How mycorrhizal associations and plant density influence intra- and inter-specific competition in two tropical tree species: Cabralea canjerana (Vell.) Mart. and Lafoensia pacari A.St.-Hil.

Arbuscular mycorrhizal fungi (AMF) associations benefit host plants due to increased ability to obtain resources and hence may influence competitive interactions. Here we experimentally examine growth in Cabralea canjerana and Lafoensia pacari at different densities and with and without AMF. In the density treatment pots had either six or 12 individuals. Half of each treatment was innoculated with AMF and the other half was not. The proportion of each species in each pot was also varied. The AMF did not apparently influence interspecific competitive interactions because growth was similar in both treatments. However, intra-specific competition was very strong in C. canjerana while more moderate in L. pacari and both were influenced by the presence of the AMF. The AMF?Cabralea canjerana interaction was parasitic, while AMF?L. pacari interactions were mutualistic. Thus, dependence upon AMF and intraspecific interactions that result as a consequence of that dependence varies among species and may be an important influence in community structure.Publicação somente on-line

Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study

Aims—Dipeptidyl-peptidase-4 inhibitors (DPP-4i) have been implicated with an increased pancreatic cancer risk. We therefore compared pancreatic cancer incidence and diagnostic work-up among initiators of DPP-4i versus sulfonylureas (SU) and thiazolidinediones (TZD). Methods—Medicare claims data were examined in a new-user active-comparator cohort study. Patients >65 years with no prescriptions for DPP-4i, SU or TZD at baseline were included if they had at least two claims for the same drug within 180 days. Using an as-treated approach and propensity score-adjusted Cox models, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for pancreatic cancer. Diagnostic work-up was compared using risk ratios (RR). RESULTS—In the DPP-4i vs SU comparison, there were 18,179 DPP4i initiators of which 26 developed pancreatic cancer (follow-up time interquartile range 5–18 months). In the DPP-4i vs TZD comparison there were 29,366 DPP-4i initiators and 52 developed pancreatic cancer. The hazard of pancreatic cancer with DPP-4i was lower relative to SU (HR=0.6, CI 0.4–0.9) and similar to TZD (HR=1.0, CI 0.7–1.4). Excluding first 6 months of follow-up to reduce the potential for reverse causality did not alter results. Probability of diagnostic work-up post-initiation among DPP-4i initiators (79.3%) was similar to TZD (74.1%) (RR=1.06, CI 1.05–1.07) and SU (74.6%) (RR=1.06, CI1.05–1.07). The probability of diagnostic workup pre-index was ~80% for all cohorts. Conclusion—Though limited by sample size and the observed duration of treatment in the US, our well-controlled population based study suggests no increased short-term pancreatic cancer risk with DPP-4i relative to SU or TZD

Comparative Propensity-Weighted Mortality After Isolated Acute Traumatic Axis Fractures in Older Adults

Introduction: In older patients with axis fractures, the survival benefit from surgery is unclear due to high baseline mortality. Comparative effectiveness research can provide evidence from population level cohorts. Propensity weighting is the preferred methodology for reducing bias when analyzing national administrative cohort data for these purposes but has not yet been utilized for this important surgical conundrum. We estimate the effect of surgery on mortality after isolated acute traumatic axis fracture in older adults. Materials and Methods: We used a retrospective population-based cohort of Medicare patients and generated a propensity score-weighted nonsurgical cohort and compared mortality with and without surgery. This balanced the comorbid conditions of the treatment groups. Incident fractures were defined using a predetermined algorithm based on enrollment, code timing, and billing location. The primary outcome was adjusted all-cause 1-year mortality. Results: From 12 372 beneficiaries with 1-year continuous enrollment and a coded axis fracture, 2676 patients met final inclusion/exclusion criteria. Estimated incidence was 16.5 per 100 000 person-years overall in 2014 (95% confidence interval [CI]: 15.0-18.0) and was stable from 2008 through 2014. Patients with axis fracture had a mean age of 82.8 years, 30.2% were male, and 91.9% were Caucasian. Mortality was 3.8 times higher (CI 3.6-4.1) compared with the general population of older US adults. Propensity-weighted mortality at 1 year for nonsurgical patients was 26.7 of 100 (CI: 24.5-29.0). Mortality for surgical patients was significantly lower (19.7/100; CI 14.5-25.0). Risk difference was 7.0 fewer surgical deaths per 100 patients (CI: 1.3-12.7). Surgical patients aged 65 to 74 years had the largest difference in mortality with 11.2 fewer deaths per 100 (CI: 1.1-21.3). Discussion: Patients with axis fractures are predominantly older Caucasian women and have a higher mortality rate than the general population. Propensity-weighted mortality at 1-year was lower in the surgical patients with the largest risk difference occurring in patients 65 to 74 years old. Conclusions: Surgery may provide an independent survival benefit in patients aged 65 to 75 years, and the mortality difference diminishes thereafter

