The impact of more restrictive hydrocodone rescheduling on unintentional pediatric opioid exposures.

PURPOSE: To evaluate the impact of rescheduling hydrocodone combination products (HCPs) from schedule III of the Controlled Substances Act to the more restrictive schedule II on unintentional pediatric exposures (≤5 years old). METHODS: Using U.S. data on outpatient retail pharmacy dispensing, emergency department (ED) visits, and poison center (PC) exposure cases, we assessed trends in prescriptions dispensed and unintentional pediatric exposure cases involving hydrocodone (rescheduled from III to II) compared to oxycodone (schedule II) and codeine (schedule III for combination products) using descriptive and interrupted time-series (ITS) analyses during the 16 quarters before and after the October 2014 rescheduling of HCPs. RESULTS: Dispensing of hydrocodone products was declining before rescheduling but declined more steeply post-rescheduling. In ITS analyses, both hydrocodone and oxycodone had significant slope decreases in PC case rates in the post versus pre-period that was larger for hydrocodone, while codeine had a small but significant slope increase in PC case rates. An estimated 4202 ED visits for pediatric hydrocodone exposures occurred in the pre-period and 2090 visits occurred in the post-period, a significant decrease of 50.3%. Oxycodone exposures showed no significant decrease. CONCLUSIONS: Pediatric hydrocodone unintentional exposure ED visits and PC cases decreased after HCP rescheduling more than would be expected had the pre-rescheduling trend continued; the acceleration in the decrease in hydrocodone PC cases was partially offset by a slowing in the decrease in codeine-involved cases. The trend changes were likely due to multiple factors, including changes in dispensing that followed the rescheduling. Unintentional pediatric medication exposures and poisonings remain a public health concern requiring ongoing, multifaceted mitigation efforts.

Improving Methods of Identifying Anaphylaxis for Medical Product Safety Surveillance Using Natural Language Processing and Machine Learning.

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015-2019 in 2 integrated health-care institutions in the Northwest United States. We used one site's manually reviewed gold-standard outcomes data for model development and the other's for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.

The impact of hydrocodone rescheduling on utilization, abuse, misuse, and overdose deaths.

PURPOSE: To evaluate the impact of increased federal restrictions on hydrocodone combination product (HCP) utilization, misuse, abuse, and overdose death. METHODS: We assessed utilization, misuse, abuse, and overdose death trends involving hydrocodone versus select opioid analgesics (OAs) and heroin using descriptive and interrupted time-series (ITS) analyses during the nine quarters before and after the October 2014 rescheduling of HCPs from a less restrictive (CIII) to more restrictive (CII) category. RESULTS: Hydrocodone dispensing declined >30% over the study period, and declines accelerated after rescheduling. ITS analyses showed that immediately postrescheduling, quarterly hydrocodone dispensing decreased by 177M dosage units while codeine, oxycodone, and morphine dispensing increased by 49M, 62M, and 4M dosage units, respectively. Postrescheduling, hydrocodone-involved misuse/abuse poison center (PC) case rates had a statistically significant immediate drop but a deceleration of preperiod declines. There were small level increases in codeine-involved PC misuse/abuse and overdose death rates immediately after HCP's rescheduling, but these were smaller than level decreases in rates for hydrocodone. Heroin-involved PC case rates and overdose death rates increased across the study period, with exponential increases in PC case rates beginning 2015. CONCLUSIONS: HCP rescheduling was associated with accelerated declines in hydrocodone dispensing, only partially offset by smaller increases in codeine, oxycodone, and morphine dispensing. The net impact on hydrocodone and other OA-involved misuse/abuse and fatal overdose was unclear. We did not detect an immediate impact on heroin abuse or overdose death rates; however, the dynamic nature of the crisis and data limitations present challenges to causal inference.

KRAS, NRAS, BRAF, and PIK3CA mutation rates, clinicopathological association, and their prognostic value in Iranian colorectal cancer patients.

