COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort.

INTRODUCTION: Infection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort. METHODS: We used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression. RESULTS: There were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38-1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95-1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98-1.25) and MI (HR 0.93, 95% CI 0.85-1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19-1.56) and PE (HR 1.82, 95% CI 1.57-2.10) in patients with COVID-19. CONCLUSION: In a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.

COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort.

INTRODUCTION: Infection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort. METHODS: We used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression. RESULTS: There were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38-1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95-1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98-1.25) and MI (HR 0.93, 95% CI 0.85-1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19-1.56) and PE (HR 1.82, 95% CI 1.57-2.10) in patients with COVID-19. CONCLUSION: In a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.

Mixed methods assessment of women's risk of intimate partner violence in Nepal.

BACKGROUND: Intimate partner violence (IPV) is a significant public health issue that affects one in three women globally and a similarly large number of women in Nepal. Although important policy and programmatic steps have been taken to address violence against women in Nepal over the past decade, there is still a gap on IPV research in Nepal, particularly with regard to social norms. METHODS: This mixed-methods study used in-depth interviews with women and their husbands as well as baseline survey data from a cluster randomized trial testing a primary prevention intervention for IPV to examine the prevalence and risk factors for IPV. Baseline survey data included 1800 women from Nawalparasi, Chitwan, and Kapilvastu districts in Nepal. Multivariate regression was used to identify risk and protective factors for exposure to physical and / or sexual IPV in the prior 12 months. Case-based analysis was used to analyze one of 18 pairs of in-depth interviews to examine risk and protective factors within marriages. RESULTS: Of 1800 eligible participants, 455 (25.28%) were exposed to IPV. In multivariate analyses, low caste, wife employment, income stress, poor marital communication, quarrelling, husband drunkenness, exposure to IPV as a child, in-law violence, and gender inequitable normative expectations were associated with IPV. The selected case interview represented common themes identified in the analysis including the wife's exposure to violence as a child, husband alcohol use, and marital quarrelling. CONCLUSIONS: Gender inequitable norms in the community and the intergenerational transmission of attitudes and behaviors supportive of IPV are important to address in intervention measures.

Networks Underpinning Symbiosis Revealed Through Cross-Species eQTL Mapping.

Organisms engage in extensive cross-species molecular dialog, yet the underlying molecular actors are known for only a few interactions. Many techniques have been designed to uncover genes involved in signaling between organisms. Typically, these focus on only one of the partners. We developed an expression quantitative trait locus (eQTL) mapping-based approach to identify cause-and-effect relationships between genes from two partners engaged in an interspecific interaction. We demonstrated the approach by assaying expression of 98 isogenic plants (Medicago truncatula), each inoculated with a genetically distinct line of the diploid parasitic nematode Meloidogyne hapla With this design, systematic differences in gene expression across host plants could be mapped to genetic polymorphisms of their infecting parasites. The effects of parasite genotypes on plant gene expression were often substantial, with up to 90-fold (P = 3.2 × 10-52) changes in expression levels caused by individual parasite loci. Mapped loci included a number of pleiotropic sites, including one 87-kb parasite locus that modulated expression of >60 host genes. The 213 host genes identified were substantially enriched for transcription factors. We distilled higher-order connections between polymorphisms and genes from both species via network inference. To replicate our results and test whether effects were conserved across a broader host range, we performed a confirmatory experiment using M. hapla-infected tomato. This revealed that homologous genes were similarly affected. Finally, to validate the broader utility of cross-species eQTL mapping, we applied the strategy to data from a Salmonella infection study, successfully identifying polymorphisms in the human genome affecting bacterial expression.

Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL.

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, tissue-resident CLL cells show prominent activation of both B-cell receptor (BCR) and NF-κB pathways. We evaluated the in vivo effects of ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor on tumor cell activation and proliferation in the blood, lymph node, and bone marrow of patients with CLL. Applying validated pathway-specific gene signatures, we detected a rapid and sustained downregulation of BCR and NF-κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment. Ibrutinib reduced phosphorylation of PLCγ2 and ERK and decreased nuclear protein expression of NF-κB p50. Ibrutinib significantly decreased tumor proliferation and expression of surface activation markers CD69 and CD86, independent of prognostic factors such as IGHV mutational status, chromosome 17p deletion, or prior treatment history. Interestingly, stronger inhibition of BCR signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2. Together, these data validate on-target effects of BTK inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo. This study is registered at www.clinicaltrials.gov as #NCT01500733.

Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients.

Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

Breaking B and T cell tolerance using cationic lipid--DNA complexes (CLDC) as a vaccine adjuvant with hepatitis B virus (HBV) surface antigen in transgenic mice expressing HBV.

Cationic lipid DNA complexes (CLDC), referred to here as JVRS-100, were evaluated as an adjuvant for hepatitis B surface antigen (HBsAg) for eliciting B and T cell responses in transgenic mice expressing hepatitis B virus (HBV). To confirm the immunogenicity of HBsAg+JVRS-1000, a study was conducted in C57BL/6 mice, the genetic background of the HBV transgenic mice used in the study. HBsAg+JVRS-100 elicited a T cell response and B cell response as evidenced by interferon-gamma (IFN-γ) secretion by re-stimulated splenocytes and anti-HBsAg IgG induction, respectively, whereas, HBsAg only elicited a B cell response. In HBV transgenic mice, HBsAg did not elicit either T or B cell responses, unlike the HBsAg+JVRS-100 that elicited both. Energix-B vaccine did perform better than the HBsAg by eliciting a B cell response in the transgenic mice, but it did not perform as HBsAg+JVRS-100 since it did not elicit a T cell response. The response by HBsAg+JVRS-100 was not sufficient to cause destruction of infected liver cells, but it did suppress HBV DNA non-cytolytically. From these results, JVRS-100 might be considered for further development as an adjuvant for HBV therapeutic vaccines.

Cationic lipid/DNA complex-adjuvanted influenza A virus vaccination induces robust cross-protective immunity.

Influenza A virus is a negative-strand segmented RNA virus in which antigenically distinct viral subtypes are defined by the hemagglutinin (HA) and neuraminidase (NA) major viral surface proteins. An ideal inactivated vaccine for influenza A virus would induce not only highly robust strain-specific humoral and T-cell immune responses but also cross-protective immunity in which an immune response to antigens from a particular viral subtype (e.g., H3N2) would protect against other viral subtypes (e.g., H1N1). Cross-protective immunity would help limit outbreaks from newly emerging antigenically novel strains. Here, we show in mice that the addition of cationic lipid/noncoding DNA complexes (CLDC) as adjuvant to whole inactivated influenza A virus vaccine induces significantly more robust adaptive immune responses both in quantity and quality than aluminum hydroxide (alum), which is currently the most widely used adjuvant in clinical human vaccination. CLDC-adjuvanted vaccine induced higher total influenza virus-specific IgG, particularly for the IgG2a/c subclass. Higher levels of multicytokine-producing influenza virus-specific CD4 and CD8 T cells were induced by CLDC-adjuvanted vaccine than with alum-adjuvanted vaccine. Importantly, CLDC-adjuvanted vaccine provided significant cross-protection from either a sublethal or lethal influenza A viral challenge with a different subtype than that used for vaccination. This superior cross-protection afforded by the CLDC adjuvant required CD8 T-cell recognition of viral peptides presented by classical major histocompatibility complex class I proteins. Together, these results suggest that CLDC has particular promise for vaccine strategies in which T cells play an important role and may offer new opportunities for more effective control of human influenza epidemics and pandemics by inactivated influenza virus vaccine.

A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects.

Cationic lipid DNA complex (CLDC) is an immunostimulatory preparation that has significant anti-leukemic effects in multiple murine models of leukemia: BCR-ABL(+) myelogenous leukemia in C3H/HeJ animals and myelomonocytic leukemia in BALB/c mice. Following leukemic challenge, CLDC treatment inhibits tumor cell growth in vivo and extends survival, sometimes resulting in apparent eradication of tumor cells. CLDC induces multiple cytokines including interferon-gamma (IFNγ), and intravenous treatment results in a more rapid and robust response than subcutaneous treatment. IFNγ is induced in a dose-dependent manner, and tachyphylaxis results from repeated doses of CLDC. Tachyphylaxis of therapeutic effects is exacerbated at higher doses, thus the optimal survival benefits are seen at intermediate doses. Animals whose leukemia has been successfully treated with CLDC exhibit a survival advantage when faced with a secondary leukemic challenge, suggesting the existence of an adaptive anti-leukemic response. This work demonstrates the effectiveness of CLDC in multiple experimental leukemias and is consistent with a stimulation of a lasting TH(1) anti-leukemic immune response.

