The prevalence of multimorbidity in primary care: a comparison of two definitions of multimorbidity with two different lists of chronic conditions in Singapore

Background: The prevalence of multimorbidity varies widely due to the lack of consensus in defining multimorbidity. This study aimed to measure the prevalence of multimorbidity in a primary care setting using two definitions of multimorbidity with two different lists of chronic conditions. Methods: We conducted a cross-sectional study of 787,446 patients, aged 0 to 99 years, who consulted a family physician between July 2015 to June 2016. Multimorbidity was defined as ‘two or more’ (MM2+) or ‘three or more’ (MM3+) chronic conditions using the Fortin list and Chronic Disease Management Program (CDMP) list of chronic conditions. Crude and standardised prevalence rates were reported, and the corresponding age, sex or ethnic-stratified standardised prevalence rates were adjusted to the local population census. Results: The number of patients with multimorbidity increased with age. Age-sex-ethnicity standardised prevalence rates of multimorbidity using MM2+ and MM3+ for Fortin list (25.9, 17.2%) were higher than those for CDMP list (22.0%; 12.4%). Sex-stratified, age-ethnicity standardised prevalence rates for MM2+ and MM3+ were consistently higher in males compared to females for both lists. Chinese and Indians have the highest standardised prevalence rates among the four ethnicities using MM2+ and MM3+ respectively. Conclusions: MM3+ was better at identifying a smaller number of patients with multimorbidity requiring higher needs compared to MM2+. Using the Fortin list seemed more appropriate than the CDMP list because the chronic conditions in Fortin’s list were more commonly seen in primary care. A consistent definition of multimorbidity will help researchers and clinicians to understand the epidemiology of multimorbidity better

Differential Functional Roles of ALDH1A1 and ALDH1A3 in Mediating Metastatic Behavior and Therapy Resistance of Human Breast Cancer Cells

Previous studies indicate that breast cancer cells with high aldehyde dehydrogenase (ALDH) activity and CD44 expression (ALDHhiCD44+ ) contribute to metastasis and therapy resistance, and that ALDH1 correlates with poor outcome in breast cancer patients. The current study hypothesized that ALDH1 functionally contributes to breast cancer metastatic behavior and therapy resistance. Expression of ALDH1A1 or ALDH1A3 was knocked down in MDA-MB-468 and SUM159 human breast cancer cells using siRNA. Resulting impacts on ALDH activity (Aldefluor® assay); metastatic behavior and therapy response in vitro (proliferation/adhesion/migration/colony formation/chemotherapy and radiation) and extravasation/metastasis in vivo (chick choroiallantoic membrane assay) was assessed. Knockdown of ALDH1A3 but not ALDH1A1 in breast cancer cells decreased ALDH activity, and knockdown of ALDH1A1 reduced breast cancer cell metastatic behavior and therapy resistance relative to control (p \u3c 0.05). In contrast, knockdown of ALDH1A3 did not alter proliferation, extravasation, or therapy resistance, but increased adhesion/migration and decreased colony formation/metastasis relative to control (p \u3c 0.05). This is the first study to systematically examine the function of ALDH1 isozymes in individual breast cancer cell behaviors that contribute to metastasis. Our novel results indicate that ALDH1 mediates breast cancer metastatic behavior and therapy resistance, and that different enzyme isoforms within the ALDH1 family differentially impact these cell behaviors

Systematic review on the instruments used for measuring the association of the level of multimorbidity and clinically important outcomes

Objectives There are multiple instruments for measuring multimorbidity. The main objective of this systematic review was to provide a list of instruments that are suitable for use in studies aiming to measure the association of a specific outcome with different levels of multimorbidity as the main independent variable in community-dwelling individuals. The secondary objective was to provide details of the requirements, strengths and limitations of these instruments, and the chosen outcomes. Methods We conducted the review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018105297). We searched MEDLINE, Embase and CINAHL electronic databases published in English and manually searched the Journal of Comorbidity between 1 January 2010 and 23 October 2020 inclusive. Studies also had to select adult patients from primary care or general population and had at least one specified outcome variable. Two authors screened the titles, abstracts and full texts independently. Disagreements were resolved with a third author. The modified Newcastle-Ottawa Scale was used for quality assessment. Results Ninety-six studies were identified, with 69 of them rated to have a low risk of bias. In total, 33 unique instruments were described. Disease Count and weighted indices like Charlson Comorbidity Index were commonly used. Other approaches included pharmaceutical-based instruments. Disease Count was the common instrument used for measuring all three essential core outcomes of multimorbidity research: Mortality, mental health and quality of life. There was a rise in the development of novel weighted indices by using prognostic models. The data obtained for measuring multimorbidity were from sources including medical records, patient self-reports and large administrative databases. Conclusions We listed the details of 33 instruments for measuring the level of multimorbidity as a resource for investigators interested in the measurement of multimorbidity for its association with or prediction of a specific outcome. © 2021 Author(s). Published by BMJ

Preoperative serum carcinoembryonic antigen, albumin and age are supplementary to UICC staging systems in predicting survival for colorectal cancer patients undergoing surgical treatment

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to determine influence of prognostic factors in addition to UICC staging systems, on cancer-specific and overall survival rates for patients with colorectal cancer (CRC) undergoing surgical treatment.</p> <p>Methods</p> <p>Between January 1996 and December 2006, a total of 1367 CRC patients who underwent surgical treatment in Kaohsiung Medical University Hospital were analyzed. We retrospectively investigated clinicopathologic features of these patients. All patients were followed up intensively, and their outcomes were investigated completely.</p> <p>Results</p> <p>Of 1367 CRC patients, there were seven hundred and fifty-seven males (55.4%) and 610 (44.6%) females. The median follow-up period was 60 months (range, 3–132 months). A multivariate analysis identified that low serum albumin level (<it>P </it>= 0.011), advanced UICC stage (<it>P </it>< 0.001), and high carcinoembryonic antigen (CEA) level (<it>P </it>< 0.001) were independent prognostic factors of cancer-specific survival. Meanwhile, a multivariate analysis showed age over 65 years (<it>P </it>< 0.001), advanced UICC stage (<it>P </it>< 0.001), and high CEA level (<it>P </it>< 0.001) were independent prognostic factors of overall survival. Furthermore, combination of UICC stage, serum CEA and albumin levels as predictors of cancer-specific survival showed that the poorer the prognostic factors involved, the poorer the cancer-specific survival rate. Likewise, combination of UICC stage, age and serum CEA level as predictors of overall survival showed that the poorer the prognostic factors involved, the poorer the overall survival rate. Of these prognostic factors, preoperative serum CEA level was the only significant prognostic factor for patients with stage II and III CRCs in both cancer-specific and overall survival categories.</p> <p>Conclusion</p> <p>Preoperative serum albumin level, CEA level and age could prominently affect postoperative outcome of CRC patients undergoing surgical treatment. In addition to conventional UICC staging system, it might be imperative to take these additional characteristics of factors into account in CRC patients prior to surgical treatment.</p

Functionalized Mesoporous SBA-15 with CeF3: Eu3+ Nanoparticle by Three Different Methods: Synthesis, Characterization, and Photoluminescence

Luminescence functionalization of the ordered mesoporous SBA-15 silica is realized by depositing a CeF3: Eu3+ phosphor layer on its surface (denoted as CeF3: Eu3+/SBA-15/IS, CeF3: Eu3+/SBA-15/SI and CeF3: Eu3+/SBA-15/SS) using three different methods, which are reaction in situ (I-S), solution impregnation (S-I) and solid phase grinding synthesis (S-S), respectively. The structure, morphology, porosity, and optical properties of the materials are well characterized by X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, N2 adsorption, and photoluminescence spectra. These materials all have high surface area, uniformity in the mesostructure and crystallinity. As expected, the pore volume, surface area, and pore size of SBA-15 decrease in sequence after deposition of the CeF3: Eu3+ nanophosphors. Furthermore, the efficient energy transfer in mesoporous material mainly occurs between the Ce3+ and the central Eu3+ ion. They show the characteristic emission of Ce3+ 5d → 4f (200–320 nm) and Eu3+5D0 → 7FJ(J = 1–4, with 5D0 → 7F1 orange emission at 588 nm as the strongest one) transitions, respectively. In addition, for comparison, the mesoporous material CeF3: Eu3+/SBA-15/SS exhibits the characteristic emission of Eu3+ ion under UV irradiation with higher luminescence intensity than the other materials

Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20( S )-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents

Twelve novel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie