Impact of Immune Checkpoint Inhibitors on COVID-19 Severity in Patients with Cancer.

BACKGROUND: Amid continued uncertainty about the management of cancer patients during the pandemic, this study sought to obtain real-world data on the use of immune checkpoint inhibitors (ICIs) before COVID-19 diagnosis and its association with severity and survival outcomes in cancer patients who contracted COVID-19. METHODS: Cancer patients diagnosed with COVID-19 were identified from a large electronic health record database; those treated with ICIs before COVID-19+ diagnosis were matched in a 1:2 ratio to those not treated with ICIs, using a 2-step matching procedure. A descriptive analysis examined the difference in COVID-19 mortality (30-day and overall) and severity outcomes between the 2 cohorts, and overall survival was compared. RESULTS: Among 17 545 adults ≥18 years with cancer who tested positive for COVID-19 between February 20, 2020, and January 28, 2021, in the US, 228 ICI-treated patients were matched to 456 non-ICI-treated patients, comprising the 2 study cohorts. Clinical characteristics differed significantly between the 2 cohorts before matching, with metastatic disease, lung cancer, a history of smoking, and the presence of pulmonary comorbidities being more common in the ICI-treated cohort; after matching, the 2 cohorts were similar. There were no significant differences between the ICI-treated and non-ICI-treated cohorts for 30-day mortality (12.7% vs. 14.9%, P = .235), overall mortality (22.4% vs. 22.4%, P = 1.000), hospitalization (38.6% vs. 39.0%, P = .912), or emergency department visits (16.7% vs. 14.7%, P = .500). Overall survival was similar between the 2 cohorts. CONCLUSION: This analysis adds to the clinical evidence base that use of ICIs before SARS-CoV-2 infection does not affect COVID-19 severity or survival outcomes, supporting the continued use of ICIs in cancer patients during the pandemic.

Impact of varying outcomes and definitions of suicidality on the associations of antiepileptic drugs and suicidality: comparisons from UK Clinical Practice Research Datalink (CPRD) and Danish national registries (DNR).

PURPOSE: The purpose of this study is to quantify the impact of the different outcomes and definitions of suicidality on the association between antiepileptic drugs (AEDs) and suicidality. METHODS: Retrospective cohort studies of selected AEDs (carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, topiramate and valproate) using data from UK Clinical Practice Research Datalink (CPRD) alone and linked to UK Hospital Episode Statistics (HES) and UK Office of National Statistics (ONS), and from Danish national registries (DNR). Follow-up started at initiation of one of the study AEDs, divided into exposure periods, a maximum 90-day post-exposure period, and the reference period starting the day after the 90-day post-exposure period ended. Primary outcomes were completed suicide (SUI)/suicide attempt (SA) for CPRD and SUI/deliberate self-harm (DSH) for DNR. We applied adjusted Cox regression analyses and sensitivity analyses with varying outcome definitions. RESULTS: We analyzed 84,524 AED users from CPRD-HES-ONS (1188 SUI/SA; 96 SUI) and 258,180 users from DNR (7561 SUI/DSH; 781 SUI). The adjusted hazard ratios (HRs) on SUI/SA ranged between 1.3 (95% confidence interval (CI): 0.84-2.00) for lamotrigine and 2.7 (1.24-5.81) for phenytoin in CPRD-HES-ONS, and between 0.9 (0.78-1.00) for valproate and 1.8 (1.10-3.07) for phenytoin on SUI/DSH in DNR. HRs for the primary outcomes varied consistently across exposure periods and data sources. HRs for SUI were in general lower, more stable and similar for periods of exposure and the 90-day post-exposure period. CONCLUSION: Applying different outcomes and definitions of suicidality had an impact on the relative risks of suicidality associated with the investigated AEDs with results for SUI being most consistent and reliable.

The characterization of trans-pecos copperhead (Agkistrodon contortrix pictigaster) venom and isolation of two new dimeric disintegrins.

