Can an educational video improve the adequacy of bowel preparation for patients undergoing their first colonoscopy? Results of the EBOPS RCT.

Background and study aims The aim of this study was to assess the effect of an educational video on the quality of bowel preparation of patients from a UK population attending for their first colonoscopy. Patients and methods A prospective, endoscopist-blinded trial with 1:1 allocation was performed. Patients referred for their first colonoscopy were recruited between February 2019 and December 2019. All participants were prescribed Moviprep and received the trial site's standard written bowel preparation instructions, with the intervention group also receiving a bespoke educational video. Adequacy of bowel preparation (defined as a Boston Bowel Preparation Scale of ≥2 in each segment of the bowel) and polyp detection rates (PDRs) were compared. Fisher's chi squared test was utilized with P <0.05 as the threshold for significance. Results A total of 509 participants completed the trial from six centers; 251 were randomized to the intervention group. The mean age was 57 years and 52.3% were female. The primary endpoint was met with an adequacy rate of 216 of 251 (86.1%) in the intervention group, compared with 205 of 259 (79.1%) in the control group ( P <0.05, odds ratio [OR] 1.626, 95% CI 1.017-2.614). The PDR was significantly higher in the intervention group (39% vs 30%, OR 1.51, 95% CI 1.04-2.19, P <0.05). Conclusions An educational video leads to improved bowel preparation for patients attending for their first colonoscopy, and is also associated with greater detection of polyps. Widespread adoption of an educational video incurs minimal investment, but would reduce the number of inadequate procedures, missed pathology, and the cost that both these incur.

Transsynaptic Assemblies Link Domains of Presynaptic and Postsynaptic Intracellular Structures across the Synaptic Cleft.

The chemical synapse is a complex machine separated into three parts: presynaptic, postsynaptic, and cleft. Super-resolution light microscopy has revealed alignment of presynaptic vesicle release machinery and postsynaptic neurotransmitter-receptors and scaffolding components in synapse spanning nanocolumns. Cryo-electron tomography confirmed that postsynaptic glutamate receptor-like structures align with presynaptic structures in proximity to synaptic vesicles into transsynaptic assemblies. In our electron tomographic renderings, nearly all transcleft structures visibly connect to intracellular structures through transmembrane structures to form transsynaptic assemblies, potentially providing a structural basis for transsynaptic alignment. Here, we describe the patterns of composition, distribution, and interactions of all assemblies spanning the synapse by producing three-dimensional renderings of all visibly connected structures in excitatory and inhibitory synapses in dissociated rat hippocampal neuronal cultures of both sexes prepared by high-pressure freezing and freeze-substitution. The majority of transcleft structures connect to material in both presynaptic and postsynaptic compartments. We found several instances of assemblies connecting to both synaptic vesicles and postsynaptic density scaffolding. Each excitatory synaptic vesicle within 30 nm of the active zone contacts one or more assembly. Further, intracellular structures were often shared between assemblies, entangling them to form larger complexes or association domains, often in small clusters of vesicles. Our findings suggest that transsynaptic assemblies physically connect the three compartments, allow for coordinated molecular organization, and may combine to form specialized functional association domains, resembling the light-level nanocolumns.SIGNIFICANCE STATEMENT A recent tomographic study uncovered that receptor-like cleft structures align across the synapse. These aligned structures were designated as transsynaptic assemblies and demonstrate the coordinated organization of synaptic transmission molecules between compartments. Our present tomographic study expands on the definition of transsynaptic assemblies by analyzing the three-dimensional distribution and connectivity of all cleft-spanning structures and their connected intracellular structures. While one-to-one component alignment occurs across the synapse, we find that many assemblies share components, leading to a complex entanglement of assemblies, typically around clusters of synaptic vesicles. Transsynaptic assemblies appear to form domains which may be the structural basis for alignment of molecular nanodomains into synapse spanning nanocolumns described by super-resolution light microscopy.

Comparing the predictive ability of the Revised Minimum Dataset Mortality Risk Index (MMRI-R) with nurses' predictions of mortality among frail older people: a cohort study.

OBJECTIVES: to establish the accuracy of community nurses' predictions of mortality among older people with multiple long-term conditions, to compare these with a mortality rating index and to assess the incremental value of nurses' predictions to the prognostic tool. DESIGN: a prospective cohort study using questionnaires to gather clinical information about patients case managed by community nurses. Nurses estimated likelihood of mortality for each patient on a 5-point rating scale. The dataset was randomly split into derivation and validation cohorts. Cox proportional hazard models were used to estimate risk equations for the Revised Minimum Dataset Mortality Risk Index (MMRI-R) and nurses' predictions of mortality individually and combined. Measures of discrimination and calibration were calculated and compared within the validation cohort. SETTING: two NHS Trusts in England providing case-management services by nurses for frail older people with multiple long-term conditions. PARTICIPANTS: 867 patients on the caseload of 35 case-management nurses. 433 and 434 patients were assigned to the derivation and validation cohorts, respectively. Patients were followed up for 12 months. RESULTS: 249 patients died (28.72%). In the validation cohort, MMRI-R demonstrated good discrimination (Harrell's c-index 0.71) and nurses' predictions similar discrimination (Harrell's c-index 0.70). There was no evidence of superiority in performance of either method individually (P = 0.83) but the MMRI-R and nurses' predictions together were superior to nurses' predictions alone (P = 0.01). CONCLUSIONS: patient mortality is associated with higher MMRI-R scores and nurses' predictions of 12-month mortality. The MMRI-R enhanced nurses' predictions and may improve nurses' confidence in initiating anticipatory care interventions.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

A Network of Three Types of Filaments Organizes Synaptic Vesicles for Storage, Mobilization, and Docking.

