Impact of antiviral therapy on short- and long-term outcomes of patients with chronic obstructive pulmonary disease after influenza infection.

Background: Respiratory complications often accompany influenza in patients with chronic obstructive pulmonary disease (COPD). In this retrospective study, we quantified the impact of antiviral therapy on exacerbations, healthcare resource utilization (HRU), and costs in patients with COPD across 5 influenza seasons. Methods: Using claims data from US MarketScan® databases, we identified patients with COPD who had an influenza diagnosis during the 2012-2016 influenza seasons. Patients who received a neuraminidase inhibitor within 48 h of diagnosis (N = 4134) were identified and propensity score-matched 1:1 to a comparator cohort of untreated patients. We determined COPD- and pneumonia-related HRU and costs during month 1, each subsequent quarter, and months 2-13. Results: Antiviral-treated patients had a significantly lower frequency of COPD-related outcomes than untreated patients during all periods (exacerbations: 10.4% vs 18.2% [month 1] and 17.7% vs 24.2% [months 2-13]; inpatient visit: 2.5% vs 7.9% [month 1] and 3.8% vs 6.7% [months 2-13]; P < 0.0001, all comparisons). Treated patients also had significantly lower outpatient and emergency department (ED) visits beyond month 1. Pneumonia-related inpatient, ED, and outpatient visits were significantly lower in antiviral-treated patients than in untreated patients over all periods (P < 0.0001, all comparisons). In all HRU categories, COPD- and pneumonia-related costs were significantly lower in treated patients over all periods (month-1 ED visit costs were higher). Conclusions: Antiviral treatment in patients with COPD and influenza is associated with significantly lower HRU and costs in the postinfection month and for an entire year following infection compared with untreated patients.

Expected and diagnosed rates of mild cognitive impairment and dementia in the U.S. Medicare population: observational analysis.

BACKGROUND: With the emergence of disease-modifying Alzheimer's treatments, timely detection of early-stage disease is more important than ever, as the treatment will not be indicated for later stages. Contemporary population-level data for detection rates of mild cognitive impairment (MCI), the stage at which treatment would ideally start, are lacking, and detection rates for dementia are only available for subsets of the Medicare population. We sought to compare documented diagnosis rates of MCI and dementia in the full Medicare population with expected rates based on a predictive model. METHODS: We performed an observational analysis of Medicare beneficiaries aged 65 and older with a near-continuous enrollment over a 3-year observation window or until death using 100% of the Medicare fee-for-service or Medicare Advantage Plans beneficiaries from 2015 to 2019. Actual diagnoses for MCI and dementia were derived from ICD-10 codes documented in those data. We used the 2000-2016 data of the Health and Retirement Study to develop a prediction model for expected diagnoses for the included population. The ratios between actually diagnosed cases of MCI and dementia over number of cases expected, the observed over expected ratio, reflects the detection rate. RESULTS: Although detection rates for MCI cases increased from 2015 to 2019 (0.062 to 0.079), the results mean that 7.4 of 8 million (92%) expected MCI cases remained undiagnosed. The detection rate for MCI was 0.039 and 0.048 in Black and Hispanic beneficiaries, respectively, compared with 0.098 in non-Hispanic White beneficiaries. Individuals dually eligible for Medicare and Medicaid had lower estimated detection rates than their Medicare-only counterparts for MCI (0.056 vs 0.085). Dementia was diagnosed more frequently than expected (1.086 to 1.104) from 2015 to 2019, mostly in non-Hispanic White beneficiaries (1.367) compared with 0.696 in Black beneficiaries and 0.758 in Hispanic beneficiaries. CONCLUSIONS: These results highlight the need to increase the overall detection rates of MCI and of dementia particularly in socioeconomically disadvantaged groups.

Outcomes of antiviral treatment for influenza in type 2 diabetes.

