Using Texture Analysis of Neck Computed Tomography Images to Differentiate Primary Hyperparathyroidism From Normal Controls.

OBJECTIVE: To investigate the utility of texture analysis in detecting osseous changes associated with hyperparathyroidism on neck CT examinations compared with control patients and to explore the best regions in the head and neck to evaluate changes in the trabecular architecture secondary to hyperparathyroidism. METHODS: Patients with hyperparathyroidism who underwent a 4D CT of the neck with contrast were included in this study. Age-matched control patients with no history of hyperparathyroidism who underwent a contrast-enhanced neck CT were also included. Mandibular condyles, bilateral mandibular bodies, the body of the C4 vertebra, the manubrium of the sternum, and bilateral clavicular heads were selected for analysis, and oval-shaped regions of interest were manually placed. These segmented areas were imported into an in-house developed texture analysis program, and 41 texture analysis features were extracted. A mixed linear regression model was used to compare differences in the texture analysis features contoured at each of the osseous structures between patients with hyperparathyroidism and age-matched control patients. RESULTS: A total of 30 patients with hyperparathyroidism and 30 age-matched control patients were included in this study. Statistically significant differences in texture features between patients with hyperparathyroidism and control patients in all 8 investigated osseous regions. The sternum showed the greatest number of texture features with statistically significant differences between these groups. CONCLUSIONS: Some CT texture features demonstrated statistically significant differences between patients with hyperparathyroidism and control patients. The results suggest that texture features may discriminate changes in the osseous architecture of the head and neck in patients with hyperparathyroidism.

Emergence and influence of sequence bias in evolutionarily malleable, mammalian tandem arrays.

BACKGROUND: The radiation of mammals at the extinction of the dinosaurs produced a plethora of new forms-as diverse as bats, dolphins, and elephants-in only 10-20 million years. Behind the scenes, adaptation to new niches is accompanied by extensive innovation in large families of genes that allow animals to contact the environment, including chemosensors, xenobiotic enzymes, and immune and barrier proteins. Genes in these "outward-looking" families are allelically diverse among humans and exhibit tissue-specific and sometimes stochastic expression. RESULTS: Here, we show that these tandem arrays of outward-looking genes occupy AT-biased isochores and comprise the "tissue-specific" gene class that lack CpG islands in their promoters. Models of mammalian genome evolution have not incorporated the sharply different functions and transcriptional patterns of genes in AT- versus GC-biased regions. To examine the relationship between gene family expansion, sequence content, and allelic diversity, we use population genetic data and comparative analysis. First, we find that AT bias can emerge during evolutionary expansion of gene families in cis. Second, human genes in AT-biased isochores or with GC-poor promoters experience relatively low rates of de novo point mutation today but are enriched for non-synonymous variants. Finally, we find that isochores containing gene clusters exhibit low rates of recombination. CONCLUSIONS: Our analyses suggest that tolerance of non-synonymous variation and low recombination are two forces that have produced the depletion of GC bases in outward-facing gene arrays. In turn, high AT content exerts a profound effect on their chromatin organization and transcriptional regulation.

An Intensive Intervention to Reduce Readmissions for Frequently Hospitalized Patients: the CHAMP Randomized Controlled Trial.

BACKGROUND: A small number of patients are disproportionally readmitted to hospitals. The Complex High Admission Management Program (CHAMP) was established as a multidisciplinary program to improve continuity of care and reduce readmissions for frequently hospitalized patients. OBJECTIVE: To compare hospital utilization metrics among patients enrolled in CHAMP and usual care. DESIGN: Pragmatic randomized controlled trial. PARTICIPANTS: Inclusion criteria were as follows: 3 or more, 30-day inpatient readmissions in the previous year; or 2 inpatient readmissions plus either a referral or 3 observation admissions in previous 6 months. INTERVENTIONS: Patients randomized to CHAMP were managed by an interdisciplinary team including social work, physicians, and pharmacists. The CHAMP team used comprehensive care planning and inpatient, outpatient, and community visits to address both medical and social needs. Control patients were randomized to usual care and contacted 18 months after initial identification if still eligible. MAIN MEASURES: Primary outcome was number of 30-day inpatient readmissions 180 days following enrollment. Secondary outcomes were number of hospital admissions, total hospital days, emergency department visits, and outpatient clinic visits 180 days after enrollment. KEY RESULTS: There were 75 patients enrolled in CHAMP, 76 in control. Groups were similar in demographic characteristics and baseline readmissions. At 180 days following enrollment, CHAMP patients had more inpatient 30-day readmissions [CHAMP incidence rate 1.3 (95% CI 0.9-1.8) vs. control 0.8 (95% CI 0.5-1.1), p=0.04], though both groups had fewer readmissions compared to 180 days prior to enrollment. We found no differences in secondary outcomes. CONCLUSIONS: Frequently hospitalized patients experienced reductions in utilization over time. Though most outcomes showed no difference, CHAMP was associated with higher readmissions compared to a control group, possibly due to consolidation of care at a single hospital. Future research should seek to identify subsets of patients with persistently high utilization for whom tailored interventions may be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03097640; https://clinicaltrials.gov/ct2/show/NCT03097640.

Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer.

Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cancer cells to a drug-tolerant state, for example through epithelial-to-mesenchymal transition or transition to a cancer stem cell state. However, many breast tumors are a heterogeneous mixture of cell types with numerous epigenetic states in addition to stem-like and mesenchymal phenotypes, and the dynamic behavior of this heterogeneous mixture in response to drug treatment is not well-understood. Recently, we showed that plasticity between differentiation states, as identified with intracellular markers such as cytokeratins, is linked to resistance to specific targeted therapeutics. Understanding the dynamics of differentiation-state transitions in this context could facilitate the development of more effective treatments for cancers that exhibit phenotypic heterogeneity and plasticity. In this work, we develop computational models of a drug-treated, phenotypically heterogeneous triple-negative breast cancer (TNBC) cell line to elucidate the feasibility of differentiation-state transition as a mechanism for therapeutic escape in this tumor subtype. Specifically, we use modeling to predict the changes in differentiation-state transitions that underlie specific therapy-induced changes in differentiation-state marker expression that we recently observed in the HCC1143 cell line. We report several statistically significant therapy-induced changes in transition rates between basal, luminal, mesenchymal, and non-basal/non-luminal/non-mesenchymal differentiation states in HCC1143 cell populations. Moreover, we validate model predictions on cell division and cell death empirically, and we test our models on an independent data set. Overall, we demonstrate that changes in differentiation-state transition rates induced by targeted therapy can provoke distinct differentiation-state aggregations of drug-resistant cells, which may be fundamental to the design of improved therapeutic regimens for cancers with phenotypic heterogeneity.

Correction: Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer.

[This corrects the article DOI: 10.1371/journal.pcbi.1006840.].

Craniofacial Manifestations of Systemic Disorders: CT and MR Imaging Findings and Imaging Approach.

Many systemic diseases or conditions can affect the maxillofacial bones; however, they are often overlooked or incidentally found at routine brain or head and neck imaging performed for other reasons. Early identification of some conditions may significantly affect patient care and alter outcomes. Early recognition of nonneoplastic hematologic disorders, such as thalassemia and sickle cell disease, may help initiate earlier treatment and prevent serious complications. The management of neoplastic diseases such as lymphoma, leukemia, or Langerhans cell histiocytosis may be different if diagnosed early, and metastases to the maxillofacial bones may be the first manifestation of an otherwise occult neoplasm. Endocrinologic and metabolic disorders also may manifest with maxillofacial conditions. Earlier recognition of osteoporosis may alter treatment and prevent complications such as insufficiency fractures, and identification of acromegaly may lead to surgical treatment if there is an underlying growth hormone-producing adenoma. Bone dysplasias sometimes are associated with skull base foraminal narrowing and subsequent involvement of the cranial nerves. Inflammatory processes such as rheumatoid arthritis and sarcoidosis may affect the maxillofacial bones, skull base, and temporomandibular joints. Radiologists should be familiar with the maxillofacial computed tomographic and magnetic resonance imaging findings of common systemic disorders because these may be the first manifestations of an otherwise unrevealed systemic process with potential for serious complications. Online supplemental material is available for this article. ©RSNA, 2018.

Global and Regional Brain Assessment with Quantitative MR Imaging in Patients with Prior Exposure to Linear Gadolinium-based Contrast Agents.

