JAG consensus statements for training and certification in colonoscopy.

Introduction: In the UK, endoscopy certification is awarded when trainees attain minimum competency standards for independent practice. A national evidence-based review was undertaken to update and develop standards and recommendations for colonoscopy training and certification. Methods: Under the oversight of the Joint Advisory Group (JAG), a modified Delphi process was conducted between 2019 and 2020 with multisociety expert representation. Following literature review and Grading of Recommendations, Assessment, Development and Evaluations appraisal, recommendation statements on colonoscopy training and certification were formulated and subjected to anonymous voting to obtain consensus. Accepted statements were peer reviewed by JAG and relevant stakeholders for incorporation into the updated colonoscopy certification pathway. Results: In total, 45 recommendation statements were generated under the domains of: definition of competence (13), acquisition of competence (20), assessment of competence (8) and postcertification support (4). The consensus process led to revised criteria for colonoscopy certification, comprising: (1) achieving key performance indicators defined within British Society of Gastroenterology standards (ie, unassisted caecal intubation rate >90%, rectal retroversion >90%, polyp detection rate >15%+, polyp retrieval rate >90%, patient comfort <10% with moderate-severe discomfort); (2) minimum procedure count 280+; (3) performing 15+ procedures over the preceding 3 months; (4) attendance of the JAG Basic Skills in Colonoscopy course; (5) terminal ileal intubation rates of 60%+ in inflammatory bowel disease; (6) satisfying requirements for formative direct observation of procedure skills (DOPS) and direct observation of polypectomy skills (Size, Morphology, Site, Access (SMSA) level 2); (7) evidence of reflective practice as documented on the JAG Endoscopy Training System reflection tool; (8) successful performance in summative DOPS. Conclusion: The UK standards for training and certification in colonoscopy have been updated, culminating in a single-stage certification process with emphasis on polypectomy competency (SMSA Level 2+). These standards are intended to support training, improve standards of colonoscopy and polypectomy, and provide support to the newly independent practitioner.

JAG consensus statements for training and certification in flexible sigmoidoscopy.

Introduction: Joint Advisory Group (JAG) certification in endoscopy is awarded when trainees attain minimum competency standards for independent practice. A national evidence-based review was undertaken to update standards for training and certification in flexible sigmoidoscopy (FS). Methods: A modified Delphi process was conducted between 2019 and 2020 with multisociety representation from experts and trainees. Following literature review and Grading of Recommendations, Assessment, Development and Evaluations appraisal, recommendation statements on FS training and certification were formulated and subjected to anonymous voting to obtain consensus. Accepted statements were peer-reviewed by national stakeholders for incorporation into the JAG FS certification pathway. Results: In total, 41 recommendation statements were generated under the domains of: definition of competence (13), acquisition of competence (17), assessment of competence (7) and postcertification support (4). The consensus process led to revised criteria for colonoscopy certification, comprising: (A) achieving key performance indicators defined within British Society of Gastroenterology standards (ie, rectal retroversion >90%, polyp retrieval rate >90%, patient comfort <10% with moderate-severe discomfort); (B) minimum procedure count ≥175; (C) performing 15+ procedures over the preceding 3 months; (D) attendance of the JAG Basic Skills in Lower gastrointestinal Endoscopy course; (E) satisfying requirements for formative direct observation of procedural skill (DOPS) and direct observation of polypectomy skill (SMSA level 1); (F) evidence of reflective practice as documented on the JAG Endoscopy Training System reflection tool and (G) successful performance in summative DOPS. Conclusion: The UK standards for training and certification in FS have been updated to support training, uphold standards in FS and polypectomy, and provide support to the newly independent practitioner.

Relational conflict and outcomes from an online divorce education program.

The impact of conflict on co-parenting outcomes of divorce education programs is not widely explored in the literature despite the prevalence of conflict in divorce. This study used outcome data from a sample of participants (N=272) who took the online Parents Forever™ course between 2012 and 2014. Participants were asked questions about positive and negative co-parenting behaviors as well their levels of conflict before and after the divorce or separation. There was on average a slight increase in conflict from post to follow-up (M=-0.397, SD=1.54). Simple linear regression analyses indicated that change in conflict explained a significant proportion of the variance in positive co-parenting scores, R2=0.07, F(1, 270)=19.98, p<0.001 and negative co-parenting scores, R2=0.08, F(1, 270)=23.78, p<0.001. Results suggest that conflict significantly impacts co-parenting behaviors targeted in the Parents Forever ™ course.

Does a choice of condoms impact sexually transmitted infection incidence? A randomized, controlled trial.

OBJECTIVE: The objective of this study was to assess whether providing a choice of condoms would increase condom acceptability, increase self-reported use, and decrease incident sexually transmitted infection. STUDY: We randomized 414 men presenting with urethral discharge in Jamaica to receive either the "standard" clinic condom or a choice of 4 different types of condoms. Men were treated presumptively at enrollment and followed up at 1, 2, 4, and 6 months. RESULTS: Participants in the choice group had a strong preference (P <0.01) for the most popular condom available in Jamaica. This preference did not translate into higher condom use (P = 0.16). The 6-month cumulative probability of first incidence of gonorrhea, chlamydia, or trichomoniasis was slightly higher in the choice group (21%; 95% confidence interval [CI], 15-28%) versus the control group (17%; 95% CI, 11-23%); the difference in the survival curves was not significant (P = 0.35). CONCLUSION: A choice of condoms may increase perceived acceptability but not lead to increased condom use and subsequently lower sexually transmitted infection rates.

Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII.

