Open-angle glaucoma and Fuchs dystrophy.

A 62-year-old woman with a history of moderate myopia, long-standing open-angle glaucoma (OAG), and Fuchs dystrophy in both eyes was referred for consultative care. She had prior trabeculectomy in 1984 and 1992 in the left and right eyes, respectively. She is 3 months post-Descemet-stripping endothelial keratoplasty (DSEK) in the left eye, now referred with uncontrolled intraocular pressure (IOP) despite maximum tolerated medical therapy. Current medical therapy for IOP consists of acetazolamide 250 mg by mouth 2 times a day, brimonidine 2 times a day in the left eye, dorzolamide 2 times a day in the left eye, and timolol 2 times a day in the left eye. The patient has a history of presumed steroid response; however, her corneal surgeon has requested that the steroid be continued for the next several months because of the recent DSEK. The IOP in the left eye has ranged from the mid-20s to mid-30s since DSEK. The right eye has consistently had pressure in the low teens and below for many years without topical antihypertensive medications. Examination revealed stable visual acuity at 20/30 and 20/40 in the right and left eyes, respectively, IOP was 12 mm Hg in the right eye and 25 mm Hg in the left eye by Goldman applanation, irregular but reactive pupils without afferent defect, and full confrontational visual fields. Slitlamp examination showed superior low avascular bleb, moderate-to-severe guttae, and posterior chamber IOL in the right eye. The left eye showed superior low diffuse bleb, clear DSEK graft, quiet chamber, superonasal iridectomy, and posterior chamber IOL with an open posterior capsule. The conjunctiva was moderately scarred but a repeat trabeculectomy or Xen Gel stent (Abbvie) appeared possible. The angles were wide open in each eye. Fundus examination was normal aside from myopic, anomalous-appearing nerves with an approximate cup-to-disc ratio of 0.90 in both eyes. Humphrey visual field showed nonspecific changes on the right and moderate nasal defect on the left eye, stable to previous examinations dating back to 2018 (Figure 1JOURNAL/jcrs/04.03/02158034-202407000-00018/figure1/v/2024-07-10T174240Z/r/image-tiff and Figure 2JOURNAL/jcrs/04.03/02158034-202407000-00018/figure2/v/2024-07-10T174240Z/r/image-tiff). Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) revealed moderated thinning in both eyes that was also stable to prior examinations (Figure 3JOURNAL/jcrs/04.03/02158034-202407000-00018/figure3/v/2024-07-10T174240Z/r/image-tiff). Her axial length measured 25.23 and 26.34 mm in the right and left eyes, respectively. Central corneal thickness was 553 µm in the right eye and 563 µm in the left eye before her DSEK procedure. What would be your approach to management of this patient's left eye, addressing the following: Rationale for your procedure of choice? Would you over-rule the corneal surgeon and stop the steroid in an attempt to obviate the need for glaucoma surgery? Does the age of onset of glaucoma affect your surgical decision making? Note that patient age at the time of trabeculectomy was 22 years. Are some procedures better suited for patients after DSEK surgery?

Minimally Invasive Glaucoma Surgery: Latest Developments and Future Challenges.

The development of minimally invasive glaucoma surgeries (MIGSs) was intended to provide safe and modestly efficacious modalities for early intervention of mild-to-moderate glaucoma, with minimal trauma and rapid recovery. They were mainly ab interno procedures that reduce intraocular pressure by facilitating the aqueous outflow by bypassing the trabecular meshwork resistance, reinforcing the uveoscleral flow via the supraciliary space, and reducing aqueous production by the ciliary body. While the cumulating evidence helps shape the role of the available MIGS, the exponential new development and advancement in this field has expanded the territory of MIGS. Apart from developing subconjunctival MIGS filtration devices (Xen gel stent and PRESERFLO MicroShunt), there is a tendency to revisit the "traditional" MIGS for alternative use and to modify the procedures with consideration of the fundamental aqueous outflow physiology. Combined MIGS has also been suggested, based on the theory that their different mechanisms may provide additive or synergistic effects. The advancement of laser procedures is also promising and could supplement unmet needs along the glaucoma treatment algorithm. This review examines the broad array of MIGS, updates the recent findings, discusses their potential alternative applications, and explores future challenges.