Healthcare costs associated with switching from brand to generic levothyroxine.

BACKGROUND: Controversy exists over the true therapeutic equivalence of branded and generic levothyroxine-the drug of choice for treating hypothyroidism-so professional societies recommend against switching between different formulations of the drug and suggest that patients who do switch be monitored. Payers typically encourage switching to generic drugs because of lower drug acquisition costs. OBJECTIVE: To evaluate the impact of switching levothyroxine formulations on actual healthcare costs. METHODS: Patients with hypothyroidism and at least 6 months of branded levothyroxine therapy were identified from a large healthcare claims database. Patients who subsequently switched to another levothyroxine formulation and could be followed for 6 months postswitch were matched to demographically similar patients who were continuous users of branded levothyroxine. Pre- and postswitch healthcare costs for each group were compared. RESULTS: The savings in prescription drug costs after switching from branded to generic levothyroxine are offset by increases in costs for other healthcare services, such that switching is actually associated with an increase, not a decrease, in total healthcare costs. CONCLUSION: In the absence of cost-savings, there is no clear rationale for switching patients from brand to generic levothyroxine.

Cationic lipid/DNA complexes (JVRS-100) combined with influenza vaccine (Fluzone) increases antibody response, cellular immunity, and antigenically drifted protection.

Safe and effective adjuvants for influenza vaccines that could increase both the levels of neutralizing antibody, including against drifted viral subtypes, and T-cell immunity would be a major advance in vaccine design. The JVRS-100 adjuvant, consisting of DOTIM/cholesterol cationic liposome-DNA complexes, is particularly promising for vaccines that require induction of high levels of antibody and T-cell immunity, including CD8(+) cytotoxic T lymphocytes (CTL). Inclusion of protein antigens with JVRS-100 results in the induction of enhanced humoral and cell-mediated (i.e., CD4(+) and CD8(+) T cells) immune responses. The JVRS-100 adjuvant combined with a split trivalent influenza vaccine (Fluzone-sanofi pasteur) elicited increased antibody and T-cell responses in mice and non-human primates compared to vaccination with Fluzone alone. Mice vaccinated with JVRS-100-Fluzone and challenged with antigenically drifted strains of H1N1 (PR/8/34) and influenza B (B/Lee/40) viruses had higher grade protection, as measured by attenuation of weight loss and increased survival, compared to recipients of unadjuvanted vaccine. The results indicate that the JVRS-100 adjuvant substantially increases immunogenicity and protection from drifted-strain challenge using an existing influenza vaccine.

A novel vaccine adjuvant for recombinant flu antigens.

Many new vaccines under development consist of rationally designed recombinant proteins that are relatively poor immunogens unless combined with potent adjuvants. There is only one adjuvant in common use in the U.S., aluminum phosphate or hydroxide (e.g. alum). This adjuvant, however, has significant limitations, particularly regarding the generation of strong cell-mediated (T-cell) immune responses. A novel adjuvant, JVRS-100, composed of cationic liposome-DNA complexes (CLDC) has been evaluated for immune enhancing activity. The JVRS-100 adjuvant has been shown to elicit robust immune responses compared to CpG oligonucleotides, alum, and MPL adjuvants, and efficiently enhances both humoral and cellular immune responses. Safety has been evaluated in preclinical studies, and the adjuvant is now in early-stage clinical development. One application of this novel adjuvant is to augment the immune responses to recombinant subunit antigens, which are often poorly immunogenic. The JVRS-100 adjuvant, when combined with a recombinant influenza hemagglutinin (H1), elicited increased specific antibody and T-cell responses in mice. Single-dose vaccination and prime/boost vaccinations with JVRS-100-H1 were both shown to be protective (i.e., survival, reduced weight loss) following H1N1 (PR/8/34) virus challenge. Enhanced immunological responses could be critically important for improved efficacy and dose-sparing of a recombinant influenza vaccine.

