Differential Impact In Vivo of Pf4-ΔCre-Mediated and Gp1ba-ΔCre-Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice.

BACKGROUND: Low-dose aspirin is widely used for the secondary prevention of cardiovascular disease. The beneficial effects of low-dose aspirin are attributable to its inhibition of platelet Cox (cyclooxygenase)-1-derived thromboxane A2. Until recently, the use of the Pf4 (platelet factor 4) Cre has been the only genetic approach to generating megakaryocyte/platelet ablation of Cox-1 in mice. However, Pf4-ΔCre displays ectopic expression outside the megakaryocyte/platelet lineage, especially during inflammation. The use of the Gp1ba (glycoprotein 1bα) Cre promises a more specific, targeted approach. METHODS: To evaluate the role of Cox-1 in platelets, we crossed Pf4-ΔCre or Gp1ba-ΔCre mice with Cox-1flox/flox mice to generate platelet Cox-1-/- mice on normolipidemic and hyperlipidemic (Ldlr-/-; low-density lipoprotein receptor) backgrounds. RESULTS: Ex vivo platelet aggregation induced by arachidonic acid or adenosine diphosphate in platelet-rich plasma was inhibited to a similar extent in Pf4-ΔCre Cox-1-/-/Ldlr-/- and Gp1ba-ΔCre Cox-1-/-/Ldlr-/- mice. In a mouse model of tail injury, Pf4-ΔCre-mediated and Gp1ba-ΔCre-mediated deletions of Cox-1 were similarly efficient in suppressing platelet prostanoid biosynthesis. Experimental thrombogenesis and attendant blood loss were similar in both models. However, the impact on atherogenesis was divergent, being accelerated in the Pf4-ΔCre mice while restrained in the Gp1ba-ΔCres. In the former, accelerated atherogenesis was associated with greater suppression of PGI2 biosynthesis, a reduction in the lipopolysaccharide-evoked capacity to produce PGE2 (prostaglandin E) and PGD2 (prostanglandin D), activation of the inflammasome, elevated plasma levels of IL-1ß (interleukin), reduced plasma levels of HDL-C (high-density lipoprotein receptor-cholesterol), and a reduction in the capacity for reverse cholesterol transport. By contrast, in the latter, plasma HDL-C and α-tocopherol were elevated, and MIP-1α (macrophage inflammatory protein-1α) and MCP-1 (monocyte chemoattractant protein 1) were reduced. CONCLUSIONS: Both approaches to Cox-1 deletion similarly restrain thrombogenesis, but a differential impact on Cox-1-dependent prostanoid formation by the vasculature may contribute to an inflammatory phenotype and accelerated atherogenesis in Pf4-ΔCre mice.

Delayed Initiation of Rescue Therapy Associated with Increased Length of Stay in Acute Severe Ulcerative Colitis.

BACKGROUND: Reducing hospitalization length of stay (LOS) for acute severe ulcerative colitis (ASUC) will reduce healthcare costs, mitigate hospitalization-associated risks (e.g., venous thromboembolism), and improve quality of life. METHODS: A chart review was performed of all adult ASUC-related hospitalizations at University of California, San Francisco, from July 1, 2014, to December 31, 2017. Univariate and multivariate analyses were performed to identify factors associated with LOS < 7 days versus ≥ 7 days. A subgroup analysis was performed excluding patients who underwent colectomy during hospitalization. RESULTS: A total of 95 ASUC-related hospitalizations were identified. The initial univariable analysis identified the following factors associated with LOS ≥ 7 days (P < 0.05): higher maximum heart rate in the first 24 h, higher C-reactive protein, being biologic therapy naïve, and a later hospital day of biologic therapy initiation. On mixed model multivariable analysis, later hospital day of biologic initiation was associated with increased LOS ≥ 7 days (OR 3.1 95% CI 1.2-7.56, p = 0.012). CONCLUSIONS: We identified multiple predictors for longer hospital LOS, including factors related to disease severity (non-modifiable) and treatment (potentially modifiable). Importantly, this study identified biologic naïve treatment status and delayed inpatient biologic therapy initiation as predictors of longer LOS (≥ 7 days) in patients who did not ultimately require colectomy during their hospital stay. Potentially modifiable strategies to reduce LOS may include early communication and patient education about biologic therapy in both the inpatient and outpatient setting.

Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease.

The management of the pregnant patient with inflammatory bowel disease is complicated by multiple providers, misinformation, and a disease entity that, particularly when active, can adversely affect pregnancy outcomes. This article seeks to frame the debate on medication safety in pregnancy and lactation using the US Food and Drug Administration's new Pregnancy and Lactation Labeling Rule and the most up-to-date safety information to discuss the risks and benefits of using each class of inflammatory bowel disease medication.

Emergency Department Patient Perspectives on the Risk of Addiction to Prescription Opioids.

OBJECTIVE: To characterize emergency department (ED) patients' knowledge and beliefs about the addictive potential of opioids. DESIGN: Mixed methods analysis of data from a randomized controlled trial. SETTING: Urban academic ED (>88,000 visits). SUBJECTS: One hundred and seventy four discharged ED patients prescribed hydrocodone-acetaminophen for acute pain. METHODS: The study analyzed data collected from a randomized controlled trial investigating patients' knowledge of opioids. ED patients discharged with hydrocodone-acetaminophen completed an audio-recorded phone interview 4­7 days later. This analysis focuses on responses about addiction. Responses were categorized using content analysis; thematic analysis identified broad themes common across different categories. RESULTS: Participants' mean age was 45.5 years (SD, 14.8), 58.6% female, 50.6% white, and the majority had an orthopedic diagnosis (24.1% back pain, 52.3% other injuries). Responses were categorized first based on whether the patient believed that opioids could be addictive (categorized as: yes, 58.7%; no, 19.5%; depends, 17.2%; or do not know, 4.6%), and second based on whether or not the patient discussed his/her own experience with the medication (categorized as: personalized, 35.6%; or not personalized, 64.4%). Cohen's Kappa was 0.84 for all categories. Three themes emerged in the thematic analysis: theme 1) patients expect to "feel" addicted if they are addicted, theme 2) patients fear addiction, and theme 3) side effects affected patient views of addiction. CONCLUSION: In this sample, patients had misconceptions about opioid addiction. Some patients did not know opioids could be addictive, others underestimated their personal risk of addiction, and others overtly feared addiction and, therefore, risked inadequate pain management. Despite limited data, we recommend providers discuss opioid addiction with their patients.

Navigating the layers of concern for safe dry needling of the rectus abdominis: a cadaveric study.

OBJECTIVES: To assess needle placement accuracy in the rectus abdominis (RA) muscle during dry needling (DN) without entering the peritoneum. METHODS: Two physical therapists performed DN on a cadaver, making 10 attempts each to needle the RA without entering the peritoneum. Techniques followed two common DN approaches. Ultrasound verified needle depth and safety. RESULTS: Seventy percent of attempts were recorded as safe needle placement, while 30% were unsafe. Accurate RA needle placement without peritoneal entry occurred in 55% of attempts. DISCUSSION/CONCLUSION: Inadvertent peritoneal needle placement during RA DN poses risks regardless of experience. Ultrasound guidance may enhance safety and precision in clinical practice.

The influence of exercise therapy dosing on pain and functional outcomes in patients with subacromial pain syndrome: A systematic review.

