The National Hospital Care Survey Is a Unique Source of Data on Rare Diseases.

OBJECTIVES: This study aims to demonstrate the usefulness of the National Hospital Care Survey (NHCS) for studying rare diseases. METHODS: NHCS contains data on millions of hospital patients from participating US hospitals, including diagnoses coded using 10th revision of International Classification of Diseases, Clinical Modification, making it likely that some of the patients have a diagnosed rare disease. The data for 2016 are unweighted and are not nationally representative. The Orphanet Nomenclature Pack lists 877 10th revision of the International Classification of Diseases codes that correspond to 536 rare diseases. Using Orphanet Nomenclature Pack, we identified NHCS patients with diagnosed rare diseases. We demonstrate the usefulness of NHCS for studying rare diseases by reporting, for each rare disease, the number of patients in NHCS with the disease, the average number of hospital encounters per patient, the average length of hospital stay, and the percent of patients who died either in-hospital or within 90 days after discharge. RESULTS: In just 1 year of NHCS, we identified hundreds of rare diseases with ≥30 patients each (313 rare diseases in the inpatient setting and 273 in the emergency department setting). Although 10th revision of the International Classification of Diseases, Clinical Modification codes identify a small percent of known rare diseases, 12.9% of inpatient patients and 3.4% of emergency department patients had a diagnosed rare disease. CONCLUSIONS: NHCS is a rich source of administrative and electronic health record data on hospital patients with rare diseases, providing unique variables and observations on many patients. Although the percent of patients with each rare disease is low, a large percent of hospital patients has a rare disease.

Association between ABO and Duffy blood types and circulating chemokines and cytokines.

Blood group antigens are inherited traits that may play a role in immune and inflammatory processes. We investigated associations between blood groups and circulating inflammation-related molecules in 3537 non-Hispanic white participants selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Whole-genome scans were used to infer blood types for 12 common antigen systems based on well-characterized single-nucleotide polymorphisms. Serum levels of 96 biomarkers were measured on multiplex fluorescent bead-based panels. We estimated marker associations with blood type using weighted linear or logistic regression models adjusted for age, sex, smoking status, and principal components of population substructure. Bonferroni correction was used to control for multiple comparisons, with two-sided p values < 0.05 considered statistically significant. Among the 1152 associations tested, 10 were statistically significant. Duffy blood type was associated with levels of CXCL6/GCP2, CXCL5/ENA78, CCL11/EOTAXIN, CXCL1/GRO, CCL2/MCP1, CCL13/MCP4, and CCL17/TARC, whereas ABO blood type was associated with levels of sVEGFR2, sVEGFR3, and sGP130. Post hoc pairwise t-tests showed that individuals with type Fy(a+b-) had the lowest mean levels of all Duffy-associated markers, while individuals with type A blood had the lowest mean levels of all ABO-associated markers. Additional work is warranted to explore potential clinical implications of these differences.

Antineoplastic drugs prescription during visits by adult cancer patients with comorbidities: findings from the 2010-2016 National Ambulatory Medical Care Survey.

PURPOSE: Cancer treatment may be affected by comorbidities; however, studies are limited. The purpose of this study is to examine the frequency of comorbidities at visits by patients with breast, prostate, colorectal, and lung cancer and to estimate frequency of a prescription for antineoplastic drugs being included in the treatment received at visits by patients with cancer and concomitant comorbidities. METHODS: We used nationally representative data on visits to office-based physicians from the 2010-2016 National Ambulatory Medical Care Survey and selected visits by adults with breast, prostate, colorectal, or lung cancer (n = 4,672). Nineteen comorbid conditions were examined. Descriptive statistics were calculated for visits by cancer patients with 0, 1, and ≥ 2 comorbidities. RESULTS: From 2010-2016, a total of 10.2 million physician office visits were made annually by adult patients with breast, prostate, colorectal, or lung cancer. Among US visits by adult patients with breast, prostate, colorectal, or lung cancer, 56.3% were by patients with ≥ 1 comorbidity. Hypertension was the most frequently observed comorbidity (37.7%), followed by hyperlipidemia (19.0%) and diabetes (12.3%). Antineoplastic drugs were prescribed in 33.5% of the visits and prescribed at a lower percentage among visits by cancer patients with COPD (21.3% versus 34.3% of visits by cancer patients without COPD) and heart disease (22.7% versus 34.2% of visits by cancer patients without heart disease). CONCLUSION: Our study provides information about comorbidities in cancer patients being treated by office-based physicians in an ambulatory setting.

Alcohol consumption and risk of multiple myeloma in the NIH-AARP Diet and Health Study.