Gene expression patterns within cell lines are predictive of chemosensitivity.

BACKGROUND: The NCI has undertaken a twenty-year project to characterize compound sensitivity patterns in a selected set of sixty tumor derived cell lines. Previous studies have explored the relationship between compound sensitivity patterns to gene expression, protein expression, and DNA copy number for these same cell lines. A strong correlation between the pattern of expression of a biomarker and sensitivity to a compound could suggest a clinically interesting biological relationship between the two. RESULTS: We isolated RNA's and measured expression of 40000 genes using cDNA microarrays from the fifty-nine publicly available cell lines. Analysis of this data set in comparison with published gene expression data sets demonstrates a high degree of reproducibility in expression level measurements even using completely independent RNA preparations and array technologies. Using the fifty-nine cell lines for discovery and an additional seven cell lines for which extensive compound sensitivity data were available as a test set, we determined that gene-compound pairs with a correlation coefficient above 0.6 had a false discovery rate of approximately 5%. Large scale features of the gene expression and chemosensitivity data, such as tissue of origin and other physiological factors, did not seem to explain the majority of correlations between gene and compound patterns. CONCLUSION: A comparison of gene expression and compound sensitivity in panels of cell lines was demonstrated to have a relatively high validation and low false discovery rate supporting the use of this approach and datasets for identifying candidate biomarkers and targeted biologically active compounds.

Temporal patterns of conditions and symptoms potentially associated with ovarian cancer.

BACKGROUND: The late stage at which ovarian cancer is typically diagnosed and its subsequent high mortality have been attributed to a lack of symptoms in its early stages. This study examined the temporal patterns of prediagnostic ovarian cancer symptoms and conditions among women with and without ovarian cancer. METHODS: We identified 920 ovarian cancer cases from 1998-2002 claims and encounters from Thomson Healthcare's Medstat MarketScan Commercial Claims and Encounters and Medicare Supplemental Databases. These were matched with 2760 comparison women based on age, geographic region, Medicare eligibility, and health plan type. The rates of ovarian cancer-related symptoms, conditions, and procedures recorded in the claims data were compared between the two groups using chi-square and Student's t tests. RESULTS: In the 270 to 31 days prior to the case diagnosis dates, cases had nearly five times more recorded abdominal symptoms (36.2% vs. 7.5%), 3.5 times more recorded female genital symptoms (9.8% vs. 2.7%), and 1.5-2 times more recorded gastrointestinal symptoms (7.7% vs. 3.5%), urethra/urinary tract disorders (12.7% vs. 6.4%), and menopausal disorders (12.4% vs. 7.5%) than the comparison women. However, when the data were examined in 30-day increments for these five diagnosed conditions, the rates for cases and comparison women only started to diverge as the cases' diagnosis drew closer-60-90 days prior. CONCLUSIONS: The presence of ovarian cancer-related symptoms and conditions prior to diagnosis among cases was documented in claims data; however, this increase was most pronounced in the 2-3 months prior to diagnosis. It is likely that physicians will see similar symptoms and conditions for women with and without ovarian cancer during most of the 9 months prior to the cases' diagnosis.

Utilization and cost of health care services associated with primary malignant brain tumors in the United States.

OBJECTIVES: To evaluate the economic burden of primary malignant brain tumors in a commercially insured population in the United States, and to identify the primary drivers of health care resource use and cost. PATIENTS AND METHODS: A retrospective cohort analysis was performed using a 1998-2000 database containing inpatient, outpatient, and pharmacy claims for employees, their dependents, and early retirees of over 50 large US employers with wide geographic distribution. Patients were followed from first brain tumor diagnosis until death, termination of health benefits coverage, or study end. Controls without any cancer diagnosis were matched at a 3:1 ratio by demographic characteristics and length of follow-up. RESULTS: Patients with malignant brain tumors (n = 653) had significantly greater health service utilization and costs for hospitalizations, emergency room visits, outpatient office visits, laboratory tests, radiology services, and pharmacy-dispensed drugs (all P < 0.05) than did controls (n = 1959). Regression-adjusted mean monthly costs were $6364 for brain tumor patients, compared with $277 for controls (P < 0.0001). The primary cost driver was inpatient care ($4502 per month). Total costs during the study period were $49,242 for those with brain tumors and $2790 for controls (P < 0.0001). CONCLUSION: Patients with malignant brain tumors accrued health care costs that were 20 times greater than demographically matched control subjects without cancer. The costs for inpatient services were the primary drivers of total health resource use. Despite their low incidence, primary malignant brain tumors produce a substantial burden on the US health care system. There is a marked need for improved and new approaches to treatment to reduce the resource use and to offset health care costs associated with this disease.