The vast amounts of toxins within the venom of snakes, while known to cause medical emergencies, display various biological functions. Trans-pecos copperhead (Agkistrodon contortrix pictigaster) crude venom separated by cation-exchange chromatography showed several fractions with fibrinolytic, hemorrhagic, gelatinase and platelet activities. Venom fractions 1, 2, 4, 5, and 12-17 contained fibrinolytic activity. Venom fractions 1, 2, 5 and 12-14 had hemorrhagic activity. Fractions 1, 2, 12, 13 and 17 contained gelatinase activity. Reverse-Phase C18 High Performance Liquid Chromatography was also used to purify and isolated disintegrins from this venom. Anti-platelet aggregation activity of the C18 fractions collected and performed on whole human blood showed that they inhibited platelet aggregation in presence of several agonists. Results from both SDS-PAGE and N-terminal sequencing determined that pictistatin 1 obtained from the Trans-Pecos copperhead venom was a dimeric disintegrin, and pictistatin 2 was a heterodimeric disintegrin. The molecules with anti-platelet activity could be considered in the development of more effective drugs, for numerous blood-related diseases such as stroke, heart attacks, thrombosis, and other medical conditions. In this study, we are presenting the first report of the purification, isolation, and partial characterization of two new dimeric disintegrins isolated from the venom of trans-pecos copperhead.

Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk.

There is an increasing expectation that computational approaches may supplement existing human decision-making. Frontloading of models for cardiac safety prediction is no exception to this trend, and ongoing regulatory initiatives propose use of high-throughput in vitro data combined with computational models for calculating proarrhythmic risk. Evaluation of these models requires robust assessment of the outcomes. Using FDA Adverse Event Reporting System reports and electronic healthcare claims data from the Truven-MarketScan US claims database, we quantify the incidence rate of arrhythmia in patients and how this changes depending on patient characteristics. First, we propose that such datasets are a complementary resource for determining relative drug risk and assessing the performance of cardiac safety models for regulatory use. Second, the results suggest important determinants for appropriate stratification of patients and evaluation of additional drug risk in prescribing and clinical support algorithms and for precision health.

Cathepsin B Dependent Cleavage Product of Serum Amyloid A1 Identifies Patients with Chemotherapy-Related Cardiotoxicity.

Improvements in long-term cancer survival rates have resulted in an increase in the prevalence of chemotherapy-linked cardiac failure, but treatment-induced cardiac injuries may not be detected until long after therapy. Monitoring cardiac function is recommended; however, cardiovascular injury in cancer patients differs from those with primary cardiac dysfunction, which limits the utility of traditional cardiac biomarkers. Here we examined plasma levels of peptides produced by cathepsin B, which is released during chemotherapy-induced cardiac injury. We applied nanotrap fractionation to enrich plasma peptides from cancer patients treated with or without chemotherapy. Peptides associated with chemotherapy-induced cardiotoxicity, but not other cardiac injury, were identified by mass spectrometry, and their dependence on cathepsin B activity was determined using enzyme inhibition experiments. We found that a peptide (SAA-1525) derived from serum amyloid A1 was significantly increased in cardiotoxicity patients, and its production was inhibited when plasma samples were pretreated with cathepsin B specific inhibitors. Plasma SAA-1525 also correlated with other markers of cardiac injury. Analysis of plasma SAA-1525 levels may hold potential as a rapid and minimally invasive method to monitor subclinical injury, thereby allowing timely intervention to mitigate further cardiac damage and avoid more severe clinical presentation.

Functional characterizations of venom phenotypes in the eastern diamondback rattlesnake (Crotalus adamanteus) and evidence for expression-driven divergence in toxic activities among populations.

Phenotypes frequently vary across and within species. The connection between specific phenotypic effects and function, however, is less understood despite being essential to our understanding of the adaptive process. Snake venoms are ideal for identifying functionally important phenotypic variation because venom variation is common, and venoms can be functionally characterized through simple assays and toxicity measurements. Previous work with the eastern diamondback rattlesnake (Crotalus adamanteus) used multivariate statistical approaches to identify six unique venom phenotypes. We functionally characterized hemolytic, gelatinase, fibrinogenolytic, and coagulant activity for all six phenotypes, as well as one additional venom, to determine if the statistically significant differences in toxin expression levels previously documented corresponded to differences in venom activity. In general, statistical differences in toxin expression predicted the identified functional differences, or lack thereof, in toxic activity, demonstrating that the statistical approach used to characterize C. adamanteus venoms was a fair representation of biologically meaningful differences. Minor differences in activity not accounted for by the statistical model may be the result of amino-acid differences and/or post-translational modifications, but overall we were able to link variation in protein expression levels to variation in function as predicted by multivariate statistical approaches.

