Pre-exercise and acute movement-evoked pain trajectories during a 24-week outdoor walking program for knee osteoarthritis (WALK).

Objectives: Exploring (1) pre-exercise and acute movement-evoked pain (AMEP) during an outdoor walking program in individuals with knee osteoarthritis (OA); and (2) comparing baseline physical performance and AMEP flares initiated by walking between participants with either a higher or lower attendance rate. Methods: Individuals with knee OA were prescribed a 24-week walking program, including one unsupervised walk and two supervised walk classes per week. Participants self-reported knee pain on a numerical rating scale (NRS; 0-10) before and after each supervised class. Mixed-effects models were used to investigate trajectories over time for pre-exercise pain and AMEP change (post-minus pre-exercise pain; positive value indicates flare-up). Baseline physical performance (6 tests) and AMEP flares were compared between participants with higher (attending ≥70% of supervised classes) and lower attendance rates. Results: Of 24 participants commencing the program, 7 (29%) withdrew. Over 24 weeks, pre-exercise pain improved by 1.20 NRS (95% CI -1.41 to -0.99), with estimated largest per class improvements during the first 8 weeks (-0.05 (-0.06 to -0.03) and plateauing around 20-weeks. The AMEP was estimated to improve by 0.19 NRS (95% CI -0.38 to -0.004) over 24-weeks, with improvements plateauing around 12-weeks. Participants with lower attendance (n â€‹= â€‹11) scored poorer on all physical performance tests and experienced a slight increase in AMEP during the first two weeks of the program. Conclusions: Participants improved in pre-exercise pain and AMEP in the first 20 and 12 weeks, respectively. Despite supervision, physical performance and AMEP flares may have contributed to lower attendance. Trial registration number: 12618001097235.

In primary visual cortex fMRI responses to chromatic and achromatic stimuli are interdependent and predict contrast detection thresholds.

Chromatic and achromatic signals in primary visual cortex have historically been considered independent of each other but have since shown evidence of interdependence. Here, we investigated the combination of two components of a stimulus; an achromatic dynamically changing check background and a chromatic (L-M or S cone) target grating. We found that combinations of chromatic and achromatic signals in primary visual cortex were interdependent, with the dynamic range of responses to chromatic contrast decreasing as achromatic contrast increased. A contrast detection threshold study also revealed interdependence of background and target, with increasing chromatic contrast detection thresholds as achromatic background contrast increased. A model that incorporated a normalising effect of achromatic contrast on chromatic responses, but not vice versa, best predicted our V1 data as well as behavioural thresholds. Further along the visual hierarchy, the dynamic range of chromatic responses was maintained when compared to achromatic responses, which became increasingly compressive.

The learning curve for using intestinal ultrasonography.

BACKGROUND AND AIMS: Intestinal ultrasonography (IUS) is challenging to learn. This prospective study examined how the accuracy of IUS increases with operator experience ("learning curve") and if prior abdominal ultrasound experience facilitates the learning process. METHODS: The study included two trainees with limited abdominal ultrasound experience (< 50 exams) and two with extensive experience (> 500 exams). Each trainee performed 99 examinations and reported four IUS findings. An expert sonographer repeated the exam, and concordance (k) between the expert and trainees was assessed in three consecutive testing periods of 33 exams each. RESULTS: A progressive improvement in concordance was observed for all IUS findings from Period 1 to Period 3, overall and for both groups of trainees, although those with experience in abdominal ultrasound had faster learning curves. The minimum number of examinations required to achieve concordance with the expert operator for detecting increased bowel wall thickness was 84 and detecting bowel dilatation was 79. However, a minimum of 97 examinations was necessary to achieve concordance for detecting intra-abdominal complications, considered an advanced IUS competence. CONCLUSION: Basic competence in IUS can be acquired with relatively few examinations, while advanced competence requires more extensive training, particularly for gastroenterologists without abdominal ultrasound experience.

Improved Structure and Function in Early-Detected Second-Eye Neovascular Age-Related Macular Degeneration: FASBAT/Early Detection of Neovascular Age-Related Macular Degeneration Report 1.

