National guidelines recommend genomic profiling of tumor tissue to guide precision therapy. We compared the specimen adequacy for genomic profiling and yield of DNA between endoscopic ultrasound ...(EUS)-guided fine-needle biopsy (FNB) and EUS-guided fine-needle aspiration (FNA).
In our tandem, randomized controlled trial, consecutive patients undergoing EUS for evaluation of pancreatic masses underwent both conventional EUS-FNA with a 25-gauge needle and paired EUS-FNB (19 or 22-gauge needle), with the order randomized (EUS-FNA first followed by EUS-FNB, or vice versa). A minimum of one pass with each needle was obtained for histology. Second and third passes were performed to collect DNA. Specimens were evaluated by a cytopathologist blinded to the needle type. Specimen adequacy for genomic profiling was calculated based on FoundationOne clinical diagnostic (CDx) adequacy requirements. We compared the adequacy for genomic profiling DNA (quantity) and histology yields with both needles.
Analysis included 50 patients (25 men; mean age 68 standard deviation (SD) 13 years), with a mean lesion size of 38 (SD 17) mm; 37 lesions (74 %) were pancreatic ductal adenocarcinoma (PDAC). The mean DNA concentrations in PDAC by FNB and FNA needles were 5.930 (SD 0.881) µg/mL vs. 3.365 (SD 0.788) µg/mL, respectively (
= 0.01). The median standardized histology score per pass with EUS-FNB was 5 (sufficient for histology) and for EUS-FNA was 2 (enough for cytology). Specimen adequacy for genomic profiling and yield of DNA was significantly higher with FNB than with FNA needles.
In this study, adequacy for genomic profiling, DNA, and histology yield were considerably superior using an EUS-FNB needle compared with an EUS-FNA needle.
Building large solar power plants requires significant long-term investment so understanding impacts from climate change will aid financial planning, technology selection, and energy output ...projections. In this article we examine how projected changes in temperature and insolation over the 21st century will affect photovoltaic (PV) and concentrated solar power (CSP) output. Projected climate data was obtained from the coupled ocean-atmosphere climate models HadGEM1 and HadCM3 under the IPCC SRES A1B scenario which describes a future world of rapid economic growth with a balanced use of renewable and fossil fuel power generation. Our calculations indicate that under this scenario PV output from 2010 to 2080 is likely to increase by a few percent in Europe and China, see little change in Algeria and Australia, and decrease by a few percent in western USA and Saudi Arabia. CSP output is likely to increase by more than 10% in Europe, increase by several percent in China and a few percent in Algeria and Australia, and decrease by a few percent in western USA and Saudi Arabia. The results are robust to uncertainty in projected temperature change. A qualitative analysis of uncertainty in projected insolation change suggests strongest confidence in the results for Europe and least confidence in the results for western USA. Changes in PV and CSP output are further studied by calculating fractional contributions from changes in temperature and insolation. For PV there is considerable variation in contribution depending on location. For CSP the contribution from changes in insolation is always dominant.
Adenoma detection rate (ADR) is a key measure of quality in colonoscopy. Low ADRs are associated with development of interval cancer after "negative" colonoscopy. Uncontrolled studies mandating ...longer withdrawal time, and other incentives, have not significantly improved ADR. We hypothesized that an endoscopist training program would increase ADRs.
Our Endoscopic Quality Improvement Program (EQUIP) was an educational intervention for staff endoscopists. We measured ADRs for a baseline period, then randomly assigned half of the 15 endoscopists to undergo EQUIP training. We then examined baseline and post-training study ADRs for all endoscopists (trained and un-trained) to evaluate the impact of training. A total of 1,200 procedures were completed in each of the two study phases.
Patient characteristics were similar between randomization groups and between study phases. The overall ADR in baseline phase was 36% for both groups of endoscopists. In the post-training phase, the group of endoscopists randomized to EQUIP training had an increase in ADR to 47%, whereas the ADR for the group of endoscopists who were not trained remained unchanged at 35%. The effect of training on the endoscopist-specific ADRs was estimated with an odds ratio of 1.73 (95% confidence interval 1.24-2.41, P=0.0013).
Our results indicate that ADRs can be improved considerably through simple educational efforts. Ultimately, a trial involving a larger number of endoscopists is needed to validate the utility of our training methods and determine whether improvements in ADRs lead to reduced colorectal cancer.
Spatial patterns of local climate feedback and equilibrium partial temperature responses are produced from eight general circulation models with slab oceans forced by doubling carbon dioxide (CO₂). ...The analysis is extended to other forcing mechanisms with the Met Office Hadley Centre slab ocean climate model version 3 (HadSM3). In agreement with previous studies, the greatest intermodel differences are in the tropical cloud feedbacks. However, the greatest intermodel spread in the equilibrium temperature response comes from the water vapor plus lapse rate feedback, not clouds, disagreeing with a previous study. Although the surface albedo feedback contributes most in the annual mean to the greater warming of high latitudes, compared to the tropics (polar amplification), its effect is significantly ameliorated by shortwave cloud feedback. In different seasons the relative importance of the contributions varies considerably, with longwave cloudy-sky feedback and horizontal heat transport plus ocean heat release playing a major role during winter and autumn when polar amplification is greatest. The greatest intermodel spread in annual mean polar amplification is due to variations in horizontal heat transport and shortwave cloud feedback. Spatial patterns of local climate feedback for HadSM3 forced with 2 × CO₂, + 2% solar, low-level scattering aerosol and high-level absorbing aerosol are more similar than those for different models forced with 2 × CO₂. However, the equilibrium temperature response to high-level absorbing aerosol shows considerably enhanced polar amplification compared to the other forcing mechanisms, largely due to differences in horizontal heat transport and water vapor plus lapse rate feedback, with the forcing itself acting to reduce amplification. Such variations in highlatitude response between models and forcing mechanisms make it difficult to infer specific causes of recent Arctic temperature change.