Medical costs associated with non-Hodgkin's lymphoma in the United States during the first two years of treatment.

OBJECTIVES: To determine the direct costs of medical care associated with aggressive and indolent non-Hodgkin's lymphoma (NHL) in the United States; to show how costs for aggressive NHL change over time by examining costs related to initial, secondary and palliative treatment phases; and to evaluate the economic consequences of treatment failure in aggressive NHL. PATIENTS AND METHODS: A retrospective cohort analysis of 1999 - 2000 direct costs in newly diagnosed NHL patients and controls (subjects without any cancer) was conducted using the MarketScan medical and drug claims database of large employers across the United States. Treatment failure analysis was conducted for aggressive NHL patients, and was defined by the need for secondary treatment or palliative care after initial therapy. Cost of treatment failure was calculated as difference in regression-adjusted costs between patients with initial therapy only and patients experiencing initial treatment failure. RESULTS: Patients with aggressive (n = 356) and indolent (n = 698) NHL had significantly greater health service utilization and associated costs (all P < 05) than controls (n = 1068 for aggressive, n = 2094 for indolent). Mean monthly costs were 5871 dollars for aggressive NHL vs. 355 dollars for controls (P < 0001) and 3833 dollars for indolent NHL vs. 289 dollars for controls (P < 0001). The primary cost drivers were hospitalization (aggressive NHL = 44% of total costs, indolent NHL = 50%) and outpatient office visits (aggressive NHL = 39%, indolent NHL = 34%). For aggressive NHL, mean monthly initial treatment phase costs (10,970 dollars) and palliative care costs (9836 dollars) were higher than costs incurred during secondary phase (3302 dollars). The mean cost of treatment failure in aggressive NHL was 14,174 dollars per month, and 85,934 dollars over the study period. CONCLUSION: The treatment of NHL was associated with substantial health care costs. Patients with aggressive lymphomas tended to accrue higher costs, compared with those with indolent lymphomas. These costs varied over time, with the highest costs occurring during the initial treatment and palliative care phases. Treatment failure was the most expensive treatment pattern. New strategies to prevent or delay treatment failure in aggressive NHL could help reduce the economic burden of NHL.

Burden of pancreatic cancer and disease progression: economic analysis in the US.

OBJECTIVES: The few studies that have estimated the costs of pancreatic cancer were limited by small sample sizes, geography or patient age range. Using a large nationwide claims database, this study examines the cost of pancreatic cancer beginning with initial diagnosis and the additional costs when disease progresses. METHODS: A retrospective cohort study was conducted using a claims database of 3 million individuals covered by large US employers. The study population consisted of patients newly diagnosed with pancreatic cancer in 1999-2000 and a demographically matched control group. Utilization and costs were summarized as monthly means. Changes in cancer severity and treatment over time were used to approximate disease progression and its associated costs. RESULTS: The study included 412 pancreatic cancer patients and 1,236 controls. The mean follow-up time was 7.5 months. Regression-adjusted monthly costs attributable to pancreatic cancer were USD 7,279; over 60% resulted from hospitalizations. Patients with disease progression (over 50%) incurred an additional USD 15,143 per month compared to patients without disease progression. CONCLUSION: Compared to patients without cancer, the costs of pancreatic cancer patients were substantial, especially when patients experienced disease progression. New therapies that prevent or delay disease progression could potentially offset the costs to patients, providers and society.

