Discovery of a Series of Orally Bioavailable Androgen Receptor Degraders for the Treatment of Prostate Cancer.

Androgen receptor (AR) signaling plays a key role in the progression of prostate cancer. This study describes the discovery and optimization of a novel series of AR PROTAC degraders that recruit the Cereblon (CRBN) E3 ligase. Having identified a series of AR ligands based on 4-(4-phenyl-1-piperidyl)-2-(trifluoromethyl)benzonitrile, our PROTAC optimization strategy focused on linker connectivity and CRBN ligand SAR to deliver potent degradation of AR in LNCaP cells. This work culminated in compounds 11 and 16 which demonstrated good rodent oral bioavailability. Subsequent SAR around the AR binding region brought in an additional desirable feature, degradation of the important treatment resistance mutation L702H. Compound 22 (AZ'3137) possessed an attractive profile showing degradation of AR and L702H mutant AR with good oral bioavailability across species. The compound also inhibited AR signaling in vitro and tumor growth in vivo in a mouse prostate cancer xenograft model.

Adherence to Healthy and Unhealthy Plant-Based Diets and the Risk of Gout.

Importance: Plant-based diets are increasing in popularity due, in part, to their health benefits for selected cardiometabolic diseases as well as favorable environmental impact. Little is known about how such a diet is related to gout risk. Objective: To examine associations between adherence to a plant-based diet (including healthy and unhealthy versions of this diet), as well as its 18 individual food groups, and incident gout. Design, Setting, and Participants: This prospective cohort study used data from population-based cohorts of US men and women enrolled in the Health Professionals Follow-Up Study (1986-2012) and Nurses' Health Study (1984-2010). Participants were men and women free of gout at baseline. Statistical analyses were performed over March 2020 to August 2023. Exposures: An overall plant-based diet index (PDI), as well as healthy (hPDI) and unhealthy (uPDI) versions of this index that emphasize healthy and less healthy plant-based foods, respectively. These diet indices were comprised of 18 food groups, assessed using a validated semiquantitative food frequency questionnaire. Main Outcomes and Measures: Incident cases of gout that were confirmed with a supplementary questionnaire to meet the preliminary American College of Rheumatology survey criteria for gout. Cox proportional hazards regression models were used to evaluate multivariable-adjusted associations of all 3 PDIs with incident gout using quintiles (Q) of adherence. Results: Among a total of 122 679 participants (mean [SD] age, 53.8 [9.8] years among 43 703 men; mean [SD] age, 50.9 [7.2] years among 78 976 women) over 2 704 899 person-years of follow-up, 2709 participants experienced incident gout. The overall PDI was not significantly associated with gout in either cohort (Q5 vs Q1 pooled hazard ratio [HR], 1.02 [95% CI, 0.89-1.17]; P for trend = .63). In the pooled analysis, hPDI was significantly inversely associated with risk of gout (Q5 vs Q1 HR, 0.79 [95% CI, 0.69-0.91]; P for trend = .002), while the uPDI was positively associated with risk of gout (Q5 vs Q1 HR, 1.17 [95% CI, 1.03-1.33]; P for trend = .02), particularly in women (Q5 vs Q1 HR, 1.31 [95% CI, 1.05-1.62]; P for trend = .01). In analysis of individual food groups, higher intakes of certain healthy plant foods, such as whole grains (pooled HR per 1 serving/d, 0.93 [95% CI, 0.89-0.97]) and tea and coffee (pooled HR per 1 serving/d, 0.95 [95% CI, 0.92-0.97]), as well as dairy (pooled HR per 1 serving/d, 0.86 [95% CI, 0.82-0.90]), were independently associated with a lower risk of gout, while selected unhealthy plant foods, such as fruit juice (pooled HR per 1 serving/d, 1.06 [95% CI, 1.00-1.13]) and sugar-sweetened beverages (pooled HR per 1 serving/d, 1.16 [95% CI, 1.07-1.26]) were associated with increased risk of gout. Conclusions and Relevance: The findings of this prospective cohort study of PDIs and gout support current dietary recommendations to increase consumption of healthy plant foods while lowering intake of unhealthy plant foods to mitigate gout risk.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Low-Carbohydrate Diet Macronutrient Quality and Weight Change.