Using separate adeno-associated viral 2 (AAV2) vectors to deliver the heavy and light chains of factor VIII (FVIII) we have overcome the packaging limitations of AAV, achieving phenotypic correction of hemophilia A in mice. AAV vectors were constructed that use a liver-specific promoter and the cDNA sequences of either the human or canine heavy and light chains of FVIII. After intraportal vein injection of these vectors in hemophilia-A mice, therapeutic to superphysiologic levels of active FVIII were achieved in plasma in a dose-dependent manner. Phenotypic correction of the bleeding diathesis was demonstrated by survival of all treated mice after tail clipping. Biochemical analysis demonstrated lower levels of heavy-chain (25- to 100-fold) compared with light-chain protein in the plasma of treated animals. Differences in gene transfer and transcription did not account for the differences in protein expression. We hypothesize that improvements in FVIII activity could be achieved by improvements in FVIII heavy-chain expression. This work demonstrates that cotransduction of liver with AAV vectors expressing the heavy and light chains of FVIII corrects hemophilia A in vivo, providing an alternative approach to the use of a single vector. This strategy may potentially be useful for other large therapeutic proteins that contain functionally distinct domains.

Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector.

Gene therapy for hemophilia A requires efficient delivery of the factor VIII gene and sustained protein expression at circulating levels of at least 1% to 2% of normal. Adeno-associated viral type 2 (AAV2) vectors have a number of advantages over other viral vectors, including an excellent safety profile and persistent gene expression. However, a major disadvantage is their small packaging capacity, which has hampered their use in treating diseases such as hemophilia A, cystic fibrosis, and muscular dystrophy, which are caused by mutations in large genes. Here we demonstrate that this can be overcome by using small regulatory elements to drive expression of a B-domain-deleted form of FVIII. The use of this vector for hepatic gene transfer in a canine model of hemophilia A resulted in the sustained (> 14 months) expression of biologically active FVIII. FVIII activity levels of 2% to 4% were achieved. These levels correlated with a partial correction in the whole-blood clotting time and cuticle bleeding time. In addition, immunoprecipitation analysis demonstrated the expression of canine FVIII of the predicted size in the plasma of injected animals. These data support the use of AAV2 vectors in human clinical trials to treat hemophilia A patients.

Quantification of adeno-associated virus particles and empty capsids by optical density measurement.

We show here that UV absorbance of denatured adeno-associated virus (AAV) vector provides a simple, rapid, and direct method for quantifying vector genomes and capsid proteins in solution. We determined the molar extinction coefficients of capsid protein to be 3.72 x 10(6) M(-1) cm(-1) at 260 nm and 6.61 x 10(6) M(-1) cm(-1) at 280 nm. For recombinant AAV vectors, extinction coefficients can be calculated by including the predicted absorbance of the vector DNA. Since the amount of empty capsids in purified vector preparations lowers the A(260)/A(280) ratio in a predictable manner, the vector genome (vg) and capsid particle (cp) titers in purified AAV vector preparations can be calculated from the absorbance at 260 nm and the A(260)/A(280) ratio. To validate this method, the vg and cp titers calculated by UV absorbance were compared with titers determined by quantitative (Q)-PCR and capsid ELISA. The vg titers determined by absorbance agreed well with titers determined by Q-PCR. The cp/vg ratio determined by the A(260)/A(280) method also correlated well with those determined by AAV capsid ELISA in conjunction with Q-PCR. This new method provides a simple and rapid means to determine AAV vg titers and the ratio of empty to full particles in purified virus preparations.

Utilization of 1-oxa-2,2-(dimesityl)silacyclopentane acetals in the stereoselective synthesis of polyols.

We have developed a route for the stereoselective synthesis of 1-oxa-2,2-(dimesityl)silacyclopentane acetals, intermediates in the synthesis of highly functionalized 1,3-diols. This route involves a diastereoselective conjugate addition reaction of a hydrosilyl anion, a subsequent diastereoselective enolate alkylation, and a fluoride-catalyzed intramolecular hydrosilylation reaction to afford the oxasilacyclopentane acetal. A highly selective nucleophilic substitution reaction, followed by oxidation of the C-Si bond, leads to the desired polyol.

A limited number of transducible hepatocytes restricts a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction.

Recombinant adeno-associated virus (rAAV) vectors are promising vehicles for achieving stable liver transduction in vivo. However, the mechanisms of liver transduction are not fully understood, and furthermore, the relationships between rAAV dose and levels of transgene expression, total number of hepatocytes transduced, and proportion of integrated vector genomes have not been well established. To begin to elucidate the liver transduction dose response with rAAV vectors, we injected mice with two different human factor IX or Escherichia coli lacZ-expressing AAV serotype 2-based vectors at doses ranging between 4.0 x 10(8) and 1.1 x 10(13) vector genomes (vg)/mouse, in three- to sixfold increments. A 2-log-range linear dose-response curve of transgene expression was obtained from 3.7 x 10(9) to 3.0 x 10(11) vg/mouse. Vector doses above 3.0 x 10(11) vg/mouse resulted in disproportionately smaller increases in both the number of transduced hepatocytes and levels of transgene expression, followed by saturation at doses above 1.8 x 10(12) vg/mouse. In contrast, a linear increase in the number of vector genomes per hepatocyte was observed up to 1.8 x 10(12) vg/mouse concomitantly with enhanced vector genome concatemerization, while the proportion of integrated vector genomes was independent of the vector dose. Thus, the mechanisms that restrict a wide-range linear dose response at high doses likely involve decreased functionality of vector genomes and restriction of transduction to fewer than 10% of total hepatocytes. Such information may be useful to determine appropriate vector doses for in vivo administration and provides further insights into the mechanisms of rAAV transduction in the liver.