OBJECTIVES: To evaluate the long-term effects of antiviral treatment on influenza-related health care resource utilization (HCRU) and costs in patients with type 2 diabetes (T2D) and a diagnosis of influenza. STUDY DESIGN: Retrospective cohort study. METHODS: Claims data from the IBM MarketScan Commercial Claims Database were used to identify patients with T2D and a diagnosis of influenza between October 1, 2016, and April 30, 2017. Patients who received antiviral treatment within 2 days of influenza diagnosis were identified and propensity score-matched 1:1 with a comparator cohort of untreated patients. HCRU (number of outpatient visits, emergency department visits, hospitalizations, and duration of hospitalization) and costs were assessed over 1 full year and over each quarter after influenza diagnosis. RESULTS: Treated and untreated matched cohorts consisted of 2459 patients each. In the treated cohort vs the untreated cohort, emergency department visits were reduced 24.6% over 1 year after influenza diagnosis (mean [SD], 0.94 [1.76] vs 1.24 [2.47] visits; P < .0001) and were also reduced significantly during each quarter; the duration of hospitalization decreased 35.6% in the treated cohort vs the untreated cohort over 1 full year (mean [SD], 0.71 [3.36] vs 1.11 [5.60] days; P < .0023). Mean (SD) total health care costs were 17.68% lower in the treated cohort ($20,212 [$58,627]) than in the untreated cohort ($24,552 [$71,830]) over a whole year following the index influenza visit (P = .0203). CONCLUSIONS: Antiviral treatment in patients with T2D and influenza was associated with significantly lower HCRU and costs over at least 1 year after infection.

Trends in Healthcare Resource Use Preceding Diagnosis of Alzheimer's Disease Dementia.

Introduction: An Alzheimer's disease (AD) dementia diagnosis is often preceded by an extended period of cognitive decline. Few studies have examined healthcare resource use (HRU) during an extended period before AD dementia diagnosis. Methods: In a historical claims-based cohort study, propensity score-matched cohorts of patients with and without AD dementia were observed for a 5-year prediagnosis period and a 1-year postdiagnosis period. Demographics, clinical characteristics, and HRU were compared between groups. Results: Individuals in the AD dementia group displayed a greater level of medical complexity in the year before diagnosis of AD dementia relative to those in the matched cohort. Both all-cause and AD dementia complication-related HRU increased gradually, with a marked spike at the time of initial AD dementia diagnosis. Discussion. Further research into the natural history of patients with AD dementia is necessary to improve identification of early AD and to better understand its broader impact.

Prescribing Alzheimer's Disease treatments by provider type and geographic region: a comparison among physicians, nurse practitioners, and physician assistants.

BACKGROUND: The estimated increase in Alzheimer's Disease (AD) caseload may present a logistical challenge to the US healthcare system. While nurse practitioners (NPs) and physician assistants (PAs) are increasingly delivering primary care to patients with chronic diseases, the nature of their prescribing of AD medications is largely unknown. The primary objective of this study was to compare the prescribing of AD medications across provider types (physician, NP, and PA) and geographic regions. METHODS: We conducted a retrospective cohort study using IBM MarketScan® commercial and Medicare supplemental claims to examine unique AD prescriptions prescribed between January 1, 2016, and December 31, 2019. Parallel analysis of prescriptions for another geriatric condition, osteoporosis (OP), was also conducted for comparison. RESULTS: A total of 103,067 AD prescriptions and 131,773 OP prescriptions were included in analyses. Physicians prescribed most AD prescriptions (95.65%), followed by NPs (3.37%) and PAs (0.98%). Small differences were identified among individual AD medications prescribed by physicians compared to NP/PAs. NPs/PAs prescribed a significantly higher proportion of AD prescriptions in rural as compared to urban areas (z = 0.023, 95%CI [0.018, 0.028]). CONCLUSION: Minimal variation exists in AD prescribing among physicians, NPs, and PAs, but NPs/PAs prescribe more AD prescriptions in rural areas. NPs/PAs, especially in rural areas, may play critical roles in alleviating projected workforce constraints. Further research assessing AD care, health outcomes, and costs by provider type and region is necessary to better guide healthcare workforce planning for AD care.

