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.

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.

Trends in pediatric nonprescription analgesic/antipyretic exposures during the COVID-19 pandemic.

OBJECTIVE: To examine pediatric exposure trends involving selected nonprescription analgesics/antipyretics, before and during the COVID-19 pandemic. METHODS: Using descriptive and interrupted time-series analyses, we assessed monthly United States poison center data involving pediatric (<18 years) exposures to nonprescription paracetamol (acetaminophen), ibuprofen, acetylsalicylic acid, and naproxen before (January 2015-February 2020) and during (March 2020-April 2021) the pandemic. Statins and proton pump inhibitors (prescription or nonprescription) served as controls. RESULTS: Most nonprescription analgesic/antipyretic exposures (75-90%) were single-substance; unintentional exposures typically involved children <6 years (84-92%), while intentional exposures involved females (82-85%) and adolescents, 13-17 years (91-93%). Unintentional exposures among children <6 years, declined for all four analgesics/antipyretics immediately after the World Health Organization declared COVID-19 a pandemic (March 11, 2020), but most significantly for ibuprofen (30-39%). Most intentional exposures were classified as suspected suicide. Intentional exposures were relatively low and stable among males. Intentional exposures in females declined immediately after the pandemic was announced but subsequently increased to pre-pandemic levels for acetylsalicylic acid and naproxen and above pre-pandemic levels for paracetamol and ibuprofen. For paracetamol, female intentional exposures increased from 513 average monthly cases in the pre-pandemic to 641 average monthly cases during the pandemic; and reached 888 cases by the end of the study period in April 2021. While for ibuprofen, average monthly cases rose from 194 in the pre-pandemic, to 223 during the pandemic; and reached 352 cases in April 2021. Patterns were similar among females 6-12 and 13-17 years. CONCLUSION: Nonprescription analgesic/antipyretic unintentional exposure cases declined among young children, while intentional exposure cases increased among females, 6-17 years, during the pandemic. Findings highlight the importance of safely storing medications and being alert to signs that adolescents may be in need of mental health support services; caregivers should seek medical care or call poison control centers for any suspected poisoning event.

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.

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.

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.

Benzonatate Exposure Trends and Adverse Events.

BACKGROUND AND OBJECTIVES: Adverse events (AE), including death, occur in children with benzonatate use. This study aims to understand recent trends in benzonatate exposure and clinical consequences in pediatric patients. METHODS: This retrospective analysis of data from IQVIA pharmacy drug dispensing, National Poison Data System, National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project, FDA Adverse Event Reporting System, and the medical literature evaluated exposure trends and medication-related AEs with benzonatate. Trends for comparator narcotic and nonnarcotic antitussive medications were analyzed where possible for context. RESULTS: During the study period, pediatric benzonatate prescription utilization increased but remained low compared with pediatric utilization of dextromethorphan-containing prescription antitussive medications. Among the 4689 pediatric benzonatate exposure cases reported to US poison control centers from 2010 to 2018, 3727 cases (80%) were for single-substance exposures. Of these, 3590 cases (77%) were unintentional exposures and most involved children 0 to 5 years old (2718 cases, 83%). Cases involving intentional benzonatate exposure increased among children 10 to 16 years old with a more pronounced increase for multiple-substance exposures. Most benzonatate cases involving misuse or abuse were for children 10 to 16 years old (59 cases, 61%). The proportion of cases with serious adverse effects was low. There were few cases annually of serious AEs with benzonatate in children. CONCLUSIONS: There were rising patterns of unintentional ingestion of benzonatate in children 0 to 5 years old and intentional benzonatate ingestion in children 10 to 16 years old. Rational prescribing and improved provider and caregiver awareness of benzonatate toxic effects may reduce risks associated with benzonatate exposure.

Anti-inflammatory function of apolipoprotein B-depleted plasma is impaired in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events. HDL exerts various protective functions on the cardiovascular system including anti-inflammatory activity by suppressing adhesion molecules expression in inflammation-induced endothelial cells. This study was designed to search if the anti-inflammatory capacity of apolipoprotein B-depleted plasma (apoB-depleted plasma) is altered in NAFLD patients. METHODS: A total of 83 subjects including 42 NAFLD and 41 control subjects were included in this cross-sectional study. Anti-inflammatory function of HDL was determined as the ability of apoB-depleted plasma to inhibit tumor necrosis factor-α (TNF-α)-induced expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). RESULTS: Incubation of inflammation-stimulated HUVECs with the NAFLD patients' apo-B depleted plasma led to higher levels of expression of adhesion molecules compared to the control subjects' plasma samples, reflecting an impaired anti-inflammatory capacity of apoB-depleted plasma in the NAFLD patients. Impaired anti-inflammatory capacity of apoB-depleted plasma was correlated with fatty liver and obesity indices. After adjustment with obesity indices, the association of anti-inflammatory capacity of apoB-depleted plasma with NAFLD remained significant. CONCLUSION: Impaired anti-inflammatory activity of apoB-depleted plasma was independently associated with NAFLD.

