Targeting the glutamine metabolism to suppress cell proliferation in mesenchymal docetaxel-resistant prostate cancer.

Docetaxel (DX) serves as a palliative treatment option for metastatic prostate cancer (PCa). Despite initial remission, acquired DX resistance is inevitable. The mechanisms behind DX resistance have not yet been deciphered, but a mesenchymal phenotype is associated with DX resistance. Mesenchymal phenotypes have been linked to metabolic rewiring, obtaining most ATP production by oxidative phosphorylation (OXPHOS) powered substantially by glutamine (Gln). Likewise, Gln is known to play an essential role in modulating bioenergetic, redox homeostasis and autophagy. Herein, investigations of Gln deprivation on DX-sensitive and -resistant (DR) PCa cells revealed that the DR cell sub-lines were susceptible to Gln deprivation. Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism. Thus, these findings highlight a possible clinical rationale for the chemical inhibition of GLS1 as a therapeutic strategy to target mesenchymal DR PCa cells, thereby delaying accelerated tumour progression.

Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche.

Clonal hematopoiesis (CH) defines a premalignant state predominantly found in older persons that increases the risk of developing hematologic malignancies and age-related inflammatory diseases. However, the risk for malignant transformation or non-malignant disorders is variable and difficult to predict, and defining the clinical relevance of specific candidate driver mutations in individual carriers has proved to be challenging. In addition to the cell-intrinsic mechanisms, mutant cells rely on and alter cell-extrinsic factors from the bone marrow (BM) niche, which complicates the prediction of a mutant cell's fate in a shifting pre-malignant microenvironment. Therefore, identifying the insidious and potentially broad impact of driver mutations on supportive niches and immune function in CH aims to understand the subtle differences that enable driver mutations to yield different clinical outcomes. Here, we review the changes in the aging BM niche and the emerging evidence supporting the concept that CH can progressively alter components of the local BM microenvironment. These alterations may have profound implications for the functionality of the osteo-hematopoietic niche and overall bone health, consequently fostering a conducive environment for the continued development and progression of CH. We also provide an overview of the latest technology developments to study the spatiotemporal dependencies in the CH BM niche, ideally in the context of longitudinal studies following CH over time. Finally, we discuss aspects of CH carrier management in clinical practice, based on work from our group and others.

Impact of atherosclerosis imaging-quantitative computed tomography on diagnostic certainty, downstream testing, coronary revascularization, and medical therapy: the CERTAIN study.

AIMS: The incremental impact of atherosclerosis imaging-quantitative computed tomography (AI-QCT) on diagnostic certainty and downstream patient management is not yet known. The aim of this study was to compare the clinical utility of the routine implementation of AI-QCT versus conventional visual coronary CT angiography (CCTA) interpretation. METHODS AND RESULTS: In this multi-centre cross-over study in 5 expert CCTA sites, 750 consecutive adult patients referred for CCTA were prospectively recruited. Blinded to the AI-QCT analysis, site physicians established patient diagnoses and plans for downstream non-invasive testing, coronary intervention, and medication management based on the conventional site assessment. Next, physicians were asked to repeat their assessments based upon AI-QCT results. The included patients had an age of 63.8 ± 12.2 years; 433 (57.7%) were male. Compared with the conventional site CCTA evaluation, AI-QCT analysis improved physician's confidence two- to five-fold at every step of the care pathway and was associated with change in diagnosis or management in the majority of patients (428; 57.1%; P < 0.001), including for measures such as Coronary Artery Disease-Reporting and Data System (CAD-RADS) (295; 39.3%; P < 0.001) and plaque burden (197; 26.3%; P < 0.001). After AI-QCT including ischaemia assessment, the need for downstream non-invasive and invasive testing was reduced by 37.1% (P < 0.001), compared with the conventional site CCTA evaluation. Incremental to the site CCTA evaluation alone, AI-QCT resulted in statin initiation/increase an aspirin initiation in an additional 28.1% (P < 0.001) and 23.0% (P < 0.001) of patients, respectively. CONCLUSION: The use of AI-QCT improves diagnostic certainty and may result in reduced downstream need for non-invasive testing and increased rates of preventive medical therapy.

Dithranol as novel co-adjuvant for non-invasive dermal vaccination.