Healthcare Resource Use and Burden Associated with Influenza Transmission Among Household Members with a Primary Infection: Commercial Claims Data Analysis.

PURPOSE: To assess the burden of influenza transmission and care-seeking patterns over 3 influenza seasons among commercially insured households with a primary influenza infection. PATIENTS AND METHODS: This retrospective cohort study used commercial claims data from the US MarketScan® Commercial and Medicare Supplemental databases for the 2014, 2015, and 2016 influenza seasons. Patients with a billed diagnosis of influenza and with coverage for at least 1 household member under the same health plan policy were included. A secondary diagnosed case was defined as a diagnosis of influenza in a second household member occurring within 14 days of the index case in a household. RESULTS: Among 1,224,808 households with ≥2 members and a primary case of influenza, a secondary case of influenza was reported in 119,883 households (9.8%). A secondary diagnosed case of influenza occurred within 4 days of the primary diagnosis in 93,883 (78.3%) of those households. Both primary and secondary diagnosed influenza cases occurred most often among children (~60%). Household size was positively correlated to both the risk of a second case (6.4% of households with 2 or 3 members versus 12.6% of households with ≥4 members, P < 0.001) and the time to diagnosis of a second case (Spearman rank correlation coefficient = 0.09; P < 0.001). CONCLUSION: Claims data for 3 influenza seasons (2014, 2015, 2016) showed that intrahousehold transmission of influenza occurs in approximately 10% of households with a primary case and poses a higher burden on larger households. Intrahousehold transmission of influenza represents a large healthcare resource use burden, with an unmet need for interventions that limit transmission.

Comorbidity and Health Care Resource Use Among Commercially Insured Non-Elderly Patients With Diabetic Macular Edema.

BACKGROUND AND OBJECTIVE: Diabetic macular edema (DME) is a leading cause of blindness for non-elderly adults; however, health care-associated burden data from this population is lacking. The authors describe health care-associated burden in non-elderly patients with DME compared to those with diabetes and no DME. PATIENTS AND METHODS: In this retrospective, large-cohort study examines enrollment and health care claims (2007 to 2011) from a national database of insured patients aged 18 to 63 years (mean: 51). Comorbidity and health care utilization differences between patients with DME (n = 24,326) and matched controls with diabetes but no DME (n = 122,710) were analyzed over 1 and 3 years. RESULTS: DME patients had significantly more baseline comorbidities, and generally developed them at a higher rate over the study. Health care resource utilization rates were significantly higher in DME patients for every category analyzed. Patients with DME averaged more than 10 health care visits more than those with diabetes but no DME (25.5 vs 14.9; P < .001). CONCLUSION: Working-age patients with DME exhibit a complicated comorbidity profile and high associated burden of health care consumption. Considering this burden is critical for managing this complex population.

Assessing patterns of use of cardio-protective polypill component medicines in Australian women.

