Nav1.2 channel mutations preventing fast inactivation lead to SCN2A encephalopathy.

SCN2A gene-related early-infantile developmental and epileptic encephalopathy (EI-DEE) is a rare and severe disorder that manifests in early infancy. SCN2A mutations affecting the fast inactivation gating mechanism can result in altered voltage dependence and incomplete inactivation of the encoded neuronal Nav1.2 channel and lead to abnormal neuronal excitability. In this study, we evaluated clinical data of seven missense Nav1.2 variants associated with DEE and performed molecular dynamics simulations, patch-clamp electrophysiology, and dynamic clamp real-time neuronal modelling to elucidate the molecular and neuron-scale phenotypic consequences of the mutations. The N1662D mutation almost completely prevented fast inactivation without affecting activation. The comparison of wild-type and N1662D channel structures suggested that the ambifunctional hydrogen bond formation between residues N1662 and Q1494 is essential for fast inactivation. Fast inactivation could also be prevented with engineered Q1494A or Q1494L Nav1.2 channel variants, whereas Q1494E or Q1494 K variants resulted in incomplete inactivation and persistent current. Molecular dynamics simulations revealed a reduced affinity of the hydrophobic IFM-motif to its receptor site with N1662D and Q1494L variants relative to wild-type. These results demonstrate that the interactions between N1662 and Q1494 underpin the stability and the orientation of the inactivation gate and are essential for the development of fast inactivation. Six DEE-associated Nav1.2 variants, with mutations mapped to channel segments known to be implicated in fast inactivation were also evaluated. Remarkably, the L1657P variant also prevented fast inactivation and produced biophysical characteristics that were similar to those of N1662D, whereas the M1501 V, M1501T, F1651C, P1658S, and A1659 V variants resulted in biophysical properties that were consistent with gain-of-function and enhanced action potential firing of hybrid neurons in dynamic action potential clamp experiments. Paradoxically, low densities of N1662D or L1657P currents potentiated action potential firing, whereas increased densities resulted in sustained depolarization. Our results provide novel structural insights into the molecular mechanism of Nav1.2 channel fast inactivation and inform treatment strategies for SCN2A-related EI-DEE. The contribution of non-inactivating Nav1.2 channels to neuronal excitability may constitute a distinct cellular mechanism in the pathogenesis of SCN2A-related DEE.

Influence of incomplete death information on cumulative risk estimates in US claims data.

Administrative claims databases often do not capture date or fact of death, so studies using these data may inappropriately treat death as a censoring event-equivalent to other withdrawal reasons-rather than a competing event. We examined 1-, 3-, and 5-year inverse-probability-of-treatment weighted cumulative risks of a composite cardiovascular outcome among 34 527 initiators of telmisartan (exposure) and ramipril (referent), who were aged ≥55 years, in Optum (United States) claims data from 2003 to 2020. Differences in cumulative risks of the cardiovascular endpoint due to censoring of death (cause-specific), as compared with treating death as a competing event (subdistribution), increased with greater follow-up time and older age, where event and mortality risks were higher. Among ramipril users, 5-year cause-specific and subdistribution cumulative risk estimates per 100, respectively, were 16.4 (95% CI, 15.3-17.5) and 16.2 (95% CI, 15.1-17.3) among ages 55-64 (difference = 0.2) and were 43.2 (95% CI, 41.3-45.2) and 39.7 (95% CI, 37.9-41.4) among ages ≥75 (difference = 3.6). Plasmode simulation results demonstrated the differences in cause-specific versus subdistribution cumulative risks to increase with increasing mortality rate. We suggest researchers consider the cohort's baseline mortality risk when deciding whether real-world data with incomplete death information can be used without concern. This article is part of a Special Collection on Pharmacoepidemiology.

Characterizing Fit-for-Purpose Real-World Data: An Assessment of a Mother-Infant Linkage in the Japan Medical Data Center Claims Database.