Background: The objective was to identify exercise therapy dosing parameters for subacromial pain syndrome (SAPS) associated with improved pain and function outcomes (via effect sizes) and determine the extent of exercise intervention reproducibility. Methods: An electronic search of PubMed/MEDLINE, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Cochrane Database of Systematic Reviews, and SportDiscus identified studies that used exercise therapy exclusively to treat SAPS. Exercise therapy dosing parameters were extracted and within-group effect sizes were calculated for all pain and functional outcomes. Template for Intervention Description and Replication and Consensus on Exercise Reporting were used to record intervention reporting. The risk of bias and Grading of Recommendations, Assessment, Development, and Evaluation were assessed by two reviewers. Results: Twenty-one trials with 674 subjects were included. Effect sizes for pain and function were large in 18 studies, medium in six studies, and small or no effect in four studies, despite the type of supervision. With moderate certainty, effect sizes of pain and function were not influenced by exercise therapy dosing parameters. Intervention reporting was generally poor. Discussion: Exercise therapy for SAPS was associated with large effect sizes for improvement in pain and function but optimal exercise therapy dosing parameters could not be identified. Strong recommendations conditionally suggest treating SAPS with a variety of exercise therapy dosing parameters.

A multicenter feasibility randomized controlled trial using a virtual reality application of pain neuroscience education for adults with chronic low back pain.

BACKGROUND: Chronic low back pain (CLBP) is a highly prevalent condition among adults and is correlated to high levels of pain, high disability, and lower quality of life. Pain neuroscience education (PNE) helps to explain the pain experience and can affect psychosocial factors, such as fear of movement, anxiety, socioeconomic status, work life satisfaction, etc. More recently, virtual reality (VR) programs have emerged allowing for immersive PNE experiences. OBJECTIVE: The purpose of this randomized clinical trial is to determine the feasibility of using a VR application for the delivery of immersive PNE (VR-PNE) and other activity training for patients with CLBP presenting to outpatient physical therapy (PT) clinics. METHODS: A two-arm, parallel group, randomized controlled feasibility trial of patients was conducted at 12 outpatient PT clinics from March 9, 2022, through September 9, 2022. The intervention group received PT as usual and VR-PNE while the control group received PT as usual. Between group feasibility, acceptability outcomes and other patient-reported outcomes were assessed at six weeks. RESULTS: A total of 595 individuals were evaluated for low back pain during the recruitment period. Seventy individuals were eligible and met definition for CLBP, 52 enrolled and 32 completed the trial. Participant adherence was 63.6% for VR-PNE and 63.2% for PT as usual. Participants found VR-PNE acceptable and reported satisfaction scores (0-100) of 87.37 ± 11.05 compared to 81.17 ± 23.72 in the PT as usual group. There were no significant differences between groups for the BBQ, BRS, FABQ-PA, FABQ-W, GROC, NPRS, NPQ, PCS, and PSEQ at 6 weeks. CONCLUSION: The results of the trial suggest that VR-PNE may be acceptable and feasible for patients with CLBP. Study procedures and PT delivery modifications should be considered for the next iteration of this study to improve follow-up assessment rates.

Safety Considerations When Dry Needling the Multifidi in the Thoracolumbar Region: A Cadaveric Study.

Background: Dry needling the lumbar multifidi is a technique used by physical therapists to effectively treat low back pain. While studies have examined the safety considerations in the upper lumbar spine related to the kidneys and lungs, none have investigated the possibility of entering the spinal canal in this region. Purpose: The purpose of this cadaveric ultrasound-guided dry needling exploration was to determine if a dry needle can penetrate the ligamentum flavum at the T12/L1 interspace and enter the spinal canal using a paramedian approach in a fresh-frozen, lightly fixed cadaver in the prone position. Study Design: Cadaveric study. Methods: The procedure was performed on a cadaver in the prone position. The needle was advanced under ultrasound guidance to determine if a 0.30 x 50 mm dry needle inserted 1.0 cm lateral to the spinous process of T12 and directed medially at a 22-degree angle could penetrate the ligamentum flavum and enter the spinal canal. Results: As determined via ultrasound, a dry needle can penetrate the ligamentum flavum and enter the spinal canal at the thoracolumbar junction using this technique. Conclusion: This interprofessional collaboration demonstrates that a dry needle can penetrate the ligamentum flavum to enter the spinal canal at T12/L1 using a documented technique for dry needling the multifidus. A thorough understanding of human anatomy along with the incorporation of available technology, such as ultrasound, may decrease the risk of adverse events when dry needling the multifidi at the thoracolumbar junction. Level of Evidence: Level IV.