AIM: Mutations in KRAS, NRAS, BRAF, and PIK3CA genes are critical factors in clinical evaluation of colorectal cancer (CRC) development and progression. In Iran, however, the data regarding genetic profile of CRC patients is limited except for KRAS exon2 and BRAF V600F mutations. This study aimed to investigate the mutational spectrum and prognostic effects of these genes and explore the relationship between these mutations and clinicopathological features of CRC. METHOD: To achieve these objectives, mutations in KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), PIK3CA (exons 9 and 20), and BRAF (exon 15) was determined using PCR and pyrosequencing in a total of 151 patients with colorectal cancer. RESULTS: KRAS, BRAF, NRAS, and PIK3CA mutations were identified in 41%, 5.96%, 3.97%, and 13.24% of the cases, respectively. There were some significant correlations between clinicopathological features and KRAS, PIK3CA, BRAF, and NRAS mutations. Mutations in KRAS and PIK3CA were shown to be independent risk factors for poor survival of the patients at stage I-IV (p < 0.0001 and p = 0.001, respectively). No significant impact on prognosis was observed in patients with BRAF mutations. CONCLUSION: Our study revealed the prevalence of CRC biomarkers mutations in Iranian patients and emphasized the role of KRAS and PIK3CA on shorter overall survival rates in this population.

Circulating levels of FAM19A5 are inversely associated with subclinical atherosclerosis in non-alcoholic fatty liver disease.

BACKGROUND: Family with sequence similarity 19 (chemokine (C-C motif)-like) member A5 (FAM19A5) is a newly identified adipokine. There is a limited number of studies linking FAM19A5 to metabolic disorders. In the current study, we aimed to explore if FAM19A5 is associated with nonalcoholic fatty liver disease (NAFLD). We also sought to determine the possibility of FAM19A5 association with subclinical atherosclerosis in NAFLD patients. METHODS: A total of 69 subjects including 37 NAFLD and 32 control subjects were included in this cross-sectional study. Plasma concentration of FAM19A5 was measured with the ELISA method. Carotid artery intima-media thickness (cIMT) was assessed by the ultrasonography. RESULTS: Plasma concentration of FAM19A5 in patients with NAFLD was significantly lower in NAFLD patients than controls. Moreover, we observed significant negative correlations between plasma level of FAM19A5 and body mass index (BMI), visceral fat, alanine amino transferase (ALT), aspartate amino transferase (AST), liver stiffness (LS), and cIMT. Following stepwise multiple linear regression analysis, ALT and cIMT were the only determinants of FAM19A5 level. CONCLUSIONS: This is the first report to describe association of circulating FAM19A5 levels with NAFLD. Our findings provide further evidence showing relation of FAM19A5 with the risk of atherosclerosis. However, more studies are necessary to unravel the contribution of lower FAM19A5 levels to the NAFLD pathogenesis and the higher risk of atherosclerosis in these patients.

Evaluating the use of bootstrapping in cohort studies conducted with 1:1 propensity score matching-A plasmode simulation study.

PURPOSE: Bootstrapping can account for uncertainty in propensity score (PS) estimation and matching processes in 1:1 PS-matched cohort studies. While theory suggests that the classical bootstrap can fail to produce proper coverage, practical impact of this theoretical limitation in settings typical to pharmacoepidemiology is not well studied. METHODS: In a plasmode-based simulation study, we compared performance of the standard parametric approach, which ignores uncertainty in PS estimation and matching, with two bootstrapping methods. The first method only accounted for uncertainty introduced during the matching process (the observation resampling approach). The second method accounted for uncertainty introduced during both PS estimation and matching processes (the PS reestimation approach). Variance was estimated based on percentile and empirical standard errors, and treatment effect estimation was based on median and mean of the estimated treatment effects across 1000 bootstrap resamples. Two treatment prevalence scenarios (5% and 29%) across two treatment effect scenarios (hazard ratio of 1.0 and 2.0) were evaluated in 500 simulated cohorts of 10 000 patients each. RESULTS: We observed that 95% confidence intervals from the bootstrapping approaches but not the standard approach, resulted in inaccurate coverage rates (98%-100% for the observation resampling approach, 99%-100% for the PS reestimation approach, and 95%-96% for standard approach). Treatment effect estimation based on bootstrapping approaches resulted in lower bias than the standard approach (less than 1.4% vs 4.1%) at 5% treatment prevalence; however, the performance was equivalent at 29% treatment prevalence. CONCLUSION: Use of bootstrapping led to variance overestimation and inconsistent coverage, while coverage remained more consistent with parametric estimation.

Relative Performance of Propensity Score Matching Strategies for Subgroup Analyses.

Postapproval drug safety studies often use propensity scores (PSs) to adjust for a large number of baseline confounders. These studies may involve examining whether treatment safety varies across subgroups. There are many ways a PS could be used to adjust for confounding in subgroup analyses. These methods have trade-offs that are not well understood. We conducted a plasmode simulation to compare relative performance of 5 methods involving PS matching for subgroup analysis, including methods frequently used in applied literature whose performance has not been previously directly compared. These methods varied as to whether the overall PS, subgroup-specific PS, or no rematching was used in subgroup analysis as well as whether subgroups were fully nested within the main analytical cohort. The evaluated PS subgroup matching methods performed similarly in terms of balance, bias, and precision in 12 simulated scenarios varying size of the cohort, prevalence of exposure and outcome, strength of relationships between baseline covariates and exposure, the true effect within subgroups, and the degree of confounding within subgroups. Each had strengths and limitations with respect to other performance metrics that could inform choice of method.

Extension of Disease Risk Score-Based Confounding Adjustments for Multiple Outcomes of Interest: An Empirical Evaluation.

Use of disease risk score (DRS)-based confounding adjustment when estimating treatment effects on multiple outcomes is not well studied. We designed an empirical cohort study to compare dabigatran initiators and warfarin initiators with respect to risks of ischemic stroke and major bleeding in 12 sequential monitoring periods (90 days each), using data from the Truven Marketscan database (Truven Health Analytics, Ann Arbor, Michigan). We implemented 2 approaches to combine DRS for multiple outcomes: 1) 1:1 matching on prognostic propensity scores (PPS), created using DRS for bleeding and stroke as independent variables in a propensity score (PS) model; and 2) simultaneous 1:1 matching on DRS for bleeding and stroke using Mahalanobis distance (M-distance), and compared their performance with that of traditional PS matching. M-distance matching appeared to produce more stable results in the early marketing period than both PPS and traditional PS matching; hazard ratios from unadjusted analysis, traditional PS matching, PPS matching, and M-distance matching after 4 periods were 0.72 (95% confidence interval (CI): 0.51, 1.03), 0.61 (95% CI: 0.31, 1.09), 0.55 (95% CI: 0.33, 0.91), and 0.78 (95% CI: 0.45, 1.34), respectively, for stroke and 0.65 (95% CI: 0.53, 0.80), 0.78 (95% CI: 0.60, 1.01), 0.75 (95% CI: 0.59, 0.96), and 0.78 (95% CI: 0.64, 0.95), respectively, for bleeding. In later periods, estimates were similar for traditional PS matching and M-distance matching but suggested potential residual confounding with PPS matching. These results suggest that M-distance matching may be a valid approach for extension of DRS-based confounding adjustments for multiple outcomes of interest.

A review of the performance of different methods for propensity score matched subgroup analyses and a summary of their application in peer-reviewed research studies.

PURPOSE: When evaluating safety signals, there is often interest in understanding safety in all patients for whom compared treatments are reasonable alternatives, as well as in specific subgroups of interest. There are numerous ways that propensity score (PS) matching can be implemented for subgroup analyses. METHODS: We conducted a systematic literature review of methods papers that compared the performance of alternative methods to implement PS matched subgroup analyses and examined how frequently different PS matching methods have been used for subgroup analyses in applied studies. RESULTS: We identified 5 methods papers reporting small improvements in covariate balance and bias with use of a subgroup-specific PS instead of a mis-specified overall PS within subgroups. Applied research papers frequently used PS for subgroups in ways not evaluated in methods papers. Thirty three percent used PS to match in the overall cohort and broke the matched sets for subgroup analysis without further adjustment. CONCLUSIONS: While the performance of several alternative ways to use PS matching in subgroup analyses has been evaluated in methods literature, these evaluations do not include the most commonly used methods to implement PS matched subgroup analyses in applied studies. There is a need to better understand the relative performance of commonly used methods for PS matching in subgroup analyses, particularly within settings encountered during active surveillance, where there may be low exposure, infrequent outcomes, and multiple subgroups of interest.

A case-control study of occupational sunlight exposure and renal cancer risk.

