ABSTRACT
BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.
Subject(s)
Anthracyclines , Neoplasms , Prediabetic State , Humans , Prediabetic State/epidemiology , Prediabetic State/chemically induced , Prediabetic State/complications , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Male , Female , Middle Aged , Neoplasms/drug therapy , Neoplasms/epidemiology , Aged , Hong Kong/epidemiology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/chemically induced , Adult , Risk Factors , Diabetes Mellitus/epidemiology , IncidenceABSTRACT
AIM: To investigate the interplay of incident chronic kidney disease (CKD) and/or heart failure (HF) and their associations with prognosis in a large, population-based cohort with type 2 diabetes (T2DM). METHODS: Patients aged ≥18 years with new-onset T2DM, without renal disease or HF at baseline, were identified from the territory-wide Clinical Data Analysis Reporting System between 2000 and 2015. Patients were followed up until December 31, 2020 for incident CKD and/or HF and all-cause mortality. RESULTS: Among 102 488 patients (median age 66 years, 45.7% women, median follow-up 7.5 years), new-onset CKD occurred in 14 798 patients (14.4%), in whom 21.7% had HF. In contrast, among 9258 patients (9.0%) with new-onset HF, 34.6% had CKD. The median time from baseline to incident CKD or HF (4.4 vs. 4.1 years) did not differ. However, the median (interquartile range) time until incident HF after CKD diagnosis was 1.7 (0.5-3.6) years and was 1.2 (0.2-3.4) years for incident CKD after HF diagnosis (P < 0.001). The crude incidence of CKD was higher than that of HF: 17.6 (95% confidence interval [CI] 17.3-17.9) vs. 10.6 (95% CI 10.4-10.9)/1000 person-years, respectively, but incident HF was associated with a higher adjusted-mortality than incident CKD. The presence of either condition (vs. CKD/HF-free status) was associated with a three-fold hazard of death, whereas concomitant HF and CKD conferred a six to seven-fold adjusted hazard of mortality. CONCLUSION: Cardiorenal complications are common and are associated with high mortality risk among patients with new-onset T2DM. Close surveillance of these dual complications is crucial to reduce the burden of disease.
Subject(s)
Diabetes Mellitus, Type 2 , Heart Failure , Kidney Failure, Chronic , Renal Insufficiency, Chronic , Humans , Female , Adolescent , Adult , Aged , Male , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Heart Failure/complications , Heart Failure/epidemiology , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/epidemiology , Kidney Failure, Chronic/complications , Prognosis , Risk FactorsABSTRACT
BACKGROUND: Evidence suggests that chronic obstructive pulmonary disease (COPD) is associated with a higher risk of lung carcinoma. Using a territory-wide clinical electronic medical records system, we investigated the association between low-dose aspirin use (≤160 mg) among patients with COPD and incidence of lung carcinoma and the corresponding risk of bleeding. METHODS AND FINDINGS: This is a retrospective cohort study conducted utilizing Clinical Data Analysis Reporting System (CDARS), a territory-wide database developed by the Hong Kong Hospital Authority. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates between aspirin nonusers (35,049 patients) with new aspirin users (7,679 patients) among all eligible COPD patients from 2005 to 2018 attending any public hospitals. The median age of the cohort was 75.7 years (SD = 11.5), and 80.3% were male. Competing risk regression with Cox proportional hazards model were performed to estimate the subdistribution hazard ratio (SHR) of lung carcinoma with low-dose aspirin and the associated bleeding events. Of all eligible patients, 1,779 (4.2%, 1,526 and 253 among nonusers and users) were diagnosed with lung carcinoma over a median follow-up period of 2.6 years (interquartile range [IQR]: 1.4 to 4.8). Aspirin use was associated with a 25% lower risk of lung carcinoma (SHR = 0.75, 95% confidence interval [CI] 0.65 to 0.87, p = <0.001) and 26% decrease in lung carcinoma-related mortality (SHR = 0.74, 95% CI 0.64 to 0.86, p = <0.001). Subgroup analysis revealed that aspirin was beneficial for patients aged above or below 75 