Importance: The associations of low-carbohydrate diets (LCDs) with long-term weight management remains unclear, and the source and quality of macronutrients within LCDs are less explored. Objectives: To prospectively examine associations between changes in LCD indices and weight change among US adults. Design, Setting, and Participants: This prospective cohort study included initially healthy participants at baseline from the Nurses' Health Study (NHS; 1986-2010), Nurses' Health Study II (NHSII; 1991-2015), and Health Professionals Follow-up Study (HPFS; 1986-2018). Data analysis was performed between November 2022 and April 2023. Exposures: Five LCD indices were examined: (1) a total LCD (TLCD) emphasizing overall lower carbohydrate intake; (2) an animal-based LCD (ALCD) that emphasized animal-sourced protein and fat; (3) a vegetable-based LCD (VLCD) that emphasized plant-sourced protein and fat; (4) a healthy LCD (HLCD) emphasizing less refined carbohydrates, more plant protein, and healthy fat; and (5) an unhealthy LCD (ULCD) emphasizing less healthful carbohydrates, more animal protein, and unhealthy fat. Main Outcomes and Measures: The outcome of interest was 4-year changes in self-reported body weight. Results: A total of 123 332 participants (mean [SD] age, 45.0 [9.7] years; 103 320 [83.8%] female) were included in this study. The median carbohydrate intake (as a percentage of energy) of the highest quintiles of TLCD score at baseline ranged from 38.3% in HPFS to 40.9% in NHSII. Mean weight gain over 4-year intervals among participants varied from 0.8 kg in the HPFS to 1.8 kg in the NHSII. After adjusting for demographics and baseline and concomitant changes of selected lifestyle factors, each 1-SD increase in TLCD score was associated with 0.06 (95% CI, 0.04-0.08) kg more weight gain over the 4-year periods. Similarly, participants gained 0.13 (95% CI, 0.11 to 0.14) kg per each 1-SD increase in ALCD score and 0.39 (95% CI, 0.37 to 0.40) kg per each 1-SD change in ULCD score. In contrast, each 1-SD increase in VLCD score was associated with 0.03 (95% CI, 0.01 to 0.04) kg less weight gain, and each 1-SD increase in HLCD score was associated with 0.36 (95% CI, 0.35 to 0.38) kg less weight gain. The associations were more pronounced among obese individuals (per 1-SD increase in HLCD score: BMI ≥30, 0.88 [95% CI, 0.80, 0.97] kg less weight gain; BMI <25, 0.23 [95% CI, 0.20, 0.26] kg less weight gain; P for interaction < .001). Conclusions and Relevance: These findings suggest that the quality of LCDs may play a critical role in modulating long-term weight change. Only LCDs that emphasized high-quality protein, fat, and carbohydrates from whole grains and other plant-based foods were associated with less weight gain.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

A South Asian Mediterranean-style diet is associated with favorable adiposity measures and lower diabetes risk: The MASALA cohort.

OBJECTIVE: The Mediterranean diet is associated with lower risks for type 2 diabetes (T2D) and cardiovascular disease in certain populations, although data among diverse groups are limited. This study evaluated cross-sectional and prospective associations between a novel South Asian Mediterranean-style (SAM) diet and cardiometabolic risk among US South Asian individuals. METHODS: The study included 891 participants at baseline in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. Culturally relevant foods were grouped into nine categories to construct the SAM score. The study examined associations of this score with cardiometabolic risk factors and incident T2D. RESULTS: At baseline, higher adherence to the SAM diet was associated with lower glycated hemoglobin (-0.43% ± 0.15% per 1-unit increase in SAM score; p = 0.004) and lower pericardial fat volume (-1.22 ± 0.55 cm3 ; p = 0.03), as well as a lower likelihood of obesity (odds ratio [OR]: 0.88, 95% CI: 0.79-0.98) and fatty liver (OR: 0.82, 95% CI: 0.68-0.98). Over the follow-up (~5 years), 45 participants developed T2D; each 1-unit increase in SAM score was associated with a 25% lower odds of incident T2D (OR: 0.75, 95% CI: 0.59-0.95). CONCLUSIONS: A greater intake of a SAM diet is associated with favorable adiposity measures and a lower likelihood of incident T2D.

Clinico-demographic and survival profile of people living with HIV on antiretroviral treatment.

