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SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes of patients with COVID-19 are infected with SARS-CoV-2. Monocyte infection depends on the uptake of antibody-opsonized virus by Fcγ receptors. The plasma of vaccine recipients does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in the supernatants of cultures of infected monocytes. Instead, infected cells undergo pyroptosis mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and gasdermin D. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from lung autopsies from patients with COVID-19 have activated inflammasomes. Taken together, these findings suggest that antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.
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COVID-19 , Inflamación , Monocitos , Receptores de IgG , SARS-CoV-2 , COVID-19/virología , Caspasa 1/metabolismo , Proteínas de Unión al ADN , Humanos , Inflamasomas/metabolismo , Inflamación/metabolismo , Inflamación/virología , Monocitos/metabolismo , Monocitos/virología , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Unión a Fosfato , Proteínas Citotóxicas Formadoras de Poros , Receptores de IgG/metabolismoRESUMEN
BACKGROUND: Mutations in TMPRSS3 are an important cause of autosomal recessive non-syndromic hearing loss. The hearing loss associated with mutations in TMPRSS3 is characterized by phenotypic heterogeneity, ranging from mild to profound hearing loss, and is generally progressive. Clinical presentation and natural history of TMPRSS3 mutations vary significantly based on the location and type of mutation in the gene. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to DFNB8/10. The heterogeneous presentation of TMPRSS3-associated disease makes it difficult to identify patients clinically. As the body of literature on TMPRSS3-associated deafness grows, there is need for better categorization of the hearing phenotypes associated with specific mutations in the gene. SUMMARY: In this review, we summarize TMPRSS3 genotype-phenotype relationships including a thorough description of the natural history of patients with TMPRSS3-associated hearing loss to lay the groundwork for the future of TMPRSS3 treatment using molecular therapy. KEY MESSAGES: TMPRSS3 mutation is a significant cause of genetic hearing loss. All patients with TMPRSS3 mutation display severe-to-profound prelingual (DFNB10) or a postlingual (DFNB8) progressive sensorineural hearing loss. Importantly, TMPRSS3 mutations have not been associated with middle ear or vestibular deficits. The c.916G>A (p.Ala306Thr) missense mutation is the most frequently reported mutation across populations and should be further explored as a target for molecular therapy.
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Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Serina Endopeptidasas/genética , Proteínas de la Membrana/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva/genética , Mutación , Estudios de Asociación Genética , Fenotipo , Proteínas de Neoplasias/genéticaRESUMEN
Background: Colorado's age-adjusted fatal opioid overdose rate increased over 400% from 2000 to 2020. Public libraries are increasingly valuable community resources for accessing health-related information. We sought to evaluate the availability and types of opioid use disorder (OUD)-related resources offered through Colorado Public Library branches using secret shoppers to collect data. Methods: This was a cross sectional study of 197 Colorado Public Libraries in 2021. Anonymous auditors posed as library patrons asking a brief standardized script about availability of OUD-related resources over the phone. We conducted descriptive analyses of the libraries contacted, the response types of OUD resources provided, and information about naloxone availability. Outcomes were compared between urban/rural and libraries within/outside the Denver Public Library (DPL) system via means comparison tests. Results: Approximately 50% of libraries were classified as urban. Most (81%) of the libraries offered a valid OUD-resource, and over half (51%) provided a referral to a treatment center offering at least one medication for OUD. Over a third (36%) of librarians referenced the statewide naloxone standing order allowing patients to obtain naloxone from a pharmacy without prescription. One in ten libraries provided at least one invalid referral resource. Libraries within the DPL system referenced Colorado's naloxone standing order at higher rates than non-DPL libraries. Conclusions: Public libraries may benefit from the development of a standard for OUD-related resource training/education that can be distributed across the state to create a space for community members to obtain resources related to substance use.