years, but was also beneficial among populations who were male, nondiabetic, and nonhypertensive. Aspirin use was not associated with an increased risk of upper gastrointestinal bleeding (UGIB) (SHR = 1.19, 95% CI 0.94 to 1.53, p = 0.16), but was associated with an increased risk of hemoptysis (SHR = 1.96, 95% CI 1.73 to 2.23, p < 0.001). The main limitations of the study were (i) that one group of patients may be more likely to seek additional medical attention, although this was partially mitigated by the use of propensity score analysis; and (ii) the observational nature of the study renders it unable to establish causality between aspirin use and lung carcinoma incidence. CONCLUSIONS: In this study, we observed that low-dose aspirin use was associated with a lower risk of lung carcinoma and lung carcinoma-related mortality among COPD patients. While aspirin was not associated with an increased risk of UGIB, the risk of hemoptysis was elevated.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aspirin/adverse effects , Carcinoma/epidemiology , Lung Neoplasms/epidemiology , Pulmonary Disease, Chronic Obstructive/epidemiology , Aged , Aged, 80 and over , Animals , Aspirin/administration & dosage , Carcinoma/complications , Cohort Studies , Dose-Response Relationship, Drug , Female , Hong Kong/epidemiology , Humans , Incidence , Lung Neoplasms/complications , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/complications , Retrospective StudiesABSTRACT
AIMS: Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse. METHODS AND RESULTS: Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 ± 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6-6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80-0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to <2 years), the adjusted SHR was 0.99 (95% CI, 0.87-1.13) for 2 to <4 years of use, 0.82 (95% CI, 0.70-0.97) for 4 to <6 years of use, and 0.78 (95% CI, 0.65-0.93) for ≥6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, -1.4 percentage points [95% CI, -1.6% to -1.2%]; adjusted SHR = 0.74; 95% CI, 0.67-0.81). CONCLUSION: Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent.
Subject(s)
Heart Failure , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Neoplasms , Aged , Aged, 80 and over , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Middle Aged , Neoplasms/epidemiology , Proportional Hazards Models , Registries , RiskABSTRACT
BACKGROUND: Cardiac arrhythmias are associated with poorer outcomes in patients with heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD). Previous studies have shown inconsistent conclusions regarding the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the risk of developing arrhythmias. This study aims to investigate the association of SGLT2i treatment with arrhythmia outcomes in clinical trials of patients with HF, DM, or CKD. METHODS: MEDLINE, EMBASE, and ClinicalTrials.gov were searched from inception up to 27 August 2020. Randomized controlled trials that randomized patients with DM, CKD, or HF to SGLT2i or placebo were included. The outcomes of interest include atrial fibrillation (AF), embolic stroke, atrial flutter (AFL), AF/AFL, ventricular tachycardia (VT), and cardiac arrest. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model. RESULTS: Out of 4,532 citations, 22 trials with altogether 52,115 patients were included (mean age 63.2 years; 33,747 [64.8%] of participants were men). SGLT2i were associated with a lower risk of AF (RR 0.82, 95% CI 0.70-0.96), embolic stroke (RR 0.32, 95% CI 0.12-0.85), AF/AFL (RR 0.82, 95% CI 0.71-0.95), and VT (RR 0.73, 95% CI 0.53-0.99), while the risk reductions in AFL (RR 0.83, 95% CI 0.58-1.17) and cardiac arrest (RR 0.83, 95% CI 0.61-1.14) did not reach statistical significance. The associations appeared to be consistent across different baseline conditions (DM vs CKD vs HF; atherosclerotic cardiovascular disease [ASCVD] vs no ASCVD) and the SGLT2i used. CONCLUSIONS: SGLT2i reduced the risk of cardiac arrhythmias. Our study provides further evidence for recommending the use of SGLT2i in patients with DM, CKD, and HF. Further research is needed to fully elucidate the mechanism by which SGLT2i protect against arrhythmias.
