Pulmonary blastomycosis presenting as primary lung cancer.

BACKGROUND: Blastomycosis is an endemic mycosis in North America that is caused by the dimorphic fungus Blastomyces dermatitidis. The illness is a systemic disease with a wide variety of pulmonary and extra-pulmonary manifestations. The initial presentation of blastomycosis may easily be mistaken for other infectious or non-infectious etiologies. CASE PRESENTATION: We present the case of a 52-year-old African-American male and former smoker that presented to his primary care provider with a 2-week history of non-productive cough, night sweats and weight loss. Initially diagnosed with primary lung malignancy, the patient was subsequently found to have pulmonary blastomycosis mimicking lung cancer. The patient underwent a successful course of treatment with posaconazole. CONCLUSIONS: Chronic blastomycosis can present with clinical and radiographic features indistinguishable from thoracic malignancies. There is no clinical syndrome specific for blastomycosis, thus a high degree of suspicion is required for early diagnosis. In this case report, we review recent evidence in radiographic features, diagnostic considerations and treatment of the disease.

The Volume-Outcome Effect: Impact on Trial-to-Permanent Conversion Rates in Spinal Cord Stimulation.

OBJECTIVES: Conversion rates from trial leads to permanent spinal cord stimulation (SCS) systems have important implications for healthcare resource utilization (HCRU) and pain management. We hypothesized that there is a volume-outcome effect, with chronic pain patients who visit high volume SCS implanters will have higher trial-to-permanent conversion rates. MATERIALS AND METHODS: We designed a large, retrospective analysis using the Truven MarketScan database analyzing adult SCS patients with provider information available, with or without IPG implantation from the years 2007 to 2012 was designed. Patients were divided into three provider-based groups: high (>25), medium (9-24), and low (3-8) volume providers. Univariate and multivariate models identified factors associated with successful conversion. RESULTS: A total of 17,850 unique trial implants were performed by 3028 providers. Of 13,879 patients with baseline data available, 8981 (64.7%) progressed to permanent SCS. Higher volume providers were associated with slightly higher conversion rates (65.9% vs. 63.3% low volume, p = 0.029), explant rates (9.2% vs. 7.7% medium volume, p = 0.026), younger age (52.0 ± 13.4 years vs. 53.0 ± 13.4 years, p = 0.0026), Medicare/Medicaid (47.8% vs. 35.0% low volume, p < 0.0001), Southern region (53.5% vs. 38.9% low volume, p < 0.0001), and higher Charlson comorbidity scores (1.0 [SD = 1.4], p = 0.0002). Multivariate regression results showed female gender (1.13 [95% CI: 1.05-1.22], p < 0.001) and high volume providers associated with higher odds of successful trial conversion (1.12 [95% CI: 1.02-1.22], p = 0.014). CONCLUSIONS: In this nationwide analysis, high volume providers achieved higher trial-to-permanent SCS conversion rates than lower volume providers. The study has implications for both training requirements and referral patterns to delineate minimum implant experience necessary for provider proficiency. Future studies may be useful to understand HCRU differences.

Explantation Rates and Healthcare Resource Utilization in Spinal Cord Stimulation.