Purpose To assess the association of global and regional brain relaxation times in patients with prior exposure to linear gadolinium-based contrast agents (GBCAs). Materials and Methods The institutional review board approved this cross-sectional study. Thirty-five patients (nine who had received GBCA gadopentetate dimeglumine injections previously [one to eight times] and 26 patients who did not) who underwent brain magnetic resonance (MR) imaging with a mixed fast spin-echo pulse sequence were assessed. The whole brain was segmented according to white and gray matter by using a dual-clustering algorithm. In addition, regions of interest were measured in the globus pallidus, dentate nucleus, thalamus, and pons. The Mann-Whitney U test was used to assess the difference between groups. Multiple regression analysis was performed to assess the association of T1 and T2 with prior GBCA exposure. Results T1 values of gray matter were significantly shorter for patients with than for patients without prior GBCA exposure (P = .022). T1 of the gray matter of the whole brain (P < .001), globus pallidus (P = .002), dentate nucleus (P = .046), and thalamus (P = .026) and T2 of the whole brain (P = .004), dentate nucleus (P = .023), and thalamus (P = .002) showed a significant correlation with the accumulated dose of previous GBCA administration. There was no significant correlation between T1 and the accumulated dose of previous GBCA injections in the white matter (P = .187). Conclusion Global and regional quantitative assessments of T1 and T2 demonstrated an association with prior GBCA exposure, especially for gray matter structures. The results of this study confirm previous research findings that there is gadolinium deposition in wider distribution throughout the brain. © RSNA, 2016 Online supplemental material is available for this article.

Sarcoidosis in the Head and Neck: An Illustrative Review of Clinical Presentations and Imaging Findings.

OBJECTIVE: Sarcoidosis is referred to as a great imitator because of its propensity to radiologically mimic a variety of pathologic entities. Symptomatic neurosarcoidosis is present in approximately 5% of patients with sarcoidosis, and it is found histopathologically in approximately 25% of asymptomatic patients. CONCLUSION: An understanding of the multifaceted imaging manifestations of head and neck sarcoidosis will aid early recognition of the diagnosis, with a goal for earlier initiation of therapy and prevention of irreversible sequelae of the disease.

Micro-Credit and Community Wildlife Management: Complementary Strategies to Improve Conservation Outcomes in Serengeti National Park, Tanzania.

Community wildlife management programs in African protected areas aim to deliver livelihood and social benefits to local communities in order to bolster support for their conservation objectives. Most of these benefits are delivered at the community level. However, many local people are also seeking more individual or household-level livelihood benefits from community wildlife management programs because it is at this level that many of the costs of protected area conservation are borne. Because community wildlife management delivers few benefits at this level, support for their conservation objectives amongst local people often declines. The study investigated the implications of this for reducing poaching in Serengeti National Park, Tanzania. Three community wildlife management initiatives undertaken by Park management were compared with regard to their capacity to deliver the individual and household-level benefits sought by local people: community conservation services, wildlife management areas and community conservation banks. Interviews were carried out with poachers and local people from four villages in the Western Serengeti including members of village conservation banks, as well as a number of key informants. The results suggest that community conservation banks could, as a complementary strategy to existing community wildlife management programs, potentially provide a more effective means of reducing poaching in African protected areas than community wildlife management programs alone.

Clinical-Radiologic Correlation of Extraocular Eye Movement Disorders: Seeing beneath the Surface.

Extraocular eye movement disorders are relatively common and may be a significant source of discomfort and morbidity for patients. The presence of restricted eye movement can be detected clinically with quick, easily performed, noninvasive maneuvers that assess medial, lateral, upward, and downward gaze. However, detecting the presence of ocular dysmotility may not be sufficient to pinpoint the exact cause of eye restriction. Imaging plays an important role in excluding, in some cases, and detecting, in others, a specific cause responsible for the clinical presentation. However, the radiologist should be aware that the imaging findings in many of these conditions when taken in isolation from the clinical history and symptoms are often nonspecific. Normal eye movements are directly controlled by the ocular motor cranial nerves (CN III, IV, and VI) in coordination with indirect input or sensory stimuli derived from other cranial nerves. Specific causes of ocular dysmotility can be localized to the cranial nerve nuclei in the brainstem, the cranial nerve pathways in the peripheral nervous system, and the extraocular muscles in the orbit, with disease at any of these sites manifesting clinically as an eye movement disorder. A thorough understanding of central nervous system anatomy, cranial nerve pathways, and orbital anatomy, as well as familiarity with patterns of eye movement restriction, are necessary for accurate detection of radiologic abnormalities that support a diagnostic source of the suspected extraocular movement disorder. ©RSNA, 2016.

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial.

IMPORTANCE: For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE: To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS: A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS: Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES: Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS: Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE: Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN33288337.

Periapical lucency around the tooth: radiologic evaluation and differential diagnosis.

