Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Integrating genomic features for non-invasive early lung cancer detection.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Long-term outcome of peripheral T-cell lymphomas: Ten-year follow-up of the International Prospective T-cell Project.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of haematological cancers with generally poor clinical outcomes. However, a subset of patients experience durable disease control, and little is known regarding long-term outcomes. The International T-cell Lymphoma Project (ITCLP) is the largest prospectively collected cohort of patients with PTCLs, providing insight into clinical outcomes at academic medical centres globally. We performed a long-term outcome analysis on patients from the ITCLP with available 10-year follow-up data (n = 735). The overall response rate to first-line therapy was 68%, while 5- and 10-year overall survival estimates were 49% and 40% respectively. Most deaths occurred prior to 5 years, and for patients alive at 5 years, the chance of surviving to 10 years was 84%. However, lymphoma remained the leading cause of death in the 5- to 10-year period (67%). Low-risk International Prognostic Index and Prognostic Index for T-cell lymphoma scores both identified patients with improved survival, while in multivariate analysis, age >60 years and Eastern Cooperative Oncology Group performance status 2-4 were associated with inferior outcomes. The favourable survival seen in patients achieving durable initial disease control emphasizes the unmet need for optimal front-line therapeutic approaches in PTCLs.

Monitoring redox stress in human airway epithelial cells exposed to woodsmoke at an air-liquid interface.

Wildland fires contribute significantly to the ambient air pollution burden worldwide, causing a range of adverse health effects in exposed populations. The toxicity of woodsmoke, a complex mixture of gases, volatile organic compounds, and particulate matter, is commonly studied in vitro using isolated exposures of conventionally cultured lung cells to either resuspended particulate matter or organic solvent extracts of smoke, leading to incomplete toxicity evaluations. This study aimed to improve our understanding of the effects of woodsmoke inhalation by building an advanced in vitro exposure system that emulates human exposure of the airway epithelium. We report the development and characterization of an innovative system that permits live-cell monitoring of the intracellular redox status of differentiated primary human bronchial epithelial cells cultured at an air-liquid interface (pHBEC-ALI) as they are exposed to unfractionated woodsmoke generated in a tube furnace in real time. pHBEC-ALI exposed to freshly generated woodsmoke showed oxidative changes that were dose-dependent and reversible, and not attributable to carbon monoxide exposure. These findings show the utility of this novel system for studying the molecular initiating events underlying woodsmoke-induced toxicity in a physiologically relevant in vitro model, and its potential to provide biological plausibility for risk assessment and public health measures.

Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). INTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

Heat abatement during the pre-weaning period: effects on lying behavior and disbudding-related responses of male Holstein calves.

Strategies to abate heat stress are seldom adopted for pre-weaned dairy calves and little is known about their effects on behavior and pain sensitivity of youngstock. Our objectives were to determine the effects of heat stress abatement on lying behavior and disbudding-related pain sensitivity, wound healing, and change in intake. Male Holstein calves (n = 60; 0 to 68 d of age) were assigned randomly at birth (d 0) to 1 of 3 treatments: hutch outdoors with 50% of its area covered with plywood (control = 20), hutch in a barn with no cooling (SH = 21), and hutch in a barn with ceiling fans (SHF = 19). Calves were fitted with lying-behavior loggers on the hind leg from d 1 to 68. On d 32 ± 8 (±SD), we disbudded calves using hot iron, 30 min after cornual nerves were blocked with lidocaine. Immediately before (0 h), and at 1, 2, and 3 h after disbudding, we evaluated calves for mechanical nociceptive threshold (MNT) and head (ear flick, head shake, head rubbing) and somatic (tail flicking, foot stamping, restlessness) behaviors. On d 1, 3, 7, and 14 after disbudding, we evaluated the MNT and, on d 7 and 14, we evaluated wound healing (1 = crust, 5 = exudate). We calculated the relative change in milk solids and starter intake from d 0 to 6 relative to disbudding compared with the average of the 72 h preceding the procedure. The lying time was 0.6 h/d greater for the SHF treatment compared with the SH treatment. The control treatment resulted in 3.2 and 4.1 more lying bouts per day than the SH and SHF treatments, respectively; consequently, the control treatment resulted in lying-bout duration 7.7 and 10.9 min/event shorter than the SH and SHF treatments, respectively. We did not detect an effect of treatment on the number of disbudding-related head and somatic behaviors and MNT. The odds of calves having abnormal wound was 3.5 and 3.2 times greater for the control treatment compared with the SH and SHF treatments, respectively. We did not detect an effect of treatment on the relative change in intake of milk solids and starter. Heat abatement improves the welfare of pre-weaned dairy calves and may hasten healing.

Heat abatement during the pre-weaning period: effects on growth, feed efficiency, metabolites, and insulin of male Holstein calves.