Association of anti-oxidative capacity of HDL with subclinical atherosclerosis in subjects with and without non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients are at a substantial risk for developing cardiovascular disease (CVD). High-density lipoprotein (HDL) is well known to have protective effects against the development of atherosclerotic CVD. One of the major antiatherogenic effects of HDL is its anti-oxidative function. OBJECTIVES: This study investigated the association of anti-oxidative capacity of HDL with subclinical atherosclerosis in NAFLD and non-NAFLD subjects. METHODS: A total of 143 subjects including 51 NAFLD and 92 control subjects were included in this case-control study. HDL oxidative index (HOI) was determined spectrophotometrically using a cell-free method in the presence of a fluorescent substrate dichlorofluorescein diacetate (DCFDA). Paraoxonase 1 (PON1) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) plasma levels were assessed in both groups. RESULTS: The NAFLD patients with impaired HDL anti-oxidative function (HOI ≥ 1) had higher MDA levels, aspartate amino transferase (AST), liver stiffness (LS), and carotid intima-media thickness (cIMT) values compared to the controls. HDL oxidative index (HOI) was positively correlated with MDA levels and cIMT and negatively correlated with SOD activity. CONCLUSIONS: Higher circulating levels of MDA were associated with the impaired anti-oxidative function of HDL in NAFLD. The impaired anti-oxidative capacity of HDL might be related to NAFLD severity and subclinical atherosclerosis in NAFLD patients.

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.

Intrinsic dual-emissive carbon dots for efficient ratiometric detection of Cu2+ and aspartic acid.

Herein, novel intrinsic dual-emitting carbon dots (CDs) are prepared through a one-step hydrothermal treatment of glucose and 3-nitroaniline in sulfuric acid solution and utilized for ratiometric determination of Cu2+ and aspartic acid (Asp). The CDs exhibited an interesting pH-switchable emission behavior displaying an intrinsic dual-emitting peak with emission maxima at 400 and 610 nm at pH 4.0-5.0. The presence of Cu2+ intensively quenched the first emission peak at 400 nm, but it had a negligible effect on the second emission peak. The ratiometric signal displayed a high selectively for Cu2+ over other metal ions and provided a linear response over the concentration range of 0.01-1.00 µM with a detection limit of 7.0 nM. Moreover, at pH 4.0, Asp was able to restore the quenched fluorescence of the CDs-Cu2+ system with a much more successful performance than other amino acids. This on-off-on fluorescence behavior provided a selective ratiometric fluorescence method for the determination of Asp in the concentration range of 0.2-15 µM. The acceptable detection results for Cu2+ in a river water sample (compared to Inductively Coupled Plasma (ICP) method) and for Asp in human serum samples confirmed the potential application of this ratiometric nanoprobe for sensing in real samples.

The Role of Nanomaterials in the Treatment of Diseases and Their Effects on the Immune System.

Nanotechnology has been widely exploited in recent years in various applications. Different sectors of medicine and treatment have also focused on the use of nanoproducts. One of the areas of interest in the treatment measures is the interaction between nanomaterials and immune system components. Engineered nanomaterials can stimulate the inhibition or enhancement of immune responses and prevent the detection ability of the immune system. Changes in immune function, in addition to the benefits, may also lead to some damage. Therefore, adequate assessment of the novel nanomaterials seems to be necessary before practical use in treatment. However, there is little information on the toxicological and biological effects of nanomaterials, especially on the potential ways of contacting and handling nanomaterials in the body and the body response to these materials. Extensive variation and different properties of nanomaterials have made it much more difficult to access their toxicological effects to the present. The present study aims to raise knowledge about the potential benefits and risks of using the nanomaterials on the immune system to design and safely employ these compounds in therapeutic purposes.

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.

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.

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.

Trends in dextromethorphan cough and cold products: 2000-2015 National Poison Data System intentional abuse exposure calls.

CONTEXT: Recent restrictions in access to and availability of dextromethorphan (DXM) cough and cold medications may correlate with changes in abuse exposures. OBJECTIVE: To extend and update existing knowledge about DXM abuse, we describe recent trends and patterns of calls to poison control centers involving DXM abuse, by demographics, geography, common brands, and medical outcomes. METHODS: We utilized data from the National Poison Data System (NPDS) maintained by the American Association of Poison Control Centers (AAPCC), which captures data on calls to U.S. poison centers on a near real-time basis. We analyzed demographic, geographic, brand and medical outcome data for single-substance DXM cough and cold product intentional abuse exposure calls in multiple age groups reported to NPDS from 2000 to 2015. RESULTS: The annual rate of single-substance DXM intentional abuse calls tripled from 2000 to 2006 and subsequently plateaued from 2006 to 2015. The highest abuse call rate was observed among adolescents 14-17 years old, where the mean annual number of calls was 1761 per year, corresponding to an annual rate of 103.6 calls per million population. From 2006 to 2015, the rate for single-substance DXM abuse calls among adolescents 14-17 years decreased by 56.3%, from 143.8 to 80.9 calls per million population. CONCLUSION: DXM intentional abuse exposure call rates have declined among adolescents 14-17 years, since their peak in 2006. The observed decline in DXM abuse call rates corresponds to a period of growing public health efforts to curtail the abuse of over-the-counter (OTC) DXM containing products, particularly among adolescents. Further evaluation of state-level sales and abuse trends among adolescents would be valuable to better understand how restricted availability of OTC DXM cough and cold products and other efforts may affect abuse rates.

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.

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.

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.

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.