PURPOSE: Visual acuity (VA) and structural biomarker assessment before and 24-months after early detection and routine treatment of second-eye involvement with neovascular age-related macular degeneration (nAMD) and additional comparison with the first eye affected. DESIGN: Prospective, 22-center observational study of participants with unilateral nAMD in the Early Detection of Neovascular AMD (EDNA) study, coenrolled into the Observing Fibrosis, Macular Atrophy and Subretinal Highly Reflective Material, Before and After Intervention with anti-VEGF Treatment (FASBAT) study for an additional 2-year follow-up. PARTICIPANTS: Older adults (> 50 years) with new onset nAMD in the first eye. METHODS: Assessment of both eyes with OCT, color fundus photography (CFP), clinic-measured VA, and quality of life (QoL). MAIN OUTCOME MEASURES: Prevalence of atrophy, subretinal hyperreflective material (SHRM), intraretinal fluid (IRF), subretinal fluid (SRF), and changes in VA over the study duration in both the first and second eyes affected with nAMD. Composite QoL scores over time. RESULTS: Of 431 participants recruited to the FASBAT study, the second eye converted to nAMD in 100 participants at a mean of 18.9 months. Visual acuity was 18 letters better at the time of early diagnosis in the second eye compared with conventional diagnosis in the first eye (72.9 vs. 55.6 letters). Visual acuity remained better in the second eye 24.9 months postconversion, at 69.5 letters compared with 59.7 letters at a similar matched time point in the first eye (18.9 months). A greater proportion of participants had vision > 70 letters in the second eye versus the first eye, 24.9 months postconversion (61 vs. 35). Prevalence of SHRM and IRF was lower in the second eye compared with the first eye 24.9 months postconversion. However, SRF prevalence was greater in the second eye 24.9 months postconversion. The development and progression of total area of atrophy appears similar in both eyes. Mean composite QoL scores increased over time, with a significant correlation between VA for the second eye only 24.9 months postconversion. CONCLUSION: This study has shown that early detection of exudative AMD in the second eye is associated with reduced prevalence of SHRM and IRF and greater VA, which is significantly correlated with maintained QoL. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study).

BACKGROUND: Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety. AIM: To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD. METHODS: We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn's disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 µg/g after 26 weeks of treatment. RESULTS: The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002). CONCLUSION: Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752).

Achromatopsia-Visual Cortex Stability and Plasticity in the Absence of Functional Cones.

Purpose: Achromatopsia is a rare inherited disorder rendering retinal cone photoreceptors nonfunctional. As a consequence, the sizable foveal representation in the visual cortex is congenitally deprived of visual input, which prompts a fundamental question: is the cortical representation of the central visual field in patients with achromatopsia remapped to take up processing of paracentral inputs? Such remapping might interfere with gene therapeutic treatments aimed at restoring cone function. Methods: We conducted a multicenter study to explore the nature and plasticity of vision in the absence of functional cones in a cohort of 17 individuals affected by autosomal recessive achromatopsia and confirmed biallelic disease-causing CNGA3 or CNGB3 mutations. Specifically, we tested the hypothesis of foveal remapping in human achromatopsia. For this purpose, we applied two independent functional magnetic resonance imaging (fMRI)-based mapping approaches, i.e. conventional phase-encoded eccentricity and population receptive field mapping, to separate data sets. Results: Both fMRI approaches produced the same result in the group comparison of achromatopsia versus healthy controls: sizable remapping of the representation of the central visual field in the primary visual cortex was not apparent. Conclusions: Remapping of the cortical representation of the central visual field is not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. A pretherapeutic imaging workup is proposed to optimize interventions.

The Emergence of Tuning to Global Shape Properties of Radial Frequency Patterns in the Ventral Visual Pathway.

Radial frequency (RF) patterns, created by sinusoidal modulations of a circle's radius, are processed globally when RF is low. These closed shapes therefore offer a useful way to interrogate the human visual system for global processing of curvature. RF patterns elicit greater responses than those to radial gratings in V4 and more anterior face-selective regions of the ventral visual pathway. This is largely consistent with work on nonhuman primates showing curvature processing emerges in V4, but is evident also higher up the ventral visual stream. Rather than contrasting RF patterns with other stimuli, we presented them at varied frequencies in a regimen that allowed tunings to RF to be derived from 8 human participants (3 female). We found tuning to low RF in lateral occipital areas and to some extent in V4. In a control experiment, we added a high-frequency ripple to the stimuli disrupting the local contour. Low-frequency tuning to these stimuli remained in the ventral visual stream, underscoring its role in global processing of shape curvature. We then used representational similarity analysis to show that, in lateral occipital areas, the neural representation was related to stimulus similarity, when it was computed with a model that captured how stimuli are perceived. We therefore show that global processing of shape curvature emerges in the ventral visual stream as early as V4, but is found more strongly in lateral occipital regions, which exhibit responses and representations that relate well to perception.SIGNIFICANCE STATEMENT We show that tuning to low radial frequencies, known to engage global shape processing mechanisms, was localized to lateral occipital regions. When low-level stimulus properties were accounted for such tuning emerged in V4 and LO2 in addition to the object-selective region LO. We also documented representations of global shape properties in lateral occipital regions, and these representations were predicted well by a proxy of the perceptual difference between the stimuli.