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Sobredosis de Droga , Sobredosis de Opiáceos , Trastornos Relacionados con Opioides , Humanos , Colorado , Estudios Transversales , Trastornos Relacionados con Opioides/tratamiento farmacológico , Naloxona/uso terapéutico , Sobredosis de Opiáceos/tratamiento farmacológico , Analgésicos Opioides/uso terapéutico , Antagonistas de Narcóticos/uso terapéuticoRESUMEN
INTRODUCTION: ED health care professionals are at the frontline of evaluation and management of patients with acute, and often undifferentiated, illness. During the initial phase of the SARS-CoV-2 outbreak, there were concerns that ED health care professionals may have been at increased risk of exposure to SARS-CoV-2 due to difficulty in early identification of patients. This study assessed the seroprevalence of SARS-CoV-2 antibodies among ED health care professionals without confirmed history of COVID-19 infection at a quaternary academic medical center. METHODS: This study used a cross-sectional design. An ED health care professional was deemed eligible if they had worked at least 4 shifts in the adult emergency department from April 1, 2020, through May 31, 2020, were asymptomatic on the day of blood draw, and were not known to have had prior documented COVID-19 infection. The study period was December 17, 2020, to January 27, 2021. Eligible participants completed a questionnaire and had a blood sample drawn. Samples were run on the Roche Cobas Elecsys Anti-SARS-CoV-2 antibody assay. RESULTS: Of 103 health care professionals (16 attending physicians, 4 emergency residents, 16 advanced practice professionals, and 67 full-time emergency nurses), only 3 (2.9%; exact 95% CI, 0.6%-8.3%) were seropositive for SARS-CoV-2 antibodies. DISCUSSION: At this quaternary academic medical center, among those who volunteered to take an antibody test, there was a low seroprevalence of SARS-CoV-2 antibodies among ED clinicians who were asymptomatic at the time of blood draw and not known to have had prior COVID-19 infection.
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COVID-19 , Adulto , Anticuerpos Antivirales , COVID-19/epidemiología , Estudios Transversales , Personal de Salud , Humanos , SARS-CoV-2 , Estudios SeroepidemiológicosRESUMEN
Keloids negatively impact the health and quality of life of many affected dermatologic patients. Treating keloids is often difficult, and suboptimal responses are frequent. Fortunately, there are many treatment options available to the clinician that may lead to improved clinical outcomes. We present a review of currently available therapeutic options. Intralesional steroid injection remains the first-line treatment for keloids. Imiquimod, direct interferon therapy, or intralesional 5-flurouracil may alleviate the need for excessive corticosteroid therapy. Radiation and laser therapy are emerging therapeutic options that have demonstrated efficacy in reviewed studies. Given the unsatisfactory outcomes associated with pressure dressings, vitamin E, ablative laser, and surgical excision, these options should be avoided in keloid management. Further research is needed to evaluate the efficacy and recurrence associated with the reviewed therapeutics.
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Corticoesteroides/administración & dosificación , Procedimientos Quirúrgicos Dermatologicos , Queloide/terapia , Fitoterapia , Radioterapia , Criocirugía , Humanos , Inyecciones Intralesiones , Cebollas , Extractos Vegetales/uso terapéuticoRESUMEN
Background: Ballistic embolism (BE) is a rare complication of firearm injuries notoriously associated with a vexing clinical picture in the trauma bay. Unless considered early, the associated confusion can lead to needless delay in the management of the patient with a gunshot wound. Despite this known entity, there is a relative paucity of high-grade evidence regarding complications, management, and follow-up in these patients. Methods: An electronic database literature search was conducted to identify cases of acute intravascular BE in pediatric and adult civilians occurring during index hospitalization, filtered to publications during the past 10 years. Exclusion criteria included non-vascular embolization, injuries occurring in the military setting, and delayed migration defined as occurring after discharge from the index hospitalization. Results: A total of 136 cases were analyzed. Nearly all cases of BE occurred within 48 hours of presentation. Compared with venous emboli, arterial emboli were significantly more likely to be symptomatic (71% vs. 7%, p<0.001), and 43% of patients developed symptoms attributable to BE in the trauma bay. In addition, arterial emboli were significantly less likely to be managed non-invasively (19% vs. 49%, p<0.001). Open retrieval was significantly more likely to be successful compared with endovascular attempts (91% vs. 29%, p<0.001). Patients with arterial emboli were more likely to receive follow-up (52% vs. 39%) and any attempt at retrieval during the hospitalization was significantly associated with outpatient follow-up (p=0.034). All but one patient remained stable or had clinically improved symptoms after discharge. Conclusion: Consideration for BE is reasonable in any patient with new or persistent unexplained signs or symptoms, especially during the first 48 hours after a penetrating firearm injury. Although venous BE can often be safely observed, arterial BE generally necessitates urgent retrieval. Patients who are managed non-invasively may benefit from follow-up in the first year after injury.