The West African climate is unique and challenging to reproduce using standard resolution climate models as a large proportion of precipitation comes from organised deep convection. For the first ...time, a regional 4.5 km convection permitting simulation was performed on a pan-African domain for a period of 10 years (1997–2006). The 4.5 km simulation (CP4A) is compared with a 25 × 40 km convection-parameterised model (R25) over West Africa. CP4A shows increased mean precipitation, which results in improvements in the mature phase of the West African monsoon but deterioration in the early and late phases. The distribution of precipitation rates is improved due to more short lasting intense rainfall events linked with mesoscale convective systems. Consequently, the CP4A model shows a better representation of wet and dry spells both at the daily and sub-daily time-scales. The diurnal cycle of rainfall is improved, which impacts the diurnal cycle of monsoon winds and increases moisture convergence in the Sahel. Although shortcomings were identified, with implications for model development, this convection-permitting model provides a much more reliable precipitation distribution than its convection-parameterised counterpart at both daily and sub-daily time-scales. Convection-permitting scales will therefore be useful to address the crucial question of how the precipitation distribution will change in the future.
Background Colonoscopy is protective against colorectal cancer, but its quality and protective benefits can vary. Adenoma detection rate (ADR) is associated with quality and the degree of protection ...against colorectal cancer and death. In a previous, single academic center, randomized, controlled trial, we demonstrated that an endoscopic quality improvement program increased ADR (EQUIP-1) and that those increases were durable (EQUIP-2). We hypothesized that EQUIP training would increase ADR in a multicenter clinical practice setting. Methods Nine large clinical practice sites were recruited. After a baseline period (phase I), 5 sites were randomized to receive supplemental in-person EQUIP training with active feedback. After follow-up (phase II), the changes in ADRs at these sites were compared with the changes at 4 control sites that did not receive training or feedback until after study completion. Results Twenty-two thousand three hundred sixteen colonoscopies were included. There was a statistically significant increase in ADR at the training sites (odds ratio OR, 1.28; P = .004) with a raw ADR of 31% in phase I and 42% in phase II after the intervention. However, raw ADRs also increased at the control sites (from 36% to 39%). As a result, there was limited evidence of a training effect (OR, 1.03; 95% confidence interval CI, 0.84-1.25; P = .78). Conclusions ADRs increased at the sites participating in the endoscopic quality improvement program. However it is not clear to what extent the training program is responsible for the changes, because raw ADRs also increased at the control sites but to a lesser extent. (Clinical Trials Registration number: NCT02325635 .)
ObjectiveSurveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett’s oesophagus (BE) are currently empiric and not based ...on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines.DesignData on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies.Results594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4–4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI −7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia).ConclusionsBE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.
Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease (AD).
APOE4
is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as ...in cerebrovascular diseases. Therefore, we examined the effects of
APOE4
, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (
n
= 60) or without CAA (
n
= 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more
APOE4
alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or
APOE4
. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or
APOE4
, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and
APOE
genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE.
IMPORTANCE: Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed ...antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD. OBJECTIVE: To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida’s memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings. MAIN OUTCOMES AND MEASURES: Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. RESULTS: In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S–positive NFTs was highest in the nbM of HpSp AD (14 9-20; n = 163), lower in typical AD (10 5-16; n = 937), and lowest in limbic predominant AD (8 5-11, n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 17-28; n = 148), higher in typical AD (25 19-30; n = 727), and highest in limbic predominant AD (26 19-32; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, −1.5; 95% CI, −2.9 to −0.15; P = .03) and typical AD (β, −3.2; 95% CI, −3.9 to −2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, −1.8; 95% CI, −3.2 to −0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases. CONCLUSIONS AND RELEVANCE: These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.
The major clinical side effect of the ERBB2-targeted breast cancer therapy, trastuzumab, is a decline in the left ventricular ejection fraction (LVEF). Improved markers are needed to better identify ...patients susceptible to cardiotoxicity.
The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or concurrent paclitaxel and trastuzumab (arm C) in patients with HER2-positive breast cancer. A genome-wide association study was performed on all patients with available DNA (N=1446). We used linear regression to identify single nucleotide polymorphisms (SNPs) associated with decline in LVEF, adjusting for age, baseline LVEF, antihypertensive medications, and the first two principle components.
In total, 618 863 SNPs passed quality control and DNA from 1191 patients passed genotyping quality control and were identified as Whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (P=7.73×10 to 8.93×10), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6, and LINC01060, in patients who received chemotherapy plus trastuzumab (arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (arm A, N=391) and did not increase in significance in the combined analysis of all patients. We did not observe association, P<0.05, with SNPs previously associated with trastuzumab-induced cardiotoxicity at ERBB2, I655V, and P1170A. We replicated association, P<0.05, with SNPs previously associated with anthracycline-induced cardiotoxicity at CBR3 and ABCB1.
Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.
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