The influence of pain-related comorbidities on pain intensity and pain-related psychological distress in patients presenting with musculoskeletal pain.

BACKGROUND: Musculoskeletal pain (MSP) is the largest contributor to chronic pain and frequently occurs alongside other medical comorbidities. OBJECTIVE: Explore the relationships between the presence of pain-related comorbidities, pain intensity, and pain-related psychological distress in patients with MSP. METHODS: A longitudinal assessment of individuals 18-90 years old in the Midwestern United States beginning a new episode of physical therapy for MSP. Electronic medical records were assessed the full year prior for care-seeking of diagnoses for pain-related comorbidities (anxiety, metabolic disorder, chronic pain, depression, nicotine dependence, post-traumatic stress disorder, sleep apnea, and sleep insomnia). Pain intensity and pain-related psychological distress (Optimal Screening for Prediction of Referral and Outcome - Yellow Flags tool) were captured during the physical therapy evaluation. Generalized linear models were used to assess the association between pain intensity, psychological distress, and pain-related co-morbidities. Models were adjusted for variables shown in the literature to influence pain. RESULTS: 532 participants were included in the cohort (56.4% female; median age of 59 years, Interquartile Range [IQR]:47, 69). Comorbid depression (beta coefficient (ß) = 0.7; 95%CI: 0.2, 1.2), spine versus lower extremity pain ((ß = 0.6; 95%CI: 0.1, 1.1), and prior surgery (ß = 0.8, 95%CI: 0.3, 1.4) were associated with higher pain intensity scores. No pain-related comorbidities were associated with pain-related psychological distress (yellow flag count or number of domains). Female sex was associated with less pain-related psychological distress (ß = -0.2, 95%CI: -0.3, -0.02). CONCLUSIONS: Depression was associated with greater pain intensity. No comorbidities were able to account for the extent of pain-related psychological distress.

Increasing complexity of clinical research in gastroenterology: implications for the training of clinician-scientists.

OBJECTIVES: Significant advances have been made in clinical and epidemiologic research methods over the past 30 years. We sought to demonstrate the impact of these advances on published gastroenterology research from 1980 to 2010. METHODS: Twenty original clinical articles were randomly selected from each of three journals from 1980, 1990, 2000, and 2010. Each article was assessed for topic, whether the outcome was clinical or physiologic, study design, sample size, number of authors and centers collaborating, reporting of various statistical methods, and external funding. RESULTS: From 1980 to 2010, there was a significant increase in analytic studies, clinical outcomes, number of authors per article, multicenter collaboration, sample size, and external funding. There was increased reporting of P values, confidence intervals, and power calculations, and increased use of large multicenter databases, multivariate analyses, and bioinformatics. CONCLUSIONS: The complexity of clinical gastroenterology and hepatology research has increased dramatically, highlighting the need for advanced training of clinical investigators.

Poor discriminatory function for endoscopic skills on a computer-based simulator.

BACKGROUND: Computer-based endoscopy simulators may enable trainees to learn and develop technical skills before performing on patients. Simulators require validation as adequate models of live endoscopy before being used for training or assessment purposes. OBJECTIVE: To evaluate content and criterion validity of the CAE EndoscopyVR Simulator colonoscopy and EGD modules as predictors of clinical endoscopic skills. DESIGN: Prospective, observational, non-randomized, parallel cohort study. SETTING: Single academic center with accredited gastroenterology training program. PARTICIPANTS: Five novice first-year gastroenterology fellows and 6 expert gastroenterology attending physicians. INTERVENTION: Participants performed 18 simulated colonoscopies and 6 simulated EGDs. The simulator recorded objective performance parameters. Participants then completed feedback surveys. MAIN OUTCOME MEASUREMENTS: The 57 objective performance parameters measured by the endoscopy simulator were compared between the two study groups. Novice and expert survey responses were analyzed. RESULTS: Significant differences between novice and expert performance were detected in only 19 of 57 (33%) performance metrics. Eight of these 19 (42%) were time-related metrics, such as total procedure time, time to anatomic landmarks, and time spent in contact with GI mucosa. Of 49 non-time related measures, the few additional statistically significant differences between novices and experts involved air insufflation, sedation management, endoscope force, and patient comfort. These findings are of uncertain clinical significance. Survey data found multiple aspects of the simulation to be unrealistic compared with human endoscopy. LIMITATIONS: Small sample size. CONCLUSION: The CAE EndoscopyVR Simulator displays poor content and criterion validity and is thereby incapable of predicting skill during in vivo endoscopy.

