Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Nanobodies as Probes and Modulators of Cardiovascular G Protein-Coupled Receptors.

ABSTRACT: Understanding the activation of G protein-coupled receptors (GPCRs) is of paramount importance to the field of cardiovascular medicine due to the critical physiological roles of these receptors and their prominence as drug targets. Although many cardiovascular GPCRs have been extensively studied as model receptors for decades, new complexities in their regulation continue to emerge. As a result, there is an ongoing need to develop novel approaches to monitor and to modulate GPCR activation. In less than a decade, nanobodies, or recombinant single-domain antibody fragments from camelids, have become indispensable tools for interrogating GPCRs both in purified systems and in living cells. Nanobodies have gained traction rapidly due to their biochemical tractability and their ability to recognize defined states of native proteins. Here, we review how nanobodies have been adopted to elucidate the structure, pharmacology, and signaling of cardiovascular GPCRs, resolving long-standing mysteries and revealing unexpected mechanisms. We also discuss how advancing technologies to discover nanobodies with tailored specificities may expand the impact of these tools for both basic science and therapeutic applications.

Do Nontechnical Skills Affect Legal Outcomes After Endoscopic Perforations?

INTRODUCTION: Health systems often emphasize technical skills to reduce iatrogenic injuries. Nontechnical skills such as clinical and communication skills are mostly overlooked or not readily retrievable from medical records. Our aim was to estimate the association of technical and nontechnical skills of endoscopists with indemnity payments to patients after endoscopic perforations. METHODS: This is an observational registry-based study of closed claims against gastroenterologists involved in endoscopic perforations. RESULTS: We analyzed 175 closed claims related to perforations, all of which involved allegations of improper performance of the endoscopic procedure. Inadequate communication (n = 71, 41%) and clinical judgment (n = 60, 34%) on the part of the endoscopists were observed. Inadequate communication and clinical judgment were associated with over 3-fold odds of indemnity payment (odds ratio [OR] 3.31; 95% confidence interval [CI], 1.46-7.48, and OR 3.18; 95% CI, 1.44-7.01, respectively). However, if there were no communication breakdown or clinical judgment issues and the only allegation was poor technical skill, the odds of indemnity payments were less than half of those cases (OR 0.43; 95% CI 0.15-0.80). There was no evidence of a statistically significant interaction among age, procedure type, trainee involvement, clinical severity, need for surgery, and procedure-related death. DISCUSSION: We observed that inadequate communication and clinical judgment were associated with indemnity payment, independent of the severity of clinical outcomes. On the other hand, cases wherein there was an allegation of poor technical skills alone, without communication breakdown or clinical judgment issues, were associated with favorable legal outcomes for the defendant. (See the Visual Abstract at http://links.lww.com/AJG/B568.).

Maladaptive Coping and Depressive Symptoms Partially Explain the Association Between Family Stress and Pain-Related Distress in Youth With IBD.

Objective: To extend existing research on the pain burden experienced by youth with inflammatory bowel disease (IBD) by examining the complexity of psychosocial factors involved in pain-related distress. Methods: Parents completed measures of family stress and their child's pain-related expressions of distress and coping. Youth with IBD rated their depressive symptoms (n = 183 dyads). Mediation analyses were performed using regression-based techniques and bootstrapping. Results: Greater family stress was positively related to children's pain-related expressions of distress and passive coping. Significant indirect effects were found in the relationship between family stress and expressed pain-related distress through parent-reported passive coping, depressive symptoms, and both passive coping and depressive symptoms sequentially. Conclusions: Results suggest that family stress can place children at risk for greater expressed pain-related distress through effects on coping and depressive symptoms. Addressing psychosocial difficulties is important for closing the gap between disability and health in youth with IBD.

Time to Put Managing Endoscopic Complications Into the Curriculum.

Proper management of complications is critical to ensure the best outcome for both the patient and the physician. The physician's response to the error or complication, promptly informing the patient and the family, and expressing empathy at the situation, ensuring transparency and excellent post-complication care, is a critical determinant of the patient's understanding of the complication, perception of the physician, and, often, the decision to sue. Articles outlining best practice approach to various legal and risk management issues may aid physicians to acquire useful skills to help their patients.

Social media in the health-care setting: benefits but also a minefield of compliance and other legal issues.

Throughout the past 20 years, the rising use of social media has revolutionized health care as well as other businesses. It allows large groups of people to create and share information, ideas, and experiences through online communications, and develop social and professional contacts easily and inexpensively. Our Gastroenterology organizations, among others, have embraced this technology. Although the health-care benefits may be many, social media must be viewed through a legal lens, recognizing the accompanying burdens of compliance, ethical, and litigation issues. Theories of liability and risk continue to evolve as does the technology. Social media usage within the medical community is fraught with potential legal issues, requiring remedial responses to meet patients' needs and comply with current laws, while not exposing physicians to medical malpractice and other tort risks.

Targeting soluble amyloid-beta oligomers with a novel nanobody.

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-ß oligomers (SAßOs) accumulate early, prior to amyloid plaque formation. SAßOs induce memory impairment and disrupt cognitive function independent of amyloid-ß plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAßO (E3) nanobody generated from an alpaca immunized with SAßO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAßOs and amyloid-ß plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAßO and amyloid-ß plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAßOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAßO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease.

TARGETING SOLUBLE AMYLOID-BETA OLIGOMERS WITH A NOVEL NANOBODY.