Higher costs and therapeutic factors associated with adherence to NCQA HEDIS antidepressant medication management measures: analysis of administrative claims.

OBJECTIVE: To determine if the type of antidepressant drug is related to adherence to National Committee for Quality Assurance (NCQA) Antidepressant Medication Management (AMM) quality measures and to assess the 6-month health care costs among newly diagnosed depressed patients. METHODS: The MarketScan Commercial Claims and Encounter database for medical and pharmacy claims from January 2001 to September 2004 was used to assess adherence to the 3 AMM quality-of-care measures. AMM measures include (a) acute phase, the percentage of eligible members who remained on antidepressant medication continuously for 3 months after the initial diagnosis as determined by at least 84 days supply of antidepressant drugs during the first 114 days following receipt of the index antidepressant; (b) continuation phase, the percentage of eligible members who remained on antidepressant medication continuously for the 6 months after the initial diagnosis as determined by at least 180 days supply of antidepressants during the first 214 days following receipt of the index antidepressant; and (c) practitioner contacts, the percentage of members who received at least 3 follow-up office visits or telephone contacts with health care providers, including at least 1 contact with a practitioner licensed to prescribe (may not necessarily be the prescriber of the antidepressant). A fourth measure, overall adherence, was added, if all 3 AMM measures were met. Multivariate regression models determined demographic, clinical (such as receipt of mental health specialty care, the Charlson Comorbidity Index score, and co-occurring bipolar or schizophrenia), and therapy-related factors associated with outcomes of adherence and costs (paid amounts for insurance-reimbursable health care services for inpatient admissions, emergency department services, outpatient services, and outpatient prescription drugs). Health care expenditures (both total and mental-health-specific costs) were measured for each patient for 6 months following the date of service for the index antidepressant. RESULTS: A total of 60,386 adult patients (10.7%) of 562,898 patients with a depression diagnosis met NCQA inclusion criteria in the AMM Technical Specifications (e.g., aged 18 years or older, newly diagnosed with depression and initiating antidepressant therapy, 365 days of continuous enrollment; patients were excluded if there were missing data on dose or quantity of index drug in pharmacy claims or initiated therapy on 2 or more antidepressants as the index medication, exclusion criteria not in the AMM Technical Specifications). Only 19% of patients achieved overall adherence. Rates for the 3 AMM measures were 39% for practitioner contacts, 65% for acute phase, and 44% for continuation phase. Receipt of mental health specialty care was the only factor that was positively associated with greater adherence on all 4 measures (overall measure: odds ratio [OR]=3.895, 95% confidence interval [CI], 3.72-4.07; acute OR=1.38, 95% CI, 1.33-1.43; continuation OR=1.46, 95% CI, 1.41-1.51; contacts OR=5.83, 95% CI, 5.62-6.06). Most patients were initiated on selective serotonin reuptake inhibitors (SSRIs, 69.5%), followed by venlafaxine (21.4%), tricyclic antidepressants (TCAs, 21.4%), bupropion (11.0%), and other antidepressants (e.g., mirtazapine, nefazadone, trazadone; 7.2%). Before adjustment for confounding factors, patients initiated on venlafaxine, TCAs, or other antidepressants had higher rates of adherence on the overall performance measure versus initiators on SSRIs, but the absolute differences were relatively small: 21.4% for venlafaxine and TCAs and 23.1% for other antidepressants versus 18.5% for SSRIs (P <0.001). Patients initiated on venlafaxine, TCAs, or other antidepressants were also more likely to receive care from a mental health specialist, 16.8%, 15.0%, and 54.8%, respectively, compared with SSRIs (13.0%, all P <0.001). Regression analysis showed that only venlafaxine had a higher OR (1.13; 95% CI, 1.05-1.22) compared with SSRIs for adherence on the overall measure. Initiating dose level was in the target range for 70.0% of all patients (24.9% were below target dose and 5.2% above target dose), and adherent patients on all 3 AMM measures were less likely than nonadherent patients (70.4% vs. 68.4%, P <0.001) to be initiated in the target dose range. After multivariate adjustment, the initiating dose (target vs. high) was a significant factor in explaining adherence to the overall measure (OR=1.26; 95% CI, 1.16- 1.37). Adherent patients had 6-month median unadjusted total health care expenses that were nearly 2 times higher compared with nonadherent patients ($5,169 vs. $2,734) and mental health expenditures that were nearly 3 times higher ($1,922 vs. $677). After adjustment, adherent patients compared with nonadherent patients incurred an additional $644 in mental health expenditures and $806 in overall health care expenditures in the 6 months following initiation of antidepressant therapy. CONCLUSIONS: Only 19% of depressed patients initiated on antidepressants met all 3 criteria set forth in the NCQA Health Plan Employer Data and Information Set (HEDIS) AMM quality-of-care performance measures. Receipt of mental health specialty care was the single factor most strongly associated with quality treatment by these measures. Type and dosage level of initial antidepressant was associated with adherence to the NCQA HEDIS AMM measures, but the absolute difference in rates of adherence were relatively small among types of antidepressants. Costs were higher for guideline-adherent individuals in the 6 months following treatment initiation. These analyses were limited to administrative claims that lack indicators of depression disease severity.

