Opioid and benzodiazepine dispensing and co-dispensing patterns among commercially insured pregnant women in the United States, 2007-2015.

BACKGROUND: Little is known about benzodiazepine and opioid-benzodiazepine co-dispensing patterns among pregnant women. Understanding these patterns is necessary to mitigate high-risk medication use during pregnancy. Our objective in this analysis was to evaluate opioid and benzodiazepine dispensing and co-dispensing patterns among commercially insured pregnant women in the United States. METHODS: This retrospective study used a 10% random sample of commercially insured enrollees from the IQVIA™ Adjudicated Health Plan Claims Data from 2007 to 2015. The study included women (12-55 years of age) with completed pregnancies who had continuous medical and prescription drug coverage from 3 months prior to the date of conception through 3 months post-delivery. We estimated the prevalence of opioid and benzodiazepine dispensing and co-dispensing before, during, and after pregnancy, and evaluated trends in dispensing patterns across the study period (2007-2015) using Cochrane-Armitage tests. Chi-square tests were used to examine differences in demographic and clinical characteristics by dispensing and co-dispensing patterns. Among women that received an opioid or benzodiazepine during pregnancy, logistic regression models were used to quantify the association between sample characteristics and dispensing patterns (co-dispensing vs single dispensing). RESULTS: Of 168,025 pregnant women that met our inclusion criteria, 10.1% received at least one opioid and 2.0% received at least one benzodiazepine during pregnancy, while 0.5% were co-dispensed these drugs. During the study period (2007 vs 2015), prevalence of opioid dispensing during pregnancy decreased from 11.2 to 8.6% (p <  0.01); while benzodiazepine dispensing increased from 1.3 to 2.9% (p <  0.01), and the prevalence of co-dispensing, while low and stable, increased slightly from 0.39 to 0.44% (p <  0.01). Older age, a higher comorbidity burden, pain diagnosis, anxiety diagnosis, and alcohol, tobacco, and drug use disorders, were all associated with an increased odds of co-dispensing during pregnancy. CONCLUSIONS: This study provides evidence that while opioid dispensing during pregnancy has decreased in the past decade, benzodiazepine dispensing has increased. The prevalence of opioid-benzodiazepine co-dispensing was rare and remained fairly stable during our study period. Those co-dispensed both drugs had a higher prevalence of adverse birth outcomes. Further research to establish the potentially causal relationship between opioid and benzodiazepine co-dispensing and adverse birth outcomes should be undertaken.

Follicular lymphoma treatment patterns between 2000 and 2014: a SEER-Medicare analysis of elderly patients.

Aim: Characterize follicular lymphoma (FL) treatment patterns among elderly patients using a dataset with longer follow-up time. Materials & methods: Using the linked Surveillance, Epidemiology and End Results-Medicare data, we identified patients diagnosed with FL between 2000 and 2013 with claims data until 2014. We investigated the treatments received and assigned them to lines of treatment. Results: We identified 10,238 elderly patients. Over a 4.7-year median follow-up, 78% of the patients received at least first-line treatment. Fewer individuals received second-line (47%) and third-line (30%) treatments. RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone), RCVP (rituximab, cyclophosphamide, vincristine and prednisolone) and rituximab monotherapy were the most common treatment regimens. Conclusion: One in five elderly patients did not receive FL-directed therapy. The most common treatment regimens were limited to RCHOP, RCVP and rituximab monotherapy.

Real-World Effectiveness of the Gla-300 + Cap + App Program in Adult Users Living with Type 2 Diabetes in Taiwan.