BACKGROUND: A low-cost 'polypill' could theoretically be one way of improving medication affordability and compliance for secondary prevention of cardiovascular and cerebrovascular disease. The polypill has also been proposed as a primary prevention strategy. Yet many of the issues surrounding the polypill are still being debated and the underlying assumptions have not been proven. In this paper, we step back from the complexities of the debate and report upon the utilization of polypill component medicines in two population cohorts of Australian women who were aged 56-61 years and 81-86 years in 2007. OBJECTIVES: The aims of this study were firstly, to describe the association between the women's characteristics (health, illness, behavioural, demographic, socioeconomic) and their use of statins and antihypertensive medicines for the treatment of heart disease, and secondly, to discuss possible health and economic benefits for women with these characteristics that may be expected to result from the introduction of a cardio-protective polypill. METHODS: Survey records from the Australian Longitudinal Study on Women's Health (ALSWH) were linked to 2007 Pharmaceutical Benefits Scheme (PBS) claims for 7,116 mid-aged women and 4,526 older-aged women. Associations between women's characteristics (self-reported in ALSWH surveys) and their use of statins and antihypertensive medicines (measured through PBS claims in 2007) were analysed using Chi-square and multivariate regression techniques. RESULTS: Between 2002 and 2007, the use of statins in combination with antihypertensives by mid- and older-aged Australian women increased. A moderate yet increasing proportion of mid-aged women were taking statins without antihypertensives, and a high proportion of older-aged women were using antihypertensives without statins. A high proportion of women who were prescribed both statins and antihypertensives were in lower socioeconomic groups and reported difficulty managing on their incomes. CONCLUSION: These results suggest that a polypill may provide an easy-to-take, cheaper alternative for Australian women already taking multiple cardiovascular disease medications, with particular benefits for older women and women in lower socioeconomic groups. Future research is needed to quantify the potential social and economic benefits of the polypill.

Inhibition of S-adenosylmethionine decarboxylase by inhibitor SAM486A connects polyamine metabolism with p53-Mdm2-Akt/protein kinase B regulation and apoptosis in neuroblastoma.

S-adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme of polyamine (PA) biosynthesis, and both AdoMetDC and PA levels are often up-regulated in cancer cells. The second-generation inhibitor SAM486A inhibits AdoMetDC enzyme activity and has been evaluated in phase II clinical cancer trials. However, little is known about the mechanism of action and potential use of this therapeutic drug in the treatment of the pediatric cancer neuroblastoma (NB). Here, we show that p53 wild-type NB cells are highly sensitive to SAM486A treatment. Most notably, SAM486A treatment resulted in the rapid accumulation of proapoptotic proteins p53 and Mdm2. Concomitant with the increase of proteins at endogenous levels, the in vivo phosphorylation of p53 at residues Ser(46)/Ser(392) and Mdm2 at residue Ser(166) was observed. Moreover, the antiapoptotic protein Akt/protein kinase B was down-regulated and also dephosphorylated at residue Ser(473) in a dose- and time-dependent manner and NB cells entered apoptotic cell death. The results presented in this study highlight the importance of PA homeostasis and provide a direct link between PA metabolism and apoptotic cell signaling pathways in p53 wild-type NB cells. PA inhibitors such as SAM486A may be effective alternative agents for the treatment of NBs with or without MYCN amplification.

Ornithine decarboxylase inhibition by alpha-difluoromethylornithine activates opposing signaling pathways via phosphorylation of both Akt/protein kinase B and p27Kip1 in neuroblastoma.

Ornithine decarboxylase (ODC) is a key enzyme in mammalian polyamine biosynthesis that is up-regulated in various types of cancer. We previously showed that treating human neuroblastoma (NB) cells with the ODC inhibitor alpha-difluoromethylornithine (DFMO) depleted polyamine pools and induced G1 cell cycle arrest without causing apoptosis. However, the precise mechanism by which DFMO provokes these changes in NB cells remained unknown. Therefore, we further examined the effects of DFMO, alone and in combination with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or Akt/protein kinase B (PKB) inhibitor IV, on the regulation of cell survival and cell cycle-associated pathways in LAN-1 NB cells. In the present study, we found that the inhibition of ODC by DFMO promotes cell survival by inducing the phosphorylation of Akt/PKB at residue Ser473 and glycogen synthase kinase-3beta at Ser9. Intriguingly, DFMO also induced the phosphorylation of p27Kip1 at residues Ser10 (nuclear export) and Thr198 (protein stabilization) but not Thr187 (proteasomal degradation). The combined results from this study provide evidence for a direct cross-talk between ODC-dependent metabolic processes and well-established cell signaling pathways that are activated during NB tumorigenesis. The data suggest that inhibition of ODC by DFMO induces two opposing pathways in NB: one promoting cell survival by activating Akt/PKB via the PI3K/Akt pathway and one inducing p27Kip1/retinoblastoma-coupled G1 cell cycle arrest via a mechanism that regulates the phosphorylation and stabilization of p27Kip1. This study presents new information that may explain the moderate efficacy of DFMO monotherapy in clinical trials and reveals potential new targets for DFMO-based combination therapies for NB treatment.