Effects of aggregation of drug and diagnostic codes on the performance of the high-dimensional propensity score algorithm: an empirical example

BACKGROUND: The High-Dimensional Propensity Score (hd-PS) algorithm can select and adjust for baseline confounders of treatment-outcome associations in pharmacoepidemiologic studies that use healthcare claims data. How hd-PS performance is affected by aggregating medications or medical diagnoses has not been assessed. METHODS: We evaluated the effects of aggregating medications or diagnoses on hd-PS performance in an empirical example using resampled cohorts with small sample size, rare outcome incidence, or low exposure prevalence. In a cohort study comparing the risk of upper gastrointestinal complications in celecoxib or traditional NSAIDs (diclofenac, ibuprofen) initiators with rheumatoid arthritis and osteoarthritis, we (1) aggregated medications and International Classification of Diseases-9 (ICD-9) diagnoses into hierarchies of the Anatomical Therapeutic Chemical classification (ATC) and the Clinical Classification Software (CCS), respectively, and (2) sampled the full cohort using techniques validated by simulations to create 9,600 samples to compare 16 aggregation scenarios across 50% and 20% samples with varying outcome incidence and exposure prevalence. We applied hd-PS to estimate relative risks (RR) using 5 dimensions, predefined confounders, ≤ 500 hd-PS covariates, and propensity score deciles. For each scenario, we calculated: (1) the geometric mean RR; (2) the difference between the scenario mean ln(RR) and the ln(RR) from published randomized controlled trials (RCT); and (3) the proportional difference in the degree of estimated confounding between that scenario and the base scenario (no aggregation). RESULTS: Compared with the base scenario, aggregations of medications into ATC level 4 alone or in combination with aggregation of diagnoses into CCS level 1 improved the hd-PS confounding adjustment in most scenarios, reducing residual confounding compared with the RCT findings by up to 19%. CONCLUSIONS: Aggregation of codes using hierarchical coding systems may improve the performance of the hd-PS to control for confounders. The balance of advantages and disadvantages of aggregation is likely to vary across research settings

Real-world evidence on sodium-glucose cotransporter-2 inhibitor use and risk of Fournier's gangrene

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with increased occurrence of Fournier's gangrene (FG), a rare but serious form of necrotizing fasciitis, leading to a warning from the Food and Drug Administration. Real-world evidence on FG is needed to validate this warning. Methods We used data from IBM MarketScan (2013-2017) to compare the incidence of FG among adult patients who initiated either SGLT2i, a dipeptidyl peptidase-4 inhibitor (DPP4i), or any non-SGLT2i antihyperglycemic medication. FG was defined using inpatient International Classification of Diseases, Ninth Edition and Tenth Edition diagnosis codes 608.83 and N49.3, respectively, combined with procedure codes for debridement, surgery, or systemic antibiotics. We estimated crude incidence rates (IRs) using Poisson regression, and crude and adjusted HRs (aHR) and 95% CIs using standardized mortality ratio-weighted Cox proportional hazards models. Sensitivity analyses examined the impact of alternative outcome definitions. Results We identified 211 671 initiators of SGLT2i (n=93 197) and DPP4i (n=118 474), and 305 329 initiators of SGLT2i (n=32 868) and non-SGLT2i (n=272 461). Crude FG IR ranged from 3.2 to 3.8 cases per 100 000 person-years during a median follow-up of 0.51-0.58 years. Compared with DPP4i, SGLT2i initiation was not associated with increased risk of FG for any outcome definition, with aHR estimates ranging from 0.25 (0.04-1.74) to 1.14 (0.86-1.51). In the non-SGLT2i comparison, we observed an increased risk of FG for SGLT2i initiators when using FG diagnosis codes alone, using all diagnosis settings (aHR 1.80; 0.53-6.11) and inpatient diagnoses only (aHR 4.58; 0.99-21.21). Conclusions No evidence of increased risk of FG associated with SGLT2i was observed compared with DPP4i, arguably the most relevant clinical comparison. However, uncertainty remains based on potentially higher risk in the broader comparison with all non-SGLT2i antihyperglycemic agents and the rarity of FG. Trial registration number EUPAS Register Number 30018