Periapical lucencies are often seen incidentally at head and neck imaging studies performed for indications not related to the teeth. These lesions are, however, occasionally manifestations of diseases that have a wide range of effects and may at times represent the source of symptoms that prompted the study. The vast majority of periapical lucencies are the result of apical periodontal or pulpal disease. If found in an advanced state or left untreated, disease related to the tooth may spread to adjacent tissues, including the sinuses, orbits, deep fascial spaces of the neck, and intracranial structures, and result in a significant increase in patient morbidity and mortality. Although the majority of periapical lucencies seen on radiographs and computed tomographic images occur secondary to apical periodontal or pulpal disease, not all lucencies near the tooth root are due to infection. Lucency near the tooth root may be seen in the setting of other diseases of odontogenic and non-odontogenic origin, including neoplasms. Although imaging findings for these lesions can include periapical lucent components, awareness of the varied secondary imaging features can aid the radiologist in developing an accurate differential diagnosis. Familiarity with the imaging features and differential diagnoses of diseases or conditions that cause lucency around the tooth root results in appropriate referral and prompt diagnosis, management, and treatment, and can prevent unnecessary additional imaging or intervention. In addition, early recognition and appropriate treatment of infectious processes will result in improved clinical outcomes and a decrease in morbidity and mortality.

Infectious and Inflammatory Sinonasal Diseases.

Rhinosinusitis is a commonly encountered disease. Imaging is not typically required in acute uncomplicated rhinosinusitis; however, it is integral in the evaluation of patients who present with prolonged or atypical symptoms or when acute intracranial complications or alternate diagnoses are suspected. Knowledge of the paranasal sinus anatomy is important to understand patterns of sinonasal opacification. Bacterial, viral, and fungal pathogens are responsible culprits and, with duration of symptoms, serve to categorize infectious sinonasal disease. Several systemic inflammatory and vasculitic processes have a predilection for the sinonasal region. Imaging, along with laboratory and histopathologic analysis, assist in arriving at these diagnoses.

IgG4-related disease of the head and neck: CT and MR imaging manifestations.

Immunoglobulin G4 (IgG4)-related disease is a recently established systemic disease that commonly involves the head and neck, including the salivary glands, lacrimal glands, orbits, thyroid gland, lymph nodes, sinonasal cavities, pituitary gland, and larynx. Although the definitive diagnosis of IgG4-related disease requires histopathologic analysis, elevated serum IgG4 levels are helpful in making the diagnosis. Because of the proposed clinical diagnostic criteria for this disease, cross-sectional imaging modalities such as computed tomography (CT) and magnetic resonance (MR) imaging play an important diagnostic role. CT and MR imaging findings of IgG4-related disease are usually nonspecific. At CT, involved organs may demonstrate enlargement or decreased attenuation; at T2-weighted MR imaging, they may have relatively low signal intensity owing to their increased cellularity and amount of fibrosis. Some pathologic entities involving the head and neck are now considered to be part of the IgG4-related disease spectrum, including idiopathic orbital inflammatory syndrome (inflammatory pseudotumor), orbital lymphoid hyperplasia, Mikulicz disease, Küttner tumor, Hashimoto thyroiditis, Riedel thyroiditis, and pituitary hypophysitis. Because involvement of multiple sites is common in IgG4-related disease, radiologists should be familiar with manifestations of this systemic process outside the head and neck, in organs such as the pancreas, bile ducts, gallbladder, kidneys, retroperitoneum, mesentery, lungs, gastrointestinal tract, and blood vessels. Moreover, IgG4-related disease usually demonstrates a dramatic response to corticosteroid therapy, and radiologists should be familiar with its clinical and imaging manifestations to avoid a delay in diagnosis or unnecessary invasive interventions.

The Comprehensive Care Plan: A Patient-Centered, Multidisciplinary Communication Tool for Frequently Hospitalized Patients.

Comprehensive care plans are dynamic documents maintained by an interdisciplinary team that contain specific, actionable information for clinicians and staff across multiple care settings. They promote communication and continuity of care by suggesting communication strategies, medical plans, and psychosocial resources. This article describes the structure and development process of comprehensive care plans for frequently hospitalized patients enrolled in a program designed to improve care for this vulnerable population. These care plans are widely used, with inpatient physicians referring to the care plan in their notes during 92.0% of admissions.

2,4,6-Tribromophenol Disposition and Kinetics in Pregnant and Nursing Sprague Dawley Rats.