Akt phosphorylates Connexin43 on Ser373, a "mode-1" binding site for 14-3-3.

Connexin43 (Cx43) is a membrane-spanning protein that forms channels that bridge the gap between adjacent cells and this allows for the intercellular exchange of information. Cx43 is regulated by phosphorylation and by interacting proteins. "Mode-1" interaction with 14-3-3 requires phosphorylation of Ser373 on Cx43 (Park et al. 2006). Akt phosphorylates and targets a number of proteins to interactions with 14-3-3. Here we demonstrate that Akt phosphorylates Cx43 on Ser373 and Ser369; antibodies recognizing Akt-phosphorylated sites or phospho-Ser "mode-1" 14-3-3-binding sites recognize a protein from EGF-treated cells that migrates as Cx43, and GST-14-3-3 binds to Cx43 phosphorylated endogenously in EGF-treated cells. Confocal microscopy supports the co-localization of Cx43 with Akt and with 14-3-3 at the outer edges of gap junctional plaques. These data suggest that Akt could target Cx43 to an interaction with 14-3-3 that may play a role in the forward trafficking of Cx43 multimers and/or their incorporation into existing gap junctional plaques.

Expression of prenylated Rab acceptor 1 domain family, member 2 (PRAF2) in neuroblastoma: correlation with clinical features, cellular localization, and cerulenin-mediated apoptosis regulation.

PURPOSE: Prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is a novel 19-kDa protein that has recently been implicated in human cancer. In the present study, we analyzed for the first time PRAF2 mRNA expression in a large set of human tumors. The high expression in neuroblastic tumors prompted us to analyze PRAF2 expression correlations with genetic and clinical features of these tumors. In addition, we determined the localization of PRAF2 protein in neuroblastoma cells and studied its regulation in apoptosis. EXPERIMENTAL DESIGN: Affymetrix microarray analysis was done with a set of 41 different tumor types (1,426 samples) in the public domain, a set of three different neuroblastic tumor types (110 samples), and a panel of 25 neuroblastoma cell lines. The subcellular localization of endogenous PRAF2 in neuroblastoma cells was identified by immunofluorescence microscopy and apoptosis detected by Annexin V staining and poly(ADP-ribose) polymerase cleavage. RESULTS: PRAF2 mRNA was detected in 970 of 1,426 samples in the public data set. All 110 neuroblastic tumors expressed PRAF2 at higher levels than any other tumor examined. Importantly, PRAF2 expression levels significantly correlated with the following clinical features: patient age at diagnosis (P = 6.19 x 10(-5)), survival (P = 1.32 x 10(-3)), International Neuroblastoma Staging System stage (P = 2.86 x 10(-4)), and MYCN amplification (P = 3.74 x 10(-3)). PRAF2 localized in bright cytoplasmic punctae and protein levels increased in neuroblastoma cells that underwent cerulenin-induced apoptosis. CONCLUSIONS: Elevated PRAF2 expression levels correlated with unfavorable genetic and clinical features, suggesting PRAF2 as a candidate prognostic marker of neuroblastoma.

Molecular dynamics and in vitro analysis of Connexin43: A new 14-3-3 mode-1 interacting protein.