The epidemiologic evidence regarding the relationship between alcohol consumption and multiple myeloma (MM) risk remains limited and inconsistent, although recent studies suggest a potential protective effect. We prospectively investigated the risk of MM in relation to alcohol consumption frequency among 499,292 participants enrolled in the National Institutes of Health (NIH)-AARP Diet and Health Study in 1995-1996. A total of 1,312 MM cases were identified during follow-up through December 2011. Hazard ratios (HR) and 95% confidence intervals (CI) for categories of alcohol consumption relative to those defined as light drinkers (<1 drink/week) were estimated using multivariate Cox proportional hazard models. Overall, increasing frequency of alcohol consumption was inversely associated with MM (p-trend = 0.01), with a statistically significant association among those who consumed 2 drinks per day (HR = 0.70, 95% CI: 0.50, 0.98); similar but not statistically significant associations were observed for greater frequency of alcohol consumption. Among women, risk of MM was reduced among those who consumed less than one drink per day (HR = 0.73, 95% CI: 0.56, 0.97) and associations with greater frequency of alcohol consumption were inverse although not statistically significant. The findings of this large prospective investigation suggest that moderate alcohol consumption may be associated with reduced future risk of MM.

Circulating resistin levels and risk of multiple myeloma in three prospective cohorts.

BACKGROUND: Resistin is a polypeptide hormone secreted by adipose tissue. A prior hospital-based case-control study reported serum resistin levels to be inversely associated with risk of multiple myeloma (MM). To date, this association has not been investigated prospectively. METHODS: We measured resistin concentrations for pre-diagnosis peripheral blood samples from 178 MM cases and 358 individually matched controls from three cohorts participating in the MM cohort consortium. RESULTS: In overall analyses, higher resistin levels were weakly associated with reduced MM risk. For men, we observed a statistically significant inverse association between resistin levels and MM (odds ratio, 0.44; 95% confidence interval (CI) 0.24-0.83 and 0.54; 95% CI 0.29-0.99, for the third and fourth quartiles, respectively, vs the lowest quartile; Ptrend=0.03). No association was observed for women. CONCLUSIONS: This study provides the first prospective evidence that low circulating resistin levels may be associated with an increased risk of MM, particularly for men.

Bone Disease in Multiple Myeloma.

Bone involvement represented by osteolytic bone disease (OBD) or osteopenia is one of the pathognomonic and defining characteristics of multiple myeloma (MM). Nearly 90 % of patients with MM develop osteolytic bone lesions, frequently complicated by skeletal-related events (SRE) such as severe bone pain, pathological fractures, vertebral collapse, hypercalcemia, and spinal cord compression. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. OBD is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Inhibition of osteolysis and stimulation of OB differentiation leads to reduced tumor growth in vivo. Therefore, novel agents targeting OBD are promising therapeutic strategies not only for the treatment of MM OBD but also for the treatment of MM. Several novel agents in addition to bisphosphonates are currently under investigation for their positive effect on bone remodeling via OC inhibition or OB stimulation. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from MM OBD but also capitalizing on the resultant antitumor activity.

Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death.

Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.

Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma.

Histone deacetylase (HDAC) enzymatic activity has been linked to the transcription of DNA in cancers including multiple myeloma (MM). Therefore, HDAC inhibitors used alone and in combination are being actively studied as novel therapies in MM. In the present study, we investigated the preclinical activity of ACY-1215, an HDAC6-selective inhibitor, alone and in combination with bortezomib in MM. Low doses of ACY-1215 combined with bortezomib triggered synergistic anti-MM activity, resulting in protracted endoplasmic reticulum stress and apoptosis via activation of caspase-3, caspase-8, and caspase-9 and poly (ADP) ribosome polymerase. In vivo, the anti-MM activity of ACY-1215 in combination with bortezomib was confirmed using 2 different xenograft SCID mouse models: human MM injected subcutaneously (the plasmacytoma model) and luciferase-expressing human MM injected intravenously (the disseminated MM model). Tumor growth was significantly delayed and overall survival was significantly prolonged in animals treated with the combination therapy. Pharmacokinetic data showed peak plasma levels of ACY-1215 at 4 hours after treatment coincident with an increase in acetylated α-tubulin, a marker of HDAC6 inhibition, by immunohistochemistry and Western blot analysis. These studies provide preclinical rationale for acetylated α-tubulin use as a pharmacodynamic biomarker in future clinical trials.

Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma.

Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study, we examined whether IRE1α-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1α endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Importantly, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress, evidenced by induction of XBP1s, which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Finally, MKC-3946 inhibited XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1α endoribonuclease domain is a potential therapeutic option in MM.

Emergency Department Visits by Homeless Status and Sex: United States, 2016-2021.

Objectives-This report describes emergency department (ED) visits by homeless status and sex. Methods-Nationally representative estimates were calculated from data collected in the 2016-2021 National Hospital Ambulatory Medical Care Survey, an annual national probability sample survey of ED visits in the United States. Visits by people experiencing homelessness were defined using data on patient residence from medical records. Visits by males and females experiencing homelessness are compared with each other and with visits by males and females not experiencing homelessness. Results-During 2016-2021, approximately 981,000 and 460,000 ED visits were made annually by males and females experiencing homelessness, respectively. Significant differences by sex were found for this population for many ED visit characteristics, including arrival by ambulance, diagnoses, and chronic conditions. ED visits by males and females experiencing homelessness also differed significantly from ED visits by males and females not experiencing homelessness based on age, geographic region, expected source of payment, primary diagnosis, chronic conditions, and other characteristics. Conclusion-This report highlights certain differences by sex among the population experiencing homelessness who visited the ED and compares them with people who visited the ED but were not experiencing homelessness.

