Comparing the prevalence of multimorbidity using different operational definitions in primary care in Singapore based on a cross-sectional study using retrospective, large administrative data.

OBJECTIVES: Multimorbidity is a norm in primary care. A consensus on its operational definition remains lacking especially in the list of chronic conditions considered. This study aimed to compare six different operational definitions of multimorbidity previously reported in the literature for the context of primary care in Singapore. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective study using anonymised primary care data from a study population of 787 446 patients. We defined multimorbidity as having three or more chronic conditions in an individual. The prevalence of single conditions and multimorbidity with each operational definition was tabulated and standardised prevalence rates (SPRs) were obtained by adjusting for age, sex and ethnicity. We compared the operational definitions based on (1) number of chronic diseases, (2) presence of chronic diseases of high burden and (3) relevance in primary care in Singapore. IBM SPSS V.23 and Microsoft Office Excel 2019 were used for all statistical calculations and analyses. RESULTS: The SPRs of multimorbidity in primary care in Singapore varied from 5.7% to 17.2%. The lists by Fortin et al, Ge et al, Low et al and Quah et al included at least 12 chronic conditions, the recommended minimal number of conditions. Quah et al considered the highest proportion of chronic diseases (92.3%) of high burden in primary care in Singapore, with SPRs of at least 1.0%. Picco et al and Subramaniam et al considered the fewest number of conditions of high relevance in primary care in Singapore. CONCLUSIONS: Fortin et al's list of conditions is most suitable for describing multimorbidity in the Singapore primary care setting. Prediabetes and 'physical disability' should be added to Fortin et al's list to augment its comprehensiveness. We propose a similar study methodology be performed in other countries to identify the most suitable operational definition in their own context.

Nanoparticle Delivery of MnO2 and Antiangiogenic Therapy to Overcome Hypoxia-Driven Tumor Escape and Suppress Hepatocellular Carcinoma.

Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO2 and sorafenib into HCC. We found that MnO2 not only alleviates hypoxia by catalyzing the decomposition of H2O2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn2+ ions in the TME. Moreover, macrophages exposed to MnO2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8+ cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.

Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer.

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

Expression Profile of Cationic Amino Acid Transporters in Rats with Endotoxin-Induced Uveitis.

Purpose. The transcellular arginine transportation via cationic amino acid transporter (CAT) is the rate-limiting step in nitric oxide (NO) synthesis, which is crucial in intraocular inflammation. In this study, CAT isoforms and inducible nitric oxide synthase (iNOS) expression was investigated in endotoxin-induced uveitis (EIU). Methods. EIU was induced in Lewis rats by lipopolysaccharide (LPS) injection. In the treatment group, the rats were injected intraperitoneally with the proteasome inhibitor bortezomib before EIU induction. After 24 hours, leukocyte quantification, NO measurement of the aqueous humor, and histopathological examination were evaluated. The expression of CAT isoforms and iNOS was determined by reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence staining. Nuclear factor-kappa B (NF-κB) binding activity was evaluated by electrophoretic mobility shift assay. The mouse macrophage cell line RAW 264.7 was used to validate the in vivo findings. Results. LPS significantly stimulated iNOS, CAT-2A, and CAT-2B mRNA and protein expression but did not affect CAT-1 in EIU rats and RAW 264.7 cells. Bortezomib attenuated inflammation and inhibited iNOS, CAT-2A, and CAT-2B expression through NF-κB inhibition. Conclusions. CAT-2 and iNOS, but not CAT-1, are specifically involved in EIU. NF-κB is essential in the induction of CAT-2 and iNOS in EIU.

Photodynamic therapy with or without intravitreal bevacizumab for polypoidal choroidal vasculopathy: two years of follow-up.