Purpose: Observational postapproval safety studies are needed to inform medication safety during pregnancy. Real-world databases can be valuable for supporting such research, but fitness for regulatory purpose must first be vetted. Here, we demonstrate a fit-for-purpose assessment of the Japan Medical Data Center (JMDC) claims database for pregnancy safety regulatory decision-making. Patients and Methods: The Duke-Margolis framework considers a database's fitness for regulatory purpose based on relevancy (capacity to answer the research question based on variable availability and a sufficiently sized, representative population) and quality (ability to validly answer the research question based on data completeness and accuracy). To assess these considerations, we examined descriptive characteristics of infants and pregnancies among females ages 12-55 years in the JMDC between January 2005 and March 2022. Results: For relevancy, we determined that critical data fields (maternal medications, infant major congenital malformations, covariates) are available. Family identification codes permitted linkage of 385,295 total mother-infant pairs, 57% of which were continuously enrolled during pregnancy. The prevalence of specific congenital malformation subcategories and maternal medical conditions were representative of the general population, but preterm births were below expectations (3.6% versus 5.6%) in this population. For quality, our methods are expected to accurately identify the complete set of mothers and infants with a shared health insurance plan. However, validity of gestational age information was limited given the high proportion (60%) of missing live birth delivery codes coupled with suppression of infant birth dates and inaccessibility of disease codes with gestational week information. Conclusion: The JMDC may be well suited for descriptive studies of pregnant people in Japan (eg, comorbidities, medication usage). More work is needed to identify a method to assign pregnancy onset and delivery dates so that in utero medication exposure windows can be defined more precisely as needed for many regulatory postapproval pregnancy safety studies.

Staging and clean room: Constructs designed to facilitate transparency and reduce bias in comparative analyses of real-world data.

PURPOSE: We describe constructs designed to protect the integrity of the results from comparative analyses using real-world data (RWD): staging and clean room. METHODS: Staging involves performing sequential preliminary analyses and evaluating the population size available and potential bias before conducting comparative analyses. A clean room involves restricted access to data and preliminary results, policies governing exploratory analyses and protocol deviations, and audit trail. These constructs are intended to allow decisions about protocol deviations, such as changes to design or model specification, to be made without knowledge of how they might affect subsequent analyses. We describe an example for implementing staging with a clean room. RESULTS: Stage 1 may involve selecting a data source, developing and registering a protocol, establishing a clean room, and applying inclusion/exclusion criteria. Stage 2 may involve attempting to achieve covariate balance, often through propensity score models. Stage 3 may involve evaluating the presence of residual confounding using negative control outcomes. After each stage, check points may be implemented when a team of statisticians, epidemiologists and clinicians masked to how their decisions may affect study outcomes, reviews the results. This review team may be tasked with making recommendations for protocol deviations to address study precision or bias. They may recommend proceeding to the next stage, conducting additional analyses to address bias, or terminating the study. Stage 4 may involve conducting the comparative analyses. CONCLUSIONS: The staging and clean room constructs are intended to protect the integrity and enhance confidence in the results of analyses of RWD.

Treatment Patterns of Bone-targeting Agents Among Solid Tumor Patients With Bone Metastases: An Analysis of Electronic Health Record Data in the United States From 2014 to 2018.

OBJECTIVES: This study evaluated real-world treatment patterns of approved bone-targeting agents (BTAs) with various mechanisms of action-pamidronate, zoledronic acid, and denosumab-for the prevention of skeletal-related events in patients with bone metastases (BM) from solid tumors. METHODS: Adult patients with BM secondary to solid tumors between January 1, 2014, and December 31, 2018, were identified from the Flatiron Health Oncology Services Comprehensive Electronic Records database and categorized by BTA use and therapy type. Time from diagnosis to initiation, persistence (mean time on treatment), and compliance (≥12 administrations/year) with BTA with up to 4 years of follow-up were examined. RESULTS: This study included 27,268 patients with BM (breast cancer, 32.7%; lung cancer, 16.5%; prostate cancer, 17.2%; and other solid tumors, 33.6%); of these, 41.4% initiated denosumab after BM diagnosis; 21.3%, zoledronic acid; 0.6%, pamidronate; and 36.7% had no treatment record. Mean (SD) time to initiation for denosumab or zoledronic acid was 68.6 (157.0) days (denosumab, 70.3 (160.4) days; zoledronic acid, 65.2 [150.2] days). Mean persistence and compliance (first year of treatment) were significantly higher for denosumab than for zoledronic acid (22.0 vs. 14.9 mo [ P <0.0001] and 42.3% vs. 34.8% [ P <0.0001], respectively). Treatment compliance was the highest in patients with breast cancer (denosumab, 48.2%; zoledronic acid, 39.1%). CONCLUSION: Real-world BTA treatment patterns in the United States suggest that over one-third of patients with BM secondary to solid tumors remain untreated and less than 50% of the patients received ≥12 administrations/year of BTA therapy.