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-ß oligomers (SAßOs) accumulate early, prior to amyloid plaque formation. SAßOs induce memory impairment and disrupt cognitive function independent of amyloid-ß plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAßO (E3) nanobody generated from an alpaca immunized with SAßO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAßOs and amyloid-ß plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAßO and amyloid-ß plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAßOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAßO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease.

Mediation of outcomes for cognitive behavioral therapy targeted to parents of children with Functional Abdominal Pain Disorders.

OBJECTIVE: There is a large body of evidence for the efficacy of Cognitive Behavioral Therapy (CBT) in treating Functional Abdominal Pain Disorders (FAPD) in children. In most CBT interventions for FAPD, parents participate together with their children. However, only one study to date has examined targeting parents alone for treatment. The aim of the current study was to examine mediators of a parent-only CBT treatment incorporating social learning (SLCBT) for FAPD in children. METHODS: We examined mediators of child outcomes in an existing randomized controlled trial (n = 316) of parent-only social learning CBT compared to an education condition. Hypothesized mediators (parental protectiveness, perceived threat of pain, catastrophizing) were assessed at 3 months post-treatment, and outcomes (parent ratings of disability, quality of life, school absences, and health care visits) were assessed at 6 months post-treatment. Mediation analyses were performed using Hayes' PROCESS macro. RESULTS: Pain catastrophizing significantly mediated treatment effects for all outcomes (B ranged from -1.65 to 2.22). Reduction in pain threat was a significant mediator for all outcomes (B ranged from -1.84 to 3.13) except school absences and health care visits. Decrease in parental protectiveness mediated effects on disability and missed school (B ranged from -1.47 to 1.34). Mediation effects did not differ by in-person or remote delivery of SLCBT. CONCLUSION: Changes in maladaptive parental thoughts and behaviors following parent-only SLCBT intervention appeared to mediate the effects of the intervention. Parental catastrophizing appears to be a particularly important target given that decreases in that variable mediated all outcomes.

Inability of the Rome III criteria to distinguish functional constipation from constipation-subtype irritable bowel syndrome.

OBJECTIVES: The Rome III classification system treats functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) as distinct disorders, but this distinction appears artificial, and the same drugs are used to treat both. This study's hypothesis is that FC and IBS-C defined by Rome III are not distinct entities. METHODS: In all, 1,100 adults with a primary care visit for constipation and 1,700 age- and gender-matched controls from a health maintenance organization completed surveys 12 months apart; 66.2% returned the first questionnaire. Rome III criteria identified 231 with FC and 201 with IBS-C. The second survey was completed by 195 of the FC and 141 of the IBS-C cohorts. Both surveys assessed the severity of constipation and IBS, quality of life (QOL), and psychological distress. RESULTS: (i) Overlap: if the Rome III requirement that patients meeting criteria for IBS cannot be diagnosed with FC is suspended, 89.5% of IBS-C cases meet criteria for FC and 43.8% of FC patients fulfill criteria for IBS-C. (ii) No qualitative differences between FC and IBS-C: 44.8% of FC patients report abdominal pain, and paradoxically IBS-C patients have more constipation symptoms than FC. (iii) Switching between diagnoses: by 12 months, 1/3 of FC transition to IBS-C and 1/3 of IBS-C change to FC. CONCLUSIONS: Patients identified by Rome III criteria for FC and IBS-C are not distinct groups. Revisions to the Rome III criteria, possibly including incorporation of physiological tests of transit and pelvic floor function, are needed.

Cognitive-behavioral therapy for children with functional abdominal pain and their parents decreases pain and other symptoms.

OBJECTIVES: Unexplained abdominal pain in children has been shown to be related to parental responses to symptoms. This randomized controlled trial tested the efficacy of an intervention designed to improve outcomes in idiopathic childhood abdominal pain by altering parental responses to pain and children's ways of coping and thinking about their symptoms. METHODS: Two hundred children with persistent functional abdominal pain and their parents were randomly assigned to one of two conditions-a three-session intervention of cognitive-behavioral treatment targeting parents' responses to their children's pain complaints and children's coping responses, or a three-session educational intervention that controlled for time and attention. Parents and children were assessed at pretreatment, and 1 week, 3 months, and 6 months post-treatment. Outcome measures were child and parent reports of child pain levels, function, and adjustment. Process measures included parental protective responses to children's symptom reports and child coping methods. RESULTS: Children in the cognitive-behavioral condition showed greater baseline to follow-up decreases in pain and gastrointestinal symptom severity (as reported by parents) than children in the comparison condition (time x treatment interaction, P<0.01). Also, parents in the cognitive-behavioral condition reported greater decreases in solicitous responses to their child's symptoms compared with parents in the comparison condition (time x treatment interaction, P<0.0001). CONCLUSIONS: An intervention aimed at reducing protective parental responses and increasing child coping skills is effective in reducing children's pain and symptom levels compared with an educational control condition.

Most doctors win: what to do if sued for medical malpractice.

All gastroenterologists are at risk of being accused of medical malpractice; few have received much training about what to do should a lawsuit occur. This article details what one can expect in a typical medical malpractice negligence claim and reviews basic relevant legal terminology. The timeline of a lawsuit is described, particularly noting the physician's role in discovery and trial. Cautions and suggestions for successful navigation of this unfamiliar and uncomfortable world are dispensed.