2,4,6-Tribromophenol (TBP, CAS no. 118-79-6) is a brominated chemical used as a precursor, flame retardant, and wood antifungal agent. TBP is detected in environmental matrices and biota, including human breast milk, placenta, and serum. To address reports of TBP accumulation in human placenta and breast milk, studies were conducted to characterize TBP disposition and toxicokinetics in timed-pregnant or nursing Sprague Dawley rats following a single oral dose to the dam. Animals were administered [14C]-TBP (10 µmol/kg, 25 µCi/kg, 4 ml/kg) by gavage on gestation day 12 and 20, or postnatal day 12 and serially euthanized between 15 min and 24 h for collection of blood and tissues from the dam and fetuses/pups. Observed plasma TBP Cmax (3 and 7 nmol/ml) occurred at 15 min in both GD12 and GD20 dams while Cmax (3 nmol/ml) was observed at 30 min for PND12 dams. Concentrations in tissues followed plasma concentrations, with kidneys containing the highest concentrations at 30 min. GD12 litters contained a sustained 0.2%-0.3% of the dose (5-9 nmol/litter) between 15 min and 6 h while GD20 fetuses (2%-3%) and placentas (0.3%-0.5%) had sustained levels between 30 min and 12 h. The stomach contents (approx. 1 nmol-eq/g, 6-12 h), livers (0.04-0.1 nmol-eq/g) and kidneys (0.1-0.2 nmol-eq/g) of PND12 pups increased over time, indicating sustained exposure via milk. Systemic exposure to TBP and its metabolites occurs in both the directly exposed mother and the indirectly exposed offspring and is rapid and persistent after a single dose in pregnant and nursing rats.

Perihematomal edema surrounding spontaneous intracerebral hemorrhage by CT: Ellipsoidal versus morphometric volumetry.

Perihematomal edema (PHE) surrounding intracerebral hemorrhage (ICH) may contribute to disease-associated morbidity. Before quantifying PHE's effects on morbidity, a fast, accurate, and reproducible method for measuring PHE volume is needed. The aim of this study is to demonstrate the use of a semiautomated dual clustering segmentation algorithm to generate PHE volumetrics on noncontrast computed tomography (CT) of the head and compare this technique to physicians' manual calculations.This is a single-center, retrospective imaging study that included head CTs performed from January 2008 to December 2014 on 154 patients with ICH. Subjects ≥ 18 years old who were admitted to the hospital with spontaneous ICH were included. Included subjects had head CTs performed upon admission and within 6 to 24 hours. Two neurologists, 2 neuroradiologists, and a computer program all calculated hemorrhage and PHE volumes. Inter-rater correlation was evaluated using 2 statistical methods: intraclass correlations (ICCs) and limits of agreement (LOA). Additionally, correlation between volumes was separately evaluated using Pearson correlation coefficient.There was an excellent correlation between measurements performed by neurologists and neuroradiologists using ABC/2 for ICH (0.93) and PHE (0.78). There was a good correlation between measurements performed by neurologists using ABC/2 and the volume measurements generated by the algorithm for ICH (0.69) and PHE (0.70). There was a fair correlation between measurements performed by neuroradiologists using ABC/2 and volume measurements generated by the algorithm for ICH (0.47) and good correlation for PHE (0.73).Although the ABC/2 method for measuring PHE is quick and practical, algorithms that do not assume ellipsoidal shape may be more accurate.

Comparative Molecular Life History of Spontaneous Canine and Human Gliomas.

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, transcriptome, and methylation sequencing of 83 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, TP53 and cell-cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA-methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.

Frequently Hospitalized Patients' Perceptions of Factors Contributing to High Hospital Use.

BACKGROUND: A small proportion of patients accounts for a large proportion of hospitalizations. OBJECTIVE: To obtain patients' perspectives of factors associated with the onset and continuation of high hospital use. DESIGN: Qualitative research study where a research coordinator conducted one-on-one semi-structured interviews. A team of researchers performed inductive coding and analysis. SETTING: A single urban academic hospital. PARTICIPANTS: Patients with two unplanned 30-day readmissions within 12 months and one or more of the following: ≥1 readmission in the last six months, a referral from a clinician, or ≥3 observation visits. RESULTS: Overall, 26 participants completed the interviews. Four main themes emerged. First, major medical problems were universal, but the onset of frequent hospital use varied. Second, participants perceived fluctuations in their course to be related to psychological, social, and economic factors. Social support was perceived as helpful and participants benefited when providing social support to others. Third, episodes of illness varied in onset and generally seemed uncontrollable and often unpredictable to the participants. Fourth, participants strongly desired to avoid hospitalization and typically sought care only after self-management failed. CONCLUSIONS: Emergent themes pointed to factors which influence patients' onset of high hospital use, fluctuations in their illness over time, and triggers to seek care during an episode of illness. These findings enable patients' perspectives to be incorporated into the design of programs serving similar populations of frequently hospitalized patients.