A novel blood-sensing capsule for rapid detection of upper GI bleeding: a prospective clinical trial.

BACKGROUND AND AIMS: Upper GI bleeding (UGIB) is a common medical emergency associated with high resource utilization, morbidity, and mortality. Timely EGD can be challenging from personnel, resource, and access perspectives. PillSense (EnteraSense Ltd, Galway, Ireland) is a novel swallowed bleeding sensor for the detection of UGIB, anticipated to aid in patient triage and guide clinical decision-making for individuals with suspected UGIB. METHODS: This prospective, open-label, single-arm comparative clinical trial of a novel bleeding sensor for patients with suspected UGIB was performed at a tertiary care center. The PillSense system consists of an optical sensor and an external receiver that processes and displays data from the capsule as "Blood Detected" or "No Blood Detected." Patients underwent EGD within 4 hours of capsule administration; participants were followed up for 21 days to confirm capsule passage. RESULTS: A total of 126 patients were accrued to the study (59.5% male; mean age, 62.4 ± 14.3 years). Sensitivity and specificity for detecting the presence of blood were 92.9% (P = .02) and 90.6% (P < .001), respectively. The capsule's positive and negative predictive values were 74.3% and 97.8%, and positive and negative likelihood ratios were 9.9 and .08. No adverse events or deaths occurred related to the PillSense system, and all capsules were excreted from patients on follow-up. CONCLUSIONS: The PillSense system is safe and effective for detecting the presence of blood in patients evaluated for UGIB before upper GI endoscopy. It is a rapidly deployed tool, with easy-to-interpret results that will affect the diagnosis and triage of patients with suspected UGIB. (Clinical trial registration number: NCT05385224.).

Effect of antiplatelet agents and tyrosine kinase inhibitors on oxLDL-mediated procoagulant platelet activity.

Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, mechanisms by which LDL affects platelet activation and atherothrombosis, and how to best therapeutically target and safely prevent such responses remain unclear. Here, we investigate how oxidized low-density lipoprotein (oxLDL) enhances glycoprotein VI (GPVI)-mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet procoagulant activity ex vivo. Human platelets were treated with oxLDL and the GPVI-specific agonist, crosslinked collagen-related peptide, and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2YR), cyclooxygenase (COX), and tyrosine kinases. Ex vivo, oxLDL enhanced GPVI-mediated platelet dense granule secretion, α-granule secretion, integrin activation, thromboxane generation and aggregation, as well as procoagulant phosphatidylserine exposure and fibrin generation. Studies of washed human platelets, as well as platelets from mouse and nonhuman primate models of hyperlipidemia, further determined that P2YR antagonists (eg, ticagrelor) and Bruton tyrosine kinase inhibitors (eg, ibrutinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (eg, aspirin) had no significant effect. Together, our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase inhibitors compared with COX inhibitors.

Platelets and tyrosine kinase inhibitors: clinical features, mechanisms of action, and effects on physiology.

Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of target-directed, small molecule inhibitors used to treat hematologic malignancies, inflammatory diseases, and autoimmune disorders. Recently, TKIs have also gained interest as potential antiplatelet-directed therapeutics that could be leveraged to reduce pathologic thrombus formation and atherothrombotic complications, while minimally affecting platelet hemostatic function. This review provides a mechanistic overview and summarizes the known effects of tyrosine kinase inhibitors on platelet signaling and function, detailing prominent platelet signaling pathways downstream of the glycoprotein VI (GPVI) receptor, integrin αIIbß3, and G protein-coupled receptors (GPCRs). This review focuses on mechanistic as well as clinically relevant and emerging TKIs targeting major families of tyrosine kinases including but not limited to Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (Syk), Src family kinases (SFKs), Janus kinases (JAK), and signal transducers and activators of transcription (STAT) and evaluates their effects on platelet aggregation and adhesion, granule secretion, receptor expression and activation, and protein phosphorylation events. In summation, this review highlights current advances and knowledge on the effects of select TKIs on platelet biology and furthers insight on signaling pathways that may represent novel druggable targets coupled to specific platelet functional responses.