Subject(s)
Arrhythmias, Cardiac/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Heart Failure/drug therapy , Renal Insufficiency, Chronic/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Aged , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/epidemiology , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Female , Heart Failure/diagnosis , Heart Failure/epidemiology , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Risk Assessment , Risk Factors , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Treatment OutcomeABSTRACT
Helminthic infections modulate host immunity and may protect their hosts from developing immunological diseases like inflammatory bowel disease. Induction of regulatory T cells (Tregs) may be an important part of this protective process. Heligmosomoides polygyrus bakeri infection also promotes the production of the regulatory cytokines TGF-ß and IL-10 in the gut. In the intestines, TGF-ß helps induce regulatory T cells. This study used Foxp3/IL-10 double reporter mice to investigate the effect of TGF-ß on the differentiation of colon and mesenteric lymph node-derived murine Foxp3- IL-10- CD4+ T cells into their regulatory phenotypes. Foxp3- IL-10- CD4+ T cells from H. polygyrus bakeri-infected mice, as opposed to T cells from uninfected animals, cultured in vitro with TGF-ß and anti-CD3/CD28 mAb differentiated into Foxp3+ and/or IL-10+ T cells. The IL-10-producing T cells nearly all displayed CD25. Smad7 is a natural inhibitor of TGF-ß signaling. In contrast to gut T cells from uninfected mice, Foxp3- IL10- CD4+ T cells from H. polygyrus bakeri-infected mice displayed reduced Smad7 expression and responded to TGF-ß with Smad2/3 phosphorylation. The TGF-ß-induced Tregs that express IL-10 blocked colitis when transferred into the Rag/CD25- CD4+ T cell transfer model of inflammatory bowel disease. TGF-ß had a greatly diminished capacity to induce Tregs in H. polygyrus bakeri-infected transgenic mice with constitutively high T cell-specific Smad7 expression. Thus, infection with H. polygyrus bakeri causes down-modulation in Smad7 expression in intestinal CD4+ T cells, which allows the TGF-ß produced in response to the infection to induce the Tregs that prevent colitis.
Subject(s)
Colitis/immunology , Interleukin-10/immunology , Nematospiroides dubius/immunology , Smad7 Protein/immunology , Strongylida Infections/immunology , T-Lymphocytes, Regulatory/immunology , Transforming Growth Factor beta/immunology , Animals , Colitis/pathology , Colitis/prevention & control , Interleukin-10/genetics , Mice , Mice, Transgenic , Smad7 Protein/genetics , Strongylida Infections/genetics , Strongylida Infections/pathology , T-Lymphocytes, Regulatory/pathology , Transforming Growth Factor beta/geneticsABSTRACT
Adipocyte fatty acid-binding protein (A-FABP), which is also known as ap2 or FABP4, is a fatty acid chaperone that has been further defined as a fat-derived hormone. It regulates lipid homeostasis and is a key mediator of inflammation. Circulating levels of A-FABP are closely associated with metabolic syndrome and cardiometabolic diseases with imminent diagnostic and prognostic significance. Numerous animal studies have elucidated the potential underlying mechanisms involving A-FABP in these diseases. Recent studies demonstrated its physiological role in the regulation of adaptive thermogenesis and its pathological roles in ischemic stroke and liver fibrosis. Due to its implication in various diseases, A-FABP has become a promising target for the development of small molecule inhibitors and neutralizing antibodies for disease treatment. This review summarizes the clinical and animal findings of A-FABP in the pathogenesis of cardio-metabolic diseases in recent years. The underlying mechanism and its therapeutic implications are also highlighted.
Subject(s)
Fatty Acid-Binding Proteins/metabolism , Metabolic Diseases/pathology , Molecular Targeted Therapy , Animals , Fatty Acid-Binding Proteins/genetics , Humans , Metabolic Diseases/genetics , Metabolic Diseases/metabolismABSTRACT
Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri-infected mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk(-/-) mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype. DCs sense gut flora and damaged epithelium via expression of C-type lectin receptors, many of which signal through the Syk signaling pathway. It was observed that gut DCs express mRNA encoding for C-type lectin (CLEC) 7A, CLEC9A, CLEC12A, and CLEC4N. H. polygyrus bakeri infection downmodulated CLEC mRNA expression in these cells. Focusing on CLEC7A, which encodes for the dectin-1 receptor, flow analysis showed that H. polygyrus bakeri decreases dectin-1 expression on the intestinal DC subsets that drive Th1/Th17 development. DCs become unresponsive to the dectin-1 agonist curdlan and fail to phosphorylate Syk after agonist stimulation. Soluble worm products can block CLEC7A and Syk mRNA expression in gut DCs from uninfected mice after a brief in vitro exposure. Thus, downmodulation of Syk expression and phosphorylation in intestinal DCs could be important mechanisms through which helminths induce regulatory DCs that limit colitis.
