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DESIGN The objective of this study was to establish whether autoinflation was an effective intervention in a paediatric audiology service. This was a pragmatic retrospective study with historical controls using a paired availability design. SETTING The study took place at a single paediatric audiology service in England. PARTICIPANTS All children seen in the clinic over a two-year period who were aged between 3 and 11 years and who had a type B tympanogram in at least one ear were included. The Otovent autoinflation device was available as a treatment option over the second year (Cohort B) but not the first (Cohort A). There were 976 children included in the study: Cohort A comprised 513 children, Cohort B comprised 463 children. MAIN OUTCOME MEASURES The aims were to evaluate whether there was improvement in hearing thresholds following introduction of an autoinflation device, and whether there was a reduction in further audiology follow-ups, and in referrals to an ear, nose and throat specialist for consideration of ventilation tube insertion. RESULTS AND CONCLUSIONS There was a statistically significant improvement in hearing thresholds in Cohort B compared to Cohort A, however the improvements were clinically minimal with small effect sizes. There was no significant difference in improvement of tympanometry results between the two cohorts. Significantly more children in Cohort B (autoinflation group) were referred to an ear, nose and throat specialist after their second appointment compared to Cohort A. It was feasible to introduce autoinflation into the care pathway, however there was no evidence of clinically meaningful improved outcomes for patients.

Objective To investigate the relationship between serum uric acid (SUA) level and renal outcome in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). Methods A total of 393 Chinese patients with T2DM and biopsy-proven DN and followed at least 1 year were enrolled in this study. Patients were stratified by the quartiles of baseline level of SUA: Q1 group: 286.02 ± 46.66 μmol/L (n = 98); Q2 group: 358.23 ± 14.03 μmol/L (n = 99); Q3 group: 405.50 ± 14.59 μmol/L (n = 98) and Q4 group: 499.14 ± 56.97μmol/L (n = 98). Renal outcome was defined by progression to end-stage renal disease (ESRD). Kaplan–Meier survival analysis and Cox proportional hazards model were used to analyze the association between SUA quartiles and the renal outcomes. Results During the median 3-year follow-up period, there were 173 ESRD outcome events (44.02%). No significant difference between SUA level and the risk of progression of DN (P = 0.747) was shown in the Kaplan–Meier survival analysis. In multivariable-adjusted model, hazard ratios for developing ESRD were 1.364 (0.621–2.992; P = 0.439), 1.518 (0.768–3.002; P = 0.230) and 1.411 (0.706–2.821; P = 0.330) for the Q2, Q3 and Q4, respectively, in comparison with the Q1 (P = 0.652). Conclusions No significant association between SUA level and renal outcome of ESRD in Chinese patients with T2DM and DN was found in our study. Besides, the role of uric acid-lowering therapy in delaying DN progression and improving ESRD outcome had not yet been proven. Further study was needed to clarify the renal benefit of the uric acid-lowering therapy in the treatment of DN.

Solid organ transplantation has seen improvements in both surgical techniques and immunosuppression, achieving prolonged survival. Essential to graft acceptance and post-transplant recovery, immunosuppressive medications are often accompanied by a high prevalence of gastrointestinal (GI) symptoms and side effects. Apart from GI side effects, long-term exposure to immunosuppressive medications has seen an increase in drug-related morbidities such as diabetes mellitus, hyperlipidaemia, hypertension, and malignancy. Non-adherence to immunosuppression can lead to an increased risk of graft failure. Recent research has indicated that any microbial imbalances (otherwise known as gut dysbiosis or leaky gut) may be associated with cardiometabolic diseases in the long term. Current evidence suggests a link between the gut microbiome and the production of putative uraemic toxins, increased gut permeability, and transmural movement of bacteria and endotoxins and inflammation. Early observational and intervention studies have been investigating food-intake patterns, various synbiotic interventions (antibiotics, prebiotics, or probiotics), and faecal transplants to measure their effects on microbiota in treating cardiometabolic diseases. It is believed high doses of synbiotics, prebiotics and probiotics are able to modify and improve dysbiosis of gut micro-organisms by altering the population of the micro-organisms. With the right balance in the gut flora, a primary benefit is believed to be the suppression of pathogens through immunostimulation and gut barrier enhancement (less permeability of the gut).To assess the benefits and harms of synbiotics, prebiotics, and probiotics for recipients of solid organ transplantation.We searched the Cochrane Kidney and Transplant Specialised Register up to 9 March 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.We included randomised controlled trials measuring and reporting the effects of synbiotics, prebiotics, or probiotics, in any combination and any formulation given to solid organ transplant recipients (any age and setting). Two authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria.Data extraction was independently carried out by two authors using a standard data extraction form. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross-checked by another. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.Five studies (250 participants) were included in this review. Study participants were adults with a kidney (one study) or liver (four studies) transplant. One study compared a synbiotic to placebo, two studies compared a probiotic to placebo, and two studies compared a synbiotic to a prebiotic. Overall, the quality of the evidence is poor. Most studies were judged to have unclear (or high) risk of bias across most domains. Of the available evidence, meta-analyses undertaken were of limited data from small studies. Across all comparisons, GRADE evaluations for all outcomes were judged to be very low certainty evidence. Very low certainty evidence implies that we are very uncertain about results (not estimable due to lack of data or poor quality). Synbiotics had uncertain effects on the change in microbiota composition (total plasma p-cresol), faecal characteristics, adverse events, kidney function or albumin concentration (1 study, 34 participants) compared to placebo. Probiotics had uncertain effects on GI side effects, infection rates immediately post-transplant, liver function, blood pressure, change in fatty liver, and lipids (1 study, 30 participants) compared to placebo. Synbiotics had uncertain effects on graft health (acute liver rejection) (2 studies, 129 participants: RR 0.73, 95% CI 0.43 to 1.25; 2 studies, 129 participants; I² = 0%), the use of immunosuppression, infection (2 studies, 129 participants: RR 0.18, 95% CI 0.03 to 1.17; I² = 66%), GI function (time to first bowel movement), adverse events (2 studies, 129 participants: RR 0.79, 95% CI 0.40 to 1.59; I² = 20%), serious adverse events (2 studies, 129 participants: RR 1.49, 95% CI 0.42 to 5.36; I² = 81%), death (2 studies, 129 participants), and organ function measures (2 studies; 129 participants) compared to prebiotics.This review highlights the severe lack of high-quality RCTs testing the efficacy of synbiotics, prebiotics or probiotics in solid organ transplant recipients. We have identified significant gaps in the evidence. Despite GI symptoms and postoperative infection being the most common reasons for high antibiotic use in this patient population, along with increased morbidity and the growing antimicrobial resistance, we found very few studies that adequately tested these as alternative treatments. There is currently no evidence to support or refute the use of synbiotics, prebiotics, or probiotics in solid organ transplant recipients, and findings should be viewed with caution. We have identified an area of significant uncertainty about the efficacy of synbiotics, prebiotics, or probiotics in solid organ transplant recipients. Future research in this field requires adequately powered RCTs comparing synbiotics, prebiotics, and probiotics separately and with placebo measuring a standard set of core transplant outcomes. Six studies are currently ongoing (822 proposed participants); therefore, it is possible that findings may change with their inclusion in future updates.

Objective To report the clinical features, treatment, and outcome in horses with cellulitis and concurrent septic tendonitis and/or desmitis. Study design Short case series. Methods Medical records from 2000 to 2019 were reviewed, identifying horses with cellulitis and concurrent septic tendonitis and/or desmitis based on sonographic examination and positive bacterial culture. Signalment, ultrasonographic results, bacterial culture, treatment, duration of hospitalization, and complications were recorded. Long-term outcome data were obtained from follow-up examinations and/or telephone interviews. Successful outcome was defined as return to intended use. Results Eight horses met the inclusion criteria. All infections occurred in hindlimbs, with septic suspensory ligament in six of eight horses, and septic superficial digital flexor tendon in one of eight horses. Surgical debridement was performed in six of eight horses. All horses were treated with systemic and regional intravenous antimicrobials and were discharged from the hospital. Long-term follow-up was available in seven of eight horses. Of these, four horses returned to their intended athletic function, two horses returned to their intended function as a broodmare or pasture pet, and one horse is still rehabilitating. Conclusion Septic tendonitis or desmitis is a rare but possible sequela of limb cellulitis. Based on the findings in this study, prognosis for return to athletic function is fair to good for horses diagnosed with cellulitis and concurrent septic tendonitis or desmitis.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( P = .87) or between BTB autografts and soft tissue allografts ( P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