Epidemiological evidence of a relationship between vitamin D and kidney cancer risk has been inconsistent despite experimental data indicating that vitamin D and its metabolites may inhibit carcinogenesis. Previously we reported an inverse association between renal cell carcinoma (RCC) risk and occupational ultraviolet (UV) exposure among European men. In this study, we examined the association between occupational UV exposure and RCC risk among US residents and investigated whether this association varied by race and sex. Lifetime occupational data for 1,217 RCC cases and 1,235 controls in a population-based case-control study, conducted from 2002 to 2007, were assessed for occupational UV exposure. We evaluated exposure metrics in quartiles based on control exposure levels and calculated associations between RCC risk and occupational UV exposure using unconditional logistic regression adjusted for sex, race, body mass index, smoking, hypertension, center, education, family history of cancer and dietary vitamin D intake. A general pattern of decreasing RCC risk with increasing UV exposure was observed. Cases had significantly lower cumulative occupational UV exposure than controls (fourth quartile vs. first: odds ratio = 0.74 [95% confidence interval = 0.56-0.99], p-trend = 0.03). Similar results were observed for other UV exposure metrics. The association with occupational UV exposure was stronger for women than for men, but did not differ by race. Our findings suggest an inverse association between occupational UV exposure and RCC, particularly among women. Given the sex finding discrepancies in this study versus our previous study, additional research is need to clarify whether the protective effects of occupational UV exposure and RCC risk are real.

Analgesic use and risk of renal cell carcinoma: A case-control, cohort and meta-analytic assessment.

Analgesics are the most commonly consumed drugs worldwide. Evidence that analgesics increase kidney cancer risk has been mixed. We investigated the association between renal cell carcinoma (RCC) and analgesic use in a large population-based case-control study and a post-trial observational cohort study. Findings were used to update a recent meta-analytic review. We analyzed data from 1,217 RCC cases and 1,235 controls in the US Kidney Cancer Study and 98,807 participants in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO: n = 137 RCCs). Self-reported acetaminophen, aspirin and nonsteroid anti-inflammatory drug (NSAID) use and duration information was assessed in relation to RCC. For the US Kidney Cancer Study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. For PLCO, we computed hazard ratios (HRs) and 95%CIs using Cox regression. Among case-control participants, RCC risk was associated with over-the-counter acetaminophen use (OR = 1.35, 95%CI = 1.01-1.83). There was a positive trend with increasing duration (p-trend = 0.01), with a two-fold risk for use ≥10 years (OR = 2.01, 95%CI = 1.30-3.12). No association with prescription acetaminophen use was detected. In PLCO, acetaminophen use was also associated with increased RCC risk (HR = 1.68, 95%CI = 1.19-2.39), although elevated risk was absent among the few long-term users. No association with RCC risk was detected for aspirin or NSAIDs use in either study. An association between acetaminophen use and kidney cancer was supported by meta-analytic cohort (n = 4; summary relative risk = 1.34; 95%CI = 1.13-1.59; p-heterogeneity = 0.40) and case-control (n = 9, summary OR = 1.20; 95%CI = 1.01-1.42; p-heterogeneity = 0.05) findings. In brief, acetaminophen use may increase the risk of developing RCC.

Telomere structure and maintenance gene variants and risk of five cancer types.

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

A prospective study of alcohol consumption and renal cell carcinoma risk.

Recent epidemiological studies suggest that alcohol consumption may reduce renal cell carcinoma (RCC) risk, although inconsistent findings have been reported by sex and alcoholic beverage type. To better understand the relationship between alcohol consumption and RCC risk, we conducted an analysis within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We followed up participants in the analytic cohort (N = 107,998) through 2010 for incident RCC (N = 408), and computed hazard ratios (HRs) and 95% confidence intervals (CIs) for alcohol intake using Cox regression with adjustment for age, sex, race, study center, hypertension, body mass index, and smoking status. In this study population increasing alcohol consumption was associated with reduced RCC risk compared to non-drinkers (>9.75 g day(-1) : HR, 0.67; 95%CI, 0.50 to 0.89; p trend = 0.002). We observed similar patterns of association for men and women as well as by alcohol beverage type. In analyses stratified by smoking status, the inverse association with consumption was apparent for ever smokers (HR, 0.51; 95%CI, 0.36 to 0.73; p trend<0.0001) but not among never smokers (HR, 1.08; 95%CI, 0.66 to 1.76; P trend = 0.78; p interaction = 0.01). Our study findings offer further support that alcohol consumption is associated with reduced RCC risk, regardless of sex or alcoholic beverage type. The finding of interaction with smoking is novel and requires confirmation.

Hysterectomy and kidney cancer risk: a meta-analysis.