OBJECTIVES: Certain patients ultimately undergo explantation of their spinal cord stimulation (SCS) devices. Understanding the predictors and rates of SCS explantation has important implications for healthcare resource utilization (HCRU) and pain management. The present study identifies explant predictors and discerns differences in HCRU for at-risk populations. METHODS: We designed a large, retrospective analysis using the Truven MarketScan Database. We included all adult patients who underwent a SCS trial from 2007 to 2012. Patients were grouped into cohorts that remained explant-free or underwent explantation over a three-year period, and multivariate models evaluated differences in healthcare resource utilization. RESULTS: A total of 8727 unique instances of trial implants between 2007 and 2012 were identified. Overall, 805 (9.2%) patients underwent device explantation. One year prior to SCS implantation, the explant cohort had significantly higher median baseline costs ($42,140.3 explant vs. $27,821.7 in non-explant groups; p < 0.0001), total number of pain encounters (180 vs. 103 p < 0.0001), and associated costs ($15,446.9 vs. $9,227.9; p < 0.0001). The explant cohort demonstrated increased use of procedures (19.0 vs. 9.0; p < 0.0001) compared to non-explanted patients. For each month after initial SCS implantation, explanted patients had a slower decrease in total costs (4% vs. 6% in non-explant; p < 0.01). At the month of explant, explant patients were expected to have incurred 2.65 times the total cost compared to the non-explant cohort (CR 2.65, 95% CI [1.83, 3.84]; p < 0.001). Medium volume providers had lower rates of explantation at one-year and three-years compared to low volume providers (p = 0.042). Increased age and Charlson index were independent predictors of explantation during the same periods. CONCLUSIONS: In this nationwide analysis, we identified that SCS device explantation is correlated with patients who have higher baseline costs, higher total cost post-SCS implantation, and increased use of procedures to control pain. The higher rates of explantation at three-years postimplant among low volume providers suggest that variations in provider experience and approach also contributes to differences in explantation rates.

Specialty-Based Variations in Spinal Cord Stimulation Success Rates for Treatment of Chronic Pain.

OBJECTIVES: Spinal cord stimulation (SCS) has emerged as an appropriate modality of treatment for intractable chronic pain. The present study examines variations in SCS trial-to-permanent conversion rates based on provider types performing the procedure. MATERIALS AND METHODS: We designed a large, retrospective analysis using the Truven MarketScan data base analyzing adult SCS patients with provider information available, with or without IPG implantation from the years 2007-2012. Patients were categorized based on provider type performing the implantation including anesthesiologists, neurosurgeons, orthopedic surgeons, and physical medicine and rehabilitation (PM&R). Univariate and multivariate models identified factors associated with successful conversion. RESULTS: A total of 7667 unique instances of SCS implants were identified across five providers. Overall, 4842 (63.2%) of those receiving trials underwent permanent SCS system implantation. Anesthesiology performed the majority of implants (62.8%), followed by neurosurgery (22.0%), orthopedic surgery (10.2%), and PM&R (5.3%). Compared to anesthesiologists, both neurosurgeons (OR 10.99, 95% CI [9.11, 13.25]; p < 0.001) and orthopedic surgeons (OR 4.64, 95% CI [3.81, 5.65]; p < 0.001) had significantly higher conversion rates, while PM&R (OR 0.71, 95% CI [0.58, 0.87]; p = 0.001) had significantly lower. Percutaneous implants comprised 5473 (71.4%) of all implants. Neurosurgeons and orthopedic surgeons performed a significantly greater number of paddle implants among the different providers (p < 0.0001). Explant rates were similar across all cohorts analyzed (average 11.6%; p = 0.546). CONCLUSIONS: In this nationwide analysis, our results suggest that over a recent five-year period, conversion rates are highest when SCS trials are performed by neurosurgeons and orthopedic surgeons. The study has important implications for establishing uniform guidelines for training, patient selection, and education of physicians across multiple disciplines.

Impact of Insurance Provider on Overall Costs in Failed Back Surgery Syndrome: A Cost Study of 122,827 Patients.