The interaction of cellular proteins with the gap junction protein Connexin43 (Cx43) is thought to form a dynamic scaffolding complex that functions as a platform for the assembly of signaling, structural, and cytoskeletal proteins. A high stringency Scansite search of rat Cx43 identified the motif containing Ser373 (S373) as a 14-3-3 binding site. The S373 motif and the second best mode-1 motif, containing Ser244 (S244), are conserved in rat, mouse, human, chicken, and bovine, but not in Xenopus or zebrafish Cx43. Docking studies of a mouse/rat 14-3-3 homology model with the modeled phosphorylated S373 or S244 peptide ligands or their serine-to-alanine mutants, S373A or S244A, revealed that the pS373 motif facilitated a greater number of intermolecular contacts than the pS244 motif, thus supporting a stronger 14-3-3 binding interaction with the pS373 motif. The alanine substitution also reduced more than half the number of intermolecular contacts between 14-3-3 and the S373 motif, emphasizing the phosphorylation dependence of this interaction. Furthermore, the ability of the wild-type or the S244A GST-Cx43 C-terminal fusion protein, but not the S373A fusion protein, to interact with either 14-3-3 or 14-3-3zeta in GST pull-down experiments clearly demonstrated that the S373 motif mediates the direct interaction between Cx43 and 14-3-3 proteins. Blocking growth factor-induced Akt activation and presumably any Akt-mediated phosphorylation of the S373 motif in ROSE 199 cells did not prevent the down-regulation of Cx43-mediated cell-cell communication, suggesting that an Akt-mediated interaction with 14-3-3 was not involved in the disruption of Cx43 function.

Genomic organization, expression profile, and characterization of the new protein PRA1 domain family, member 2 (PRAF2).

PRA1 domain family, member 2 (PRAF2) is a new 19 kDa protein with four putative transmembrane (TM) domains. PRAF2 (formerly designated JM4) belongs to a new protein family, which plays a role in the regulation of intracellular protein transport. Recently, PRAF2 was found to interact with the chemokine receptor CCR5. In order to further study the function and regulation of PRAF2, we determined its genomic structure and its protein expression pattern in normal and cancerous human tissues. PRAF2 encodes a 178-residue protein, whose sequence is related to PRAF1 (PRA1/prenylin) and PRAF3 (JWA/GTRAP3-18). The human PRAF2 gene contains three exons separated by two introns and is located on human chromosome Xp11.23. The recombinant PRAF2 protein was readily expressed in Schneider 2 (S2) insect cells, and the native protein was detected in human tissues with strong expression in the brain, small intestine, lung, spleen, and pancreas. The protein was undetectable in tissue of the testes. Strong PRAF2 protein expression was also found in human tumor tissues of the breast, colon, lung, and ovary, with a weaker staining pattern in normal tissues of the same patient. Our studies show for the first time that the CCR5-interacting PRAF2 protein is expressed in several human tissues with a possible function in ER/Golgi transport and vesicular traffic.

Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells.

Alpha-difluoromethylornithine (DFMO) inhibits the proto-oncogene ornithine decarboxylase (ODC) and is known to induce cell cycle arrest. However, the effect of DFMO on human neuroblastoma (NB) cells and the exact mechanism of DFMO-induced cell death are largely unknown. Treatment with DFMO in combination with SAM486A, an S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor, has been shown to enhance polyamine pool depletion. Therefore, we analysed the mechanism of action of DFMO and/or SAM486A in two established MYCN-amplified human NB cell lines. DFMO and SAM486A caused rapid cell growth inhibition, polyamine depletion, and G1 cell cycle arrest without apoptosis in cell lines LAN-1 and NMB-7. These effects were enhanced with combined inhibitors and largely prevented by cotreatment with exogenous polyamines. The G1 cell cycle arrest was concomitant with an increase in cyclin-dependent kinase inhibitor p27Kip1. In a similar fashion, DFMO and DFMO/SAM486A inhibited the phosphorylation of the G1/S transition-regulating retinoblastoma protein Rb at residues Ser795 and Ser807/811. Moreover, we observed a dramatic decrease in MYCN protein levels. Overexpression of MYCN induces an aggressive NB phenotype with malignant behavior. We show for the first time that DFMO and SAM486A induce G1 cell cycle arrest in NB cells through p27Kip1 and Rb hypophosphorylation.