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Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the power to identify disease-associated loci. SGS analysis identifies genomic segments shared among disease cases that are likely identical by descent and anchored by a disease locus. This approach revealed statistically significant signals for major histocompatibility complex (MHC) class I and class III alleles, particularly HLA-A∗02:01, which was observed at a high frequency among cases. Furthermore, we identified an additional risk locus at 12q23.2-23.3, containing genes primarily expressed by naive B cells, natural killer cells, and monocytes. The recognition of additional risk beyond HLA-DRB1 provides a new perspective on immune cell dynamics in JIA. These findings contribute to our understanding of JIA and may guide future research and therapeutic strategies.
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Artritis Juvenil , Humanos , Artritis Juvenil/genética , Cadenas HLA-DRB1/genética , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Factores de Riesgo , GenómicaRESUMEN
INTRODUCTION: Whole blood (WB) resuscitation has reemerged as a resuscitation strategy for injured patients. However, the effect of WB-based resuscitation on outcomes has not been established. The primary objective of this guideline was to develop evidence-based recommendations on whether WB should be considered in civilian trauma patients receiving blood transfusions. METHODS: An Eastern Association for the Surgery of Trauma working group performed a systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation methodology. One Population, Intervention, Comparison, and Outcomes question was developed to analyze the effect of WB resuscitation in the acute phase on mortality, transfusion requirements, infectious complications, and intensive care unit length of stay. English language studies including adult civilian trauma patients comparing in-hospital WB to component therapy were included. Medline, Embase, Cochrane CENTRAL, CINAHL Plus, and Web of Science were queried. GRADEpro (McMaster University; Evidence Prime, Inc.; Ontario) was used to assess quality of evidence and risk of bias. The study was registered on International Prospective Register of Systematic Reviews (CRD42023451143). RESULTS: A total of 21 studies were included. Most patients were severely injured and required blood transfusion, massive transfusion protocol activation, and/or a hemorrhage control procedure in the early phase of resuscitation. Mortality was assessed separately at the following intervals: early (i.e., emergency department, 3 hours, or 6 hours), 24 hours, late (i.e., 28 days or 30 days), and in-hospital. On meta-analysis, WB was not associated with decreased mortality. Whole blood was associated with decreased 4-hour red blood cell (mean difference, -1.82; 95% confidence interval [CI], -3.12 to -0.52), 4-hour plasma (mean difference, -1.47; 95% CI, -2.94 to 0), and 24-hour red blood cell transfusions (mean difference, -1.22; 95% CI, -2.24 to -0.19) compared with component therapy. There were no differences in infectious complications or intensive care unit length of stay between groups. CONCLUSION: We conditionally recommend WB resuscitation in adult civilian trauma patients receiving blood transfusions, recognizing that data are limited for certain populations, including women of childbearing age, and therefore this guideline may not apply to these populations. LEVEL OF EVIDENCE: Systematic Review/Meta-Analysis; Level III.