Transcutaneous immunization (TCI) utilizing the TLR7 agonist imiquimod (IMQ-TCI) induces T cell-driven protective immunity upon application onto intact skin. In our present work, we combine the anti-psoriatic agent dithranol with IMQ-TCI to boost vaccination efficacy (Dithranol/IMQ-based transcutaneous vaccination (DIVA)). Using ovalbumin-derived peptides as model antigens in mice, DIVA induced superior cytolytic CD8+ T cells and CD4+ T cells with a TH1 cytokine profile in the priming as well as in the memory phase. Regarding the underlying mechanisms, dithranol induced an oxidant-dependent, monocyte-attracting inflammatory milieu in the skin boosting TLR7-dependent activation of dendritic cells and macrophages leading to superior T cell priming and protective immunity in vaccinia virus infection. In conclusion, we introduce the non-invasive vaccination method DIVA to induce strong primary and memory T cell responses upon a single local treatment. This work provides relevant insights in cutaneous vaccination approaches, paving the way for clinical development in humans.

First interobserver agreement of optical coherence tomography in the bile duct: A multicenter collaborative study.

Background and study aims Optical coherence tomography (OCT) is a new technology available for evaluation of indeterminate biliary strictures. It allows under-the-surface visualization and preliminary studies have confirmed standardized characteristics associated with malignancy. The aim of this study is to evaluate the first interobserver agreement in identifying previously agreed upon OCT criteria and diagnosing of malignant versus benign disease. Patients and methods Fourteen endoscopists were asked to review an atlas of reference clips and images of eight criteria derived from expert consensus A total of 35 de-identified video clips were then evaluated for presence of the eight criteria and for final diagnosis of malignant versus benign using the atlas as reference Intraclass correlation (ICC) analysis was done to evaluate interrater agreement. Results Clips of 23 malignant lesions and 12 benign lesions were scored. Excellent interobserver agreement was seen with dilated hypo-reflective structures (0.85) and layering effacement (0.89); hyper-glandular mucosa (0.76), intact layering (0.81), and onion-skin layering (0.77); fair agreement was seen with scalloping (0.58), and thickened epithelium (0.4); poor agreement was seen with hyper-reflective surface (0.36). The diagnostic ICC for both neoplastic (0.8) and non-neoplastic (0.8) was excellent interobserver agreement. The overall diagnostic accuracy was 51 %, ranging from 43 % to 60 %. Conclusions Biliary OCT is a promising new modality for evaluation of indeterminate biliary strictures. Interobserver agreement ranged from fair to almost perfect on eight previously identified criteria. Interobserver agreement for malignancy diagnosis was substantial (0.8). Further studies are needed to validate this data.

Cardiac safety and clinical efficacy of high-dose domperidone for long-term treatment of gastroparesis symptoms.

Domperidone is an effective antiemetic used worldwide, but there have been reports of possible cardiotoxicity. Our goal was to explore the cardiac safety and clinical efficacy of long-term domperidone, titrated as high as 120 mg/day, in patients not responding or unable to tolerate other therapies for gastroparesis (GP).This retrospective cohort study was conducted at a single tertiary care academic center. We objectively assessed the safety and efficacy of domperidone through questionnaires, clinical follow-up and frequent ECGs as mandated by the Food and Drug Administration. We excluded patients with a history of dangerous arrhythmias, prolonged QTc, clinically significant electrolyte disturbances, gastrointestinal hemorrhage or obstruction, presence of a prolactinoma, pregnant or breastfeeding females, or allergy to domperidone. A total of 21 patients met the inclusion criteria for eligibility in this study (52.4% white, 42.9% Hispanic; mean age 50.1 years; 90.5% female). The mean duration of domperidone therapy was 52.3 (range 16-97) months with a mean highest dose of 80 mg/day (range 40-120 mg). Two patients (9.5%) taking 120 mg/day experienced asymptomatic meaningful QTc prolongation (>450 ms in males, >470 ms in females). One-third of patients had asymptomatic non-meaningful QTc prolongation. Palpitations or chest pain was reported in 19% of patients without ECG abnormalities or adverse cardiac events. The mean severity of vomiting and nausea was improved by 82% and 55%, respectively.Long-term treatment with high doses of domperidone (40-120 mg/day) improved GP symptoms in patients previously refractory to other medical therapies and with a satisfactory cardiovascular risk profile.

Short-term aspirin and statin chemoprophylaxis did not reduce the risk of developing advanced adenomatous polyps in Black patients.

BACKGROUND: Chemoprevention of colorectal neoplasia with aspirin and statins is under-investigated in Black patients. Since Black patients suffer disproportionately from colon cancer incidence and mortality compared to other populations, we investigated the utility of aspirin and statin in reducing advanced adenomatous polyp (AAP) risk in Black patients. METHODS: We carried out a retrospective cohort study of screening colonoscopies performed at a large urban academic center from 1/1/2011 through 12/31/2019. We analyzed self-identified Black patients with > 1 colonoscopy and no personal history of either inflammatory bowel disease or colon cancer syndromes. Our primary endpoint was first AAP development after index colonoscopy among Black patients taking both aspirin and a statin compared to those taking one or neither medication. We used multivariate logistic regression modeling to investigate our outcomes. RESULTS: We found data on chemoprophylaxis use in 560 patients. The mean observation period between index colonoscopy and AAP identification was 4 years. AAP developed in 106/560 (19%) of our cohort. We found no difference in AAP risk among Black patients taking both chemoprevention medications compared to partial or no chemoprophylaxis (20% vs 18% respectively, p = 0.49). This finding remained after adjusting for age, body mass index, and tobacco use (odds ratio 1.04, 95% CI 0.65-1.67; p = 0.87). CONCLUSIONS: Short-term aspirin-statin chemoprevention did not reduce the risk of AAP development in our cohort of Black patients. Larger and long-term prospective investigations are needed to investigate the utility of chemoprophylaxis in this population. TRIAL REGISTRATION: Not applicable.

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia.

Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism's lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called "niche" that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

The Danger of Testing by Selecting Controlled Subsets, with Applications to Spoken-Word Recognition.

When examining the effects of a continuous variable x on an outcome y, a researcher might choose to dichotomize on x, dividing the population into two sets-low x and high x-and testing whether these two subpopulations differ with respect to y. Dichotomization has long been known to incur a cost in statistical power, but there remain circumstances in which it is appealing: an experimenter might use it to control for confounding covariates through subset selection, by carefully choosing a subpopulation of Low and a corresponding subpopulation of High that are balanced with respect to a list of control variables, and then comparing the subpopulations' y values. This "divide, select, and test" approach is used in many papers throughout the psycholinguistics literature, and elsewhere. Here we show that, despite the apparent innocuousness, these methodological choices can lead to erroneous results, in two ways. First, if the balanced subsets of Low and High are selected in certain ways, it is possible to conclude a relationship between x and y not present in the full population. Specifically, we show that previously published conclusions drawn from this methodology-about the effect of a particular lexical property on spoken-word recognition-do not in fact appear to hold. Second, if the balanced subsets of Low and High are selected randomly, this methodology frequently fails to show a relationship between x and y that is present in the full population. Our work uncovers a new facet of an ongoing research effort: to identify and reveal the implicit freedoms of experimental design that can lead to false conclusions.

Compromised DNA Repair and Signalling in Human Granulocytes.

In previous studies, we showed impaired DNA repair in human monocytes. Here, we addressed the question of whether human neutrophilic granulocytes that arise from the same precursor as monocytes exhibit a similar phenotype and are impaired in repairing their DNA. We show that neutrophilic granulocytes isolated from peripheral blood display a lack of the same repair proteins that are missing in monocytes and do not show repair of their DNA when damaged by ionising radiation (IR) or chemical ROS. Contrary to T cells, we observed no decline in the number of single-strand breaks following γ-radiation. Also, granulocytes did not show γH2AX foci formation while T cells and peripheral blood lymphocytes (PBL) responded. In comparison to PBL, XRCC1, PARP-1 and ligase III were not expressed and there was also no discernible signal for key damage response proteins ATM, ATR and DNA-PKCS as well as γH2AX in neutrophils. Time course and dose-response experiments confirmed the absence of H2AX phosphorylation after radiation treatment although an accumulation of double-strand breaks was detected in the neutral Comet assay. Overall, the data indicate that terminally differentiated neutrophilic granulocytes in the peripheral blood display strong downregulation of DNA repair and DNA damage response factors, which should be taken into account if studies with whole peripheral blood containing granulocytes are performed, causing a significant intra-experimental variation in the cellular repair capacity.

Schema learning for the cocktail party problem.

The cocktail party problem requires listeners to infer individual sound sources from mixtures of sound. The problem can be solved only by leveraging regularities in natural sound sources, but little is known about how such regularities are internalized. We explored whether listeners learn source "schemas"-the abstract structure shared by different occurrences of the same type of sound source-and use them to infer sources from mixtures. We measured the ability of listeners to segregate mixtures of time-varying sources. In each experiment a subset of trials contained schema-based sources generated from a common template by transformations (transposition and time dilation) that introduced acoustic variation but preserved abstract structure. Across several tasks and classes of sound sources, schema-based sources consistently aided source separation, in some cases producing rapid improvements in performance over the first few exposures to a schema. Learning persisted across blocks that did not contain the learned schema, and listeners were able to learn and use multiple schemas simultaneously. No learning was evident when schema were presented in the task-irrelevant (i.e., distractor) source. However, learning from task-relevant stimuli showed signs of being implicit, in that listeners were no more likely to report that sources recurred in experiments containing schema-based sources than in control experiments containing no schema-based sources. The results implicate a mechanism for rapidly internalizing abstract sound structure, facilitating accurate perceptual organization of sound sources that recur in the environment.

Political transition and emergent forest-conservation issues in Myanmar.

Political and economic transitions have had substantial impacts on forest conservation. Where transitions are underway or anticipated, historical precedent and methods for systematically assessing future trends should be used to anticipate likely threats to forest conservation and design appropriate and prescient policy measures to counteract them. Myanmar is transitioning from an authoritarian, centralized state with a highly regulated economy to a more decentralized and economically liberal democracy and is working to end a long-running civil war. With these transitions in mind, we used a horizon-scanning approach to assess the 40 emerging issues most affecting Myanmar's forests, including internal conflict, land-tenure insecurity, large-scale agricultural development, demise of state timber enterprises, shortfalls in government revenue and capacity, and opening of new deforestation frontiers with new roads, mines, and hydroelectric dams. Averting these threats will require, for example, overhauling governance models, building capacity, improving infrastructure- and energy-project planning, and reforming land-tenure and environmental-protection laws. Although challenges to conservation in Myanmar are daunting, the political transition offers an opportunity for conservationists and researchers to help shape a future that enhances Myanmar's social, economic, and environmental potential while learning and applying lessons from other countries. Our approach and results are relevant to other countries undergoing similar transitions.

Headphone screening to facilitate web-based auditory experiments.

Psychophysical experiments conducted remotely over the internet permit data collection from large numbers of participants but sacrifice control over sound presentation and therefore are not widely employed in hearing research. To help standardize online sound presentation, we introduce a brief psychophysical test for determining whether online experiment participants are wearing headphones. Listeners judge which of three pure tones is quietest, with one of the tones presented 180° out of phase across the stereo channels. This task is intended to be easy over headphones but difficult over loudspeakers due to phase-cancellation. We validated the test in the lab by testing listeners known to be wearing headphones or listening over loudspeakers. The screening test was effective and efficient, discriminating between the two modes of listening with a small number of trials. When run online, a bimodal distribution of scores was obtained, suggesting that some participants performed the task over loudspeakers despite instructions to use headphones. The ability to detect and screen out these participants mitigates concerns over sound quality for online experiments, a first step toward opening auditory perceptual research to the possibilities afforded by crowdsourcing.

The effect of solid pancreatic mass lesions on pancreatic duct diameter at endoscopic ultrasound.

OBJECTIVES: To evaluate the effect of solid pancreatic masses on the pancreatic duct (PD) at the endoscopic ultrasound (EUS) and the relationship of the location/size of a mass and PD dilation. MATERIALS AND METHODS: Patients who underwent EUS for pancreatic indications from 2011 to 2013 at a single center were retrospectively identified. Those with biopsies that revealed adenocarcinoma or neuroendocrine tumors in the pancreas were identified and PD size was ascertained from EUS, computed tomography, or magnetic resonance imaging. RESULTS: Of the 475 patients who had a pancreatic EUS, 239 had a dilated PD and 236 had a normal PD. Patients with a dilated PD had a significantly higher incidence of pancreatic malignancy than those with a normal PD diameter (106/239, 44.4% vs. 32/236, 13.6%, P< 0.001). Of the 138 patients with a pancreatic malignancy, 106 (76.8%) had a dilated PD at some location in the pancreas. Over 80% of patients with a mass within the head, neck, or body had a dilated PD. For a mass located at the uncinate process or the tail, PD dilation was 65% and 23%, respectively. Fifty-six (80.0%) of the masses in the head, 11 (78.6%) masses in the neck, and 16 (76.2%) masses in the body had a dilated PD upstream of the mass. In addition, a step-wise increase in the incidence of PD dilation was correlated with an increase in mass size. About 67.6% of patients with masses measuring in the 1st quartile had dilated a PD, while 77.8%, 91.0%, and 71.4% of those with masses measuring in the 2nd, 3rd, and 4th quartiles, respectively, had a dilated PD. CONCLUSION: PD dilation is a warning sign for pancreatic malignancies, however, small masses or masses at the uncinate process or the tail of the pancreas may not affect the size of the PD.

Establishing Theoretical Stability and Treatment Integrity for Motivational Interviewing.

BACKGROUND: There is increasing evidence claiming the effectiveness of motivational interviewing (MI) in promoting behavioural change. However, ongoing changes to MI theory and practice have implications for its transferability, accessibility and for the validity of previous findings. Lack of practice consistency may make its effectiveness difficult to evaluate. AIMS: This paper explores the complexity of MI and issues in the development of evidence-based practice in delivery, before describing issues related to practitioner application. METHOD: Theoretical and practice developments over the last 30 years are reviewed under the headings theory, practice and efficacy. Specifically, developments across the three editions of the core MI texts are examined. RESULTS: Findings from the literature suggest a lack of theoretical stability and practice integrity, with recent fundamental changes to the underpinning structure of MI. Issues relating to the transferability and acquisition of MI skills, consistency of delivery and mechanisms underlying change are discussed. CONCLUSIONS: The authors call for greater theoretical stability, more transparency over how developments are based on theoretical principles and empirical outcomes, and clearer guidance about how this informs practice development and delivery of MI.

An Ecological Study of Anterior Cruciate Ligament Reconstruction, Part 2: Functional Performance Tests Correlate With Return-to-Sport Outcomes.

BACKGROUND: Additional high-quality prospective studies are needed to better define the objective criteria used in relation to return-to-sport decisions after anterior cruciate ligament (ACL) reconstruction in active populations. PURPOSE: To investigate prospectively the relationship between functional performance test results at 24 weeks postoperative and return-to-sport activity (Tegner activity score) at 12 and 24 months, respectively, after synthetic (ligament advanced reinforcement system [LARS]) and autograft (doubled semitendinosus/gracilis [2ST/2GR]) ACL reconstructions. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 64 patients who underwent ACL reconstruction (32 LARS, 32 2ST/2GR autograft; mean age, 27.9 years; body mass index [BMI], 24.9 kg/m2) were assessed preoperatively and at staged intervals postoperatively up to 24 weeks for isokinetic testing of quadriceps and hamstring average power per repetition at 60 deg/s and 180 deg/s, a battery of hop tests, peak vertical ground-reaction force (vGRF), and time to peak vGRF (in seconds) during a step- and jump-down task onto a force platform and peak speed (m/s) using a global positioning system (GPS unit) during a running task. A cohort of 32 healthy matched participants (mean age, 26.31 years; BMI, 25.7 kg/m2) were also tested to act as reference. Pearson correlation was calculated to assess correlation of each performance measure at 24 weeks postoperative with activity outcomes (Tegner score) at 12 and 24 months. RESULTS: The strongest correlation between physical performance tests and return-to-sport outcomes was observed with peak speed during running. Large correlations were also observed for hamstring isokinetic power and hop test for distance. Moderate correlations were observed for timed hop, peak vGRF during a jump-down task, and quadriceps isokinetic power. No statistical correlations were observed for time to peak vGRF during a step-down and jump-down task as well as peak vGRF during a step-down task. When the performance tests were pooled together, mean postoperative improvements of 24% were observed from preoperative to 24 weeks within the surgical cohort. For each performance test, preoperative level of function strongly correlated with performance levels on the same test at 24 weeks. DISCUSSION: The results of this study indicate that clinicians might seek to prioritize these tests and the rehabilitation themes they imply when seeking to maximize postoperative ACL activity outcomes. The observed strength between pre- and postoperative performance tests and return-to-sport outcomes within this study highlights the potential value of preoperative conditioning before undergoing ACL reconstruction. Future research should examine absolute predictive criterion thresholds for functional performance-based tests and reinjury risk reduction after ACL reconstruction.

Safety and efficacy of single-balloon enteroscopy in management of gastrointestinal bleeding in patients with a left ventricular assist device.

Background and study aims Left ventricular assist devices (LVADs) are currently the standard of care in treatment of patients with end-stage heart failure waiting for heart transplant as well as destination therapy for non-transplant candidates. However, patients with LVADs are at increased risk of gastrointestinal bleeding due to the device's unique effects on hemodynamics. A major source of gastrointestinal bleeding in these patients are gastrointestinal angioectasias located within the small bowel that can only be reached with deep enteroscopy. The goal of our study was to determine the safety and efficacy of single-balloon enteroscopy (SBE) in treating gastrointestinal bleeding in patients with LVADs. Patients and methods We present a retrospective case series performed on patients with LVADs who underwent SBE to treat episodes of gastrointestinal bleeding. All procedures were performed at Emory University Hospital by a single endoscopist. Patient demographics, diagnosis and treatment of gastrointestinal bleeding, episodes of re-bleeding, and procedure-related complications were examined. Results A total of 27 SBE procedures performed in 14 patients were reviewed. SBE was performed in an antegrade approach in 89 % (24/27) of cases. Deep intubation was achieved in all antegrade procedures, with the distal jejunum reached in 79 % (19/24) of cases. The diagnostic yield was 78 %. There were no reported complications associated with the procedures. Conclusions SBE is a safe and effective modality to manage gastrointestinal bleeding in patients with LVADs.

Pancreatic Insufficiency Secondary to Tobacco Exposure: A Controlled Cross-Sectional Evaluation.

OBJECTIVES: Tobacco exposure is an established risk factor for pancreatic cancer and chronic pancreatitis; however, its role in pancreatic insufficiency is not clear. METHODS: This controlled, cross-sectional study examined smokers and nonsmokers with no history of pancreatic disease. Histories and validated inventories of alcohol and tobacco use were obtained, and pancreatic insufficiency was assessed using the fecal elastase-1 assay. RESULTS: Of 7854 patients approached, 226 were interviewed and 200 enrolled. The rates of pancreatic insufficiency [18% (18/100)] and severe pancreatic insufficiency [10% (10/100)] were significantly higher in smokers than in controls [6% (6/100), P = 0.009 and 1% (1/100), P = 0.010, respectively]. On multivariate logistic regression, the risk of pancreatic insufficiency in smokers was significantly increased [odds ratio, 4.34 (1.37-13.75); P = 0.012], controlling for alcohol use and relevant covariates. Tobacco exposure was associated with the highest odds ratio for pancreatic insufficiency. Alcohol consumption was strongly associated with tobacco exposure (P < 0.001), but not with pancreatic insufficiency by multivariate analysis (P = 0.792). CONCLUSIONS: This study suggests that tobacco exposure is independently associated with pancreatic exocrine insufficiency in patients without a prior diagnosis of pancreatic disease. Tobacco exposure seems to have greater detrimental effects on pancreatic function than alcohol in this population.

An Ecological Study of Anterior Cruciate Ligament Reconstruction, Part 1: Clinical Tests Do Not Correlate With Return-to-Sport Outcomes.

BACKGROUND: Additional high-quality prospective studies are needed to better define the objective criteria used in relation to return-to-sport decisions after synthetic (ligament advanced reinforcement system [LARS]) and autograft (hamstring tendon [2ST/2GR]) anterior cruciate ligament (ACL) reconstruction in active populations. PURPOSE: To prospectively investigate and describe the recovery of objective clinical outcomes after autograft (2ST/2GR) and synthetic (LARS) ACL reconstructions, as well as to investigate the relationship between these clinimetric test outcomes and return-to-sport activity (Tegner activity scale [TAS] score) at 12 and 24 months postoperatively. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 64 patients who underwent ACL reconstruction (32 LARS, 32 2ST/2GR autograft) and 32 healthy reference participants were assessed for joint laxity (KT-1000 arthrometer), clinical outcome (2000 International Knee Documentation Committee [IKDC] knee examination), and activity (TAS score) preoperatively and at 12, 16, 20, and 24 weeks and 12 and 24 months postoperatively. RESULTS: There was no significant correlation observed between clinical results using the 2000 IKDC knee examination and TAS score at 24 months (rs = 0.188, P = .137), nor were results for side-to-side difference (rs = 0.030, P = .814) or absolute KT-1000 arthrometer laxity of the surgical leg at 24 months postoperatively (rs = 0.076, P = .553) correlated with return-to-sport activity. Nonetheless, return-to-sport rates within the surgical cohort were 81% at 12 months and 83% at 24 months, respectively. No statistically significant differences were observed between physiological laxity of the uninjured knee within the surgical group compared with healthy knees within the reference group (P = .522). CONCLUSION: The results indicate that although relatively high levels of return-to-sport outcomes were achieved at 24 months compared with those previously reported in the literature, correlations between objective clinical tests and return-to-sport outcomes may not occur. Clinical outcome measures may provide suitable baseline information; however, the results of this study suggest that clinicians may need to place greater emphasis on other outcome measures when seeking to objectively promote safe return to sport.