Cardiovascular Safety in Postmenopausal Women and Men With Osteoporosis Treated With Denosumab and Zoledronic Acid: A Post-Authorization Safety Study.

Osteoporosis and cardiovascular disease are common in older adults. Treatment of osteoporosis reduces the burden of debilitating fractures; however, it is important to understand the benefit versus risk of treatment. This study evaluates the risk of stroke (ischemic or hemorrhagic) and myocardial infarction (MI) among postmenopausal women and men initiating osteoporosis treatment with denosumab (receptor activator of nuclear factor κB ligand [RANKL] inhibitor) or zoledronic acid (bisphosphonate) between October 2010 and June 2019. A retrospective cohort study employing the new user/active comparator design was conducted. Analyses were conducted separately in two national US commercial databases, MarketScan® and Optum® for reproducibility. Inverse probability of treatment and censoring weighting was employed to control for confounding and informative censoring. Cumulative risks at 6-month, 12-month, and 36-month time points were calculated and adjusted risk ratios and differences (with 95% confidence intervals [CIs]) were estimated. In MarketScan® and Optum® databases, 96,611 and 73,127 patients met all study eligibility criteria, respectively. At 36 months, the risk ratio estimates (zoledronic acid referent group) were 1.22 (95% CI, 0.77-1.66) and 0.97 (95% CI, 0.63-1.32) for MI and 1.00 (95% CI, 0.61-1.40) and 0.87 (95% CI, 0.56-1.17) for stroke in MarketScan and Optum, respectively. Most of the treatment associations across the other time periods and outcomes also had 95% CIs including the null value. In these large samples of real-world US patients, no increased risk in MI and stroke were identified for up to 36 months of treatment in denosumab users compared with zoledronic acid users. © 2023 Amgen. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pragmatic considerations for negative control outcome studies to guide non-randomized comparative analyses: A narrative review.

PURPOSE: This narrative review describes the application of negative control outcome (NCO) methods to assess potential bias due to unmeasured or mismeasured confounders in non-randomized comparisons of drug effectiveness and safety. An NCO is assumed to have no causal relationship with a treatment under study while subject to the same confounding structure as the treatment and outcome of interest; an association between treatment and NCO then reflects the potential for uncontrolled confounding between treatment and outcome. METHODS: We focus on two recently completed NCO studies that assessed the comparability of outcome risk for patients initiating different osteoporosis medications and lipid-lowering therapies, illustrating several ways in which confounding may result. In these studies, NCO methods were implemented in claims-based data sources, with the results used to guide the decision to proceed with comparative effectiveness or safety analyses. RESULTS: Based on this research, we provide recommendations for future NCO studies, including considerations for the identification of confounding mechanisms in the target patient population, the selection of NCOs expected to satisfy required assumptions, the interpretation of NCO effect estimates, and the mitigation of uncontrolled confounding detected in NCO analyses. We propose the use of NCO studies prior to initiating comparative effectiveness or safety research, providing information on the potential presence of uncontrolled confounding in those comparative analyses. CONCLUSIONS: Given the increasing use of non-randomized designs for regulatory decision-making, the application of NCO methods will strengthen study design, analysis, and interpretation of real-world data and the credibility of the resulting real-world evidence.

Changes in Medication Use During Pregnancy for Women with Chronic Conditions: An Analysis of Claims Data.