S-Cone Photoreceptors Regulate Daily Rhythms and Light-Induced Arousal/Wakefulness in Diurnal Grass Rats (Arvicanthis niloticus).

Beyond visual perception, light has non-image-forming effects mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). The present study first used multielectrode array recordings to show that in a diurnal rodent, Nile grass rats (Arvicanthis niloticus), ipRGCs generate rod/cone-driven and melanopsin-based photoresponses that stably encode irradiance. Subsequently, two ipRGC-mediated non-image-forming effects, namely entrainment of daily rhythms and light-induced arousal, were examined. Animals were first housed under a 12:12 h light/dark cycle (lights-on at 0600 h) with the light phase generated by a low-irradiance fluorescent light (F12), a daylight spectrum (D65) stimulating all photoreceptors, or a narrowband 480 nm spectrum (480) that maximized melanopsin stimulation and minimized S-cone stimulation (λmax 360 nm) compared to D65. Daily rhythms of locomotor activities showed onset and offset closer to lights-on and lights-off, respectively, in D65 and 480 than in F12, and higher day/night activity ratio under D65 versus 480 and F12, suggesting the importance of S-cone stimulation. To assess light-induced arousal, 3-h light exposures using 4 spectra that stimulated melanopsin equally but S-cones differentially were superimposed on F12 background lighting: D65, 480, 480 + 365 (narrowband 365 nm), and D65 - 365. Compared to the F12-only condition, all four pulses increased in-cage activity and promoted wakefulness, with 480 + 365 having the greatest and longest-lasting wakefulness-promoting effects, again indicating the importance of stimulating S-cones as well as melanopsin. These findings provide insights into the temporal dynamics of photoreceptor contributions to non-image-forming photoresponses in a diurnal rodent that may help guide future studies of lighting environments and phototherapy protocols that promote human health and productivity.

Assessing the structure of the posterior visual pathway in bilateral macular degeneration.

Macular degeneration (MD) embodies a collection of disorders causing a progressive loss of central vision. Cross-sectional MRI studies have revealed structural changes in the grey and white matter in the posterior visual pathway in MD but there remains a need to understand how such changes progress over time. To that end we assessed the posterior pathway, characterising the visual cortex and optic radiations over a ~ 2-year period in MD patients and controls. We performed cross-sectional and longitudinal analysis of the former. Reduced cortical thickness and white matter integrity were observed in patients compared to controls, replicating previous findings. While faster, neither the rate of thinning in visual cortex nor the reduction in white matter integrity during the ~ 2-year period reached significance. We also measured cortical myelin density; cross-sectional data showed this was higher in patients than controls, likely as a result of greater thinning of non-myelinated tissue in patients. However, we also found evidence of a greater rate of loss of myelin density in the occipital pole in the patient group indicating that the posterior visual pathway is at risk in established MD. Taken together, our results revealed a broad decline in grey and white matter in the posterior visual pathway in bilateral MD; cortical thickness and fractional anisotropy show hints of an accelerated rate of loss also, with larger effects emerging in the occipital pole.

KMT2D acetylation by CREBBP reveals a cooperative functional interaction at enhancers in normal and malignant germinal center B cells.