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Transfusión Sanguínea , Resucitación , Heridas y Lesiones , Humanos , Transfusión Sanguínea/normas , Transfusión Sanguínea/métodos , Transfusión Sanguínea/estadística & datos numéricos , Resucitación/métodos , Resucitación/normas , Heridas y Lesiones/terapia , Heridas y Lesiones/mortalidad , Heridas y Lesiones/complicacionesRESUMEN
OBJECTIVE: We aimed to evaluate the effects of a multidisciplinary pulmonary embolism (PE) response team (PERT) on the management and outcomes of patients with acute PE. METHODS: We retrospectively reviewed all patients presenting to our institution with a diagnosis of PE from July 2020 to April 2022. The primary outcome measures were in-hospital mortality, major bleeding events defined by the International Society on Thrombosis and Haemostasis, and use of catheter-directed interventions (CDIs). The secondary outcome measures included 30-day and 12-month mortality, hospital and intensive care unit (ICU) lengths of stay, vasopressor requirement, and cardiac arrest. Continuous variables were assessed using the Mann-Whitney U test and categorical variables using the χ2 or Fisher exact test, as appropriate. RESULTS: A total of 279 patients with acute PE were identified, of whom 79 (28%), 173 (62%), and 27 (10%) were considered to have low risk, intermediate risk, and high risk, respectively. The PERT was activated for 133 patients (47.7%). Saddle and main pulmonary artery embolisms (P < .001), right ventricular strain (P= .001), right ventricular dysfunction (P < .001), coexisting deep vein thrombosis (P < .001), and dyspnea as a presenting symptom (P = .008) were significantly associated with PERT activation. Patients evaluated by the PERT were more likely to undergo CDI (49% vs 27%; P < .001) across all risk groups and less likely to have an inferior vena cava filter placed (1% vs 5%; P = .04). PERT consultation showed numerical, but nonstatistically significant, trends toward reduced in-hospital (2% vs 5%; P = .2) and 30-day (2% vs 8%; P = .06) mortality but similar rates of 12-month mortality (7% vs 8%; P = .7). PERT activation was also associated with a trend toward reduced rates of major bleeding (2% vs 7%), cardiac arrest (2% vs 7%), and vasopressor requirement (9% vs 18%). PERT consultations decreased the median number of ICU days by one half; however, we did not observe any differences in the total hospital length of stay between the groups. CONCLUSIONS: At our institution, PERT consultations were associated with significantly higher usage of CDIs and improved clinical outcomes, including reduced mortality and a lower rate of major bleeding events. PERT consultations were also associated with fewer ICU days, suggesting a possible economic benefit for implementing PERTs, although further research is needed to confirm that conclusion.
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Background: Preoperative type and screen and type and cross are routinely obtained in patients undergoing elective cervical spine surgeries. This is despite low perioperative transfusion rates, particularly in patients undergoing anterior cervical discectomy and fusion (ACDF). Methods: We conducted a retrospective cohort study at a single tertiary medical center of all patients 18 years of age or older undergoing elective ACDF for degenerative cervical spine disease between January 2016 and January 2021. Our primary outcome measures included the frequency of type and screen/crossmatch orders, rate of perioperative transfusion, and crossmatch to transfusion (C/T) ratio. Secondary outcomes included differences between preoperative and postoperative hemoglobin and hematocrit. Results: In total, 1,162 patients were identified. There were no cases of intraoperative transfusion. The overall transfusion rate was less than 1%, with only 1 patient receiving a blood product transfusion during their hospital admission. This patient received 2 units of platelets for severe preoperative thrombocytopenia. Yet, 961 patients (83%) received ABO/Rh blood typing and screening and 647 patients (56%) had their blood typed and crossed. A total of 1,318 units of blood were crossmatched, with no units of packed red blood cells (pRBCs) transfused and only 2 units of platelets transfused, achieving a high crossmatch to transfusion (C/T) ratio of 659:1. Conclusions: Among 1,162 patients who underwent elective ACDF at our institution, there were no patients who required an intraoperative or emergent blood transfusion. Furthermore, routine type and screen and crossmatch in patients undergoing elective ACDF at our insitution is associated with a high C/T ratio, suggestive of inefficient usage of blood products.
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Vitiligo is a depigmenting disorder characterized by the progressive loss of melanocytes. In cases of extensive vitiligo that is unresponsive to treatment and involves noticeable areas, such as the face and hands, total depigmentation is a clinical option. The choice to depigment is a difficult one for the patient given the irreversible nature of treatment and the psychosocial implications of skin color change. This issue can be particularly complex for black patients. Depigmentation has been practiced for decades and documented in the literature, but the practice in Fitzpatrick skin type VI is not well-documented. We present a case of depigmentation in a patient with Fitzpatrick skin type VI, as well as technical options for depigmentation, the clinical approach, patient preparation, and psychosocial issues involved with this treatment option.