The comparative risk of acute kidney injury of vancomycin relative to other common antibiotics

The glycopeptide antibiotic vancomycin is a mainstay in the treatment of Gram-positive infection. While its association with acute kidney injury (AKI) has waxed and waned, recent data suggest nephrotoxicity, even as mono-therapy. Our study aimed to evaluate the 2-week risk of AKI after at least 3 days of intravenous vancomycin mono-therapy initiated within 5 days of hospitalization compared to other intravenous antibiotics used for similar indications. We used a new user-active comparator study design and identified patients with a first hospitalization during which they received vancomycin or comparator, from commercial claims based in the United States. We estimated incidence rates, hazard ratios using adjusted cox-regression models, and standardized mortality/morbidity ratio weighted cox-regression models. In the 32,997 patients vancomycin was used in 17% of patients and 129 cases of AKI were observed. Overall incidence of AKI was 9.3 (95% CI 0.78–1.22) per 100 person-years. The adjusted hazard ratio for vancomycin versus all other comparators was 0.74 (95% CI 0.45–1.21). Separate models for respective comparators resulted in hazard ratios below the null, except for vancomycin vs. cefazolin. Intravenous vancomycin mono-therapy does not increase the risk of AKI compared to other intravenous antibiotics used for similar indication in this cohort of hospitalized patients

Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase-4 inhibitors: An analysis of Medicare claims data from 2007 to 2015

Aims: To examine the outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitor initiation with and without concurrent metformin treatment. Materials and methods: We identified Medicare enrollees initiating a DPP-4 inhibitor, a sulphonylurea or a thiazolidinedione. Using propensity-score-weighted Poisson models, we evaluated 1-year cardiovascular (CV) outcome incidence among initiators of DPP-4 inhibitors versus comparators in subgroups with and without concurrent metformin use, and assessed the interaction between initiation drug and metformin. Outcomes included mortality, non-fatal myocardial infarction (MI), stroke, and a composite outcome. Results: For the DPP-4 inhibitor (n = 13 391) versus sulphonylurea (n = 33 206) comparison, rate differences in composite outcome incidence favoured DPP-4 inhibitors: −2.0/100 person-years among metformin users (95% confidence interval [CI] −2.7 to −1.3) and − 1.0/100 person-years (95% CI −1.8 to −0.2) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (−1.5/100 person-years [95% CI −2.1 to −0.9] and −0.7/100 person-years [95% CI −1.4 to 0.0]) and non-fatal MI (−0.5/100 person-years [95% CI −0.8, −0.3] and 0.1/100 person-years [95% CI −0.2 to 0.4]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for non-fatal MI (P = 0.008). For the DPP-4 inhibitor (n = 22 210) versus thiazolidinedione (n = 9517) comparison, rate differences in composite outcome incidence for DPP-4 inhibitor initiation were −0.6/100 person-years (95% CI −1.5 to 0.2) among metformin users and 1.0 (95% CI 0.0 to 2.0) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (−0.5/100 person-years [95% CI −1.3 to 0.1] and 0.8/100 person-years [95% CI −0.0 to 1.7]) and non-fatal MI (−0.1/100 person-years [95% CI −0.4 to 0.2] and 0.2/100 person-years [95% CI −0.1 to 0.6]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for the composite outcome (P = 0.024) and mortality (P = 0.023). Conclusion: Incidence rate differences in multiple CV outcomes appeared more favourable when DPP-4 inhibitor initiation occurred in the presence of metformin, suggesting a possible interaction between DPP-4 inhibitors and metformin