Acute Esophageal Necrosis: A Retrospective Cohort Study Highlighting the Mayo Clinic Experience.

OBJECTIVE: To describe the clinical, endoscopic, and histologic features in patients with acute esophageal necrosis (AEN). PATIENTS AND METHODS: In this retrospective cohort study, patients who were diagnosed as having AEN at Mayo Clinic sites in Minnesota, Florida, and Arizona between January 1, 1996, and January 31, 2021, were included. Data were collected on patient clinical characteristics and endoscopic and pathologic findings. RESULTS: The study included 79 patients with AEN with a median (range) age of 64 years (12 to 91 years); 53 (67.1%) were men. Predominant presenting symptoms were hematemesis (49 of 79 [62.0%]), abdominal pain (29 [36.7%]), and melena (20 [25.3%]). Shock was the triggering event for AEN in 49 (62.0%). The 30- and 90-day mortality were 24.0% (19 of 79) and 31.6% (25), respectively. The presence of coexisting infection or bacteremia was significantly associated with 90-day mortality (P<.01). Endoscopically, involvement of the distal third only, distal two-thirds only, and entire esophagus was observed in 31.6% (24 of 76), 39.5% (30), and 29.0% (22), respectively. The length of esophageal involvement correlated with duration of hospitalization (P=.05). The endoscopic appearance of the esophageal mucosa ranged from predominantly white (21 of 44 [47.7%]) to mixed white and black (13 [29.6%]) to predominantly black (10 [22.7%]), and sloughing was present in 18 (40.9%). In the 26 patients with histopathologic findings available for review, 25 (96.1%) had necrosis and/or ulceration with abundant pigmentation. Among the 79 patients, 39 (49.4%) had a follow-up esophagogastroduodenoscopy; 26 of these 39 patients (66.7%) had resolution while 5 had persistent AEN, 4 of whom had improvement. Esophageal strictures developed in 7 of the 39 patients (18.0%). CONCLUSION: Acute esophageal necrosis is a serious condition observed in critically ill patients. Its endoscopic appearance can be highly variable. In patients with an unclear diagnosis, esophageal biopsies may be helpful given the characteristic histologic findings.

Collaborative improvement on acute opioid prescribing among diverse health systems.

BACKGROUND: Despite broad awareness of the opioid epidemic and the understanding that patients require much fewer opioids than traditionally prescribed, improvement efforts to decrease prescribing have only produced modest advances in recent years. METHODS AND FINDINGS: By using a collaborative model for shared expertise and accountability, nine diverse health care systems completed quality improvement projects together over the course of one year to reduce opioid prescriptions for acute pain. The collaborative approach was flexible to each individual system's goals, and seven of the nine participant institutions definitively achieved their desired results. CONCLUSIONS: This report demonstrates the utility of a collaborative model of improvement to bring about real change in opioid prescribing practices and may inform quality improvement efforts at other institutions.

Janus kinase inhibitors ruxolitinib and baricitinib impair glycoprotein-VI mediated platelet function.

Several Janus kinase (JAK) inhibitors (jakinibs) have recently been approved to treat inflammatory, autoimmune and hematological conditions. Despite emerging roles for JAKs and downstream signal transducer and activator of transcription (STAT) proteins in platelets, it remains unknown whether jakinibs affect platelet function. Here, we profile platelet biochemical and physiological responses in vitro in the presence of five different clinically relevant jakinibs, including ruxolitinib, upadacitinib, oclacitinib, baricitinib and tofacitinib. Flow cytometry, microscopy and other assays found that potent JAK1/2 inhibitors baricitinib and ruxolitinib reduced platelet adhesion to collagen, as well as platelet aggregation, secretion and integrin αIIbß3 activation in response to the glycoprotein VI (GPVI) agonist collagen-related peptide (CRP-XL). Western blot analysis demonstrated that jakinibs reduced Akt phosphorylation and activation following GPVI activation, where ruxolitinib and baricitinib prevented DAPP1 phosphorylation. In contrast, jakinibs had no effects on platelet responses to thrombin. Inhibitors of GPVI and JAK signaling also abrogated platelet STAT5 phosphorylation following CRP-XL stimulation. Additional pharmacologic experiments supported roles for STAT5 in platelet secretion, integrin activation and cytoskeletal responses. Together, our results demonstrate that ruxolitinib and baricitinib have inhibitory effects on platelet function in vitro and support roles for JAK/STAT5 pathways in GPVI/ITAM mediated platelet function.

Assessment of Floor Heave Associated with Bumps in a Longwall Mine Using the Discrete Element Method.

This study was developed as part of an effort by the National Institute for Occupational Safety and Health (NIOSH) to better understand rock-mass behavior in longwall coal mines in highly stressed, bump-prone ground. The floor-heave and no-floor-heave phenomena at a western US coal mine could not be properly simulated in numerical models using conventional shear-dominant failure criteria (i.e., Mohr-Coulomb or Hoek-Brown failure criterion). The previous numerical study demonstrated these phenomena using a user-defined model of the s-shaped brittle failure criterion in conjunction with a spalling process in the FLAC3D numerical modeling software. The results of the FLAC3D modeling agreed with the observations of the relative amounts of heave from each gate-road system. However, the FLAC3D model adopted many assumptions and simplifications that were not very realistic from a physical or mechanical perspective. To overcome the limitations of the FLAC3D model, 3DEC modeling in conjunction with the discrete fracture network (DFN) technique was performed to better understand the true behavior of floor heave associated with underground mining in an anisotropic stress field. The effect of stress rotation in the mining-induced stress field was considered by using a different geometry of rock fractures in the coal seam. The heterogeneity of the engineering properties (i.e., cohesion and tensile strength) were also considered by using Monte Carlo simulations. Consequently, the 3DEC models using the DFN technique resulted in predictions of floor heave that agreed with observations of the relative amounts of heave from each gate-road system, but the cause of heave was mainly related to the degree of anisotropy instead of the size of the pillar.

A Practice Redesign Collaborative for Reducing Hospital Readmission for Chronic Obstructive Pulmonary Disease in an Affiliated Network of Health Care Organizations.

BACKGROUND: Patients discharged following admissions for acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) frequently require unplanned readmissions, increasing costs and morbidity for thousands of patients suffering from COPD. The Hospital Readmissions Reduction Program provided financial incentives to reduce 30-day readmissions for AE-COPD, but although risk factors for readmission are known, few evidence-based interventions achieve this goal. Members of the Mayo Clinic Care Network (MCCN) formed a collaborative to seek ways to reduce 30-day readmission for patients admitted with AE-COPD. METHODS: Seventeen MCCN organizations participated in an improvement collaborative in 2016 and 2017. Mayo Clinic subject matter experts shared improvement webinars, protocols, and educational materials related to AE-COPD and delivered individualized coaching to facilitate improvement at each site over a six-month engagement. Among other recommended interventions, organizations worked to increase the proportion of COPD patients who had a standardized disease severity staging during admission, inhaler appropriateness evaluations, a COPD treatment action plan, and clinical contact at < 48 hours and 10 ± 4 days postdischarge. RESULTS: Same-hospital readmission rates improved from 17.7% ± 3.6 to 14.5% ± 4.0 (weighted difference -4.38, p = 0.008, paired t-test). In addition, participating teams stated that the collaborative framework helped them develop strategies that improved patient care and organizational capacity for improvement in other domains. CONCLUSION: The collaborative framework, beginning with education delivered in person and via webinars, combined with telephonically delivered coaching and knowledge sharing, assisted most members to improve care. Fourteen of 17 participating sites experienced a reduced AE-COPD readmission rate.

Laboratory investigation of the anisotropic confinement-dependent brittle-ductile transition of a Utah coal.

This paper was developed as part of an effort by the National Institute for Occupational Safety and Health (NIOSH) to identify risk factors associated with bumps in the prevention of fatalities and accidents in highly stressed, bump-prone ground conditions. Changes of failure mechanism with increasing confinement, from extensional-to shear-dominated failure, are widely observed in the rupture of intact specimens at the laboratory scale and in rock masses. In the previous analysis conducted in 2018, both unconfined and triaxial compressive tests were conducted to investigate the strength characteristics of some specimens of a Utah coal, including the spalling limits, the ratio of apparent unconfined compressive strength (AUCS) to unconfined compressive strength (UCS), the damage characteristics, and the post-yield dilatancy. These mechanical characteristics were found to be strongly anisotropic as a function of the orientation of the cleats relative to the loading direction. However, the transition from extensional to shear failure at the given confinements was not clearly identified. In this study, a total of 20 specimens were additionally prepared from the same coal sample used in the previous study and then tested under both unconfined and triaxial compressive conditions. The different confining stresses are used as analogs for different width-to-height (W/H) ratios of pillar strength. Although the W/H ratios of the specimens were not directly considered during testing, the equivalent W/H ratios of a pillar as a function of the confining stresses were estimated using an existing empirical solution. According to this relationship, the W/H at which in-situ pillar behavior would be expected to transition from brittle to ductile is identified.

Randomized Phase II Trial of Polyphenon E versus Placebo in Patients at High Risk of Recurrent Colonic Neoplasia.

Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects (N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (-2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm (P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. PREVENTION RELEVANCE: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer.

Evaluating a combined bowel preparation for small-bowel capsule endoscopy: a prospective randomized-controlled study.

BACKGROUND: Capsule endoscopy (CE) is frequently hindered by intra-luminal debris. Our aim was to determine whether a combination bowel preparation would improve small-bowel visualization, diagnostic yield, and the completion rate of CE. METHODS: Single-blind, prospective randomized-controlled study of outpatients scheduled for CE. Bowel-preparation subjects ingested 2 L of polyethylene glycol solution the night prior to CE, 5 mL simethicone and 5 mg metoclopramide 20 minutes prior to CE and laid in the right lateral position 30 minutes after swallowing CE. Controls had no solid food after 7 p.m. the night prior to CE and no liquids 4 hours prior to CE. Participants completed a satisfaction survey. Capsule readers completed a small-bowel-visualization assessment. RESULTS: Fifty patients were prospectively enrolled (56% female) with a median age of 54.4 years and 44 completed the study (23 patients in the control group and 21 in the preparation group). There was no significant difference between groups on quartile-based small-bowel visualization (all P > 0.05). There was no significant difference between groups in diagnostic yield (P = 0.69), mean gastric (P = 0.10) or small-bowel transit time (P = 0.89). The small-bowel completion rate was significantly higher in the preparation group (100% vs 78%; P = 0.02). Bowel-preparation subjects reported significantly more discomfort than controls (62% vs 17%; P = 0.01). CONCLUSIONS: Combined bowel preparation did not improve small-bowel visualization but did significantly increase patient discomfort. The CE completion rate improved in the preparation group but the diagnostic yield was unaffected. Based on our findings, a bowel preparation prior to CE does not appear to improve CE performance and results in decreased patient satisfaction (ClinicalTrials.gov, No. NCT01243736).

Bouveret's syndrome and cholecystogastric fistula: a case-report and review of the literature.

An exceptionally rare cause of gastric outlet obstruction, Bouveret's syndrome results from proximal impaction of an ectopic gallstone, enabled by fistulization that aberrantly connects the biliary and luminal gastrointestinal tract, typically a cholecystoduodenal fistula. It occurs with a 2:1 female predominance, most often in the eighth decade of life. Endoscopic treatment is the preferred first-line strategy in management, followed by surgical intervention if unsuccessful. Endoscopy failed to retrieve the stone due to its size, despite attempted lithotripsy, which prompted laparoscopic retrieval. Bouveret's syndrome compels a high index of suspicion in proximal gastrointestinal obstruction even when presenting in a male a decade younger than the median age of diagnosis (74 years), with no preceding biliary symptoms particularly as early intervention can considerably reduce morbidity and mortality.

Investigation of the anisotropic confinement-dependent brittleness of a Utah coal.

Changes of failure mechanism with increasing confinement, from extensional to shear-dominated failure, are widely observed in the rupture of intact specimens at the laboratory scale and in rock masses. In an analysis published in 2018, both unconfined and triaxial compressive tests were conducted to investigate the strength characteristics of 84 specimens of a Utah coal, including the spalling limits, the ratio of apparent unconfined compressive strength to unconfined compressive strength (UCS), the damage characteristics, and the post-yield dilatancy. These mechanical characteristics were found to be strongly anisotropic as a function of the orientation of the cleats relative to the loading direction, defined as the included angle. A total of four different included angles were used in the work performed in 2018. The authors found that the degree of anisotropic strength differed according to the included angle. However, the transition from extensional to shear failure at the given confinements was not clearly identified. In this study, a total of 20 specimens were additionally prepared from the same coal sample used in the previous study and then tested under both unconfined and triaxial compressive conditions. Because the authors already knew the most contrasting cases of the included angles from the previous work using the four included angles, they chose only two of the included angles (0° and 30°) for this study. For the triaxial compressive tests, a greater confining stress than the mean UCS was applied to the specimens in an attempt to identify the brittle-ductile transition of the coal. The new results have been compiled with the previous results in order to re-evaluate the confinement-dependency of the coal behavior. Additionally, the different confining stresses are used as analogs for different width-to-height (W/H) conditions of pillar strength. Although the W/H ratios of the specimens were not directly considered during testing, the equivalent W/H ratios of a pillar as a function of the confining stresses were estimated using an existing empirical solution. According to this relationship, the W/H at which in situ pillar behavior would be expected to transition from brittle to ductile is identified.

Efficacy of Difluoromethylornithine and Aspirin for Treatment of Adenomas and Aberrant Crypt Foci in Patients with Prior Advanced Colorectal Neoplasms.

Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, was shown to act synergistically with a NSAID for chemoprevention of colorectal neoplasia. We determined the efficacy and safety of DFMO plus aspirin for prevention of colorectal adenomas and regression of rectal aberrant crypt foci (ACF) in patients with prior advanced adenomas or cancer. A double-blinded, placebo-controlled trial was performed in 104 subjects (age 46-83) randomized (1:1) to receive daily DFMO (500 mg orally) plus aspirin (325 mg) or matched placebos for one year. All polyps were removed at baseline. Adenoma number (primary endpoint) and rectal ACF (index cluster and total) were evaluated at a one year colonoscopy. ACF were identified by chromoendoscopy. Toxicity was monitored, including audiometry. Eighty-seven subjects were evaluable for adenomas or ACF modulation (n = 62). At one year of treatment, adenomas were detected in 16 (38.1%) subjects in the DFMO plus aspirin arm (n = 42) versus 18 (40.9%) in the placebo arm (n = 44; P = 0.790); advanced adenomas were similar (n = 3/arm). DFMO plus aspirin was associated with a statistically significant reduction in the median number of rectal ACF compared with placebo (P = 0.036). Total rectal ACF burden was also reduced in the treatment versus the placebo arm relative to baseline (74% vs. 45%, P = 0.020). No increase in adverse events, including ototoxicity, was observed in the treatment versus placebo arms. While adenoma recurrence was not significantly reduced by one year of DFMO plus aspirin, the drug combination significantly reduced rectal ACF number consistent with a chemopreventive effect.

Predicting the effects of supplemental EPA and DHA on the omega-3 index.

BACKGROUND: Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. OBJECTIVE: The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. METHODS: Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. RESULTS: Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products. CONCLUSIONS: Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.

Patient-oriented education and visual-aid intervention are inadequate to identify patients with potential capsule retention: a prospective randomized study.

Background/aims: The key procedure-related risk with video capsule endoscopy (VCE) is capsule retention, which should be suspected in patients who have not reported capsule passage. The study aims were to determine the frequency of capsule passage visualization and the difference in self-reporting of capsule passage between patients who receive patient-oriented education (POE) and patients who receive POE and a visual aid intervention in the form of a wrist band (WB). Methods: This was a prospective randomized study that enrolled patients undergoing VCE. Patients were randomly assigned to a POE group versus a POE and WB group. POE consisted of verbal education and an information booklet. Both groups received instructions to notify the study team regarding capsule passage. Results: Sixty patients (mean age 57 ± 18 years; 61% female) were included. A total of 57 patients were included in the analysis (3 lost to follow-up; 28 in POE group; 29 in WB group). Capsule passage status was reported by 68% without significant difference between POE and WB groups (72% vs. 64%; p = .51). Capsule passage status was obtained from all 57 patients with the addition of a proactive follow-up. Only 56% (n = 32) reported visualizing capsule passage. Of the remaining patients who did not visualize capsule passage, 60% (n = 15) reported on this without significant difference between the POE and WB groups (p = .23). Conclusions: Lack of visualization of capsule passage is a poor indicator of retention. Self-reporting of VCE passage status is suboptimal and the addition of a visual aid did not improve this parameter.

Development of a fault-rupture environment in 3D: A numerical tool for examining the mechanical impact of a fault on underground excavations.

While faults are commonly simulated as a single planar or non-planar interface for a safety or stability analysis in underground mining excavation, the real 3D structure of a fault is often very complex, with different branches that reactivate at different times. Furthermore, these branches are zones of nonzero thickness where material continuously undergoes damage even during interseismic periods. In this study, the initiation and the initial evolution of a strike-slip fault was modeled using the FLAC3D software program. The initial and boundary conditions are simplified, and mimic the Riedel shear experiment and the constitutive model in the literature. The FLAC3D model successfully replicates and creates the 3D fault zone as a strike-slip type structure in the entire thickness of the model. The strike-slip fault structure and normal displacement result in the formation of valleys in the model. Three panels of a longwall excavation are virtually placed and excavated beneath a main valley. The characteristics of stored and dissipated energy associated with the panel excavations are examined and observed at different stages of shear strain in the fault to evaluate bump potential. Depending on the shear strain in the fault, the energy characteristics adjacent to the longwall panels present different degrees of bump potential, which is not possible to capture by conventional fault simulation using an interface.

In vivo modeling of docosahexaenoic acid and eicosapentaenoic acid-mediated inhibition of both platelet function and accumulation in arterial thrombi.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are associated with a variety of cellular alterations that mitigate cardiovascular disease. However, pinpointing the positive therapeutic effects is challenging due to inconsistent clinical trial results and overly simplistic in vitro studies. Here we aimed to develop realistic models of n-3 PUFA effects on platelet function so that preclinical results can better align with and predict clinical outcomes. Human platelets incubated with the n-3 PUFAs docosahexaenoic acid and eicosapentaenoic acid were stimulated with agonist combinations mirroring distinct regions of a growing thrombus. Platelet responses were then monitored in a number of ex-vivo functional assays. Furthermore, intravital microscopy was used to monitor arterial thrombosis and fibrin deposition in mice fed an n-3 PUFA-enriched diet. We found that n-3 PUFA treatment had minimal effects on many basic ex-vivo measures of platelet function using agonist combinations. However, n-3 PUFA treatment delayed platelet-derived thrombin generation in both humans and mice. This impaired thrombin production paralleled a reduced platelet accumulation within thrombi formed in either small arterioles or larger arteries of mice fed an n-3 PUFA-enriched diet, without impacting P-selectin exposure. Despite an apparent lack of robust effects in many ex-vivo assays of platelet function, increased exposure to n-3 PUFAs reduces platelet-mediated thrombin generation and attenuates elements of thrombus formation. These data support the cardioprotective value of-3 PUFAs and strongly suggest that they modify elements of platelet function in vivo.