PURPOSE: Evaluation of drug safety during pregnancy is dependent on the number of exposed women during routine clinical practice with data available for analysis. We examined medication fills in pregnant and nonpregnant women within select disease cohorts: general population, migraine, diabetes, and hyperlipidemia to explore the potential use of claims data to assess medication use and safety during pregnancy. METHODS: This cohort study, using IBM MarketScan® Research Databases claims data, included women 10-54 years of age with pregnancy resulting in a liveborn infant between January 2010 and September 2015 and matched nonpregnant women. Medication use (antidepressants, antihypertensives, sedatives, glucose-lowering medications, antiepileptics, antipsychotics, lipid-lowering medications) was abstracted from pharmacy claims 180 days before last menstrual period through 180 days postdelivery. RESULTS: Among 753,760 women in the general pregnancy population (including 73,268 migraine, 50,155 hyperlipidemia, and 8361 diabetes; non-exclusive cohorts), antidepressants, antihypertensives, and sedatives were the most commonly used medications during pregnancy. Medications of interest were less commonly used in the pregnancy cohort than in the matched nonpregnant cohort within each time period (e.g., 3.7% vs 13.1% antidepressant use in 1st trimester). Most prescription fills were less common during pregnancy then pre-pregnancy. Post-pregnancy, prescription fills increased to or exceeded pre-pregnancy levels, except antihypertensive and glucose-lowering medications, which increased during pregnancy. CONCLUSIONS: Medication use among pregnant women was low and different from that among matched nonpregnant women. The underlying size of large commercial claims databases offer opportunities for efficient evaluation of potential safety concerns, particularly for rare drug exposures, compared to traditional pregnancy registries.

Bioleaching of Heavy Metals by Streptomyces avermitilis - BBA4 Isolate from Coal Mine Soil of Tamil Nadu.

Printed Circuit Board (PCB) includes precious metals, heavy metals and brominated flame retardants. The usage of PCB is increasing exponentially, generated in vast quantities, and considered an E-waste contaminating the environment. The bioleaching potential of a novel isolated Streptomyces BBA4 strain from a coal mine soil was studied and discussed here. A total of twelve isolates were isolated from coal mine soil (Neyveli area). The metal-resistant activity of the isolated cultures was examined using a dot plot and agar well diffusion assay. Both assays revealed that the isolate BBA4 showed resistance and survival ability in the copper (Cu) and chromium (Cr)-rich environment up to 1000 mg/kg and in the iron (Fe) and silver (Ag)-rich environment up to 500 mg/kg, respectively. Based on the phenotypic, physiological, biochemical and molecular characteristics, the novel and potential strain (BBA4) isolated from coal mine soil matched with Streptomyces avermitilis. The strain showed bioleaching ability to recover 73.3% Cobalt and 36.4% Chromium within 120 h under pH 5 (in vitro conditions) from the PCB. The heavy metal content in the PCB was analyzed using quantitative analytical techniques, such as Atomic Absorption Spectroscopy (AAS) and Powder X-ray diffraction (XRD). The analysis of XRD peaks exhibited an increase in crystallinity with the Cr, associated with the accumulation of Cr in the bioleached residues. Thus, generated data from this investigation reveal that BBA4 is an effective bioleaching strain on PCB over other environmentally hazardous chemical leaching methods.

Koolen-de Vries syndrome associated with continuous spike-wave in sleep

Koolen-de Vries syndrome (KdVS) is a genetic condition caused by 17q21.31 microdeletions or pathogenic variants in KANSL1. Affected patients most commonly exhibit some or all of the following: neonatal hypotonia, developmental impairment, facial dysmorphic features, and congenital malformations. Epilepsy occurs in approximately half, often with phenotypes on the epilepsyaphasia spectrum. We describe six children with KdVS found to have continuous spike-wave in sleep (CSWS) on EEG, four of whom were diagnosed with epileptic encephalopathy with CSWS and two with Landau-Kleffner syndrome. When compared with other children with CSWS on EEG, patients with KdVS may present at slightly later ages and with a longer interval between seizure diagnosis and identification of CSWS. There is no clear best treatment for children with CSWS, but two patients in our cohort were trialed on a variation of the ketogenic diet, and both reported clinical improvement. In one of the patients, the response was dramatic, and CSWS recurred when weaning of the ketogenic diet was attempted. Based on our findings, an EEG capturing a prolonged period of sleep should be arranged in any child with KdVS presenting with developmental regression or plateau, particularly if they have a preceding history of seizures.