Optimal treatment of full‐thickness skin injuries requires dermal and epidermal replacement. To spare donor dermis, dermal substitutes can be used ahead of split‐thickness skin graft (STSG) application. However, this two‐stage procedure requires an additional general anaesthetic, often prolongs hospitalisation, and increases outpatient services. Although a few case series have described successful single‐stage reconstructions, with application of both STSG and dermal substitute at the index operation, we have little understanding of how the physical characteristics of dermal substitutes affects the success of a single‐stage procedure. Here, we evaluated several dermal substitutes to optimise single‐stage skin replacement in a preclinical porcine model. A porcine full‐thickness excisional wound model was used to evaluate the following dermal substitutes: autologous dermal graft (ADG; thicknesses 0.15‐0.60 mm), Integra (0.4‐0.8 mm), Alloderm (0.9‐1.6 mm), and chitosan‐based hydrogel (0.1‐0.2 mm). After excision, each wound was treated with either a dermal substitute followed by STSG or STSG alone (control). Endpoints included graft take at postoperative days (PODs) 7 and 14, wound closure at POD 28, and wound contracture from POD 28‐120. Graft take was highest in the STSG alone and hydrogel groups at POD 14 (86.9% ± 19.5% and 81.3% ± 12.3%, respectively; P

To compare logistic regression to elastic net for identifying and ranking clinical risk factors for blunt cerebrovascular injury (BCVI). Consecutive trauma patients undergoing screening CTA at a level 1 trauma center over a 2-year period. Each internal carotid artery (ICA) and vertebral artery (VA) was independently graded by 2 neuroradiologists using the Denver grading scale. Unadjusted odds ratios were calculated by univariate and adjusted odds ratios by multiple logistic regression with FDR correction. We applied logistic regression with the elastic net penalty and tenfold cross-validation. Total of 467 patients; 73 patients with BCVI. Maxillofacial fracture, basilar skull fracture, and GCS had significant unadjusted odds ratios (OR) for ICA injury and C-spine fracture, spinal ligamentous injury, and age for VA injury. Only transverse foramen fracture had significant adjusted OR for VA injury, with none for ICA injury, after FDR correction. Using elastic net, ICA injury variables included maxillofacial fracture, basilar skull fracture, GCS, and carotid canal fracture. For VA injury, these included cervical spine transverse foramen fracture, ligamentous injury, C1–C3 fractures, posterior element fracture, and vertebral body fracture. Elastic net statistical learning methods identified additional risk factors and outperformed multiple logistic regression for BCVI. Elastic net allows the study of a large number of variables, and is useful when covariates are correlated.

Purpose To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). Methods Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). Results Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. Conclusion Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

OBJECTIVE To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90–1.19) in the frail versus 0.84 (95% CI 0.74–0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

Background: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson’s disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD. Objective: We hypothesized that gait disturbances in people with mild-to-moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA. Methods: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n = 22) and normal REM sleep muscle tone (PD-RSWA-, n = 19). Gait characteristics were compared between groups and correlated to RSWA. Results: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group. Conclusion: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD.

Several studies show that patients with early-onset diabetes have higher risk of diabetic complications than those diagnosed in middle age. However, whether early-onset of type 2 diabetes mellitus (T2DM) is a risk factor for diabetic nephropathy (DN) progression remains unclear, especially a lack of data in biopsy-confirmed cohort. In This study, we enrolled 257 patients with T2DM and biopsy-confirmed DN to investigate the role of early-onset T2DM in DN progression. Participants were divided into two groups according to the age of T2DM diagnosis: early-onset group (less than 40 years) and later-onset group (40 years or older). We found that patients with early-onset T2DM had higher glomerular grades and arteriolar hyalinosis scores than those in later-onset group. After adjusted for confounding factors, early-onset of T2DM remained an independent predictor of end-stage renal disease (ESRD) for patients with DN. In conclusion, although with the comparable renal function and proteinuria, patients with early-onset T2DM and DN had worse renal pathological changes than those with later-onset. Early-onset of T2DM might be an important predictor of ESRD for patients with DN, which called more attention to early supervision and prevention for patients with early-onset T2DM and DN.