Heat stress abatement strategies for pre-weaned dairy calves are seldom evaluated. An experiment was conducted to evaluate the effects of housing calves under a barn and provision of fans to calves housed under a barn on calfhood performance. The experiment was conducted in a dairy in southern Georgia, USA. Male Holstein calves (n = 60; 0 to 68 day of age) were assigned randomly at birth (day 0) to 1 of 3 treatments: hutch outdoors with 50% of its area covered with plywood (control = 20), hutch in a barn with no cooling (SH = 21), and hutch in a barn with ceiling fans (SHF = 19). Body weight (BW) was measured at birth, and total serum protein and wither-height were measured 24 to 48 h after birth. A sub-set of hutches was evaluated for air speed and temperature, and rectal temperature (RT) and respiratory frequency (RF) of calves housed in these hutches were measured at 0900 and 1500 h. Intakes of liquid feed (days 14 to 63) and starter (days 14 to 68) were recorded daily, BW and wither-height were measured weekly, and feed efficiency was calculated weekly. Blood was sampled on days 1, 14, 28, 42, 49, 52, 56, 58, 63, and 65 for the measurement of fatty acids, ß-hydroxybutyrate, glucose, and insulin. The SHF treatment resulted in air velocity 0.56 to 0.83 m/s greater (P < 0.01) than the control and SH treatments, respectively, whereas the control treatment resulted in air temperature 1.2 to 3.2 °C greater (P < 0.01) than the SH and SHF treatments, respectively. The RT of calves in the control treatment was 0.1 to 1.1 °C greater (P ≤ 0.03) than the SH and SHF treatments, respectively, and the control treatment resulted in RF 39.4 to 60.2 mov/min greater (P < 0.01) than the SH and SHF treatments, respectively. Treatment did not (P ≥ 0.27) affect feed efficiency and concentrations of metabolites and insulin, but calves in the control treatment were 2.6 cm shorter (P = 0.03) than calves in the SHF treatments at weaning. Provision of fans to calves housed under a barn reduced RT, RF, but only had a minute impact on wither-height.

Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy.

RATIONALE: The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown. OBJECTIVE: To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart. METHODS AND RESULTS: We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased, while hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models. CONCLUSION: Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.

Circulating Tumor DNA Analysis for Detection of Minimal Residual Disease After Chemoradiotherapy for Localized Esophageal Cancer.

BACKGROUND & AIMS: Biomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy. METHODS: We performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6-8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy). RESULTS: The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P < .0001), formation of distant metastases (hazard ratio, 32.1; P < .0001), and shorter disease-specific survival times (hazard ratio, 23.1; P < .0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P = .03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P < .001 for comparison of either technique to combined analysis). CONCLUSIONS: In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.

Human Anti-HIV-1 gp120 Monoclonal Antibodies with Neutralizing Activity Cloned from Humanized Mice Infected with HIV-1.

Broadly neutralizing, anti-HIV-1 gp120 mAbs have been isolated from infected individuals, and there is considerable interest in developing these reagents for Ab-based immunoprophylaxis and treatment. As a means to identify potentially new anti-HIV Abs, we exploited humanized NOD-scid IL2rγnull mice systemically infected with HIV-1 to generate a wide variety of Ag-specific human mAbs. The Abs were encoded by a diverse range of variable gene families and Ig classes, including IgA, and several showed significant levels of somatic mutation. Moreover, the isolated Abs not only bound target Ags with similar affinity as broadly neutralizing Abs, they also demonstrated neutralizing ability against multiple HIV-1 clades. The use of humanized mice will allow us to use our knowledge of HIV-1 gp120 structure and function, and the immune response targeting this protein, to generate native human prophylactic Abs to reduce the infection and spread of HIV-1.

The tragedy of the canon; or, path dependence in the history and philosophy of science.

We have previously argued that historical cases must be rendered canonical before they can plausibly serve as evidence for philosophical claims, where canonicity is established through a process of negotiation among historians and philosophers of science (Bolinska and Martin, 2020). Here, we extend this proposal by exploring how that negotiation might take place in practice. The working stock of historical examples that philosophers tend to employ has long been established informally, and, as a result, somewhat haphazardly. The composition of the historical canon of philosophy of science is therefore path dependent, and cases often become stock examples for reasons tangential to their appropriateness for the purposes at hand. We show how the lack of rigor around the canonization of case studies has muddied the waters in selected philosophical debates. This, in turn, lays the groundwork for proposing ways in which they can be improved.

Non-inferiority randomised phase 3 trial comparing two radiation schedules (single vs. five fractions) in malignant spinal cord compression.

