Formation of a conceptual framework during the development of a patient-reported outcome measure for early gastrointestinal recovery: phase I of the PRO-diGi study.

AIM: Patients admitted to hospital for abdominal surgery often experience gastrointestinal dysfunction. Many studies have reported outcomes following gastrointestinal dysfunction, yet there is no unified definition of recovery or a validated patient-reported outcome measure (PROM). The first stage of PROM development requires formation of a conceptual framework to identify key themes to patients. The aim of this study was to utilize semistructured interviews to identify core themes and concepts relevant to patients to facilitate development of a conceptual framework. METHOD: Adult patients admitted to hospital for major gastrointestinal, urological or gynaecological surgery, in an emergency or elective setting, were eligible to participate. Patients treated nonoperatively for small bowel obstruction were also eligible. Interviews were conducted by telephone, audio-recorded, transcribed, coded and analysed using NVivo software by two researchers and reviewed by lay members of the steering group. Interviews continued until data saturation was reached. Ethical approval was gained prior to interviews (21/WA/0231). RESULTS: Twenty nine interviews were completed (17 men, median age 64 years) across three specialties (20 gastrointestinal, six gynaecological, three urological). Two overarching themes of 'general recovery' and 'gastrointestinal symptoms' were identified. General recovery included three themes: 'life impact', 'mental impact', including anxiety, and 'physical impact', including fatigue. Gastrointestinal symptoms included three themes: 'abdominal symptoms' such as pain, 'diet and appetite' and 'expulsory function', such as stool frequency. A total of 18 gastrointestinal symptoms were identified during patient recovery-many of which lasted several weeks following discharge. CONCLUSION: This study reports a range of gastrointestinal and nongastrointestinal symptoms experienced by patients during early gastrointestinal recovery. Identified symptoms have been synthesized into a conceptual framework to enable development of a definitive PROM for early gastrointestinal recovery.

Remote Ischemic Preconditioning in Non-cardiac Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Remote ischemic preconditioning (RIPC) may mitigate physiological stress related to surgery. There is no clear consensus on conduct of RIPC studies, or whether it is effective. The aim of this study was to (i) assess delivery of RIPC, (ii) identify reported outcomes, (iii) measure effect on key clinical outcomes. METHODS: This review was registered on PROSPERO (CRD:42020180725). EMBASE and Medline databases were searched, and results screened by two reviewers. Full-texts were assessed for eligibility by two reviewers. Data extracted were methods of RIPC and outcomes reported. Meta-analysis of key clinical events was performed using a Mantel-Haenszel random effects model. The TIDieR framework was used to assess intervention reporting, and Cochrane risk of bias tool was used for all studies included. RESULTS: Searches identified 25 studies; 25 were included in the narrative analysis and 18 in the meta-analysis. RIPC was frequently performed by occluding arm circulation (15/25), at 200 mmHg (9/25), with three cycles of 5 min ischemia and 5 min of reperfusion (16/25). No study fulfilled all 12 TIDieR items (mean score 7.68). Meta-analysis showed no benefit of RIPC on MI (OR 0.71 95% CI 0.48-1.04, I2 = 0%), mortality (OR 0.56, 95% CI 0.31-1.01, I2 = 0%), or acute kidney injury (OR 0.72 95% CI 0.48-1.08). CONCLUSIONS: RIPC could be standardized as 200 mmHg pressure in 3 × 5 min on and off cycles. The signal of benefit should be explored in a larger well-designed randomized trial.

A Systematic Review of Internet Decision-Making Resources for Patients Considering Surgery for Ulcerative Colitis.

