Impact of deliberate practice on evidence-based medicine attitudes and behaviours of health care professionals

Introduction Although evidence-based medicine (EBM) teaching activities may improve short-term EBM knowledge and skills, they have little long-term impact on learners' EBM attitudes and behaviour. This study examined the effects of learning EBM through stand-alone workshops or various forms of deliberate EBM practice. Methods We assessed EBM attitudes and behaviour with the evidence based practice inventory questionnaire, in paediatric health care professionals who had only participated in a stand-alone EBM workshop (controls), participants with a completed PhD in clinical research (PhDs), those who had completed part of their paediatric residency at a department (Isala Hospital) which systematically implemented EBM in its clinical and teaching activities (former Isala residents), and a reference group of paediatric professionals currently employed at Isala's paediatric department (current Isala participants). Results Compared to controls (n = 16), current Isala participants (n = 13) reported more positive EBM attitudes (p < 0.01), gave more priority to using EBM in decision making (p = 0.001) and reported more EBM behaviour (p = 0.007). PhDs (n = 20) gave more priority to using EBM in medical decision making (p < 0.001) and reported more EBM behaviour than controls (p = 0.016). Discussion Health care professionals exposed to deliberate practice of EBM, either in the daily routines of their department or by completing a PhD in clinical research, view EBM as more useful and are more likely to use it in decision making than their peers who only followed a standard EBM workshop. These findings support the use of deliberate practice as the basis for postgraduate EBM educational activities

Right-Sided Location Not Associated With Missed Colorectal Adenomas in an Individual-Level Reanalysis of Tandem Colonoscopy Studies

Background & Aims Interval cancers occur more frequently in the right colon. One reason could be that right-sided adenomas are frequently missed in colonoscopy examinations. We reanalyzed data from tandem colonoscopies to assess adenoma miss rates in relation to location and other factors. Methods We pooled data from 8 randomized tandem trials comprising 2218 patients who had diagnostic or screening colonoscopies (adenomas detected in 49.8% of patients). We performed a mixed-effects logistic regression with patients as cluster effects with different independent parameters. Factors analyzed included location (left vs right, splenic flexure as cutoff), adenoma size, form, and histologic features. Analyses were controlled for potential confounding factors such as patient sex and age, colonoscopy indication, and bowel cleanliness. Results Right-side location was not an independent risk factor for missed adenomas (odds ratio [OR] compared with the left side, 0.94; 95% CI, 0.75–1.17). However, compared with adenomas ≤5 mm, the OR for missing adenomas of 6–9 mm was 0.62 (95% CI, 0.44–0.87), and the OR for missing adenomas of ≥10 mm was 0.51 (95% CI, 0.33–0.77). Compared with pedunculated adenomas, sessile (OR, 1.82; 95% CI, 1.16–2.85) and flat adenomas (OR, 2.47; 95% CI, 1.49–4.10) were more likely to be missed. Histologic features were not significant risk factors for missed adenomas (OR for adenomas with high-grade intraepithelial neoplasia, 0.68; 95% CI, 0.34–1.37 and OR for sessile serrated adenomas, 0.87; 95% CI, 0.47–1.64 compared with low-grade adenomas). Men had a higher number of adenomas per colonoscopy (1.27; 95% CI, 1.21–1.33) than women (0.86; 95% CI, 0.80–0.93). Men were less likely to have missed adenomas than women (OR for missed adenomas in men, 0.73; 95% CI, 0.57–0.94). Conclusions In an analysis of data from 8 randomized trials, we found that right-side location of an adenoma does not increase its odds for being missed during colonoscopy but that adenoma size and histologic features do increase risk. Further studies are needed to determine why adenomas are more frequently missed during colonoscopies in women than men

Human regulatory T cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint

Objective: Tregs are crucial for immune regulation, and environment-driven adaptation of effector (e)Tregs is essential for local functioning. However, the extent of human Treg heterogeneity in inflammatory settings is unclear. Methods: We combined single-cell RNA- and TCR-sequencing on Tregs derived from three to six patients with juvenile idiopathic arthritis (JIA) to investigate the functional heterogeneity of human synovial fluid (SF)-derived Tregs from inflamed joints. Confirmation and suppressive function of the identified Treg clusters was assessed by flow cytometry. Results: Four Treg clusters were identified; incoming, activated eTregs with either a dominant suppressive or cytotoxic profile, and GPR56 +CD161 +CXCL13 + Tregs. Pseudotime analysis showed differentiation towards either classical eTreg profiles or GPR56 +CD161 +CXCL13 + Tregs supported by TCR data. Despite its most differentiated phenotype, GPR56 +CD161 +CXCL13 + Tregs were shown to be suppressive. Furthermore, BATF was identified as an overarching eTreg regulator, with the novel Treg-associated regulon BHLHE40 driving differentiation towards GPR56 +CD161 +CXCL13 + Tregs, and JAZF1 towards classical eTregs. Conclusion: Our study reveals a heterogeneous population of Tregs at the site of inflammation in JIA. SF Treg differentiate to a classical eTreg profile with a more dominant suppressive or cytotoxic profile that share a similar TCR repertoire, or towards GPR56 +CD161 +CXCL13 + Tregs with a more distinct TCR repertoire. Genes characterising GPR56 +CD161 +CXCL13 + Tregs were also mirrored in other T-cell subsets in both the tumor and the autoimmune setting. Finally, the identified key regulators driving SF Treg adaptation may be interesting targets for autoimmunity or tumor interventions

Homeostatic function and inflammatory activation of ileal CD8+ tissue-resident T cells is dependent on mucosal location