BACKGROUND: The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. METHODS: Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = 'Walk unaided', 2 = 'With walking aid' and 3 = 'Bed-bound'. The margin used to establish non-inferiority was a detrimental change of -0.4 in the mean difference between arms. RESULTS: One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30-87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was -0.12 to 0.6. Since -0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2-3 AE compared with six (11%) patients in the SF arm (p = 0.093). CONCLUSION: For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. CLINICAL TRIAL REGISTRATION: Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.

Association of adoption of transradial access for percutaneous coronary intervention in ST elevation myocardial infarction with door-to-balloon time.

OBJECTIVES: We aimed to study adoption of transradial primary percutaneous coronary intervention (TR-PPCI) for ST elevation myocardial infarction (STEMI) ("radial first" approach) and its association with door-to-balloon time (D2BT). BACKGROUND: TR-PPCI for STEMI is underutilized in the United States due to concerns about prolonging D2BT. Whether operators and hospitals adopting a radial first approach in STEMI incur prolonged D2BT is unknown. METHODS: In 1,272 consecutive cases of STEMI with PPCI at our hospital from January 1, 2011, to December 31, 2016, we studied TR-PPCI adoption and its association with D2BT including a propensity matched analysis of similar risk TR-PPCI and trans-femoral primary PCI (TF-PPCI) patients. RESULTS: With major increases in hospital-level TR-PPCI (hospital TR-PPCI rate: 2.6% in 2011 to 79.4% in 2016, p-trend<.001) and operator-level TR-PPCI (mean operator TR-PPCI rate: 2.9% in 2011 to 81.1% in 2016, p-trend = .005), median hospital level D2BT decreased from 102 min [81, 142] in 2011 to 84 min [60, 105] in 2016 (p-trend<.001). TF crossover (10.3%; n = 57) was not associated with unadjusted D2BT (TR-PPCI success 91 min [72, 112] vs. TF crossover 99 min [70, 115], p = .432) or D2BT adjusted for study year and presenting location (7.2% longer D2BT with TF crossover, 95% CI: -4.0% to +18.5%, p = .208). Among 273 propensity-matched pairs, unadjusted D2BT (TR-PPCI 98 [78, 117] min vs. TF-PPCI 101 [76, 132] min, p = .304), and D2BT adjusted for study year and presenting location (5.0% shorter D2BT with TR-PPCI, 95% CI: -12.4% to +2.4%, p = .188) were similar. CONCLUSIONS: TR-PPCI can be successfully implemented without compromising D2BT performance.

Negotiating history: Contingency, canonicity, and case studies.

Objections to the use of historical case studies for philosophical ends fall into two categories. Methodological objections claim that historical accounts and their uses by philosophers are subject to various biases. We argue that these challenges are not special; they also apply to other epistemic practices. Metaphysical objections, on the other hand, claim that historical case studies are intrinsically unsuited to serve as evidence for philosophical claims, even when carefully constructed and used, and so constitute a distinct class of challenge. We show that attention to what makes for a canonical case can address these problems. A case study is canonical with respect to a particular philosophical aim when the features relevant to that aim provide a reasonably complete causal account of the results of the historical process under investigation. We show how to establish canonicity by evaluating relevant contingencies using two prominent examples from the history of science: Eddington's confirmation of Einstein's theory of general relativity using his data from the 1919 eclipse and Watson and Crick's determination of the structure of DNA.

Trauma-Induced Nanohydroxyapatite Deposition in Skeletal Muscle is Sufficient to Drive Heterotopic Ossification.

Heterotopic ossification (HO), or the pathologic formation of bone within soft tissues, is a significant complication following severe injuries as it impairs joint motion and function leading to loss of the ability to perform activities of daily living and pain. While soft tissue injury is a prerequisite of developing HO, the exact molecular pathology leading to trauma-induced HO remains unknown. Through prior investigations aimed at identifying the causative factors of HO, it has been suggested that additional predisposing factors that favor ossification within the injured soft tissues environment are required. Considering that chondrocytes and osteoblasts initiate physiologic bone formation by depositing nanohydroxyapatite crystal into their extracellular environment, we investigated the hypothesis that deposition of nanohydroxyapatite within damaged skeletal muscle is likewise sufficient to predispose skeletal muscle to HO. Using a murine model genetically predisposed to nanohydroxyapatite deposition (ABCC6-deficient mice), we observed that following a focal muscle injury, nanohydroxyapatite was robustly deposited in a gene-dependent manner, yet resolved via macrophage-mediated regression over 28 days post injury. However, if macrophage-mediated regression was inhibited, we observed persistent nanohydroxyapatite that was sufficient to drive the formation of HO in 4/5 mice examined. Together, these results revealed a new paradigm by suggesting the persistent nanohydroxyapatite, referred to clinically as dystrophic calcification, and HO may be stages of a pathologic continuum, and not discrete events. As such, if confirmed clinically, these findings support the use of early therapeutic interventions aimed at preventing nanohydroxyapatite as a strategy to evade HO formation.

Conflict of Interest Mitigation Procedures May Have Little Influence on the Perceived Procedural Fairness of Risk-Related Research.

Two between-subject experiments explored perceived conflict of interest (COI)-operationalized as perceived procedural unfairness-in a hypothetical public-private research partnership to study the health risks of trans fats. Perceived fairness was measured as subjects' perceptions that health researchers would be willing to listen to a range of voices and minimize bias (i.e., COI) in the context of a research project. Experiment 1 (n = 1,263) randomly assigned research subjects to a partnership that included (1) a combination of an industry partner, a university partner, and a nongovernmental organization (NGO) partner; and (2) one of three processes aimed at mitigating the potential for COI to harm the quality of the research. The procedures included an arm's-length process meant to keep the university-based research team from being influenced by the other partners, an independent advisory board to oversee the project, and a commitment to making all data and analyses openly available. The results suggest that having an industry partner has substantial negative effects on perceived fairness and that the benefit of employing a single COI-mitigation process may be relatively small. Experiment 2 (n = 1,076) assessed a partnership of (1) a university and either an NGO or industry partner and (b) zero, one, two, or three of the three COI-mitigation procedures. Results suggest there is little value in combining COI-mitigation procedures. The study has implications for those who aim to foster confidence in scientific findings for which the underlying research may benefit from industry funding.

Prospective Study of the Impact of Liver Biopsy Core Size on Specimen Adequacy and Procedural Complications.

OBJECTIVE: An American Association for the Study of Liver Diseases (AASLD) consensus document stressed the importance of obtaining sufficient liver biopsy specimens to minimize sampling errors. Many centers continue to use smaller-diameter core systems to minimize perceived complication risks. The objective of this study was to assess the impact of core gauge (18- vs 16-gauge) on specimen adequacy and procedural complications. SUBJECTS AND METHODS: One hundred fifty patients referred for liver biopsy were randomized to undergo 16- or 18-gauge ultrasound (US)-guided core biopsy. Hemorrhage was qualitatively evaluated, and pain was assessed using a 10-point rating scale. The length and number of portal tracts per specimen were assessed. On the basis of the AASLD guidelines, specimen adequacy was defined as 11 or more portal tracts. Differences in pathology metrics and pain scoring were assessed using chi-square and linear regression models. RESULTS: No significant hemorrhage occurred in either group, and there was no difference in postbiopsy pain scores. The mean specimen length obtained with 16-gauge needles was less than that obtained with 18-gauge needles (1.7 vs 1.9 cm, p = 0.03). The mean number of portal tracts obtained with 16-gauge biopsies was greater than obtained with 18-gauge systems (14 vs 13, p = 0.03); 85% of 16-gauge biopsy specimens and 80% of 18-gauge biopsy specimens were adequate on the basis of the AASLD criteria, although this difference was not statistically significant. CONCLUSION: US-guided 18- and 16-gauge core biopsies are similarly safe. A large percentage of 18- or 16-gauge specimens are inadequate when AASLD quality control adequacy thresholds are applied, and specimen adequacy is not significantly affected by biopsy gauge.

High Frequency Data Exposes Nonlinear Seasonal Controls on Dissolved Organic Matter in a Large Watershed.

We analyzed a five year, high frequency time series generated by an in situ fluorescent dissolved organic matter (fDOM) sensor installed near the Connecticut River's mouth, investigating high temporal resolution DOM dynamics in a larger watershed and longer time series than previously addressed. We identified a gradient between large, saturating summer fDOM responses to discharge and linear, subdued responses during colder months. Seasonal response patterns were not consistent with multiple linear regression. Alternatively, we binned measurements across the yearly cycle using environmental indices, such as temperature, and applied moving regression, a novel approach which produced superior fits to calendar day binning. Spatially averaged watershed soil temperature at 10 cm was the best overall index of discharge-fDOM response. DOM fractionation showed fDOM was primarily a surrogate for hydrophobic organic acid (HPOA) concentrations. HPOAs were highly correlated with discharge, but hydrophilics (HPIs) were not. Discharge dependent DOM concentrations driven by the HPOA fraction may be controlled by soil temperature and water table position relative to organic and mineral soil horizons. HPI concentrations were correlated with average watershed soil temperature at 10 cm but were rather stationary throughout the year, further indicating a consistent groundwater source for this nonfluorescent DOM. We present a resolved subseasonal empirical model of DOM concentrations and fluxes, showing that riverine DOM flux and quality depend heavily on seasonal terrestrial carbon dynamics and hydrologic flow paths. High frequency monitoring reveals readily discernible patterns demonstrating that upland biogeochemical signals are maintained even at this large watershed scale.