INTRODUCTION: Health2Sync (H2S) is a digital health technology platform that provides coaching and titration support to patients with diabetes. The Mallya cap converts a conventional insulin pen into a smart connected device that can automatically synchronize dose values and associated timestamps (upon injection) to the H2S platform. This single-arm real-world study evaluated the effectiveness of insulin glargine 300 U/mL (Gla-300) combined with H2S and Mallya cap (Gla-300 + Cap + App program) on clinical outcomes among users with type 2 diabetes (T2D) in Taiwan. METHODS: Adults (aged ≥ 20 years) with T2D who were registered H2S users and initiated Mallya cap for a new/existing Gla-300 regimen (identification period May 1, 2021-May 31, 2022) were included in this retrospective cohort study. Follow-up data from H2S were collected for 90 days. Glycated hemoglobin (HbA1c) change (baseline to follow-up) and HbA1c goal attainment were primary outcomes. Hypoglycemia incidence and usage metrics of Mallya cap were secondary outcomes. RESULTS: Of 83 participants, 38.6% were new Gla-300 users. HbA1c was reduced in both new (- 2.4 [2.7] %, - 26.2 [29.5] mmol/mol) and previous Gla-300 users (- 0.5 [1.6] %, - 5.5 [17.5] mmol/mol). Reduction in HbA1c was significant (p < 0.05) in both groups. At follow-up, 43.4% of users had a reduction of > 0.5%. Mean HbA1c reductions increased numerically with higher baseline HbA1c and with longer duration of Mallya cap usage. CONCLUSIONS: Use of digital technology within a connected ecosystem such as Gla-300 + Cap + App program could help people with type 2 diabetes to improve their glycemic condition.

Tumor loss-of-function mutations in STK11/LKB1 induce cachexia.

Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.

Discharges against medical advice and 30-day healthcare costs: an analysis of commercially insured adults.

Aim: Prior literature detailing the consequences of a discharge against medical advice (DAMA) has not focused on costs. We examine costs following a DAMA. Materials & methods: This retrospective cohort study utilized the IQVIA PharMetrics® Plus database to identify adults hospitalized during 2007-2015. We compared 30-day postdischarge healthcare costs between matched DAMA and routinely discharged groups. Results: Thirty-day healthcare costs for the DAMA group were US$1078 (95% CI: US$434-1730) higher, driven by inpatient readmissions (US$979; 95% CI: US$415-1543) and emergency department visits (US$79; 95% CI: US$56-102). Costs due to prescription drug fills were lower in the DAMA group. Conclusion: A DAMA was associated with higher 30-day postdischarge healthcare costs compared with routine discharges.

Adverse Discharge Outcomes Associated With the Medicare Hospital Readmissions Reduction Program Among Commercially Insured Adults.

ABSTRACT: It is unknown if changes in the rate of discharges against medical advice (DAMA) are related to the implementation of the Medicare Hospital Readmissions Reduction Program (HRRP). We performed an interrupted time series analysis of monthly DAMA rates per 1,000 discharges of all enrolled individuals 18-64 years old with a hospitalization between January 1, 2006, and December 31, 2015, in a commercially insured population. We performed a segmented linear regression with two interruptions: (1) April 2010 to coincide with the passage of the HRRP and (2) October 2012 to coincide with the implementation of HRRP penalties. There were 1,087,812 discharges representing 668,823 individuals over 120 months. The downward trend in monthly DAMA rates was reversed significantly after April 2010 with a sustained 0.1 increase in the monthly rate that continued after the implementation of penalties in October 2012. Allowing for the two interruptions, there was a statistically significant positive trend (0.10; 0.06-0.13, p < .01) in April 2010. Relative to the first interruption, there was no statistically significant change in the slope in October 2012; the estimated slope was -0.04 (-0.08 to 0.002). Monthly DAMA rates increased in anticipation of and after HRRP implementation, suggesting a potential relationship between the HRRP and DAMA.

Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia.

Adipose tissue inflammation is observed in multiple metabolically-altered states including cancer-associated cachexia and obesity. Although cachexia is a syndrome of adipose loss and obesity is a disease of adipose excess, both pathologies demonstrate increases in circulating levels of IL-6 family cytokines, ß-adrenergic signaling, and adipocyte lipolysis. While ß-adrenergic-stimulated adipocyte lipolysis is well described, there is limited mechanistic insight into how cancer cachexia-associated inflammatory cytokines contribute to adipocyte lipolysis under pathologic conditions. Here, we set out to compare adipocyte lipolysis signaling by cancer cachexia-associated IL-6 family cytokines (IL-6 and LIF) to that of the ß-adrenergic agonist isoproterenol. Unlike isoproterenol, the IL-6 family of cytokines required JAK/STAT3-dependent transcriptional changes to induce adipocyte lipolysis. Furthermore, cachexia-associated cytokines that used STAT3 to induce lipolysis were primarily dependent on the lipase ATGL and its cofactor CGI-58 rather than lipases HSL and MAGL. Finally, administration of JAK but not ß-adrenergic inhibitors suppressed adipose STAT3 phosphorylation and associated adipose wasting in a murine model of cancer cachexia characterized by increased systemic IL-6 family cytokine levels. Combined, our results demonstrate how the IL-6 family of cytokines diverge from ß-adrenergic signals by employing JAK/STAT3-driven transcriptional changes to promote adipocyte ATGL/CGI-58-dependent lipolysis contributing to adipose wasting in cancer cachexia.