Recent cohort findings suggest that women who underwent a hysterectomy have an elevated relative risk of kidney cancer, although evidence from past studies has been inconsistent. We conducted a systematic review and meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence investigating hysterectomy and kidney cancer. Studies published from 1950 through 2012 were identified through a search of PubMed and of references from relevant publications. Meta-analyses were conducted using random-effects models to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for hysterectomy, age at hysterectomy (<45, 45+ years) and time since hysterectomy (<10, 10+ years). The SRR for hysterectomy and kidney cancer for all published studies (seven cohort, six case-control) was 1.29 (95% CI, 1.16-1.43), with no evidence of between-study heterogeneity or publication bias. The summary effect was slightly weaker, although still significant, for cohorts (SRR, 1.26; 95% CI, 1.11-1.42) compared with case-control findings (1.37; 95% CI, 1.09-1.73) and was observed irrespective of age at hysterectomy, time since the procedure and model adjustment for body mass index, smoking status and hypertension. Women undergoing a hysterectomy have an approximate 30% increased relative risk of subsequent kidney cancer. Additional research is needed to elucidate the biological mechanisms underlying this association.

Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.

Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC) and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs). VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5). Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20-1.31) and current: OR = 0.56 (0.32-0.99); P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.

Reductive carbon dots for reduction, ratiometric fluorescence determination, and intracellular imaging of Au3.

Many studies show that ortho-phenylenediamine (OPD) produces an oxidized fluorescent product when exposed to an oxidizing agent that enables the direct or indirect fluorescence detection of a range chemical and biochemical analytes. However, there is no report on this unique optical behavior for other two isomers of phenylenediamine. This study demonstrates that a simple hydrothermal treatment of para-phenylenediamine (PPD) in the presence of sulfuric acid results in the formation of fluorescent N, S-doped carbon dots (CDs) with triple functionalities including the reduction of Au3+ into gold nanoparticles (AuNPs), the stabilization of the produced AuNPs, and the determination of Au3+ concentration through an intrinsic ratiometric fluorescence signal. In the presence of Au3+, the blue emission of CDs at 437 nm quenched, and a green emission at 540 nm emerged. The linear concentration range for the determination of Au3+ was 20 nM-16 µM with a detection limit of 16 nM. Additionally, the dual emissive CDs-AuNPs hybrid probe showed potential for the indirect fluorescence ratiometric determination of cysteine and sulfide ions. The linear concentration range for cysteine and sulfide ions were 0.25-8 µM and 0.1-6 µΜ, with detection limits of 0.095 µM and 0.041 µM, respectively. Accordingly, CDs were applied to detect Au3+ and S2- in real water samples. Moreover, the synthesized CDs showed no cytotoxicity for HeLa cells up to 300 µg mL-1, as determined by the MTT assay. Therefore, their potential for intracellular imaging of Au3+ in living cells was also investigated.

Reproductive factors and kidney cancer risk in 2 US cohort studies, 1993-2010.

Clinical and experimental findings suggest that female hormonal and reproductive factors could influence kidney cancer development. To evaluate this association, we conducted analyses in 2 large prospective cohorts (the National Institutes of Health-AARP Diet and Health Study (NIH-AARP), 1995-2006, and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), 1993-2010). Cohort-specific and aggregated hazard ratios and 95% confidence intervals relating reproductive factors and kidney cancer risk were computed by Cox regression. The analysis included 792 incident kidney cancer cases among 283,952 postmenopausal women. Women who had undergone a hysterectomy were at a significantly elevated kidney cancer risk in both NIH-AARP (hazard ratio = 1.28, 95% confidence interval: 1.09, 1.50) and PLCO (hazard ratio = 1.41, 95% confidence interval: 1.06, 1.88). Similar results were observed for both cohorts after analyses were restricted to women who had undergone a hysterectomy with or without an oophorectomy. For the NIH-AARP cohort, an inverse association was observed with increasing age at menarche (P for trend = 0.02) and increasing years of oral contraceptive use (P for trend = 0.02). No clear evidence of an association with parity or other reproductive factors was found. Our results suggest that hysterectomy is associated with increased risk of kidney cancer. The observed associations with age at menarche and oral contraceptive use warrant further investigation.

The association between chronic renal failure and renal cell carcinoma may differ between black and white Americans.

PURPOSE: In the United States, renal cell carcinoma (RCC) incidence is higher among blacks than among whites. Risk of RCC is elevated among end-stage renal disease patients, although no studies have looked at differences by race in the relationship between chronic renal failure and RCC. METHODS: We investigated RCC risk in relation to chronic renal failure in a population-based case-control study of blacks and whites in Chicago and Detroit. Data, including information on kidney disease, were collected from interviews with 1,217 RCC cases (361 blacks, 856 whites) and 1,235 controls (523 blacks, 712 whites). Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression. RESULTS: Risk of RCC was increased in relation to chronic renal failure (OR 4.7, 95 % CI 2.2-10.1) and dialysis (OR 18.0, 95 % CI 3.6-91). The association remained after defining exposure as those who had chronic renal failure ≥10 years prior to RCC diagnosis. Chronic renal failure was more strongly associated with RCC among blacks than among whites (OR 8.7, 95 % CI 3.3-22.9 and 2.0, 0.7-5.6, respectively; p (interaction) = 0.03) and among those without a history of diabetes relative to diabetic subjects (OR 8.3, 95 % CI 3.1-22.7 and 1.9, 0.6-5.9, respectively; p (interaction) = 0.03). CONCLUSIONS: These results suggest that chronic renal failure is a strong risk factor for RCC, particularly among black and non-diabetic subjects. Our findings of differences in risk estimates by race, to our knowledge the first such report, require replication.

Occupational trichloroethylene exposure and risk of lymphatic and haematopoietic cancers: a meta-analysis.

The carcinogenic potential of trichloroethylene (TCE) continues to generate much controversy, even after the US Environmental Protection Agency raised its classification to 'carcinogenic to humans'. We conducted a meta-analysis of published cohort and case-control studies exploring occupational TCE exposure in relation to five different lymphatic and haematopoietic cancers: non-Hodgkin's lymphoma (NHL, N=24), Hodgkin's lymphoma (HL, N=13), multiple myeloma (MM, N=11), leukaemia (N=12) and chronic/small lymphocytic leukaemia (CLL/SLL, N=7).  Studies published between 1950 and 2011 were identified through a PubMed Medline search. All studies included in analyses were classified as those that assessed either occupational TCE exposure specifically ('TCE-exposure' studies) or a broader classification of all chlorinated solvents ('chlorinated solvent-exposure' studies).  A significantly raised summary estimate for NHL was seen for all cohort and case-control 'TCE-exposure' studies combined (N=19; relative risk (RR)=1.32, 95% CI 1.14 to 1.54; I(2)=25.20; p-heterogeneity=0.12) and for cohort 'TCE-exposure' studies (N=10; RR=1.52, 95% CI 1.29 to 1.79; I(2)=7.09; p-heterogeneity=0.63). A non-significant but raised summary estimate was seen for NHL case-control 'TCE-exposure' studies. No significant association with NHL risk was detected overall for any 'chlorinated solvent-exposure' studies. Summary estimates for occupational TCE exposure were not associated with risk of HL, MM, leukaemia or CLL/SLL.  Our updated meta-analysis of NHL, which incorporates new analytical results from three cohort and four case-control studies, supports an association between occupational TCE exposure and NHL.

Cannabidiol exposures in the United States, National Poison Data System, July 2014-June 2021.

INTRODUCTION: There has been an increase in the interest and availability of products asserting to contain cannabidiol (CBD). OBJECTIVE: To describe demographic and clinical patterns in cases involving CBD exposures documented by the America's Poison Centers (AAPCC). METHODS: We extracted human exposure cases involving CBD from the U.S. National Poison Data System between July 2014 and June 2021. We described monthly case counts and data on demographics, exposure reason, clinical effects, medical outcomes, and co-exposures, overall and by U.S. Food and Drug Administration (FDA) approval status. RESULTS: We identified 6,496 cases, of these, 85.2% involved exposures to non-FDA approved CBD. The monthly number of cases peaked at 336 in March 2021. Cases often occurred in children ages 2-12 years (36.2%). Although in this age group unintentional exposures represented most cases (94.1%), we identified therapeutic errors (3.9%), intentional use (3.0%), and adverse reactions (1.6%) in cases involving exposures to non-FDA approved CBD. Among the 5,248 (80.8%) cases involving exposure to a single product, we identified 44 major medical outcomes, all related to exposures to non-FDA approved CBD. The most frequent clinical effects included neurological, cardiac, and gastrointestinal effects. Among the 1,248 (19.2%) involving exposure to more than one product, the most frequent co-exposures included stimulants and street drugs, sedatives-hypnotics, antipsychotics, and analgesics. CONCLUSIONS: This case series identified an increasing trend in CBD exposure cases managed by AAPCC. It showed serious medical outcomes in temporal association with exposure to non-FDA approved CBD products. Our findings also suggest both unintentional and intentional use of non-FDA approved CBD in children. Consumers should keep these products out of reach of children and exercise caution when purchasing and using non-FDA approved CBD products.