Neoadjuvant chemotherapy and less invasive surgery for the management of early stage cervical cancer: A brief report from Botswana.

The majority of deaths from cervical cancer occur in low- and middle- income countries (LMICs). The standard of care for early-stage cervical cancer (FIGO 2018 IA2-IB1) is radical hysterectomy, a procedure performed by trained gynecologic oncologists. However, the lack of gynecologic oncologists in LMICs has required exploration into other methods of treatment for early-stage cervical cancer. A potential course of treatment for early-stage cervical cancer is neoadjuvant chemotherapy followed by simple hysterectomy and pelvic lymph node sampling, which can be performed by a general gynecologist. We gathered data for 8 women who underwent this method of treatment and found that cause-specific survival was 100% over a 3.5-year median follow-up. These findings support the exploration for this method of treatment for early-stage cervical cancer in LMICs, which would improve access to treatment for these women and hopefully reduce the high burden of cervical cancer related deaths in LMICs.

Association Between Granulocyte Colony-Stimulating Factor (G-CSF) Use and Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) Among Elderly Patients with Breast, Lung, or Prostate Cancer.

INTRODUCTION: Patients diagnosed with cancer have an increased risk both for myelodysplastic syndromes (MDS) and for acute myeloid leukemia (AML) following treatment. METHODS: Using SEER-Medicare data, we selected patients aged 66 years and older who completed systemic therapy between 2002 and 2014 for breast (stage I-III), lung (stage I-III), or prostate (stage I-IV) cancer. For each cancer, we estimated the risk of a composite endpoint of MDS or AML in patients receiving granulocyte colony-stimulating factor (G-CSF) vs. not. RESULTS: The 10-year cumulative risk difference (granulocyte colony-stimulating factor [G-CSF] - no G-CSF) for MDS-AML was 0.45% (95% CI 0.13-0.77%) in breast cancer and 0.39% (95% CI 0.15-0.62%) in lung cancer. G-CSF use was associated with a hazard ratio of 1.60 (95% CI 1.07-2.40) in breast cancer and 1.50 (95% CI 0.99-2.29) in lung cancer. Filgrastim use was associated with a hazard ratio of 1.01 (95% CI 1.00-1.03) per administration in breast cancer and 1.02 (95% CI 0.99-1.05) per administration in lung cancer. Pegfilgrastim was associated with a hazard ratio of 1.08 (95% CI 1.01-1.15) per administration in breast cancer and 1.12 (95% CI 1.00-1.25) per administration in lung cancer. Analyses in prostate cancer were limited because of the low number of events. CONCLUSIONS: The use of G-CSF in patients diagnosed with breast and lung cancer is associated with an increased risk of MDS-AML. However, the MDS-AML absolute risk difference is very low.

Gynecologic radiation therapy in low and middle income countries during the COVID-19 pandemic.

The COVID-19 pandemic has forever affected healthcare and posed an incredible challenge to our society to care for our sick. Patients with cancer were found early on to have higher rates of complications with COVID-19. Radiation therapy is an integral part of treatment for many types of gynecologic cancer and adaptation on its utilization during the pandemic varied across the globe. In this review, we detail certain guidelines for the use of radiation in gynecologic cancers during the pandemic as well as real world accounts of how different countries adapted to these guidelines or created their own based on individualized resources, staffing, government restrictions, and societal norms. Critically, this review demonstrates the breadth of fractionation schemes and technologies used when resources were limited but highlights the importance of long term follow-up for many of our patients during this time.

Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy.

A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1ß3δ and α4ß2δ GABAA receptors. This was accompanied by analysis of electroclinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1ß3δ and α4ß2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects, whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence and no seizure history, but has a diagnosis of autism spectrum disorder and suffers from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electroclinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor overactivity is observed in a broader range of patients with neurodevelopmental disorders, because SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, as a substantial portion of available antiseizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

Risk of infections and mortality in Danish patients with cancer diagnosed with bone metastases: a population-based cohort study.