The economic burden of Parkinson disease among Medicare beneficiaries.

BACKGROUND: The progressive nature of Parkinson disease (PD), together with a lack of curative treatments, contributes to its economic burden. OBJECTIVE: To estimate the longitudinal incremental costs attributable to PD among Medicare beneficiaries. METHODS: In this retrospective cohort study, we used data from the Chronic Conditions Data Warehouse to identify Medicare beneficiaries with and without PD-related claims identified from 2006 to 2014 with follow-up until 2015. We grouped PD cases and controls based on their survival profiles using a grouping algorithm that used the following baseline measures: age, race, sex, and comorbidity. We identified 3 survival groups and used them to stratify the descriptive annual cost estimates in the 9 years after the index date. We estimated the incremental 1-, 3-, and 5-year costs of PD using generalized linear models (GLM) that controlled for baseline factors. RESULTS: We identified 27,394 cases and controls who were grouped into 3 survival groups. The mean age of the full study sample was 73 years. No material differences were found in the incremental cost of PD across the survival groups. Based on the multivariable GLM, the 1-year incremental cost of PD was $9,625 (95% CI, $9,054-$10,197). The 3-year incremental cost of PD was $20,832 (95% CI, $19,390-$22,274). The 5-year incremental cost of PD was $27,466 (95% CI, 25,088-$29,844). CONCLUSIONS: Among Medicare beneficiaries, PD is associated with excess costs compared with controls. We did not identify substantial differences in the incremental cost of PD across the survival groups. DISCLOSURES:This study was funded by Pfizer Inc. The funding agreement did not impact the authors' independence in designing the study, collecting the data, interpreting the data, writing the manuscript, and submitting the manuscript for publication. Dr Onukwugha reports grants from Pfizer Inc for the conduct of this study and is an employee of University of Maryland, Baltimore, which received financial support from Pfizer Inc in connection with the development of this manuscript; Dr Shulman reports research funding from Pfizer Inc related to the current work, is an employee of University of Maryland, Baltimore, which received financial support from Pfizer Inc in connection with the development of this manuscript, and reports research funding from the NIH, The Rosalyn Newman Foundation, and the Eugenia and Michael Brin family unrelated to the current work and royalties from Oxford University Press and Johns Hopkins University Press; Ms Myers and Dr Alvir are employees and stockholders of Pfizer Inc; Dr Gray was an employee and stockholder of Pfizer Inc at the time of analysis.

Health Care Resource Utilization Associated With Parkinson Disease Among Medicare Beneficiaries.

OBJECTIVE: To compare differences in health care resource utilization (HcRU) over time between Medicare beneficiaries with and without Parkinson disease (PD). METHODS: This retrospective observational study used the Chronic Conditions Data Warehouse (5% Medicare sample) between 2005 and 2015. In a propensity score-matched (age, sex, race, and comorbidity adjusted) sample of beneficiaries with and without PD, we examined all-cause HcRU due to inpatient admissions, emergency department (ED) admissions, skilled nursing facility (SNF) admissions, health care provider encounters, neurologist visits, rehabilitation service visits, and non-PD medication fills. Relative to beneficiaries without PD, we reported adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for beneficiaries with PD using generalized linear models with log link and negative binomial variance functions. RESULTS: A total of 467,064 Medicare enrollees (unmatched sample) met the inclusion criteria. Of these, 3.3% had PD. In the matched sample and relative to beneficiaries without PD, beneficiaries with PD displayed higher rates of inpatient admissions (IRR 1.29, 95% CI 1.24-1.34), ED admissions (IRR 1.31, 95% CI 1.27-1.34), SNF admissions (IRR 2.00, 95% CI 1.92-2.09), health care provider encounters (IRR 1.18, 95% CI 1.16-1.20), neurologist visits (IRR 5.57, 95% CI 5.35-5.78), rehabilitation service visits (IRR 1.47, 95% CI 1.41-1.53), and non-PD medication fills (IRR 1.10, 95% CI 1.08-1.11) over time. CONCLUSION: These results reflect patterns of medical care among Medicare beneficiaries with PD. The findings can help clinicians, payers, and policy makers make evidence-based decisions for the allocation of scarce health care resources for PD management. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that Medicare beneficiaries with PD use more health care resources than matched controls without PD.