Imported Lassa fever, Pennsylvania, USA, 2010.

We report a case of Lassa fever in a US traveler who visited rural Liberia, became ill while in country, sought medical care upon return to the United States, and subsequently had his illness laboratory confirmed. The patient recovered with supportive therapy. No secondary cases occurred.

Improving the Quality of Inpatient Ulcerative Colitis Management: Promoting Evidence-Based Practice and Reducing Care Variation With an Inpatient Protocol.

BACKGROUND: Hospitalization for ulcerative colitis is a high-risk period associated with increased risk of Clostridium difficile infection, thromboembolism, and opiate use. The study aim was to develop and implement a quality-improvement intervention for inpatient ulcerative colitis management that standardizes gastroenterology consultant recommendations and improves delivery of evidence-based care. METHODS: All adult patients hospitalized for ulcerative colitis between July 1, 2014, and December 31, 2017, who received intravenous corticosteroids were included. On July 1, 2016, the UCSF Inpatient Ulcerative Colitis Protocol was implemented, featuring standardized core recommendations and a daily checklist for gastroenterology consultant notes, a bundled IBD electronic order set, and an opiate awareness campaign. The composite primary outcome was adherence to all 3 evidence-based care metrics: C. difficile testing performed, pharmacologic venous thromboembolism (VTE) prophylaxis ordered, and opiates avoided. RESULTS: Ninety-three ulcerative colitis hospitalizations occurred, including 36 preintervention and 57 postintervention. Age, gender, disease duration, disease extent, and medication use were similar preintervention and postintervention. C. difficile testing was performed in 100% of hospitalizations. Venous thromboembolism prophylaxis was ordered on 84% of hospital days before intervention compared with 100% after intervention (P ≤ 0.001). Opiates were administered in 67% of preintervention hospitalizations, compared with 53% of postintervention hospitalizations (P = 0.18). The median daily dose of oral morphine equivalents decreased from 12.1 mg before intervention to 0.5 mg after intervention (P = 0.02). The composite outcome of adherence to all 3 metrics was higher after intervention (25% vs. 47%, P = 0.03). CONCLUSIONS: Evidence-based inpatient ulcerative colitis management may be optimized with standardized algorithms that reinforce core principles, reduce care variation, and do not require IBD specialists to implement.

An unusually low microsatellite mutation rate in Dictyostelium discoideum, an organism with unusually abundant microsatellites.

The genome of the social amoeba Dictyostelium discoideum is known to have a very high density of microsatellite repeats, including thousands of triplet microsatellite repeats in coding regions that apparently code for long runs of single amino acids. We used a mutation accumulation study to see if unusually high microsatellite mutation rates contribute to this pattern. There was a modest bias toward mutations that increase repeat number, but because upward mutations were smaller than downward ones, this did not lead to a net average increase in size. Longer microsatellites had higher mutation rates than shorter ones, but did not show greater directional bias. The most striking finding is that the overall mutation rate is the lowest reported for microsatellites: approximately 1 x 10(-6) for 10 dinucleotide loci and 6 x 10(-6) for 52 trinucleotide loci (which were longer). High microsatellite mutation rates therefore do not explain the high incidence of microsatellites. The causal relation may in fact be reversed, with low mutation rates evolving to protect against deleterious fitness effects of mutation at the numerous microsatellites.