PURPOSE: To compare the long-term results of the efficacy of photodynamic therapy (PDT) with or without intravitreal bevacizumab (IVB) injections for polypoidal choroidal vasculopathy. DESIGN: Retrospective, comparative, interventional case series. METHODS: We included 69 eyes of 69 patients with macula-involved polypoidal choroidal vasculopathy. All patients were followed up for more than 2 years. We compared the treatment outcomes between groups and investigated the factors influencing visual improvement at 24 months of follow-up. RESULTS: Thirty-six patients received PDT combined with IVB and 33 patients received PDT monotherapy. At 3 months, the mean logarithm of minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) improved from 0.73 to 0.53 in the combined therapy group (P < .001) and from 0.79 to 0.72 in the PDT monotherapy group (P = .02), with a significant difference in treatment efficacy between the 2 groups (P < .001). However, the improvements in BCVA were not statistically significant after 21 months in the combined therapy group and 15 months in the monotherapy group. The difference in treatment efficacy between the 2 groups was not significant after 6 months. Initial BCVA (P = .005), lesion size (P = .011), patient age (P = .018), and location of polyps (P = .006) significantly predicted the final visual outcome rather than treatment modality (P = .243). CONCLUSIONS: PDT combined with IVB for symptomatic PCV was temporarily superior to PDT monotherapy, and the treatment efficacy decreased with time. Initial BCVA, lesion size, and location were more significant than treatment modality as the factors influencing final visual improvement.

Association between high myopia and progression of visual field loss in primary open-angle glaucoma.

BACKGROUND/PURPOSE: Taiwan has a very high prevalence rate of myopia. We retrospectively studied the influence of myopia on the progression of visual field (VF) loss in primary open-angle glaucoma (POAG) patients. METHODS: We studied 515 POAG patients for a minimum follow-up period of 5 years. VF examination was performed with Humphrey perimeter, 30-2 SITA standard program, every 6 months. A point-wise numerical comparison was applied to judge the VF changes. Test points showing more than 1.0 dB of sensitivity loss in mean defect were identified. A location was considered to have progression if it was detected on two consecutive visits. Progression of VF loss was confirmed if three or more test points deteriorated. Multivariate logistic regression was used to evaluate the association between progression of VF loss and various risk factors. RESULTS: There were 262 cases. Progression of VF loss occurred in 57 eyes (21.8%) during the 5-year follow-up period. Logistic regression revealed that the deterioration was associated with older age, higher mean intraocular pressure, larger vertical cup-to-disc ratio, and greater myopic refraction status. The incidence of VF loss progression was 15.1% in the group of eyes with myopia less than -3 D, 10.5% in the group with -3 D to -6 D, 34.4% in the group with -6 D to -9 D, and 38.9% in the group with myopia greater than -9 D. CONCLUSION: POAG patients with myopia greater than -6 D had a greater progression of VF loss.

Use of therapeutic drug monitoring for multidrug-resistant tuberculosis patients.

STUDY OBJECTIVES: Therapeutic drug monitoring (TDM) is the process of obtaining the serum concentration of a medication and modifying the dose based on the results. Little is known about the application of TDM in the treatment of patients with multidrug-resistant (MDR) tuberculosis (TB) in clinical practice. This study characterized how TDM was applied in the management of MDR TB patients, and examined the clinical indications for ordering TDM, the process for obtaining drug concentrations, and the clinician response to the drug concentrations. DESIGN: In a retrospective study, we compared the clinical and demographic characteristics of MDR TB patients who received TDM with those who did not. The clinical application of TDM also was described in patients who received TDM. SETTING: A municipal TB control program. PATIENTS OR PARTICIPANTS: Patients in whom TB was diagnosed that was caused by an isolate resistant to at least isoniazid and rifampin, and who received treatment for TB in one of the health department chest clinics between July 1, 1993, and August 31, 1997, were studied. RESULTS: Forty-nine patients receiving TDM had a longer time to culture conversion and treatment duration, more pulmonary TB in combination with an extrapulmonary site, drug resistance, and visits to the health department clinics (p < 0.05) than the 60 patients without TDM. Of the 49 patients who had initial TDM, 73.5% of them had the reason for being tested specified. A total of 85.7% of initial TDM results were collected at the appropriate time of blood sampling. Clinician response to TDM results varied with the drug that was being tested. CONCLUSIONS: The use of TDM depended largely on the patient's clinical presentation. Site-specific guidelines on the use of TDM for managing TB patients may maximize the benefit of TDM.