Subject(s)
Colitis/prevention & control , Dendritic Cells/immunology , Dendritic Cells/metabolism , Intestines/cytology , Signal Transduction , Syk Kinase/metabolism , Animals , Colitis/immunology , Colitis/parasitology , Disease Models, Animal , Intestines/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Nematospiroides dubius/immunology , RNA, Messenger/genetics , RNA, Messenger/immunology , Strongylida Infections/immunology , Strongylida Infections/parasitology , Syk Kinase/deficiency , Syk Kinase/geneticsSubject(s)
COVID-19/epidemiology , Risk Assessment , Adult , Aged , Aged, 80 and over , Chronic Disease/epidemiology , Comorbidity , Female , Humans , Male , Middle Aged , Nutrition Surveys , Pandemics , Risk Factors , SARS-CoV-2 , Severity of Illness IndexABSTRACT
Helminthic infections protect mice from colitis in murine models of inflammatory bowel disease and also may protect people. Helminths like Heligmosomoides polygyrus bakeri can induce regulatory T cells (Treg). Experiments explored whether H. polygyrus bakeri infection could protect mice from colitis through activation of colonic Treg and examined mechanisms of action. We showed that H. polygyrus bakeri infection increased the number of T cells expressing Foxp3 in the colon. More importantly, Foxp3(+)/IL-10(-) and Foxp3(+)/IL-10(+) T cell subsets isolated from the colon of H. polygyrus bakeri-infected mice prevented colitis when adoptively transferred into a murine model of inflammatory bowel disease, whereas Treg from uninfected mice could not provide protection. Only the transferred colonic Foxp3(+)/IL-10(-) T cells from H. polygyrus bakeri-infected mice readily accumulated in the colon and mesenteric lymph nodes of recipient mice, and they reconstituted the Foxp3(+)/IL-10(-) and Foxp3(+)/IL-10(+) T cell subsets. However, transferred Foxp3(+)/IL-10(+) T cells disappeared. IL-10 expression by Foxp3(+) T cells was necessary for colitis prevention. Thus, H. polygyrus bakeri infection activates colonic Foxp3(+) T cells, making them highly regulatory. The Foxp3(+) T cells that fail to express IL-10 may be critical for populating the colon with the Foxp3(+)/IL-10(+) T cells, which are required to control colitis.
Subject(s)
Colitis/prevention & control , Colon/immunology , Intestinal Diseases, Parasitic/immunology , Nematospiroides dubius/immunology , Strongylida Infections/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Therapy with Helminths , Animals , Colitis/immunology , Colitis/parasitology , Colon/parasitology , Cytokines/biosynthesis , Cytokines/metabolism , DNA-Binding Proteins/deficiency , Disease Models, Animal , Forkhead Transcription Factors/analysis , Forkhead Transcription Factors/deficiency , Genes, Reporter , Graft Survival , Helminthiasis, Animal/immunology , Immunotherapy, Adoptive , Inflammatory Bowel Diseases/therapy , Interleukin-10/analysis , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Lymph Nodes/immunology , Lymph Nodes/pathology , Mesentery , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Specific Pathogen-Free Organisms , Spleen/immunology , Spleen/pathology , T-Lymphocyte Subsets/chemistry , T-Lymphocyte Subsets/transplantation , T-Lymphocytes, Regulatory/chemistry , T-Lymphocytes, Regulatory/transplantationSubject(s)
Chiroptera , Coronavirus , Pneumonia , Animals , Disease Outbreaks , Humans , ProbabilityABSTRACT
Immunological diseases such as inflammatory bowel disease (IBD) are infrequent in less developed countries, possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri prevents colitis. It was determined whether H. polygyrus bakeri mediated IBD protection by altering dendritic cell (DC) function. We used a Rag IBD model where animals were reconstituted with IL10â»/â» T cells, making them susceptible to IBD and with OVA Ag-responsive OT2 T cells, allowing study of a gut antigenic response. Intestinal DC from H. polygyrus bakeri-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFN-γ/IL-17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from H. polygyrus bakeri-infected mice into Rag mice reconstituted with IL10â»/â» T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered Ag nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be regulatory T cell independent. Thus, H. polygyrus bakeri modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which H. polygyrus bakeri suppresses colitis. IFN-γ and IL-17 are colitogenic. The capacity of these DC to block a gut Ag-specific IFN-γ/IL-17 T cell response also is significant.
Subject(s)
Colitis/immunology , Dendritic Cells/immunology , Immune Tolerance , Inflammatory Bowel Diseases/immunology , Strongylida Infections/immunology , T-Lymphocyte Subsets/immunology , Adoptive Transfer , Animals , Cells, Cultured , Colitis/parasitology , Colitis/prevention & control , Dendritic Cells/parasitology , Dendritic Cells/pathology , Disease Models, Animal , Enterocolitis/immunology , Enterocolitis/parasitology , Enterocolitis/prevention & control , Epitopes, T-Lymphocyte/immunology , Inflammatory Bowel Diseases/parasitology , Inflammatory Bowel Diseases/prevention & control , Interleukin-10/administration & dosage , Interleukin-10/deficiency , Interleukin-10/genetics , Intestinal Mucosa/immunology , Intestinal Mucosa/parasitology , Intestinal Mucosa/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Nematospiroides dubius/immunology , Strongylida Infections/pathology , Strongylida Infections/prevention & control , T-Lymphocyte Subsets/parasitology , T-Lymphocyte Subsets/pathologyABSTRACT
Background: Published data on the epidemiology of interstitial lung disease (ILD) in Asia is scarce. Understanding the epidemiology is important for authorities in the health management planning. This study aimed to estimate the prevalence, incidence, and survival of ILD in Hong Kong from 2005 to 2020 and evaluate the change of trend over time. Methods: In this retrospective cohort study, we identified ILD patients between 2005 and 2020 using a territory-wide electronic health record database. Prevalence, incidence rates, and age- and sex-standardised incidence rates with United Nations population in 2020 as a reference were estimated. Trends in prevalence and incidence were analysed using joinpoint regression and the average annual percent change (AAPC) was estimated. Median survival, and risk factors of mortality were evaluated using Cox proportional hazard regression. Findings: We identified 5924 patients and included 5884 of them for analysis. The prevalence of ILD increased from 24.7 to 33.6 per 100,000 population from 2005 to 2020 with an AAPC of 1.94 (95% confidence interval, CI: 1.69-2.34). The standardized incidence rate decreased from 5.36 to 2.57 per 100,000 person from 2005 to 2020 (AAPC -3.56, 95% CI, -4.95 to -1.78). The median survival of ILD was 2.50 (95% CI, 2.32-2.69) years. Male, older age, higher Charlson comorbidity index, and IIP subtype were associated with increased mortality with statistical significance. Interpretation: This study provided the first epidemiological evaluation of ILD in Hong Kong. Further studies on ILD in multiple Asian cities and countries are warranted. Funding: None.
ABSTRACT
Substance P (SP) is a proinflammatory mediator implicated in inflammatory bowel disease (IBD) and other inflammatory states. SP acts by stimulating the neurokinin-1 receptor (NK-1R) on T lymphocytes and other cell types, and regulates these cells in a complex interplay with multiple cytokines. The mechanisms of interaction among these inflammatory mediators are not yet fully understood. Here, we demonstrate that function of the NK-1R, a member of the G protein-coupled receptor (GPCR) superfamily, is modulated by TGF-beta. The latter acts not on a GPCR but via serine-threonine kinase-class receptors. By flow confocal image analysis, we demonstrate that TGF-beta delays SP-induced NK-1R internalization on mucosal T cells isolated from a mouse model of IBD and on granuloma T cells in murine schistosomiasis. Furthermore, luciferase reporter-gene assays revealed that NK-1R stimulation activates the nuclear factor of activated T cell- and activator protein-1-dependent signaling pathways, which are known triggers of effector T-cell cytokine production. TGF-beta markedly increases SP-induced activation of these signaling cascades, suggesting that delayed NK-1R internalization results in enhanced signaling. Providing a link to amplified immune function, SP and TGF-beta, when applied in combination, trigger a strong release of the proinflammatory cytokines IFN-gamma and IL17 from intestinal inflammatory T cells, whereas either agonist alone shows no effect. These observations establish precedent that members of two distinct receptor superfamilies can interact via a previously unrecognized mechanism, and reveal a paradigm of GPCR transregulation that is relevant to IBD and possibly other disease processes.