Biological and biochemical characterization of venom from the broad-banded copperhead (Agkistrodon contortrix laticinctus): isolation of two new dimeric disintegrins.

Disintegrins represent a family of effective cell-cell and cell-matrix inhibitors by binding to integrin receptors. Integrins are heterodimeric, transmembrane receptors that are the bridges for these cell interactions. Disintegrins have been shown to have many therapeutic implications for the treatment of strokes, heart attacks, and cancer. Two novel heterodimeric disintegrins were isolated from the venom of the broad-banded copperhead (Agkistrodon contortrix laticinctus). Crude venom separated by cation-exchange chromatography resulted in several fractions possessing hemorrhagic, fibrinolytic, gelatinase, and platelet activities. Venom fractions 2-3 and 17-19 showed fibrinolytic activity. Fractions 2-6, 8-11, and 16-21 had hemorrhagic activity. Gelatinase activity was found in fractions 3, 11, and 19. The isolation of laticinstatins 1 and 2 was accomplished by fractionating crude venom using reverse phase chromatography. Data from both SDS-PAGE and N-terminal sequencing determined that laticinstatins 1 and 2 were heterodimeric disintegrins, and both were assayed for their ability to inhibit platelet aggregation in human whole blood. Future functional evaluation of snake venom disintegrins shows considerable promise for elucidating the biochemical mechanisms of integrin-ligand interactions that will allow the development of adequate medications for hemostatic pathologies such as thrombosis, stroke, and cerebral and cardiac accidents. In this study, we are presenting the first report of the purification, and partial characterization of two new dimeric disintegrins isolated from the venom of broad-banded copperhead snakes.

A European inventory of data elements for patient recruitment.

INTRODUCTION: In the last few years much work has been conducted in creating systems that support clinical trials for example by utilizing electronic health record data. One of these endeavours is the Electronic Health Record for Clinical Research project (EHR4CR). An unanswered question that the project aims to answer is which data elements are most commonly required for patient recruitment. METHODS: Free text eligibility criteria from 40 studies were analysed, simplified and elements were extracted. These elements where then added to an existing inventory of data elements for protocol feasibility. RESULTS: We simplified and extracted data elements from 40 trials, which resulted in 1170 elements. From these we created an inventory of 150 unique data elements relevant for patient identification and recruitment with definitions and referenced codes to standard terminologies. DISCUSSION: Our list was created with expertise from pharmaceutical companies. Comparisons with related work shows that identified concepts are similar. An evaluation of the availability of these elements in electronic health records is still ongoing. Hospitals that want to engage in re-use of electronic health record data for research purposes, for example by joining networks like EHR4CR, can now prioritize their effort based on this list.

Effects of behavioral interventions on disruptive behavior and affect in demented nursing home residents.

BACKGROUND: Disruptive behaviors are prevalent in nursing home residents with dementia and often have negative consequences for the resident, caregiver, and others in the environment. Behavioral interventions might ameliorate them and have a positive effect on residents' mood (affect). OBJECTIVES: This study tested two interventions-an activities of daily living and a psychosocial activity intervention-and a combination of the two to determine their efficacy in reducing disruptive behaviors and improving affect in nursing home residents with dementia. METHODS: The study had three treatment groups (activities of daily living, psychosocial activity, and a combination) and two control groups (placebo and no intervention). Nursing assistants hired specifically for this study enacted the interventions under the direction of a master's prepared gerontological clinical nurse specialist. Nursing assistants employed at the nursing homes recorded the occurrence of disruptive behaviors. Raters analyzed videotapes filmed during the study to determine the interventions' influence on affect. RESULTS: Findings indicated significantly more positive affect but not reduced disruptive behaviors in treatment groups compared to control groups. CONCLUSIONS: The treatments did not specifically address the factors that may have been triggering disruptive behaviors. Interventions much more precisely designed than those employed in this study require development to quell disruptive behaviors. Nontargeted interventions might increase positive affect. Treatments that produce even a brief improvement in affect indicate improved quality of mental health as mandated by federal law.