Objective: To assess the demographic, clinical, and survival profile of people living with HIV. Methods: A retrospective cohort study was conducted among patients enrolled at a single antiretroviral therapy center in North Karnataka. A total of 11,099 were recruited from April 2007 to January 2020, out of which 3,676 were excluded and the final 7,423 entries were subjected to analysis. The outcome of interest was the time to death in months of people living with HIV on antiretroviral therapy (ART). The clinical and demographic characteristics were examined as potential risk factors for survival analysis. To investigate the factors that influence the mortality of patients using ART, univariate and multivariate Cox regression were performed. Hazard ratio (HR), 95% confidence interval (CI), and p-values were presented to show the significance. The log-rank test was used to determine the significance of the Kaplan-Meier survival curve. Results: Out of 7,423 HIV-positive people, majority were female (51.4%), heterosexual typology (89.2%), and in the age group 31-45 years (45.5%). The risk of death in male patients was 1.24 times higher (95% CI: 1.14-1.35) than female patients. Patients with age >45 were 1.67 times more likely to die than patients ≤30 (95% CI: 1.50-1.91). In the multivariable analysis, the hazards of mortality increased by 3.11 times (95% CI: 2.09-2.79) in patients with baseline CD4 count ≤50 as compared to those who had baseline CD4 count >200. The risk of death in patients who were diagnosed with TB was 1.30 times more (95% CI: 1.19-1.42) than in those who did not have TB. The survival probabilities at 3 and 90 months were more in female patients (93%, 70%) compared with male patients (89, 54%), respectively. Conclusion: This study proved that age, sex, baseline CD4 count, and tuberculosis (TB) status act as risk factors for mortality among people with HIV. Prevention strategies, control measures, and program planning should be done based on the sociodemographic determinants of mortality.

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.

Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.

Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model.

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase.

Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.

A Randomized Pilot Study of DASH Patterned Groceries on Serum Urate in Individuals with Gout.

The Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate (SU); however, the impact of the DASH diet has not been previously evaluated among patients with gout. We conducted a randomized, controlled, crossover pilot study to test the effects of ~$105/week ($15/day) of dietitian-directed groceries (DDG), patterned after the DASH diet, on SU, compared with self-directed grocery shopping (SDG). Participants had gout and were not taking urate lowering therapy. Each intervention period lasted 4 weeks; crossover occurred without a washout period. The primary endpoint was SU. Compliance was assessed by end-of-period fasting spot urine potassium and sodium measurements and self-reported consumption of daily servings of fruit and vegetables. We randomized 43 participants (19% women, 49% black, mean age 59 years) with 100% follow-up. Mean baseline SU was 8.1 mg/dL (SD, 0.8). During Period 1, DDG lowered SU by 0.55 mg/dL (95% CI: 0.07, 1.04) compared to SDG by 0.0 mg/dL (95% CI: -0.44, 0.44). However, after crossover (Period 2), the SU difference between groups was the opposite: SDG reduced SU by -0.48 mg/dL (95% CI: -0.98, 0.01) compared to DDG by -0.05 mg/dL (95% CI: -0.48, 0.38; P for interaction by period = 0.11). Nevertheless, DDG improved self-reported intake of fruit and vegetables (3.1 servings/day; 95% CI: 1.5, 4.8) and significantly reduced total spot urine sodium excretion by 22 percentage points (95% CI: -34.0, -8.6). Though relatively small in scale, this pilot study suggests that dietitian-directed, DASH-patterned groceries may lower SU among gout patients not on urate-lowering drugs. However, behavior intervention crossover trials without a washout period are likely vulnerable to strong carryover effects. Definitive evaluation of the DASH diet as a treatment for gout will require a controlled feeding trial, ideally with a parallel-design.

Epidemiology of Depression and Anxiety in Gout: A Systematic Review and Metaanalysis.

OBJECTIVE: To conduct a systematic review of depression and anxiety among patients with gout that specifically evaluates the prevalence, incidence, determinants, and effects of these mental health comorbidities. METHODS: We conducted a literature search in Medline, Embase, Cochrane Database of Systematic Reviews, CINAHL, and PsycINFO using indexed terms and key words to identify studies reporting on depression/anxiety in patients with gout. This review included full-text articles published in English that reported on patients with gout, evaluated depression/anxiety using a routinely reported measure, and provided estimates or sufficient data on the prevalence, incidence, determinants, or effects of depression/anxiety. Metaanalyses were conducted using random effects models. RESULTS: Twenty of 901 articles identified through the search strategy met our inclusion criteria. All 20 studies evaluated depression, while only 10 assessed anxiety (50%). Metaanalyses suggest a positive association between mental health disorders and gout, as resultant pooled OR were 1.29 (95% CI 1.07-1.56) for depression and 1.29 (95% CI 0.96-1.73) for anxiety. Findings from four studies reporting on the incidence of depression in patients with gout resulted in a pooled HR of 1.17 (95% CI 1.01-1.36). Significant determinants of depression included number of tophi, frequency of flares, and oligo/polyarticular gout. CONCLUSION: Our systematic review suggests that depression and anxiety are significantly associated with gout, highlighting the need for future research to focus on the onset of mental disorders after gout diagnosis. We also identify potential targets for intervention.