Subject(s)
Endocytosis , Receptors, Neurokinin-1/immunology , T-Lymphocytes/immunology , Transforming Growth Factor beta/physiology , Animals , Cell Line , Flow Cytometry , Humans , Inflammatory Bowel Diseases/immunology , Interleukin-10/genetics , Interleukin-10/physiology , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Receptors, Neurokinin-1/metabolism , Signal Transduction , Substance PABSTRACT
Hydrochlorothiazide is the most common thiazide diuretic used for hypertension in the US. Yet, hypokalaemia is a well-recognised adverse effect. To evaluate the prevalence and factors associated with hypokalaemia (serum potassium < 3.5 mmol/L) among hydrochlorothiazide users, we included US adults aged ≥20 years in the 1999-2018 National Health and Nutrition Examination Survey. Participants were categorised according to the use of hydrochlorothiazide and other antihypertensive agents. Factors associated with hypokalaemia, including demographics and prescription patterns (monotherapy vs single-pill fixed-dose combination vs polytherapy) were studied using multivariable logistic regression. Hypokalaemia was present in 12.6% of the hydrochlorothiazide users, equivalent to ~2.0 million US adults. Women (adjusted OR, 2.22; 95% CI, 1.74-2.83), non-Hispanic blacks (adjusted OR, 1.65; 95% CI, 1.31-2.08), underweight (adjusted OR, 4.33; 95% CI, 1.34-13.95), and participants taking hydrochlorothiazide for five years or more (adjusted OR, 1.47; 95% CI, 1.06-2.04) had a higher risk of hypokalaemia. Compared to monotherapy, fixed-dose combination therapy (adjusted OR, 0.32; 95% CI, 0.21-0.48) was associated with the lowest risk. Among those taking potassium supplements, hypokalaemia was found in 27.2% of participants on monotherapy and 17.9% on polytherapy. The prevalence of hypokalaemia among hydrochlorothiazide users was considerable, even among participants who also took potassium supplements. Women, ethnic minorities, underweight, monotherapy, and participants with long-term therapy are more likely to have hypokalaemia. Regular monitoring of potassium and combination with potassium-sparing drugs are needed.
Subject(s)
Hypertension , Hypokalemia , Adult , Female , Humans , Hydrochlorothiazide/adverse effects , Antihypertensive Agents/adverse effects , Hypokalemia/chemically induced , Hypokalemia/diagnosis , Hypokalemia/epidemiology , Nutrition Surveys , Thinness/chemically induced , Thinness/drug therapy , Hypertension/diagnosis , Hypertension/drug therapy , Hypertension/epidemiology , Potassium/therapeutic use , Drug Therapy, CombinationABSTRACT
BACKGROUND: Direct oral anticoagulants (DOACs) have been increasingly utilised over warfarin. However, little is known about the relative consumption trends and costs of each DOAC at the global level. METHODS: An ecological study using pharmaceutical sales data from IQVIA-MIDAS database was used to estimate consumption and cost of individual DOACs in 65 countries from 2008 to 2019. Consumption was estimated from the volume of DOACs sold, expressed as defined-daily-dose/1000-inhabitants/day (DDDTID). Compound and absolute annual growth rates were reported to quantify consumption changes over time. Costs were estimated as manufacturer price per day-of-therapy. RESULTS: Global consumption of dabigatran, rivaroxaban, apixaban and edoxaban were 0.31, 1.05, 1.08 and 0.78 DDDTID, respectively, in Q2-2019, compared to 0.23, 0.54, 0.21 and 0.03 in Q2-2015, with highest consumption in Western Europe, Northern Europe and Oceania (18.2, 14.07, 13.14 DDDTID). In most countries (46/65, 70%), rivaroxaban contributed to most DOAC consumption (35%-100%), whereas dabigatran accounted for less than one-third. Edoxaban accounted for < 20% of the total in Northern America and Europe but contributed significant proportions in Japan (28.58%) and South Korea (31.37%). Longer median time-to-adoption from FDA approval for apixaban and edoxaban was observed. Costs of all DOACs were ~2-4 times higher in the USA, Puerto Rico and Thailand than in other countries. CONCLUSIONS: Regional differences exist in consumption pattern and trends of individual DOACs over the past decade. Consumption of rivaroxaban and apixaban overtook dabigatran in most countries, whereas use of edoxaban remains limited except in East Asian countries. The USA pays higher prices for DOACs than other countries.