Synaptic transmission between neurons requires precise management of synaptic vesicles. While individual molecular components of the presynaptic terminal are well known, exactly how the molecules are organized into a molecular machine serving the storage and mobilization of synaptic vesicles to the active zone remains unclear. Here we report three filament types associated with synaptic vesicles in glutamatergic synapses revealed by electron microscope tomography in unstimulated, dissociated rat hippocampal neurons. One filament type, likely corresponding to the SNAREpin complex, extends from the active zone membrane and surrounds docked vesicles. A second filament type contacts all vesicles throughout the active zone and pairs vesicles together. On the third filament type, vesicles attach to side branches extending from the long filament core and form vesicle clusters that are distributed throughout the vesicle cloud and along the active zone membrane. Detailed analysis of presynaptic structure reveals how each of the three filament types interacts with synaptic vesicles, providing a means to traffic reserved and recycled vesicles from the cloud of vesicles into the docking position at the active zone. SIGNIFICANCE STATEMENT: The formation and release of synaptic vesicles has been extensively investigated. Explanations of the release of synaptic vesicles generally begin with the movement of vesicles from the cloud into the synaptic active zone. However, the presynaptic terminal is filled with filamentous material that would appear to limit vesicular diffusion. Here, we provide a systematic description of three filament types connecting synaptic vesicles. A picture emerges illustrating how the cooperative attachment and release of these three filament types facilitate the movement of vesicles to the active zone to become docked in preparation for release.

Electron microscopic tomography reveals discrete transcleft elements at excitatory and inhibitory synapses.

Electron microscopy has revealed an abundance of material in the clefts of synapses in the mammalian brain, and the biochemical and functional characteristics of proteins occupying synaptic clefts are well documented. However, the detailed spatial organization of the proteins in the synaptic clefts remains unclear. Electron microscope tomography provides a way to delineate and map the proteins spanning the synaptic cleft because freeze substitution preserves molecular details with sufficient contrast to visualize individual cleft proteins. Segmentation and rendering of electron dense material connected across the cleft reveals discrete structural elements that are readily classified into five types at excitatory synapses and four types at inhibitory synapses. Some transcleft elements resemble shapes and sizes of known proteins and could represent single dimers traversing the cleft. Some of the types of cleft elements at inhibitory synapses roughly matched the structure and proportional frequency of cleft elements at excitatory synapses, but the patterns of deployments in the cleft are quite different. Transcleft elements at excitatory synapses were often evenly dispersed in clefts of uniform (18 nm) width but some types show preference for the center or edges of the cleft. Transcleft elements at inhibitory synapses typically were confined to a peripheral region of the cleft where it narrowed to only 6 nm wide. Transcleft elements in both excitatory and inhibitory synapses typically avoid places where synaptic vesicles attach to the presynaptic membrane. These results illustrate that elements spanning synaptic clefts at excitatory and inhibitory synapses consist of distinct structures arranged by type in a specific but different manner at excitatory and inhibitory synapses.

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Co-segregation of AMPA receptors with G(M1) ganglioside in synaptosomal membrane subfractions.

Biochemical studies have suggested that certain synaptic proteins associate with lipid rafts to perform key functions within the synapse. However, variability in biochemical preparations raises questions as to which synaptic proteins actually associate with lipid rafts. In the present study, we use both electron microscopy and biochemistry to investigate AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor localization in synaptic membrane subfractions prepared in two different ways, by Triton X-100 detergent treatment or without detergent by sonication at high pH. Immunogold electron microscopy shows that a detergent-resistant synaptosomal membrane subfraction consists of empty vesicles 0.1-1.0 microm in diameter. A subpopulation of these vesicles labelled for glycosphingolipid GM1 ganglioside, a marker of lipid rafts, and 46% of the labelled vesicles also labelled for the AMPA receptor subunit GluR2. This co-segregation into specific vesicles does not depend on effects of detergent because a similar distribution of label was found in vesicles isolated without the use of detergent. Our results suggest that AMPA receptors localize within specific regions of synaptic membranes rich in GM1 ganglioside.

Neonatal care: time for action on the shortage of nurses.

A survey by the charity Bliss of the 213 hospitals in the UK with neonatal units (response rate 92%) found a serious shortage of neonatal nurses. Minimum nurse staffing ratios recommended by the British Association of Perinatal Medicine (BAPM) were not being met, especially in neonatal intensive care units (NICUs). Only one in five neonatal units reported meeting the BAPM standard. Cot occupancy rates in NICUs exceeded the recommended 70% on occasions. Fifty-five per cent of units had to close to new admissions at some point during the survey period 1 April to 1 September 2007; the average duration for closure was two weeks. Staff shortages and 100% cot occupancy resulted in babies having to be transported to other units, sometimes long distances away. As well as clinical considerations, shortfalls in staffing and service capacity added to parents' difficulties at a stressful time in their lives. The one to one campaign being spearheaded by Bliss with endorsement from several professional bodies is actively promoting the recommended 1:1 nurse-to-cot ratio in NICUs. In England, the need for action on this issue has been acknowledged by the National Audit Office, the House of Commons Public Accounts Committee and the Healthcare Commission.

Nurse-administered femoral nerve block after hip fracture.

Hip fracture is a common injury that predominantly affects older people. Pain following fracture of the neck of the femur is present throughout the illness trajectory, including the preoperative and postoperative periods. This article describes how nurses at one trust implemented an innovative nurse-administered femoral nerve block service.