OBJECTIVES: Risk of infections in patients with solid cancers and bone metastases (BM) and the subsequent impact on prognosis is unclear. We examined the risk of infections among patients with cancer diagnosed with BM and the subsequent impact of infections on mortality. DESIGN: Population-based cohort study. SETTING: Danish medical databases holding information on all hospital contacts in Denmark. PARTICIPANTS: Adult patients with solid cancers and BM between 1 January 1994 and 30 November 2013. OUTCOME MEASURES: In the risk analyses, the outcome was time to hospitalisation for common severe infections, pneumonia, sepsis and urinary tract infections. In the mortality analysis, we used Cox regression to compute HRs of death, modelling infection as time-varying exposure, stratifying for primary cancer type and adjusting for age, sex and comorbidities. RESULTS: Among 23 336 patients with cancer and BM, cumulative incidences of common severe infections were 4.6%, 14.0% and 20.0% during 1 month, 1 year and 10 years follow-up. The highest incidence was observed for pneumonia, followed by urinary tract infections and sepsis. Infection was a strong predictor of 1 month mortality (adjusted HR: 2.1 (95% CI 1.8 to 2.3)) and HRs increased after 1 and 10 years: 2.4 (95% CI 2.3 to 2.6) and 2.4 (95% CI 2.4 to 2.6). Sepsis and pneumonia were the strongest predictors of death. Results were consistent across cancer types. CONCLUSION: Patients with cancer and BM were at high risk of infections, which was associated with a more than twofold increased risk of death for up to 10 years of follow-up. The findings underscore the importance of preventing infections in patients with cancer and BM.

Disinformation: analysis and identification.

We present an extensive study on disinformation, which is defined as information that is false and misleading and intentionally shared to cause harm. Through this work, we aim to answer the following questions:Can we automatically and accurately classify a news article as containing disinformation?What characteristics of disinformation differentiate it from other types of benign information? We conduct this study in the context of two significant events: the US elections of 2016 and the 2020 COVID pandemic. We build a series of classifiers to (i) examine linguistic clues exhibited by different types of fake news articles, (ii) analyze "clickbaityness" of disinformation headlines, and (iii) finally, perform fine-grained, veracity-based article classification through a natural language inference (NLI) module for automated disinformation verification; this utilizes a manually curated set of evidence sources. For the latter, we built a new dataset that is annotated with generic, veracity-based labels and ground truth evidence supporting each label. The veracity labels were formulated based on examining standards used by reputable fact-checking organizations. We show that disinformation derives features from both propaganda and mainstream news, making it more challenging to detect. However, there is significant potential for automating the fact-checking process to incorporate the degree of veracity. We provide error analysis that illustrates the challenges involved in the automated fact-checking task and identifies factors that may improve this process in future work. Finally, we also describe the implementation of a web app that extracts important entities and actions from a given article and searches the web to gather evidence from credible sources. The evidence articles are then used to generate a veracity label that can assist manual fact-checkers engaged in combating disinformation.

Cardiovascular events in cancer patients with bone metastases-A Danish population-based cohort study of 23,113 patients.