Heterozygous inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B cell lymphoma and co-occur in 40 to 60% of follicular lymphoma (FL) and 30% of EZB/C3 diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be coselected. Here, we show that combined germinal center (GC)-specific haploinsufficiency of Crebbp and Kmt2d synergizes in vivo to promote the expansion of abnormally polarized GCs, a common preneoplastic event. These enzymes form a biochemical complex on select enhancers/superenhancers that are critical for the delivery of immune signals in the GC light zone and are only corrupted upon dual Crebbp/Kmt2d loss, both in mouse GC B cells and in human DLBCL. Moreover, CREBBP directly acetylates KMT2D in GC-derived B cells, and, consistently, its inactivation by FL/DLBCL-associated mutations abrogates its ability to catalyze KMT2D acetylation. Genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation lead to reduced levels of H3K4me1, supporting a role for this posttranslational modification in modulating KMT2D activity. Our data identify a direct biochemical and functional interaction between CREBBP and KMT2D in the GC, with implications for their role as tumor suppressors in FL/DLBCL and for the development of precision medicine approaches targeting enhancer defects induced by their combined loss.

A pilot randomized controlled trial evaluating outdoor community walking for knee osteoarthritis: walk.

OBJECTIVES: To determine the feasibility of a randomized controlled trial (RCT) examining outdoor walking on knee osteoarthritis (KOA) clinical outcomes and magnetic resonance imaging (MRI) structural changes. METHOD: This was a 24-week parallel two-arm pilot RCT in Tasmania, Australia. KOA participants were randomized to either a walking plus usual care group or a usual care control group. The walking group trained 3 days/week. The primary outcome was feasibility assessed by changes being required to the study design, recruitment, randomization, program adherence, safety, and retention. Exploratory outcomes were changes in symptoms, physical performance/activity, and MRI measures. RESULTS: Forty participants (mean age 66 years (SD 1.4) and 60% female) were randomized to walking (n = 24) or usual care (n = 16). Simple randomization resulted in a difference in numbers randomized to the two groups. During the study, class sizes were reduced from 10 to 8 participants to improve supervision, and exclusion criteria were added to facilitate program adherence. In the walking group, total program adherence was 70.0% and retention 70.8% at 24 weeks. The walking group had a higher number of mild adverse events and experienced clinically important improvements in symptoms (e.g., visual analogue scale (VAS) knee pain change in the walking group: - 38.7 mm [95% CI - 47.1 to - 30.3] versus usual care group: 4.3 mm [- 4.9 to 13.4]). CONCLUSIONS: This study supports the feasibility of a full-scale RCT given acceptable adherence, retention, randomization, and safety, and recruitment challenges have been identified. Large symptomatic benefits support the clinical usefulness of a subsequent trial. TRIAL REGISTRATION NUMBER: 12618001097235. Key Points • This pilot study is the first to investigate the effects of an outdoor walking program on knee osteoarthritis clinical outcomes and MRI joint structure, and it indicates that a full-scale RCT is feasible. • The outdoor walking program (plus usual care) resulted in large improvements in self-reported knee osteoarthritis symptoms compared to usual care alone. • The study identified recruitment challenges, and the manuscript explores these in more details and provides recommendations for future studies.

Deep learning-based classifier of diffuse large B-cell lymphoma cell-of-origin with clinical outcome.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma with poor response to R-CHOP therapy due to remarkable heterogeneity. Based on gene expression, DLBCL cases were divided into two subtypes, i.e. ABC and GCB, where ABC subtype is associated with poor outcomes. Due to its association with clinical outcome, this classification, also known as cell-of-origin (COO), is an efficient way to predict the response to R-CHOP therapy. Previous COO classification methods have some shortcomings, e.g. limited number of samples in the training dataset. These shortcomings challenge the robustness of methods and make it difficult to implicate these methods at clinical level. To overcome the shortcomings of previous methods, we developed a deep learning-based classifier model on a cohort of 381 DLBCL patients using expression data of 20 genes. We implemented multilayer perceptron (MLP) to train deep learning-based classifier, named MLP-COO. MLP-COO achieved accuracy of 99.70% and 94.70% on training and testing datasets, respectively, with 10-fold cross-validation. We also assessed its performance on an independent dataset of 294 DLBCL patients. On independent dataset, we achieved an accuracy of 95.90% with MCC of 0.917. To show its broader applicability, we used this classifier to predict the clinical outcome using survival data from two large cohorts of DLBCL patients. In survival analysis, MLP-COO recapitulates the survival probabilities of DLBCL patients based on their COO in both cohorts. We anticipate that MLP-COO model developed in this study will benefit in the accurate COO prediction of DLBCL patients and their clinical outcomes.