OBJECTIVES: Failed back surgery syndrome (FBSS) affects 40% of patients following spine surgery with estimated costs of $20 billion to the US health care system. The aim of this study was to assess the cost differences across the different insurance providers for FBSS patients. METHODS: A retrospective longitudinal study was performed using the Truven MarketScan® database to identify FBSS patients from 2001 to 2012. Patients were grouped into Commercial, Medicaid, or Medicare cohorts. We collected one-year prior to FBSS diagnosis (baseline), then at year of spinal cord stimulation (SCS)-implantation and nine-year post-SCS implantation cost outcomes. RESULTS: We identified 122,827 FBSS patients, with 117,499 patients who did not undergo an SCS-implantation (Commercial: n = 49,075, Medicaid: n = 23,180, Medicare: n = 45,244) and 5328 who did undergo an SCS implantation (Commercial: n = 2279, Medicaid: n = 1003, Medicare: n = 2046). Baseline characteristics were similar between the cohorts, with the Medicare-cohort being significantly older. Over the study period, there were significant differences in overall cost metrics between the cohorts who did not undergo SCS implantation with the Medicaid-cohort had the lowest annual median (interquartile range) total cost (Medicaid: $4530.4 [$1440.6, $11,973.5], Medicare: $7292.0 [$3371.4, $13,989.4], Commercial: $4944.3 [$363.8, $13,294.0], p < 0.0001). However, when comparing the patients who underwent SCS implantation, the commercial-cohort had the lowest annual median (interquartile range) total costs (Medicaid: $4045.6 [$1146.9, $11,533.9], Medicare: $7158.1 [$3160.4, $13,916.6], Commercial: $2098.1 [$0.0, $8919.6], p < 0.0001). CONCLUSIONS: Our study demonstrates a significant difference in overall costs between various insurance providers in the management of FBSS, with Medicaid-insured patients having lower overall costs compared to Commercial- and Medicare-patients. SCS is cost-effective across all insurance groups (Commercial > Medicaid > Medicare) beginning at two years and continuing through nine-year follow-up. Further studies are necessary to understand the cost differences between these insurance providers, in hopes of reducing unnecessary health care expenditures for patients with FBSS.

Association of Medicare Program Type with Health Care Access, Utilization, and Affordability among Cancer Survivors.

BACKGROUND: The Medicare Advantage program provides care to nearly half of Medicare beneficiaries, including a rapidly growing population of cancer survivors. Despite its increased adoption, it is still unknown whether or not the program improves healthcare access, outcomes, and affordability for cancer survivors. METHODS: We performed a cross-sectional study of Medicare beneficiaries aged ≥ 65 years with a self-reported history of cancer from the 2019 National Health Interview Survey. We used multivariable logistic regression to evaluate the association between Medicare program type (Medicare Advantage vs. traditional Medicare) and measures of healthcare access, acute care utilization, and affordability. RESULTS: We identified 4451 beneficiaries with a history of cancer, corresponding to 26.6 million weighted cancer survivors in 2019. Of the beneficiaries, 35.8% were enrolled in Medicare Advantage, whereas 64.2% were enrolled in traditional Medicare. The age, sex, racial and ethnic composition, household income, primary site of cancer, and comorbidity burden of Medicare Advantage and traditional Medicare beneficiaries were similar. In the adjusted analysis, there were no differences in healthcare access or acute care utilization between traditional Medicare and Medicare Advantage beneficiaries. However, cancer survivors enrolled in Medicare Advantage were more likely to worry about (34.3% vs. 29.4%; aOR, 1.3 (95% CI, 1.1-1.5)) or have problems paying (13.6% vs. 11.1%; aOR, 1.4 (95% CI, 1.1-1.8)) medical bills. CONCLUSIONS: We found no evidence that Medicare Advantage beneficiaries with cancer had better healthcare access, affordability, or acute care utilization than traditional Medicare beneficiaries did. Furthermore, Medicare Advantage beneficiaries were more likely to report financial strain and have difficulty paying for their medical bills than were those with traditional Medicare. Despite the generous benefits and attractive incentives, Medicare Advantage plans may not be more cost-effective than traditional Medicare is for cancer survivors. Our study informs ongoing congressional deliberations to re-evaluate the role of Medicare Advantage in promoting equity among beneficiaries with cancer.

sFRP3 inhibition improves age-related cellular changes in BubR1 progeroid mice.

Wnt signaling is a well-known molecular pathway in age-related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1H/H mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1H/H mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.

Prevalence of Specific Types of Pain Diagnoses in a Sample of United States Adults.