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Fármacos Dermatológicos/uso terapéutico , Pigmentación de la Piel/efectos de los fármacos , Vitíligo/terapia , Población Negra , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The anti-Müllerian hormone (AMH) plays an essential role in sex determination in early embryonic development. Through a series of sequential steps that follows inheriting an XY chromosome, Sertoli cell differentiation upregulates the expression of AMH-suppressing Müllerian duct development and maintains the AMH at a high level until puberty. In females, the AMH is produced by granulosa cells of follicles beginning in the second half of fetal life and continues through adulthood, with a steady decline through the reproductive years and severe decline at menopause, until levels eventually become undetectable. The AMH is essential for the regulation of follicular maturation via the recruitment of primordial follicles throughout folliculogenesis. AMH serum concentration in women strongly correlates with ovarian reserve quantity and reflects ovulation potential. Because the AMH is expressed almost exclusively by growing follicles before FSH-dependent selection, it commonly serves as a marker for ovarian function in various clinical situations, including in the diagnosis and pathogenesis of polycystic ovarian syndrome, artificial reproductive technology, and predictions of menopause or premature ovarian failure.
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SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes are sentinel blood cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that ~10% of blood monocytes in COVID-19 patients are dying and infected with SARS-CoV-2. Monocyte infection, which depends on antiviral antibodies, activates NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD cleavage and relocalization. Signs of pyroptosis (IL-1 family cytokines, LDH) in the plasma correlate with development of severe disease. Moreover, expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes triggers inflammation that contributes to severe COVID-19 disease pathogenesis. ONE SENTENCE SUMMARY: Antibody-mediated SARS-CoV-2 infection of monocytes activates inflammation and cytokine release.
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SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in a minority of patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes and macrophages are sentinel immune cells in the blood and tissue, respectively, that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). We find that about 10% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on viral antibody opsonization and uptake of opsonized virus by the Fc receptor CD16. After uptake, SARS-CoV-2 begins to replicate in monocytes, as evidenced by detection of double-stranded RNA and subgenomic RNA and expression of a fluorescent reporter gene. However, infection is aborted, and infectious virus is not detected in infected monocyte supernatants or patient plasma. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of the NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial cells, from COVID-19 lung autopsy specimens showed evidence of inflammasome activation. These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to severe COVID-19 disease pathogenesis.
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BACKGROUND: Type 2 diabetes mellitus (T2DM) is a coronary heart disease (CHD) risk equivalent warranting aggressive management of dyslipidemia and tight glycemic control. Recent reports demonstrate a paradoxic decrease in high-density lipoprotein cholesterol (HDL-C) with thiazolidinedione (TZD) and fibrate combination therapy. OBJECTIVE: Evaluate change in HDL-C from start of combination therapy to 1 year and assess the proportion, characteristics, and regimens of patients who developed a ≥20% decrease in HDL-C from baseline. METHODS: Patients with T2DM treated concurrently with a combination of TZD and fibrate were identified through retrospective query from a Veterans Affairs medical center database. HDL-C was recorded for 1 year after patients started combination therapy. Logistic regression analysis was performed to determine any predictors of HDL-C change. RESULTS: A total of 322 patients were included in the analysis. There was no significant differences in mean ± standard deviation HDL-C from baseline to end point (36.8 ± 8.5 to 40.3 ± 11.8 mg/dL; P = 0.097). There was a subset of patients identified (13%; n = 43) on combination therapy who experienced a ≥20% reduction in HDL-C. Of these patients, a decrease in HDL-C was more likely to occur with fenofibrate-based regimens (odds ratio 3.08, 95% confidence interval 1.22 to 7.75; P = 0.018). There was a trend toward more of these patients in this subset to have the combination of rosiglitazone and fenofibrate in their profiles (odds ratio 2.82, 95% confidence interval 0.98 to 8.0; P = 0.064). CONCLUSION: Our study demonstrated that a subset of patients with T2DM experienced a paradoxic decrease in HDL-C when taking a fibrate and TZD combination.