The direct cost of stress urinary incontinence among women in a Medicaid population.

OBJECTIVE: To describe health care utilization and costs for women diagnosed with stress urinary incontinence in a Medicaid population. STUDY DESIGN: We utilized a pooled database of claims for women enrolled in Medicaid in 1 of 3 states. Health care utilization and costs were compared for 12 months before and 12 months after a woman's urinary incontinence diagnosis. Additional analyses utilized data from a fourth state. RESULTS: Of 13,672 women with diagnosed stress urinary incontinence, average urinary incontinence-related costs were approximately 800 dollars in the 12-month study period, less than 0.1% of total Medicaid spending. Thirteen percent of women underwent a surgery for stress urinary incontinence in the study period, with sling procedures performed most commonly. CONCLUSION: Although population prevalence estimates of any stress urinary incontinence symptoms often are high, diagnosis and health care utilization in the Medicaid population is low. Overall costs of stress urinary incontinence treatment in Medicaid currently are minimal. Further efforts to understand the appropriate detection, diagnosis, and treatment of women with stress urinary incontinence are needed.

The economic burden of lung cancer and the associated costs of treatment failure in the United States.

The economic burden of lung cancer was examined with a retrospective case-control cohort study on a database containing inpatient, outpatient and drug claims for employees, dependents and retirees of multiple large US employers with wide geographic distribution. Patients were followed for maximum of 2 years from first cancer diagnosis until death, health benefits dis-enrollment or study end (31 December 2000). Compared with controls (subjects without any cancer), patients with lung cancer (n = 2040) had greater health care service utilization and costs for hospitalization, emergency room visits, outpatient office visits, radiology procedures, laboratory procedures and pharmacy-dispensed drugs (all P < 0.05). Regression-adjusted mean monthly total costs were US dollar 6520 for patients versus US dollar 339 for controls (P < 0.0001), and overall costs across the study period (from diagnosis to death or maximum of 2 years) were US dollar 45,897 for patients and US dollar 2907 for controls (P < 0.0001). The main cost drivers were hospitalization (49.0% of costs) and outpatient office visits (35.2% of costs). Monthly initial treatment phase costs (US dollar 11,496 per patient) were higher than costs during the secondary treatment phase (US dollar 3733) or terminal care phase (US dollar 9399). Failure of initial treatment was associated with markedly increased costs. Compared with patients requiring only initial treatment, patients experiencing treatment failure accrued an additional US dollar 10,370 per month in initial treatment phase costs and US dollar 8779 more per month after starting the secondary and/or terminal care phase. Over the course of the study period, these patients had total costs of US dollar 120,650, compared with US dollar 45,953 for those receiving initial treatment only. Thus, the incremental costs associated with treatment failure were US dollar 19,149 per month and US dollar 74,697 across the study period. Other types of clinical and epidemiological analysis are needed to identify risks for treatment failure. The economic burden of lung cancer on the US health care system is significant and increased prevention, new therapies or adjuvant chemotherapy may reduce both resource use and healthcare costs. New strategies for lung cancer that reduce hospitalizations and/or prevent or delay treatment failure could offset some of the economic burden associated with the disease.