Trends in Emergency Department Visits Among People Younger Than Age 65 by Insurance Status: United States, 2010-2021.

Purpose-This report describes trends in emergency department visits among people younger than age 65 from 2010 through 2021, by health insurance status and selected demographic and hospital characteristics. Methods-Estimates in this report are based on data collected in the 2010-2021 National Hospital Ambulatory Medical Care Survey. Data were weighted to produce annual national estimates. Patient and hospital characteristics are presented by primary expected source of payment. Results-Private insurance and Medicaid were the most common primary expected sources of payment at emergency department visits by people younger than age 65 from 2010 through 2013. Medicaid was the most common primary expected source of payment from 2014 through 2021. Among children younger than age 18 years, the most common primary expected source of payment was Medicaid across the entire period. The percentage of visits by children with no insurance decreased from 7.4% in 2010 to 3.0% in 2021. Among adults, the percentage of visits with Medicaid increased from 25.5% in 2010 to 38.9% in 2021, and the percentage of visits by those with no insurance decreased from 24.6% to 11.1% during this period. Among Black non-Hispanic and Hispanic people, Medicaid was the most frequent primary expected source of payment during the entire period. Among White non-Hispanic people, private insurance was the most frequent primary expected source of payment through 2015, while private insurance and Medicaid were the most frequent primary expected sources of payment from 2016 through 2021.

The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors.

The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34(+) bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease.

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.

Emergency Department Visit Rates for Assault: United States, 2019-2021.

Nonfatal injuries are major causes of emergency department (ED) visits in the United States (1). The National Center for Injury Prevention and Control estimated that, in 2020, 22.9 million ED visits related to nonfatal injuries occurred (1). Visits for assault (excluding sexual assault) represented 5.8% of these visits (1). This report uses the most recent data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) to present assault-related ED visit (excluding sexual assault) rates by selected demographic and hospital characteristics.

Opioids Prescribed to Adults at Discharge From Emergency Departments: United States, 2017-2020.

Opioids may be an effective treatment for chronic and acute pain when properly used (1). However, receiving an opioid prescription in the emergency department (ED) has been identified as a potential risk factor for long-term use (2). Between 2010-2011 and 2016-2017, the percentage of opioids prescribed at ED discharge decreased from 21.5% to 14.6% (3,4). This report provides more recent changes in rates and percentages of opioids prescribed to adults (aged 18 and over) at discharge from the ED by patient and visit characteristics through 2020, using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS).

Emergency Department Visit Rates by Adults With Diabetes: United States, 2020-2021.

In 2021, diabetes was the eighth leading cause of death in the United States (1). Over 37 million Americans have diabetes (2). While it most often develops in people older than age 45 (3), its frequency is increasing in young adults (4). Among people with diabetes, increasing age is a risk factor for hospitalization (5). Emergency department (ED) visits by people with diabetes have been used to monitor access to care and healthcare use (6). This report describes ED visits made by adults with diabetes, and presents selected characteristics by age.

Emergency Department Visits Related to Mental Health Disorders Among Adults, by Race and Hispanic Ethnicity: United States, 2018-2020.

Objective-This report describes emergency department (ED) visits related to mental health disorders among adults and assesses differences in mental health-related ED visit characteristics by race and Hispanic ethnicity.

Cytotoxicity and Antibiofilm Activity of Silver-Polypropylene Nanocomposites.

The development of biocompatible nanomaterials that interface with human skin and tissue is critical for advancing prosthetics and other therapeutic medical needs. In this perspective, the development of nanoparticles with cytotoxicity and antibiofilm properties and biocompatibility characteristics are important. Metallic silver (Ag) exhibits good biocompatibility, but it is often challenging to integrate it into a nanocomposite without compromising its antibiofilm properties for optimal applications. In this study, new polymer nanocomposites (PNCs) with ultra-low filling content (0.0023-0.046 wt%) of Ag nanoplates were manufactured and tested. The cytotoxicity and antibiofilm activity of different composites with polypropylene (PP) matrix were examined. At first, PNCs surface were analyzed by means of AFM (atomic force microscopy) with phase contrast evaluation and FTIR (Fourier-transform infrared spectroscopy) to study the Ag nanoplates distribution. Subsequently, the cytotoxicity and growth properties of biofilms were assessed by MTT assay protocol and detection of nitric oxide radicals. Antibacterial and antibiofilm activities were measured against Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (K. pneumoniae). The PNCs with silver exhibited antibiofilm activity although they did not inhibit regular planktonic bacterial growth. Moreover, the PNCs were not cytotoxic to mammalian cells and did not induce significant immune response. These features reveal the potential of the PNCs developed in this study for usage in fabrication of prosthetics and other smart structures for biomedical applications.