Comparative safety of pioglitazone versus clinically meaningful treatment alternatives concerning the risk of bladder cancer in older US adults with type 2 diabetes

Aims: To compare bladder cancer incidence between patients initiating pioglitazone treatment and patients initiating treatment with dipeptidyl-peptidase-4 inhibitors [DPP-4s] or sulfonylureas. Methods: We identified Medicare beneficiaries aged >65 years who initiated treatment with pioglitazone (N = 38 700), DPP-4s (N = 82 552) or sulfonylureas (N = 126 104) between 2007 and 2014 after at least 6 months without prescriptions for these drug classes. Patients were followed from second prescription until bladder cancer outcome (2 claims within 60 days) using a 6-month induction/latency period, censoring for treatment change, death or end of 2014. We used propensity score-weighted Cox proportional-hazards models to obtain adjusted hazard ratios (aHR) and their 95% confidence intervals. Results: Overall mean age of participants was 75 years and 41% were men. Over a median of 1.2 treatment years, 727 beneficiaries developed bladder cancer. Pioglitazone initiators had an increased incidence of bladder cancer (308 vs 204 [DPP-4s] or 231 [sulfonylureas] per 100 000 person-years; aHR, 1.57 [1.23-2.00] vs DPP-4s and 1.32 [1.02-1.70] vs sulfonylureas). The increased risk emerged within the first 2 years of treatment (aHR, 1.63 [1.22-2.17] vs DPP-4s and 1.32 [0.98-1.78] vs sulfonylureas). If treatment was discontinued within the first 2 years, the risk after 2 years post initiation was attenuated (aHR, 0.89 [0.61-1.28]) compared with patients treated for more than 2 years (aHR, 1.45 [0.93-2.26]) both vs DPP-4s. Findings were consistent across secondary and sensitivity analyses. Conclusions: Pioglitazone was associated with an elevated risk of bladder cancer compared with DPP-4s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after discontinuing. Pioglitazone's relative effectiveness should be weighed against a small absolute increase in risk of bladder cancer

The risk of acute pancreatitis after initiation of dipeptidyl peptidase 4 inhibitors: Testing a hypothesis of subgroup differences in older U.S. adults

OBJECTIVE To examine whether dipeptidyl peptidase 4 inhibitors (DPP-4I) increase acute pancreatitis risk in older patients and whether the association varies by age, sex, and history of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS We conducted a cohort study of DPP-4I initiators versus thiazolidinedione (TZD) or sulfonylurea initiators using U.S.Medicare beneficiaries, 2007-2014. Eligible initiators were aged 66 years or older without history of pancreatic disease or alcohol-related diseases. Patients were followed up for hospitalization due to acute pancreatitis and censored at 90 days after treatment changes. Weighted Cox models were used to estimate the hazard ratio (HR) for acute pancreatitis. Analyses were performed overall as well as within subgroups defined by age, sex, and CVD history. RESULTS We found no increased risk of acute pancreatitis comparing 49,374 DPP-4I initiators to 132,223 sulfonylurea initiators (weighted HR 1.01; 95% CI 0.83-1.24) and comparing 57,301 DPP-4I initiators to 32,612 TZD initiators (weighted HR 1.11; 95% CI 0.76-1.62). Age and sex did not modify the association. Among patients with CVD, acute pancreatitis incidence was elevated in initiators of DPP-4I and sulfonylurea (2.3 and 2.4 per 1,000 person-years, respectively) but not in TZD initiators (1.5). Among patients with CVD, higher risk of acute pancreatitis was observed with DPP- 4I compared with TZD (weighted HR 1.84; 95% CI 1.02-3.35) but not compared with sulfonylurea. CONCLUSIONS Our study provides evidence that DPP-4I is not associated with an increased risk of acute pancreatitis in older adults overall. The positive association observed in patients with CVD could be due to chance or bias but merits further investigation