AgNP/Alginate Nanocomposite hydrogel for antimicrobial and antibiofilm applications.

The synthesis and specific surface functionalization of antimicrobial silver nanoparticles (AgNPs) and their incorporation into an alginate hydrogel is described. Divalent cation-mediated ionic crosslinking was used to disperse the AgNPs throughout the gel, made possible by -COO- cross-linking sites provided by the surface-enhanced nanoparticles, inspired by the classic egg-box model crosslinking of calcium alginate. An AgNP concentration, 10-20 µg g-1 increased hygrogel elasticity, viscosity, and shear resistance by 45, 30, and 31% respectively. Cryo-TEM revealed evenly distributed AgNP assemblies of discrete AgNPs throughout the gel matrices. FTIR-ATR indicated AgNPs were involved in alginate carboxylate-Ca2+-COO-AgNP crossbridging, which was not achieved through mixing of AgNPs into preformed gels. Live/dead fluorometric assays determined a minimal bactericidal concentration of 25 µg g-1 Ag for 6 microorganisms. Anti-biofilm assays showed species-dependent cell death of 44 -61%, with limited silver ion release of 0.41% and 1.1% after 7 days for Gram positive and negative bacteria, respectively.

Estimation of Primary Prevention of Gout in Men Through Modification of Obesity and Other Key Lifestyle Factors.

Importance: The population impact of modifying obesity and other key risk factors for hyperuricemia has been estimated in cross-sectional studies; however, the proportion of incident gout cases (a clinical end point) that could be prevented by modifying such factors has not been evaluated. Objective: To estimate the proportion of incident gout cases that could be avoided through simultaneous modification of obesity and other key risk factors. Design, Setting, and Participants: The Health Professionals Follow-up Study is a US prospective cohort study of 51 529 male health professionals enrolled in 1986 and followed up through questionnaires every 2 years through 2012. Self-reported gout cases were confirmed through June 2015. Clean and complete data used for this analysis were available in June 2016, with statistical analyses performed from July 2016 to July 2019. Exposures: From data collected in the validated questionnaires, men were categorized to low-risk groups according to combinations of the following 4 factors: normal body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; <25), no alcohol intake, adherence to Dietary Approaches to Stop Hypertension (DASH)-style diet (highest quintile of DASH diet score), and no diuretic use. Main Outcomes and Measures: Population attributable risks (PARs) for incident gout meeting the preliminary American College of Rheumatology survey criteria, overall and stratified by BMI. Results: We analyzed 44 654 men (mean [SD] age, 54.0 [9.8] years) with no history of gout at baseline. During 26 years of follow-up, 1741 (3.9%) developed incident gout. Among all participants, PAR for the 4 risk factors combined (BMI, diet, alcohol use, and diuretic use) was 77% (95% CI, 56%-88%). Among men with normal weight (BMI <25.0) and overweight (BMI 25.0-29.9), we estimated that more than half of incident gout cases (69% [95% CI, 42%-83%] and 59% [95% CI, 30%-75%], respectively) may have been prevented by the combination of DASH-style diet, no alcohol intake, and no diuretic use. However, among men with obesity (BMI ≥30), PAR was substantially lower and not significant (5% [95% CI, 0%-47%]). Conclusions and Relevance: The findings of this cohort study suggest that addressing excess adiposity and other key modifiable factors has the potential to prevent the majority of incident gout cases among men. Men with obesity may not benefit from other modifications unless weight loss is addressed.

Effects of Low-Fat, Mediterranean, or Low-Carbohydrate Weight Loss Diets on Serum Urate and Cardiometabolic Risk Factors: A Secondary Analysis of the Dietary Intervention Randomized Controlled Trial (DIRECT).

