917 research outputs found

    MRI Staging of Anorectal Malignancy—A Reporting Dilemma: Is It Adenocarcinoma or Squamous Cell Carcinoma?

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    Aim Magnetic resonance imaging (MRI) of anorectal malignancy is often reported assuming low rectal adenocarcinoma (LRC). The biopsy may, however, reveal squamous cell carcinoma (SCC). Thus, the aim was to compare the imaging findings of SCC and LRC. Methods This was a retrospective study of patients who underwent staging MRI for anorectal malignancy (<5 cm from the anal verge) for adenocarcinoma or squamous cell carcinoma between 2016 and 2021. Two radiologists blinded to biopsy reviewed MRI. Imaging findings and apparent diffusion coefficient (ADC) values were compared between SCC and LRC. Results We studied 137 patients (n = 60 SCC, n = 77 LRC) with a mean age of 50.4 (standard deviation: 12.4) years and tumor length of 5.6 ± 1.9 cm. SCC patients were older, and their distal tumor margin was closer to the anal verge (5.3 vs. 22 mm for LRC; p <0.001). T2 intermediate signal and diffusion restriction was seen in 97 and 98.2% of SCC and 75.3 and 77% of LRC, respectively. SCC had lower ADC values (0.910 × 10−3 mm2/s) than LRC (1.126 × 10−3 mm2/s; p < 0.001). But there was no difference in the ADC values when T2 hyperintense tumors were excluded (p = 0.132). Extramural vascular invasion (EMVI) was more frequent in LRC (35.1 vs. 16.7%; p = 0.013). A combination of distance from the anal verge of less than 11 mm, absent EMVI, and the presence of internal iliac and inguinal nodes had an area under the curve (95% confidence interval) of 0.810 (0.737–0.884). Conclusion ADC values are unhelpful in differentiating SCC and LRC. Tumors closer to anal verge, absence of EMVI, and the presence of inguinal and internal-iliac nodes may point towards SCC

    Feasibility of Symptom monitoring WIth Feedback Trial (SWIFT) for adults on hemodialysis:a registry-based cluster randomized pilot trial Author’s full names and academic degrees

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    Background: Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants’ treating team, for severe or worsening symptoms as identifed by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. Methods: This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. Results: There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. Conclusions: Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A defnitive national RCT is underway.Neeru Agarwal, Karan K. Shah, Kathryn Dansie, Paul N. Bennett, Lavern Greenham, Chris Brown, Brendan Smyth, Stephen McDonald, Shilpanjali Jesudason, Andrea K. Viecelli, Rachael L. Morton, and on behalf of the Symptom monitoring With Feedback Trial (SWIFT) Investigator

    IUSM-Purdue TREAT-AD Center Target Enabling Component Evaluation of Literature Compounds as Lyn Chemical Probes

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    A Target Enabling Component evaluating literature compounds as chemical probes for LY

    Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

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    Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)

    Touch localisation after nerve repair in the hand: Insights from a new measurement tool.

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    Errors of touch localisation after injury to the nerves of the hand are common, and their measurement is of considered importance for evaluating functional recovery. Available empirical accounts have significant methodological limitations, however, and a quantitatively rigorous and detailed description of touch localisation in nerve injury is lacking. Here we develop a new method of measuring touch localisation and evaluate its value for use in nerve injury. Eighteen patients with transection injuries to the median/ulnar nerves and thirty-three healthy controls were examined. The hand was blocked from the participant's view and points were marked on the volar surface using a UV pen. These points served as targets for touch stimulation. Two photographs were taken, one with and one without UV lighting, rendering targets seen and unseen, respectively. The experimenter used the photograph with visible targets to register their locations, and participants reported the felt position of each stimulation on the photograph with unseen targets. The error of localisation and its directional components were measured, separate from misreferrals-errors made across digits, or from a digit to the palm. Nerve injury was found to significantly increase the error of localisation. These effects were specific to the territory of the repaired nerve, and showed considerable variability at the individual level, with some patients showing no evidence of impairment. A few patients also made abnormally high numbers of misreferrals, and the pattern of misreferrals in patients differed from that observed in healthy controls

    Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial

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    OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant handgrip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≄ 95 cm, serum total testosterone ≀ 14 nmol/L (immunoassay) and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle program and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2-years (OGTT ≄ 11.1 mmol/L and change in 2-hour glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG was performed. RESULTS: For type 2 diabetes at 2-years, the unadjusted OR for treatment was 0.53 (95% CI:0.35-0.79), which became 0.48 (95% CI:0.30-0.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:0.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; p < 0.001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.Kristy P. Robledo, Ian C. Marschner, David J. Handelsman, Karen Bracken, Bronwyn G.A. Stuckey, Bu B. Yeap, Warrick Inder, Mathis Grossmann, David Jesudason, Carolyn A. Allan, and Gary Witter

    Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

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    Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≄18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to &lt;60 mL/min per 1·73 m2 and ≄60 mL/min per 1·73 m2) and urine protein excretion at screening (≀1·75 g/day and &gt;1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein–creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein–creatinine ratio was statistically significantly greater in the sparsentan group (–49·8%) than the irbesartan group (–15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51–0·69; p&lt;0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics

    Pre-eclampsia after Kidney Transplantation: Rates and Association with Graft Survival and Function.

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    BACKGROUND: Transplanted women have high rates of pre-eclampsia. However, determinants of pre-eclampsia and association with graft survival and function remain uncertain. We aimed to determine rates of pre-eclampsia and its association with kidney transplant survival and function. METHODS: Retrospective cohort study analyzing post-kidney transplantation pregnancies (≄20 weeks gestation) from the Australia and New Zealand Dialysis and Transplant Registry (2000-2021). Graft survival was assessed in 3 models accounting for repeated pregnancies and episodes of pre-eclampsia. RESULTS: Pre-eclampsia status was captured in 357/390 pregnancies and occurred in 133 pregnancies (37%). The percentage of pregnancies reported to have pre-eclampsia rose from 27% in 2000-2004, to 48% from 2018-2021. Reported prior exposure to calcineurin inhibitors was high overall, and higher in women who had pre-eclampsia (97% vs 88%, p=0.005). Seventy-two (27%) graft failures were identified after a pregnancy, with median follow-up of 8.08 years. Although women with pre-eclampsia had higher median preconception serum creatinine concentration (1.24 ((IQR) 1.00-1.50) vs. 1.13 (0.99-1.36) mg/dL; p=0.02), in all survival models, pre-eclampsia was not associated with higher death-censored graft failure. In multivariable analysis of maternal factors (age, body mass index, primary kidney disease and transplant-pregnancy interval, preconception serum creatinine concentration, era of birth event and Tacrolimus or Cyclosporin exposure) only era and preconception serum creatinine concentration ≄1.24 mg/dL (odds ratio 2.48, 95% CI 1.19-5.18) was associated with higher pre-eclampsia risk. Both preconception eGFR <45 ml/min/1.73m 2 (adjusted HR 5.55, 95% CI 3.27-9.44, p<0.001) and preconception serum creatinine concentration ≄1.24 mg/dL (adjusted HR 3.06, 95% CI 1.77-5.27, p<0.001) were associated with a higher risk of graft failure even after adjusting for maternal characteristics. CONCLUSIONS: In this large and contemporaneous registry cohort, pre-eclampsia was not associated with worse graft survival or function. Preconception kidney function was the main determinant of graft survival.Lu, Joe; Hewawasam, Erandi; Davies, Christopher E.; Clayton, Philip A.; McDonald, Stephen P.; Jesudason, Shilpanjal

    Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

    No full text
    Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≄18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics
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