INTRODUCTION: The incidence of cardiovascular events among cancer patients with bone metastases is poorly understood. We examined rates of cardiovascular events among cancer patients with bone metastases and mortality following such events. METHODS: Using Danish health registries, we identified all Danish cancer patients diagnosed with bone metastases (1994-2013) and followed them from bone metastasis diagnosis. We computed incidence rates (IR) per 100 person-years and cumulative incidence for first-time inpatient hospitalization or outpatient clinic visit for cardiovascular events, defined as myocardial infarction, ischemic stroke, or venous thromboembolism (VTE). We also analyzed all-cause mortality rates including cardiovascular events as time-varying exposure with adjustment for age, sex, and Charlson Comorbidity Index score. All analyses were performed overall and stratified by cancer type (prostate, breast, lung, and other). RESULTS: We included 23,113 cancer patients with bone metastases. The cumulative incidence of cardiovascular events was 1.3% at 30 days, 3.7% at 1 year, and 5.2% at 5 years of follow-up. The highest IR was observed for VTE, followed by ischemic stroke and myocardial infarction, both overall and by cancer types. Lung cancer patients with bone metastases had the highest incidence of cardiovascular events followed by prostate and breast cancer. Occurrence of any cardiovascular event was a strong predictor of death (5 years following the event, the adjusted hazard ratio was 1.8 [95% confidence interval: 1.7-1.9]). CONCLUSION: Cancer patients with bone metastases had a substantial risk of developing cardiovascular events, and these events were associated with a subsequent increased mortality. Our findings underscore the importance of continuous optimized prevention of and care for cardiovascular disease among cancer patients with bone metastases.

Use of bisphosphonates in multiple myeloma patients in Denmark, 2005-2015.

PURPOSE: To describe use of bisphosphonates in newly diagnosed multiple myeloma patients in Denmark. METHODS: Using data from the Danish National Multiple Myeloma Registry, we conducted a population-based cohort study. Among patients newly diagnosed with multiple myeloma from 2005 to 2015, we examined use of bisphosphonates at first- and at progression/second-line anti-myeloma treatment overall, by patient characteristics, and myeloma complications. RESULTS: Of 2947 patients starting first-line anti-myeloma treatment, 2207 patients (74.9%) received bisphosphonates. During a median follow-up of 27.6 (quartiles, 10.6-52.5) months, disease progression post-first-line treatment was recorded in 1546 patients, of whom 1065 (68.9%) were treated with bisphosphonates. Altogether, 80.9% of patients with and 37.6% of patients without myeloma bone disease were treated with bisphosphonates at first line and 73.0% and 42.7%, respectively, at progression/second line. Moreover, the proportion of patients treated with bisphosphonates decreased with increasing severity of renal impairment at first and at progression/second-line treatment. CONCLUSION: The proportion of patients treated with bisphosphonates as part of first- and second-line anti-myeloma treatment increased with presence of myeloma bone disease and decreased by presence and severity of renal impairment. Overall, 25% of newly diagnosed multiple myeloma patients had no record of bisphosphonate treatment, potentially indicating an unmet need.

Discharge status and post-discharge healthcare costs after skeletal-related event hospitalizations among medicare patients with bone metastatic solid tumors or multiple myeloma.

BACKGROUND: Previous studies have quantified direct inpatient costs of skeletal-related events (SREs); however, costs associated with subsequent post-SRE care have not been examined. METHODS: We identified two study cohorts using 2011-2015 Medicare 20% sample data: patients diagnosed with 1) bone metastases from solid tumors or 2) multiple myeloma (MM), both with SRE-related hospitalization discharge dates January 1, 2011-September 30, 2015. We assessed discharge status and costs from discharge to the earliest of death, end of Medicare enrollment, or December 31, 2015. Discharge status was defined as: skilled nursing facility (SNF), rehabilitation facility, hospice, home health agency (HHA), long-term care (LTC) nursing home, LTC hospital, or rehospitalization within or after 30 days. Percentage, stay duration, and Medicare costs were calculated for each setting. All analyses were descriptive. RESULTS: We identified 7988 bone metastases patients and 4277 MM patients discharged from index SRE-related hospitalizations; corresponding mean ages were 76.9 and 76.6 years. The largest proportion of bone metastases patients were discharged to SNF (32.9%), then HHA (13.7%), hospice (13.5%), and LTC (11.3%); the pattern was similar for MM patients (SNF, 35.9%; HHA, 18.2%; hospice, 7.2%; LTC, 1.5%). Almost 10% of patients in both cohorts were re-hospitalized within 30 days. Mean Medicare cost per patient per facility stay was < $10,000 for hospice, and from $15,517 for LTC nursing home to $49,729 for LTC hospital for MM patients. CONCLUSION: Most elderly cancer patients (>75%) require healthcare facility support after SRE-related hospitalization, with substantial associated costs. Post-discharge management is clinically and economically important.