Background & Aims: Tissue-resident memory T (Trm) cells, both of the CD4 and CD8 lineage, have been implicated in disease flares in inflammatory bowel disease. However, data are conflicting regarding the profile of human CD8 + Trm cells, with studies suggesting both proinflammatory and regulatory functions. It is crucial to understand the functional profile of these cells in the context of (new) therapeutic strategies targeting (trafficking of) gut Trm cells. Methods: Here, we performed imaging mass cytometry, flow cytometry, and RNA-sequencing to compare lamina propria and intraepithelial CD103 +/–CD69 +CD8 + Trm cells in healthy control subjects and patients with active ileal Crohn's disease. Results: Our data revealed that lamina propria CD103 +CD69 +CD8 + T cells have a classical Trm cell profile with active pathways for regulating cell survival/death and cytokine signaling, whereas intraepithelial CD103 +CD69 +CD8 + T cells display tightly regulated innate-like cytotoxic profile. Furthermore, within lamina propria CD8 +CD103 – Trm cells, an Itgb2 +GzmK +KLRG1 + population distinct from CD103 + CD8 + Trm cells is found. During chronic inflammation, especially intraepithelial CD103 +CD69 +CD8 + T cells displayed an innate proinflammatory profile with concurrent loss of homeostatic functions. Conclusions: Altogether, these compartmental and inflammation-induced differences indicate that therapeutic strategies could have a different impact on the same immune cells depending on the local compartment and presence of an inflammatory milieu, and should be taken into account when investigating short- and long-term effects of new gut T cell–targeting drugs

Compartment-driven imprinting of intestinal CD4 T cells in inflammatory bowel disease and homeostasis

The mucosal immune system is implicated in the etiology and progression of inflammatory bowel diseases. The lamina propria and epithelium of the gut mucosa constitute two separate compartments, containing distinct T-cell populations. Human CD4 T-cell programming and regulation of lamina propria and epithelium CD4 T cells, especially during inflammation, remain incompletely understood. We performed flow cytometry, bulk, and single-cell RNA-sequencing to profile ileal lamina propria and intraepithelial CD4 T cells (CD4CD8αα, regulatory T cells (Tregs), CD69- and CD69high Trm T cells) in controls and Crohn's disease (CD) patients (paired non-inflamed and inflamed). Inflammation results in alterations of the CD4 T-cell population with a pronounced increase in Tregs and migrating/infiltrating cells. On a transcriptional level, inflammation within the epithelium induced T-cell activation, increased IFNγ responses, and an effector Treg profile. Conversely, few transcriptional changes within the lamina propria were observed. Key regulators including the chromatin remodelers ARID4B and SATB1 were found to drive compartment-specific transcriptional programming of CD4 T(reg) cells. In summary, inflammation in CD patients primarily induces changes within the epithelium and not the lamina propria. Additionally, there is compartment-specific CD4 T-cell imprinting, driven by shared regulators, between the lamina propria and the epithelium. The main consequence of intraepithelial adaptation, irrespective of inflammation, seems to be an overall dampening of broad (pro-inflammatory) responses and tight regulation of lifespan. These data suggest differential regulation of the lamina propria and epithelium, with a specific regulatory role in the inflamed epithelium

Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients

BACKGROUND & AIMS: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs. METHODS: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex- and BMI-matched controls, and 99 unrelated IBD patients. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared between healthy-cotwins, IBD-twins, unrelated IBD patients, and healthy controls with multivariable, i.e. adjusted for potential confounding, generalized linear models. RESULTS: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate (FDR)<0.10). Compared to healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy-cotwins, IBD-twins and unrelated IBD patients, respectively (FDR<0.10). Of these, 8/19 (42.1%) and 1/18 (5.6%) species, and 37/105 (35.2%) and 30/153 (19.6%) pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated IBD patients respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example: an increase in propionate degradation and L-arginine degradation pathways. CONCLUSIONS: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow up studies are needed to infer a causal relationship

Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis

PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%-8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6-10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4-10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target

Taenia martis Neurocysticercosis-Like Lesion in Child, Associated with Local Source, the Netherlands

A neurocysticercosis-like lesion in an 11-year-old boy in the Netherlands was determined to be caused by the zoonotic Taenia martis tapeworm. Subsequent testing revealed that 15% of wild martens tested in that region were infected with T. martis tapeworms with 100% genetic similarity; thus, the infection source was most likely local

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor colitis

Colitis is a prevalent adverse event associated with immune checkpoint inhibitor (ICI) therapy with similarities to inflammatory bowel disease. Incomplete mechanistic understanding of ICI colitis curtails evidence-based treatment. Given the often-overlooked connection between tissue architecture and mucosal immune cell function, we here applied imaging mass cytometry (IMC) to gain spatial proteomic insight in ICI colitis in comparison to ulcerative colitis (UC). Using a cell segmentation pipeline that simultaneously utilizes high-resolution nuclear imaging and high-multiplexity IMC, we show that intra-epithelial CD8+ T cells are significantly more abundant (and numerically dominant) in anti-PD-1 ± anti-CTLA-4-induced colitis compared to anti-CTLA-4-induced colitis and UC. We identified activated, cycling CD8+ tissue-resident memory T(RM) cells at the lamina propria-epithelial interface as drivers of cytotoxicity in ICI colitis and UC. Moreover, we found that combined ICI-induced colitis featured highest granzyme B levels both in tissue and serum. Together, these data reinforce CD8+ TRM cells as potentially targetable drivers of ICI colitis

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo