed PRCP-regulated IGF1R/HER3 signaling using immunoblotting in the ER+ MCF7 cell line. We analyzed the therapeutic effect of a PRCP specific inhibitor (PRCPi) and/or endoxifen on tumor growth of ER+ PDX tumors and MCF7 tumors in immunocompromised mice. ResultsWe found high PRCP protein levels in tumors associates with worse outcome and earlier recurrence in breast cancer patients, including patients treated with TAM. Analyses of clinical databases showed that PRCP expression correlates with IGF1 and NRG1 expression and their target genes and earlier recurrence in endocrine-treated ER+/HER2- breast cancer patients. Overexpression of PRCP increased IGF1R/HER3 signaling. PRCPi blocked IGF1R/HER3 signaling and enhanced the response of ER+ breast cancer tumors in mice to endoxifen, the active metabolite of TAM. ConclusionsPRCP is an adverse prognostic marker in breast cancer and a potential target to improve endocrine therapy in ER+ breast cancers.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Brandon Kimes ◽  
Thein Zhu

Background/Objective: There are few studies in the literature focused on rural hip fracture epidemiology, and fewer still that consider hip fractures at a specific county level or trauma center (TC) region. The aim of this study is to elucidate patterns of injury events and injury burden of hip fractures in a rural trauma center in northeast Indiana.    Patients and Measurements: We ascertained 2019 hip fracture cases that consisted of three sets of data, namely, emergency department visits (ED), hospitalizations (IP), and deaths from clinical databases. We analyzed the cases by fracture type, measured incidence rates (IRs) per 1,000 county residents and described the injury pattern of hip fractures by variables such as county of residence, age, and sex. We considered the mechanism of injury (cause) of the fractures as well as the injury burden based on the above three sets.    Results: A ratio of roughly 2:1 was found for extracapsular to intracapsular hip fractures. Injury patterns showed that the study counties had similar incidence rates with a range of 0.96 to 1.41 per 1,000 residents. Males and females ages 0-69 years had similar incidences of hip fracture. Overall, females had a 41% higher incidence rate of hip fractures than males. Injury burden indicated a similar distribution of ED to IP to mortality cases across the five study counties, and the majority (98.4%) of hip fractures with known causes of injury were due to falls.    Conclusions and Potential Impact: We elucidated the injury patterns and burden of hip fractures in a verified level II trauma center region. The results of this study have the potential benefit for the future development of hip fracture prevention programs for rural, elderly populations in northeast Indiana.  


2021 ◽  
pp. 00597-2021
Author(s):  
Ole Hilberg ◽  
Anna-Maria Hoffmann-Vold ◽  
Vanessa Smith ◽  
Demosthenes Bouros ◽  
Maritta Kilpelainen ◽  
...  

The PERSEIDS study aimed to estimate incidence/prevalence of interstitial lung diseases (ILDs), fibrosing Interstitial lung diseases (F-ILDs), idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated ILD (SSc-ILD), other non-IPF F-ILDs and their progressive-fibrosing (PF) forms in six European countries, as current data are scarce.This retrospective, two-phase study used aggregate data (2014–2018). In Phase 1, incident/prevalent cases of ILDs above were identified from clinical databases through an algorithm based on codes/keywords, and incidence/prevalence was estimated. For non-IPF F–ILDs, the relative percentage of subtypes was also determined. In Phase 2, a subset of non-IPF F-ILD cases was manually reviewed to determine the percentage of PF behaviour and usual interstitial pneumonia-like (UIP-like) pattern. A weighted mean percentage of progression was calculated for each country and used to extrapolate incidence/prevalence of progressive-fibrosing ILDs (PF–ILDs).In 2018, incidence/105 person-years ranged between 9.4–83.6(ILDs), 7.7–76.2(F-ILDs), 0.4–10.3(IPF), 6.6–71.7(non-IPF F-ILDs) and 0.3–1.5(SSc-ILD); and prevalence/105 persons ranged between 33.6–247.4(ILDs), 26.7–236.8(F-ILDs), 2.8–31.0(IPF), 22.3–205.8(non-IPF F-ILDs) and 1.4–10.1(SSc-ILD). Among non-IPF F-ILDs, sarcoidosis was the most frequent subtype. PF behaviour and UIP-like pattern were present in a third of non-IPF F-ILD cases each and hypersensitivity pneumonitis showed the highest percentage of progressive behaviour. Incidence of PF-ILDs ranged between 2.1–14.5/105 person-years, and prevalence between 6.9–78.0/105 persons.To our knowledge, PERSEIDS is the first study assessing incidence, prevalence and rate of progression of ILDs across several European countries. Still below the threshold for orphan diseases, the estimates obtained were higher and more variable than reported in previous studies, but differences in study design/population must be considered.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4503-4503
Author(s):  
Jahanzaib Khwaja ◽  
Aisha S Patel ◽  
Suzanne O Arulogun ◽  
Ali Rismani ◽  
Simon Salter ◽  
...  

Abstract Introduction Type 1 cryoglobulinaemia (CG) is characterised by monoclonal immunoglobulins which precipitate at temperatures below 37°C and redissolve on warming. They may be associated with lymphoproliferative disorders including Waldenström's macroglobulinemia (WM), other non-Hodgkin lymphoma (NHL), chronic lymphocytic leukaemia (CLL) or monoclonal gammopathy of undetermined significance (MGUS). Due to their rarity and heterogeneous clinical manifestations, incidence and outcomes are not well characterised and they are likely underdiagnosed. We retrospectively reviewed our cohort of patients (pts) with IgM paraprotein-associated type 1 CG. Methods Data from consecutive pts during 2013 and 2021, aged >18 years were extracted from clinical databases at two specialist centres [UCLH, United Kingdom (UK) and AMC, Netherlands]. Results A total of 62 pts (38 male, 24 female) were identified (Table 1); 59 from UK and 4 from Netherlands: 49 (79%) had WM, 7 (11%) IgM MGUS and 6 (10%) NHL (5 other lymphoma, 1 CLL). Median age at CG diagnosis was 66 (range 39-90) years; 32 (52%) were >65 years. MYD88 was mutated in 23/25 (92%) evaluable cases of WM. All cases were negative for hepatitis C. CG was detected after the monoclonal disorder in 46 (74%), with a median time to CG diagnosis of 8 (range 0-1390) months, concurrently in 11 (18%) pts and at a median of 1 month (range 0-4) in 5 (8%) pts prior to the monoclonal disorder. These patients were diagnosed due to CG symptoms. Eight pts (of which 50% had WM) also had active cold agglutinin disease (CAD). CG symptoms were present at time of testing in 25 (40%) pts; the others were diagnosed as a part of asymptomatic screening. CG symptoms were more common in those with MGUS / NHL compared to WM, most frequently in MGUS compared to WM (33% v 71%, p=0.05). Skin manifestations including acrocyanosis, purpura, ulcer and necrosis were noted in 14 (23%); 11 (18%) had peripheral neuropathy (6 sensory, 5 mixed) and 8 (13%) hyperviscosity. Median plasma viscosity was >7 (range 4.7 - >7) mPa of 5/8 pts measured with hyperviscosity and a median paraprotein of 29 (range 5-63) g/l. One patient with WM had cryoglobulinaemic glomerulopathy demonstrated by renal biopsy. In all, 53 (85%) pts received treatment, 10 (16%) for the CG and 43 for the monoclonal disorder, including plasma exchange (11/53). Thirty had Rituximab-based therapy (Table 1), and one received Ibrutinib. All achieved complete resolution of symptoms and 3/6 (50%) treated for CG had complete biochemical response with cryoglobulins undetectable after treatment. Two (20%) required further lines of therapy >4 years later. Overall at a follow up of 21 (range 0-94) months, median survival was not reached. Nine (14%) pts died, with 1 (2%) CG-related death due to relapse disease. Estimated 5-year overall survival (OS) was 67% (95% CI 40-84%) (figure 1). Conclusions In our cohort of 62 pts with type I IgM paraprotein-associated CG, the majority had WM compared to other NHL and MGUS, likely reflecting the clinical bias of the centres and our policy of screening for CG at first visit. A greater proportion of cases (40%) were symptomatic than previous reports (16%; Néel et al, 2014); when present, symptoms were dominated by skin manifestations, neuropathy and hyperviscosity. Patients tested for CG with IgM MGUS were more likely to be symptomatic compared to WM. CAD co-existed in a proportion. Those with CG symptoms treated had good clinical responses; treatment subgroups were too small to draw conclusions as to relative efficacy, but Rituximab-based therapy appeared effective in most cases. CG-related mortality was low with an estimated 5-year OS 67%. Figure 1 Figure 1. Disclosures Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. D'Sa: Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi166-vi167
Author(s):  
Bachchu Lal ◽  
Aditya Kulkarni ◽  
Joseph McDermott ◽  
Umesh Kathad ◽  
Kishor Bhatia ◽  
...  

Abstract Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to prolong survival of patients with newly diagnosed MGMT-methylated GBM. Blood-brain barrier permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT unmethylated GBM) are desperately needed. Lantern Pharma is currently developing LP-184, a hydroxyurea methyl acylfulvene derivative of irofulven guided by its AI platform RADRⓇ analysis showing that tumor cell sensitivity to LP-184 correlates positively with genes commonly upregulated in GBM and either associated with TMZ resistance (e.g. MGMT, UGDH) or tumor promotion (e.g. EGFR, ANXA2). In an in vitro 3D model that mimics the human BBB, the apparent permeability for LP-184 was 1.53E-04 cm/s at 30 minutes, comparable to 1.72E-04 cm/s for TMZ under identical conditions. LP-184 predominantly alkylates DNA at 3’-adenine predicting insensitivity to MGMT expression. In vitro cell toxicity assays in a panel of GBM cell lines and neurospheres reveal an IC50 range of 30 - 400 nM with the MGMT unmethylated cell line LN-18 being among the most sensitive. A single cycle of LP-184 (4 mg/kg, i.v, every other day X 4 doses) induced rapid and near complete regression of subcutaneous U87 xenografts pre-established in immune-deficient mice and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 xenografts (p < 0.0001). LP-184-induced DNA damage is associated with synthetic lethality in tumor cell lines with decreased expression of Nucleotide Excision Repair (NER) genes. Furthermore, interrogation of clinical databases for expression of 112 NER genes revealed that 25 - 37% of clinical GBM clusters in a low NER expression subgroup, predicting high sensitivity of low NER GBM subsets to LP-184. These findings identify LP-184 as a promising new alkylating agent and support its further development for GBM therapy.


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