LIFR-α-dependent adipocyte signaling in obesity limits adipose expansion contributing to fatty liver disease.

The role of chronic adipose inflammation in diet-induced obesity (DIO) and its sequelae including fatty liver disease remains unclear. Leukemia inhibitory factor (LIF) induces JAK-dependent adipocyte lipolysis and altered adipo/cytokine expression, suppressing in vivo adipose expansion in normal and obese mouse models. To characterize LIF receptor (LIFR-α)-dependent cytokine signaling in DIO, we created an adipocyte-specific LIFR knockout mouse model (Adipoq-Cre;LIFR fl/fl ). Differentiated adipocytes derived from this model blocked LIF-induced triacylglycerol lipolysis. Adipoq-Cre;LIFR fl/fl mice on a high-fat diet (HFD) displayed reduced adipose STAT3 activation, 50% expansion in adipose, 20% body weight increase, and a 75% reduction in total hepatic triacylglycerides compared with controls. To demonstrate that LIFR-α signals adipocytes through STAT3, we also created an Adipoq-Cre;STAT3 fl/fl model that showed similar findings when fed a HFD as Adipoq-Cre;LIFR fl/fl mice. These findings establish the importance of obesity-associated LIFR-α/JAK/STAT3 inflammatory signaling in adipocytes, blocking further adipose expansion in DIO contributing to ectopic liver triacylglyceride accumulation.

Healthcare Resource Utilization Following a Discharge Against Medical Advice: An Analysis of Commercially Insured Adults.

BACKGROUND: A discharge against medical advice (DAMA) is associated with adverse health outcomes. Its association with postdischarge healthcare resource utilization (HcRU) outside an inpatient setting is unknown. This information can help us understand how a DAMA may affect healthcare-seeking behavior following a hospital stay. We evaluated the relationship between a DAMA and 30-day postdischarge HcRU. METHODS: This retrospective cohort study uses a 10% random sample of enrollees in the IQVIA PharMetrics® Plus database. We included individuals aged 18 to 64 years with an inpatient admission during 2007-2015 and continuous insurance coverage. We defined comparison groups as DAMA and routine discharge. Both groups were matched on baseline covariates. We quantified the association between a DAMA and 30-day HcRU, as well as 90-day for sensitivity analysis, with use of generalized linear models for binary outcomes (inpatient readmissions, emergency department [ED] visits) and count outcomes (physician office visits, nonphysician outpatient encounters, prescription drug fills). RESULTS: Of the 457,530 individuals in the unmatched sample, 2,245 (0.5%) had a DAMA. In the matched sample, a DAMA was positively associated with an ED visit (adjusted odds ratio, 2.28; 95% confidence interval, 1.90-2.72) but not with an inpatient readmission. There were no differences between groups based on the count outcomes. A DAMA was positively associated with 90-day HcRU (ie, inpatient readmission, ED visit, and prescription drug fills). CONCLUSION: The relationship between a DAMA and HcRU varied with the HcRU category and postdischarge time interval. This examination of HcRU in the inpatient and outpatient settings provides important information about outcomes following a DAMA.

Patient-level Factors Associated With the Initial Management of Older Adults Diagnosed With Follicular Lymphoma: A Surveillance, Epidemiology, and End Results-Medicare Analysis.

INTRODUCTION: We evaluated patient-level factors associated with the initial management of older adults diagnosed with follicular lymphoma (FL). MATERIALS AND METHODS: Using linked Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) data; we identified 11,500 beneficiaries aged ≥ 66 years, diagnosed with FL between 2000 and 2013. A logistic regression model was used to estimate adjusted odds ratios (AORs) for factors associated with the receipt of active treatment versus watchful waiting (WW) as an initial management strategy. A multinomial logistic regression model was used to predict factors associated with receipt of specific active treatments, namely chemoimmunotherapy, rituximab monotherapy, chemotherapy, or radiation as compared with WW. RESULTS: Overall, the initial management strategies adopted were WW (49%), chemoimmunotherapy (25%), radiation (10%), rituximab monotherapy (9%), and chemotherapy (7%). In reference to WW, grade III FL (AOR, 2.21; 95% confidence interval [CI], 1.99-2.46), increasing disease stage (Stage IV AOR, 1.80; 95% CI, 1.62-2.00), and use of preventive services (AOR, 1.18; 95% CI, 1.07-1.30) were associated with increased odds of active treatment receipt. Age > 80 years (AOR, 0.79; 95% CI, 0.71-0.87), Non-Hispanic African-American race (AOR, 0.64; 95% CI, 0.50-0.80), and state buy-in coverage (AOR, 0.81; 95% CI, 0.70-0.94) were associated with decreased odds of active treatment receipt. In reference to WW, the multinomial logistic regression model displayed differences in the receipt of rituximab-based therapies by age and comorbidity burden. Non-Hispanic African-American race and state buy-in coverage were associated with decreased odds of receiving rituximab-based therapies. CONCLUSION: The present analysis identifies disparities in the initial management of older adults with FL owing to race and socioeconomic status. Future research should examine implications for subsequent treatment and health outcomes.

Co-use of alcohol, tobacco, and licit and illicit controlled substances among pregnant and non-pregnant women in the United States: Findings from 2006 to 2014 National Survey on Drug Use and Health (NSDUH) data.

BACKGROUND: The use, misuse and co-use of alcohol, cannabis, tobacco, and other licit and illicit controlled substances has increased in past decades leading to higher rates of morbidity, overdose, and mortality in women of reproductive age. Co-use compounds the adverse health effects of substance use compared to single-use of similar substances. Little is known about the full range of substance combinations used by pregnant and non-pregnant women. We sought to describe patterns of co-use of alcohol, tobacco, and controlled substances, and examine correlates of co-use in a nationally-representative sample of women. METHODS: Cross-sectional study using self-reported survey data from 2006 to 2014 for women ages 18-49 years (N = 160,371) in National Survey on Drug Use and Health data. We use weighted proportions and 95% confidence intervals (CI) to report differences in substance use patterns in pregnant and non-pregnant women. Multivariate logistic regression models assessed association between characteristics and type of substance use pattern. RESULTS: Prevalence of substance co-use among pregnant women is 5.1% and among non-pregnant women is 23.6%. Nearly all of the most frequent co-use patterns included alcohol, cannabis, or tobacco. Determinants of co-use among pregnant women included: younger age (18-25 years) compared to ≥ 26 years [AOR (95% CI): 1.81 (1.18, 2.80)]; and past year history of substance use [AOR 5.42 (3.59, 8.20)]. CONCLUSIONS: Co-use of several substances, including and especially of tobacco, alcohol and cannabis, persists among pregnant women in the United States. Efforts that aim to improve maternal and child health should address the complexity of substance use during pregnancy, including and beyond opioids.

Chronic non-cancer pain and its association with healthcare use and costs among individuals with obstructive sleep apnea.

Aim: To evaluate the impact of chronic non-cancer pain (CNCP) on healthcare use and costs among individuals diagnosed with obstructive sleep apnea (OSA). Materials & methods: Using the IQVIA PharMetrics® Plus database, we identified individuals (18-64 years old) during 2007-2014, divided into two groups: OSA + CNCP versus OSA-only. Generalized linear models were used to analyze binary and count outcomes. Results: Relative to OSA-only controls, OSA + CNCP cases had increased odds for inpatient and emergency department visits and higher rates for physician office visits, non-physician outpatient visits, and prescription drug fills. Relative to controls, direct healthcare costs for cases were higher, primarily driven by inpatient and non-physician outpatient visit costs. Conclusion: Relative to OSA-only controls, OSA + CNCP cases displayed increased healthcare use and costs across all points of service.