BACKGROUND: Guidance from the Royal College of Surgeons advocates patient use of on-line resources to assist in decision making. Our aim was to assess the quality of on-line resources to facilitate decision making for patients considering surgery for ulcerative colitis (UC). METHODS: We undertook a systematic review based on PRISMA guidelines. This was registered on the PROSPERO database (CRD42016047177). We searched Google and repositories using several lay search terms for patient information discussing surgery for UC, published in English. Quality of content on websites was assessed using the validated DISCERN instrument and by minimum standards for decision aids (IPDASi v4.0 checklist). Decision aids were also assessed by the IPDAS checklist. Readability of written content was ascertained using the Flesch-Kincaid score. RESULTS: Our searches identified 175 websites and one decision aid-119 results were excluded at initial screen and 32 were excluded at full text assessment, leaving 25 sources for review. The mean Flesch-Kincaid score for websites was 44.9 (±9.73, range 28.1-61.4), suggesting material was difficult to read. No websites compared surgery to medical management or traded off patient preferences. The median IPDAS score was 5/12 (range 1-7). The median global score based on the DISCERN rating was 1/5 (range 1-5), identifying most websites as poor quality. The decision aid scored 9/12 on the IPDAS checklist, not meeting minimum standards. CONCLUSIONS: Available information for patients considering surgery for UC is generally low quality. The development of a new decision aid to support patients considering surgery for UC is recommended.

Inhibition of WISE preserves renal allograft function.

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of ß-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68(+) macrophages and CD8(+) T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.

Pancreatic islet expression profiling in diabetes-prone C57BLKS/J mice reveals transcriptional differences contributed by DBA loci, including Plagl1 and Nnt.

BACKGROUND: C57BLKS/J (BLKS) mice are susceptible to islet exhaustion in insulin-resistant states as compared with C57BL6/J (B6) mice, as observed by the presence of the leptin receptor (Lepr) allele, Leprdb/db. Furthermore, DBA2/J (DBA) mice are also susceptible to beta-cell failure and share 25% of their genome with BLKS; thus the DBA genome may contribute to beta-cell dysfunction in BLKS mice. RESULTS: Here we show that BLKS mice exhibit elevated insulin secretion, as evidenced by improved glucose tolerance and increased islet insulin secretion compared with B6 mice, and describe interstrain transcriptional differences in glucose response. Transcriptional differences between BLKS and B6 mice were identified by expression profiling of isolated islets from both strains. Genomic mapping of gene expression differences demonstrated a significant association of expression differences with DBA loci in BLKS mice (P = 4x10-27). CONCLUSION: Two genes, Nicotinamide nucleotide transhydrogenase (Nnt) and Pleiomorphic adenoma gene like 1 (Plagl1), were 4 and 7.2-fold higher respectively in BLKS islets, and may be major contributors to increased insulin secretion by BLKS islets. Contrary to reports for B6 mice, BLKS mice do not harbor a mutant Nnt gene. We detected 16 synonymous polymorphisms and a two-amino acid deletion in the Plagl1 gene in BLKS mice. Several inflammatory glucose-responsive genes are expressed at a higher level in BLKS, suggesting an inflammatory component to BLKS islet dysfunction. This study describes physiological differences between BLKS and B6 mice, and provides evidence for a causative role of the DBA genome in beta-cell dysfunction in BLKS mice.

Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice.

We conducted a genome-wide screen using the mutagen N-ethyl-N-nitrosourea to identify recessive mutations in genes that lead to altered lipid traits in mice. We screened 7,546 G3 mice that were of mixed C57BL/6J (B6) x C3.SW-H2(b)/SnJ (C3) genomes and identified three pedigrees with differences in plasma HDL-cholesterol. Genome scan analyses mapped three distinct loci to chromosomes 3, 4, and 7. An S1748L missense mutation was identified in ABCA1 in one pedigree with undetectable levels of HDL-cholesterol and resulted in reduced protein levels. This phenotype was completely penetrant, semi-dominant, and cosegregated with high plasma triglycerides. Mice in a second pedigree had very high levels of plasma total cholesterol and HDL-cholesterol (up to 800 mg/dl total cholesterol). Despite a high degree of phenotype lability and reduced penetrance, an I68N missense mutation was identified in the transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha). Finally, a second high HDL-cholesterol pedigree of mice, again with a highly labile phenotype and reduced penetrance, was mapped to a 7 Mb locus on chromosome 3. These results illustrate the use of a hybrid background for simultaneous screening and mapping of mutagenized pedigrees of mice and identification of three novel alleles of HDL-cholesterol phenotypes.