BACKGROUND: Patients with pain conditions place significant demands on health care services globally. Health economists have reported the annual economic cost of pain in the United States as high as $635 billion. A common challenge in treating patients suffering from chronic pain conditions is accurate diagnosis and treatment. OBJECTIVE: The aim of this study was to determine the modern-day prevalence of individual types of pain diagnoses in adults. STUDY DESIGN: Retrospective analysis of Truven MarketScan® Commercial and Medicare Supplemental database. SETTING: United States patient population with a pain diagnoses from 2000 to 2012. METHODS: Multivariate analysis was used to determine the individual prevalence of specific types of pain diagnoses over a 13-year period. PATIENTS: We grouped the 6,575,999 patients with ICD-9 pain diagnoses into pain groupings. RESULTS: We determined the prevalence of pain groupings as back pain (74.7%), chronic pain (10.4%), complex regional pain syndrome (1.2%), degenerative spine disease (63.6%), limb pain (50.0%), neuritis/radiculitis (52.8%), and post-laminectomy syndrome (14.8%). LIMITATIONS: Retrospective and non-randomized study, with a patient cohort that is weighted towards recent years and commercial insurance. Coding discrepancies that are recorded and collected for patients. CONCLUSIONS: The demographic differences and similarities within the subgroups highlighted the concept that pain diagnoses should be considered as separate, but related entities. The present study helps us to better understand the frequency of specific pain diagnoses, and directs future studies to appropriately focus on pain diagnoses based on prevalence. This will allow increased understanding of the variation in pain diagnoses and prevent over-generalization in studies examining pain patients to more accurately reflect the varied subtypes and their economic impact.Duke University Institutional Review Board Protocol: 00053624Key words: Pain diagnoses, CRPS, neuritis, radiculitis, limb pain, degenerative spine disease, back pain, chronic pain, post-laminectomy pain, prevalence, MarketScan.

Age-related decline in BubR1 impairs adult hippocampal neurogenesis.

Aging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age-related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging-related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age-related cognitive deficits.

The progeroid gene BubR1 regulates axon myelination and motor function.

Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant. We found that oligodendrocyte progenitor cell proliferation and oligodendrocyte density is markedly reduced in mutant mice with low amounts of BubR1 (BubR1H/H mice), causing axonal hypomyelination in both brain and spinal cord. Expression of essential myelin-related genes such as MBP and PLP1 was significantly reduced in these tissues. Consistent with defective myelination, BubR1H/H mice exhibited various motor deficits, including impaired motor strength, coordination, and balance, irregular gait patterns and reduced locomotor activity. Collectively, these data suggest that BubR1 is a key determinant of oligodendrocyte production and function and provide a molecular entry point to understand age-related degenerative changes in axon myelination.

Wnt signaling in neuropsychiatric disorders: ties with adult hippocampal neurogenesis and behavior.

In an effort to better understand and treat mental disorders, the Wnt pathway and adult hippocampal neurogenesis have received increased attention in recent years. One is a signaling pathway regulating key aspects of embryonic patterning, cell specification and adult tissue homeostasis. The other is the generation of newborn neurons in adulthood that integrate into the neural circuit and function in learning and memory, and mood behavior. In this review, we discuss the growing relationship between Wnt signaling-mediated regulation of adult hippocampal neurogenesis as it applies to neuropsychiatric disorders. Evidence suggests dysfunctional Wnt signaling may aberrantly regulate new neuron development and cognitive function. Indeed, altered expression of key Wnt pathway components are observed in the hippocampus of patients suffering from neuropsychiatric disorders. Clinically-utilized mood stabilizers also proceed through modulation of Wnt signaling in the hippocampus, while Wnt pathway antagonists can regulate the antidepressant response. Here, we review the role of Wnt signaling in disease etiology and pathogenesis, regulation of adult neurogenesis and behavior, and the therapeutic targeting of disease symptoms.

Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity.

Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.