JAK Inhibitors Suppress Cancer Cachexia-Associated Anorexia and Adipose Wasting in Mice.

BACKGROUND: Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitory factor (LIF) which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss and anorexia in mice through JAK-dependent changes in adipose and hypothalamic tissues. METHODS: Cachexia was induced in vivo with the heterotopic allotransplanted administration of C26c20 colon adenocarcinoma cells or the intraperitoneal administration of recombinant LIF in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cyto/adipokine ELISAs, immunoblot analysis, and quantitative RT-PCR. Cachexia-associated lipolysis was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or IL-6 in the absence or presence of lipase or JAK inhibitors. These adipocytes were processed for glycerol release into the media, immunoblot analysis, and RT-PCR. RESULTS: Tumor-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing cachexia-associated adipose wasting and anorexia. We identified two JAK inhibitors that block IL-6 family-mediated adipocyte lipolysis and IL-6 induction using an in vitro cachexia lipolysis assay. JAK inhibitors administered to the in vivo C26c20 cancer cachexia mouse models led to 1) a decrease in STAT3 phosphorylation in hypothalamic and adipose tissues, 2) a reverse in the cachexia serum cyto/adipokine signature, 3) a delay in cancer cachexia-associated anorexia and adipose loss, and 4) an improvement in overall survival. CONCLUSIONS: JAK inhibitors suppress LIF-associated adipose loss and anorexia in both in vitro and in vivo models of cancer cachexia.

Patterns of prescription opioid utilization among adolescents and adults with comorbid chronic pain and mental health diagnosis.

Our goal was to examine the association between mental health disorders (MHD) and subsequent risk of opioid use among commercially insured youth and adults (aged 14-64 years) with comorbid chronic noncancer pain (CNCP) conditions. We conducted a retrospective cohort study using IQVIA Health Plan Claims database from January 1, 2006, to December 31, 2015. Chronic noncancer pain was defined as any diagnosis of back, head, neck, arthritis, or chronic pain (index date). Mental health disorders were assessed in the 12 months before the index pain diagnosis. Based on days supply (none, acute, and chronic) and average daily dose (none, low, medium, and high), we constructed a 7-level categorical dependent measure of opioid use. We estimated the overall prevalence of MHD and opioid receipt. Among those with CNCP, multinomial logistic regression (AOR; 95 confidence interval) was used to estimate the association of MHD with opioid receipt. Among 879,815 individuals diagnosed with CNCP, 143,923 (16.4%) had comorbid MHD. Chronic/high-dose use of opioids was more common among those with CNCP and MHD compared to those with only CNCP. After adjusting for demographic and clinical factors, individuals with comorbid CNCP and MHD were significantly more likely to be prescribed opioids compared to those with only CNCP conditions. This effect varied by average daily dose and days supply: acute/low dose (1.08; 1.07-1.08); chronic/low dose (1.49; 1.49-1.50); acute/medium dose (1.07; 1.07-1.08); chronic/medium dose (1.61; 1.61-1.62); acute/high dose (1.03; 1.02-1.03); and chronic/high dose (1.53; 1.53-1.54). In individuals with CNCP, having a MHD was a strong predictor of prescription opioid use, particularly chronic use.

Costs associated with follicular lymphoma among individuals diagnosed with non-Hodgkin lymphoma: a longitudinal analysis using SEER-Medicare data.

There is limited information on the cost burden associated with follicular lymphoma (FL) and how it compares to other non-Hodgkin lymphoma (NHL) subtypes. We examined the direct medical costs associated with FL and estimated the incremental 3-year cost of FL compared to other NHL subtypes. Using the linked Surveillance, Epidemiology and End Results-Medicare dataset, we identified 16,691 NHL patients aged 66 years or older who were diagnosed with NHL between 2007 and 2013. The mean 3-year cost among the full NHL sample was $120,120 (standard error (SE) 839). The mean 3-year cost per patient was $114,443 (SE 1738) for FL and $121,402 (SE 950) for non-FL subtypes. The incremental 3-year cost of FL compared to non-FL was US$-5458 (95% confidence interval: US$-9325 to US$-1590). Longitudinally, FL was less costly than other NHL subtypes in the first year only, and became more expensive in the second and third years.

Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites.

In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation.IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.