Prediction of knee pain improvement over two years for knee osteoarthritis using a dynamic nomogram based on MRI-derived radiomics: a proof-of-concept study.

OBJECTIVES: To develop and validate a nomogram to detect improved knee pain in osteoarthritis (OA) by integrating magnetic resonance imaging (MRI) radiomics signature of subchondral bone and clinical characteristics. METHODS: Participants were selected from the Vitamin D Effects on Osteoarthritis (VIDEO) study. The primary outcome was 20% improvement of knee pain score over 2 years in participants administrated either vitamin D or placebo. Radiomics features of subchondral bone and clinical characteristics from 216 participants were extracted and analyzed. The participants were randomly split into the training and validation cohorts at a ratio of 8:2. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and generate radiomics signatures. The optimal radiomics signature and clinical indicators were fitted into a nomogram using multivariable logistic regression model. RESULTS: The nomogram showed favorable discrimination performance [AUCtraining, 0.79 (95% CI: 0.72-0.79), AUCvalidation, 0.83 (95% CI: 0.70-0.96)] as well as a good calibration. Additional contributing value of fusion radiomics signature to the nomogram was statistically significant (NRI, 0.23; IDI, 0.14, P < 0.001 in training cohort and NRI, 0.29; IDI, 0.18, P < 0.05 in validating cohort). Decision curve analysis confirmed the clinical usefulness of nomogram. CONCLUSION: The radiomics-based nomogram comprising the MR radiomics signature and clinical variables achieves a favorable predictive efficacy and accuracy in differentiating improvement in knee pain among OA patients. This proof-of-concept study provides a promising way to predict clinically meaningful outcomes.

Pharmacist-Driven Therapeutic Infliximab Monitoring at the Point of Care Using Rapidly Assessed Drug Levels in Patients with Inflammatory Bowel Disease.

BACKGROUND: Therapeutic monitoring of infliximab is limited by the time lag between drug-level measurement and dose adjustment, along with the cost of dose escalation. Strategies for dose reduction in stable patients on maintenance infliximab at supratherapeutic levels are uncertain. This study determined the feasibility of a pharmacist-driven strategy for immediate dose adjustment using a sliding scale at the point of care in stable patients with inflammatory bowel disease on maintenance therapy. METHODS: Adult patients with stable disease undergoing maintenance therapy with infliximab infusions, 5 mg/kg every 8 weeks, were prospectively studied. Trough drug levels were assessed by a rapid assay (and later by ELISA) at all infusions for up to 12 months with immediate but quantitatively small dose adjustment according to a sliding scale targeting a therapeutic range of 3-7 mcg/mL. Disease activity was assessed both clinically and biochemically. RESULTS: The rapid assay and ELISA detected similar infliximab levels, and the strategy added approximately 30 minutes to the duration of infusion events. Only 20% of 48 patients (77% with Crohn disease) had baseline trough infliximab concentrations within the therapeutic range. This value increased 3-fold after 24 and 48 weeks of interventions. One in 2 patients had baseline supratherapeutic levels, and most were brought into the therapeutic range without a discernible impact on disease activity by 1 dose adjustment, but 2 or 3 adjustments were generally needed for 29% of patients with subtherapeutic levels. Overall, drug costs were reduced by 4%. CONCLUSIONS: Immediate dose adjustment after infliximab rapid assay performed by a pharmacist using a sliding scale is a feasible strategy. Supratherapeutic infliximab levels can be safely and quickly brought into the therapeutic range using small dose adjustments without affecting disease activity, offsetting (at least partly) costs associated with dose escalation.

Feasibility of 'parkrun' for people with knee osteoarthritis: A mixed methods pilot study.

Objective: To investigate the feasibility of 'parkrun' for people with knee osteoarthritis (OA) and examine its potential to improve symptoms and increase physical activity. Design: This uncontrolled mixed methods pilot study enrolled people with knee OA not meeting physical activity guidelines. Participants were asked to walk in four consecutive parkrun events supervised by an exercise physiologist/physiotherapist. Feasibility was assessed by recruitment data (numbers screened and time to enrol 15 participants), adherence to the protocol, acceptability (measured by confidence, enjoyment, difficulty ratings and qualitative interviews), and safety (adverse events). Secondary measures were changes in knee pain, function, stiffness, and physical activity levels. Results: Participants (n â€‹= â€‹17) were enrolled over 11 months and recruitment was slower than anticipated. Fourteen participants attended all four parkruns and three of these participants shortened the 5 â€‹km course to ∼3 â€‹km. Across all four parkruns, 75% of participants reported high confidence that they could complete the upcoming parkrun and the majority (87%) enjoyed participating. Most participants rated parkrun either "slightly difficult" (38.5%) or "moderately difficult" (35%) and two mild adverse events were reported. Participants showed improvements in knee pain, function, stiffness, and physical activity levels. Conclusions: This pilot study demonstrates parkrun's feasibility, acceptability, safety and, its potential to improve knee OA symptoms and physical activity levels. Participating in parkrun was acceptable and enjoyable for some, but not all participants. The scalability, accessibility and wide appeal of parkrun supports the development of larger programs of research to evaluate the use of parkrun for people with knee OA.

In a case of longstanding low vision regions of visual cortex that respond to tactile stimulation of the finger with Braille characters are not causally involved in the discrimination of those same Braille characters.

Braille reading and other tactile discrimination tasks recruit the visual cortex of both blind and normally sighted individuals undergoing short-term visual deprivation. Prior functional magnetic resonance imaging (fMRI) work in patient 'S', a visually impaired adult with the rare ability to read both highly magnified print visually and Braille by touch, found that foveal representations of S's visual cortex were recruited during tactile perception, whereas peripheral regions were recruited during visual perception. Here, we test the causal nature of tactile responses in the visual cortex of S by combining tactile and visual psychophysics with repetitive transcranial magnetic stimulation. First, we replicate the previous fMRI findings in S. Second, we demonstrate that transient disruption of S's foveal visual cortex has no measurable impact on S's tactile processing performance compared to that of healthy controls - a pattern not predicted by the fMRI results. Third, stimulation of foveal visual cortex maximally disrupted visual processing performance in both S and controls, suggesting the possibility of preserved visual processing within S's foveal representation. Finally, stimulation of somatosensory cortex induced the expected disruption to tactile processing performance in both S and controls. These data suggest that tactile responses in S's foveal representation reflect unmasking of latent connections between visual and somatosensory cortices and not behaviourally relevant cross-modal plasticity. Unlike studies in congenitally blind individuals, it is possible that the absence of complete visual loss in S has limited the degree of causally impactful cross-modal reorganisation.

Super-enhancer hypermutation alters oncogene expression in B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets1-5. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the BCL6, BCL2 and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting BCL6) and the steroid receptor NR3C1 (targeting BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.

Nonspecific ileitis: Impact of histopathology and gastrointestinal ultrasound in achieving the diagnosis of Crohn's disease.

Background and Aim: Nonspecific ileitis is inflammation of the ileum without specific diagnostic features. A minority may go on to develop Crohn's disease, but optimal pathways of further investigation have not been established. This study aimed to identify a cohort of patients with nonspecific ileitis and to determine the value of ileal histology and gastrointestinal ultrasound in identifying/excluding Crohn's disease. Patients and Methods: In a retrospective analysis, all patients having nonspecific ileitis at colonoscopy from January 2010 to August 2021 were identified. Clinical associations with those subsequently diagnosed with Crohn's disease were examined with specific reference to ileal histology and gastrointestinal ultrasound. Results: Of 29 638 procedures, 147 patients (0.5%) had nonspecific ileitis. Crohn's disease was subsequently diagnosed in 8 patients (5.4%) at a median of 148 (range 27-603) days after colonoscopy. The presence of chronic inflammation on ileal biopsies was more common in those subsequently diagnosed with Crohn's disease (63% vs 20%; P = 0.0145). On gastrointestinal ultrasound, none of the 26 patients with normal bowel wall thickness (<3 mm) were subsequently diagnosed with Crohn's disease, and repeat ultrasound in 15 patients 1 year later showed no change. Of the nine patients with abnormal sonographic findings, three were diagnostic for Crohn's disease. Repeat ultrasound revealed Crohn's disease in two, while four had resolution of the abnormal findings. Conclusion: Although ileal histology was of limited value in identifying patients with nonspecific ileitis who were subsequently diagnosed with Crohn's disease, gastrointestinal ultrasound was highly informative. Prospective studies are needed to confirm the value of gastrointestinal ultrasound as a diagnostic and monitoring tool in this setting.