OBJECTIVE: Weight loss diets may reduce serum urate (SU) by lowering insulin resistance while providing cardiometabolic benefits, something urate-lowering drugs have not shown in trials. We aimed to examine the effects of weight loss diets on SU and cardiometabolic risk factors. RESEARCH DESIGN AND METHODS: This secondary study of the Dietary Intervention Randomized Controlled Trial (DIRECT) used stored samples from 235 participants with moderate obesity randomly assigned to low-fat, restricted-calorie (n = 85); Mediterranean, restricted-calorie (n = 76); or low-carbohydrate, non-restricted-calorie (n = 74) diets. We examined SU changes at 6 and 24 months overall and among those with hyperuricemia (SU ≥416 µmol/L), a relevant subgroup at risk for gout. RESULTS: Among all participants, average SU decreases were 48 µmol/L at 6 months and 18 µmol/L at 24 months, with no differences between diets (P > 0.05). Body weight, HDL cholesterol (HDL-C), total cholesterol:HDL-C ratio, triglycerides, and insulin concentrations also improved in all three groups (P < 0.05 at 6 months). Adjusting for covariates, changes in weight and fasting plasma insulin concentrations remained associated with SU changes (P < 0.05). SU reductions among those with hyperuricemia were 113, 119, and 143 µmol/L at 6 months for low-fat, Mediterranean, and low-carbohydrate diets (all P for within-group comparison < 0.001; P > 0.05 for between-group comparisons) and 65, 77, and 83 µmol/L, respectively, at 24 months (all P for within-group comparison < 0.01; P > 0.05 for between-group comparisons). CONCLUSIONS: Nonpurine-focused weight loss diets may simultaneously improve SU and cardiovascular risk factors likely mediated by reducing adiposity and insulin resistance. These dietary options could provide personalized pathways to suit patient comorbidity and preferences for adherence.

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

Population Impact Attributable to Modifiable Risk Factors for Hyperuricemia.

OBJECTIVE: To examine modifiable risk factors in relation to the presence of hyperuricemia and to estimate the proportion of hyperuricemia cases in the general population that could be prevented by risk factor modification, along with estimates of the variance explained. METHODS: Using data obtained from 14,624 adults representative of the US civilian noninstitutionalized population, we calculated adjusted prevalence ratios for hyperuricemia, population attributable risks (PARs), and the variance explained according to the following 4 factors: body mass index (BMI; ≥25 kg/m2 ), alcohol intake, nonadherence to a Dietary Approaches to Stop Hypertension (DASH) diet, and diuretic use. RESULTS: BMI, alcohol intake, adherence to a DASH-style diet, and diuretic use were all associated with serum urate levels and the presence of hyperuricemia in a dose-dependent manner. The corresponding PARs of hyperuricemia cases for overweight/obesity (prevalence 60%), nonadherence to a DASH-style diet (prevalence 82%), alcohol use (prevalence 48%), and diuretic use (prevalence 8%) were 44% (95% confidence interval [95% CI] 41%, 48%), 9% (95% CI 3%, 16%), 8% (95% CI 5%, 11%), and 12% (95% CI 11%, 14%), respectively, whereas the corresponding variances explained were 8.9%, 0.1%, 0.5%, and 5.0%. Our simulation study showed the variance nearing 0% as exposure prevalence neared 100%. CONCLUSION: In this nationally representative study, 4 modifiable risk factors (BMI, the DASH diet, alcohol use, and diuretic use) could be used to individually account for a notable proportion of hyperuricemia cases. However, the corresponding serum urate variance explained by these risk factors was very small and paradoxically masked their high prevalences, providing real-life empirical evidence for its limitations in assessing common risk factors.

Heart disease and the risk of allopurinol-associated severe cutaneous adverse reactions: a general population-based cohort study.

BACKGROUND: Allopurinol is commonly prescribed for gout, and its clinical use may expand with ongoing trials assessing its potential cardiorenal benefits. Because heart disease has been suggested to be a risk factor for allopurinol-associated severe cutaneous adverse reactions, we sought to confirm this association in a Canadian general population cohort. METHODS: We used population data from British Columbia, Canada, to identify all incident allopurinol users between 1997 and 2015. We examined the association between heart disease (ischemic heart disease and heart failure) and the risk of hospital admission for severe cutaneous adverse reactions, adjusting for known and purported risk factors. We also evaluated the joint effects of combined clinical and demographic risk factors. RESULTS: Among 130 325 allopurinol initiators, 109 hospital admissions occurred for allopurinol-associated severe cutaneous adverse reactions. The multivariable relative risk among those with heart disease was 1.55 (95% confidence interval 1.01-2.37). Patients with heart disease and chronic kidney disease who were started on an allopurinol dosage of greater than 100 mg/d had an 11-fold higher risk. Allopurinol initiation at a lower dosage among patients with heart disease and chronic kidney disease resulted in a fivefold reduction in risk. Older women with heart disease from regions with large Asian populations had a 23-fold higher risk of allopurinol-associated severe cutaneous adverse reactions than younger men without heart disease from other regions. INTERPRETATION: Heart disease is independently associated with risk of allopurinol-associated severe cutaneous adverse reactions, similar to chronic kidney disease, and low-dosage allopurinol initiation may substantially mitigate this risk. Risk factors for these rare but serious reactions should be considered when initiating allopurinol.