Pregnancy and the Patient with Inflammatory Bowel Disease: Fertility, Treatment, Delivery, and Complications.

For many women with inflammatory bowel disease (IBD), the illness coincides with their childbearing years. IBD increases the risk of pregnancy complications and adverse pregnancy outcomes. The multidisciplinary care team should emphasize the importance of medication adherence to achieve preconception disease control and maintain corticosteroid-free remission throughout pregnancy. Medication adjustments to reduce fetal exposure may be considered on an individualized basis in quiescent disease; however, any benefits of such adjustments remain theoretic and there is risk of worsening disease activity. Mode of delivery is determined by obstetric indications, except for women with active perianal disease who should consider cesarean delivery.

Use of Immunomodulators and Biologics Before, During, and After Pregnancy.

Immunomodulators and biologic medications, alone or in combination, form the core therapeutic strategy for managing moderate-to-severe inflammatory bowel disease (IBD). IBD incidence peaks during the prime reproductive years, raising concerns about the impact of disease and its treatment on fertility, maternal and fetal health during pregnancy, breastfeeding safety, and childhood development. Although IBD increases risk of pregnancy complications independent of disease activity, adverse pregnancy outcomes are more common when disease is active. To mitigate fetal risk, women should conceive while disease is quiescent. Aside from methotrexate, immunomodulators and biologics may be used during pregnancy to achieve and maintain disease control. Based on available safety data, there is no increased risk of congenital anomalies among infants exposed to these medications. Active thiopurine metabolites and most monoclonal antibodies cross the placenta and are detectable in neonates. They are detectable in breast milk in minute levels as well. The impact of this exposure on neonatal outcomes is discussed. Adjusted dosing schedules during gestation may reduce fetal drug exposure, though the maternal risks of such manipulation require careful consideration. Ongoing prospective studies will further inform risk assessment, including for newer medications such as the anti-integrin agents.

Using a Post-Intubation Checklist and Time Out to Expedite Mechanical Ventilation Monitoring: Observational Study of a Quality Improvement Intervention.

BACKGROUND: Delayed mechanical ventilation monitoring may impede recognition of life-threatening acidemia. Coordination of multidisciplinary processes can be improved by using a checklist and time-out procedure. The study objective was to evaluate process-related outcomes after implementation of a post-intubation checklist and time out. METHODS: An observational study of a 24-bed medical ICU in Philadelphia, Pennsylvania, was conducted from January to December 2011. A random sample of mechanically ventilated adults was selected from the pre-intervention (n = 80) and post-intervention (n = 144) periods. The primary outcome was the proportion of subjects with an arterial blood gas (ABG) result within 60 min of mechanical ventilation initiation. Secondary outcomes included rates of respiratory acidosis, moderate-severe acidemia (pH <7.25), checklist initiation, and project sustainability. Chi-square analysis was used to evaluate differences in outcomes between time periods. RESULTS: After the intervention, the proportion of subjects with an ABG result within 60 min increased (56% vs 37%, P = .01), and time to ABG result improved (58 min vs 79 min, P = .004). Adjusting for illness severity, the proportion with an ABG result within 60 min remained significantly higher in the post-intervention period (odds ratio 2.42, 95% CI 1.25-4.68, P = .009). Checklist adherence was higher with ICU intubations than for intubations performed outside the ICU (71% vs 27% checklist initiation rate, P < .001). Transfer from referring institutions (23% checklist initiation rate, P = .006) negatively impacted checklist use. Implementation challenges included frequent stakeholder turnover, undefined process ownership, and lack of real-time performance feedback. CONCLUSIONS: A post-intubation checklist and time out improved the timeliness of mechanical ventilation monitoring through more rapid assessment of arterial blood gases. Implementing this peri-intubation procedure may reduce the risks associated with transitioning to full mechanical ventilatory support. Optimal implementation necessitates strategies to surmount organizational and behavioral barriers to change.