Subject(s)
Atrial Fibrillation , Stroke , Humans , Rivaroxaban/therapeutic use , Dabigatran/therapeutic use , Anticoagulants/therapeutic use , Stroke/drug therapy , Atrial Fibrillation/drug therapy , Pyridones/therapeutic use , Administration, OralABSTRACT
Objectives: To enhance the public awareness and facilitate diagnosis of osteoporosis, we aim to develop a new Chinese Osteoporosis Screening Algorithm (COSA) to identify people at high risk of osteoporosis. Methods: A total of 4747 postmenopausal women and men aged ≥ 50 from the Hong Kong Osteoporosis Study were randomly split into a development (N = 2373) and an internal validation cohort (N = 2374). An external validation cohort comprising 1876 community-dwelling subjects was used to evaluate the positive predictive value (PPV). Results: Among 11 predictors included, age, sex, weight, and history of fracture were significantly associated with osteoporosis after correction for multiple testing. Age- and sex-stratified models were developed due to the presence of significant sex and age interactions. The area under the curve of the COSA in the internal validation cohort was 0.761 (95% CI, 0.711-0.811), 0.822 (95% CI, 0.792-0.851), and 0.946 (95% CI, 0.908-0.984) for women aged < 65, women aged ≥ 65, and men, respectively. The COSA demonstrated improved reclassification performance when compared to Osteoporosis Self-Assessment Tool for Asians. In the external validation cohort, the PPV of COSA was 40.6%, 59.4%, and 19.4% for women aged < 65, women aged ≥ 65, and men, respectively. In addition, COSA > 0 was associated with an increased 10-year risk of hip fracture in women ≥ 65 (OR, 4.65; 95% CI, 2.24-9.65) and men (OR, 11.51; 95% CI, 4.16-31.81). Conclusions: We have developed and validated a new osteoporosis screening algorithm, COSA, specific for Hong Kong Chinese.
ABSTRACT
OBJECTIVE: To investigate for potential protective effects of statin use among patients with infective endocarditis (IE) with consideration for underlying diseases and bacterial culture - variables which have prognostic implications and show considerable geographic variation yet are unappreciated in previous pharmacoepidemiological studies. PATIENTS AND METHODS: Patients diagnosed with IE between January 1, 1996, and December 31, 2019, were identified. We estimated the effect on mortality of pre-admission statin use (≥90 cumulative days of use before index date) and in-hospital use (use beginning within 2 days of admission), compared with nonusers and discontinued users, respectively, through propensity score analytics. RESULTS: Of 6700 IE patients (mean age, 58.0 years; 63.3% male [n=4251]), 776 patients had pre-admission statin use, with 626 continuing statin use following admission (in-hospital users). Pre-admission statin users had a 31% lower risk of 1-year mortality (HR, 0.69; 95% CI, 0.58 to 0.82) compared with nonusers. In-hospital users had a 48% lower risk of 1-year mortality (HR, 0.52; 95% CI, 0.34 to 0.78) compared with discontinued users. Subgroup analyses showed significant protective effects of statin use for patients with varying causative agents, underlying diseases, and with or without prosthetic valves. Results were consistent across different statins, and were dose-dependent. CONCLUSION: In patients with IE, pre-admission and in-hospital use of statin, when compared with statin nonusers and discontinued users, respectively, were associated with a lower risk of 1-year mortality.