Hypertensive heart disease refers to changes in the myocardium that result from hypertension. The relationship between hypertensive heart disease and sudden cardiac death is well established, but there are few pathological studies. We examined the clinical and pathological features of hypertensive heart disease in sudden cardiac death victims from a national cardiovascular pathology registry. We investigated 5239 cases of sudden cardiac death between 1994 and 2018. Hearts were examined by two expert cardiac pathologists. Diagnostic criteria included history of hypertension, increased heart weight and left ventricular wall thickness in the absence of other causes. Collagen was quantified using picrosirius red staining and imaging software. Of 75 sudden cardiac death cases due to hypertensive heart disease (age at death: 54 ± 16 years; 56% males), 56 (75%) reported no prior cardiac symptoms. Thirty-four (45%) recorded a BMI ≥ 30. Only two (2.7%) had hypertensive heart disease diagnosed antemortem. Four (5%) were diagnosed clinically with hypertrophic cardiomyopathy, but lacked myocyte disarray at autopsy. All hearts showed concentric left ventricular hypertrophy and myocyte hypertrophy. Fibrosis was identified microscopically in 59 cases (81%). The posterior left ventricular wall showed the greatest increase in the percentage of collagen in hypertensive diseased hearts compared to controls (25.2% vs 17.9%, p = 0.034). Most sudden deaths due to hypertensive heart disease occur without prior cardiac symptoms; thus, clinical risk stratification is challenging. Hypertensive heart disease can be misdiagnosed in life as hypertrophic cardiomyopathy which has major implications for relatives. Pathologists require a history of hypertension and histology for a definitive diagnosis of hypertensive heart disease.

Objective: People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis. Approach and Results: This was achieved by targeting the antiapoptotic protein Bcl-x L (B-cell lymphoma-extra large; which is essential for platelet viability) via distinct genetic and pharmacological approaches. In the former, we transplanted bone marrow from mice carrying the Tyr15 to Cys loss of function allele of Bcl-x (known as Bcl-x Plt20 ) or wild-type littermate controls into atherosclerotic-prone Ldlr +/− mice made diabetic with streptozotocin and fed a Western diet. Reduced Bcl-x L function in hematopoietic cells significantly decreased platelet numbers, exclusive of other hematologic changes. This led to a significant reduction in atherosclerotic lesion formation in Bcl-x Plt20 bone marrow transplanted Ldlr +/− mice. To assess the potential therapeutic relevance of reducing platelets in atherosclerosis, we next targeted Bcl-x L with a pharmacological strategy. This was achieved by low-dose administration of the BH3 (B-cell lymphoma-2 homology domain 3) mimetic, ABT-737 triweekly, in diabetic Apoe −/− mice for the final 6 weeks of a 12-week study. ABT-737 normalized platelet numbers along with platelet and leukocyte activation to that of nondiabetic controls, significantly reducing atherosclerosis while promoting a more stable plaque phenotype. Conclusions: These studies suggest that selectively reducing circulating platelets, by targeting Bcl-x L to promote platelet apoptosis, can reduce atherosclerosis and lower cardiovascular disease risk in diabetes. Graphic Abstract: A graphic abstract is available for this article.

AIMS: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (

Background Assessing postural stability in Parkinson’s disease (PD) often relies on measuring the stepping response to an imposed postural perturbation. The standard clinical technique relies on a brisk backwards pull at the shoulders by the examiner and judgement by a trained rater. In research settings, various quantitative measures and perturbation directions have been tested, but it is unclear which metrics and perturbation direction differ most between people with PD and controls. Objectives (1) Use standardized forward vs. backward perturbations of a support surface to evaluate reactive stepping performance between PD and control participants. (2) Evaluate the utility of using principal components analysis to capture the dynamics of the reactive response and differences between groups. Methods Sixty-two individuals participated (40 mild-to-moderate PD, off medication). Standardized rapid translations of the support surface were applied, requiring at least one step, backward or forward, to restore balance. The number of steps taken and the projection of the first principal component (PC1) of the center of pressure (COP) time series were entered in linear repeated-measures mixed effect models. Results Forward falls required significantly fewer steps to recover than backward falls. PC1 captured more than half of the variance in the COP trajectory. Analysis of the PC1 projection revealed a significant interaction effect of group (PD vs. controls) by direction, such that there was a group difference in forward stepping, but not backward. Significance Forward reactive stepping in PD differed from controls more than backward-stepping. PC1 projections of the COP trajectory capture the dynamics of the postural response and differ between PD and controls.

Background Chronic kidney disease (CKD) and diabetes mellitus increase atherosclerotic cardiovascular diseases (ASCVD) risk. However, the association between renal outcome of diabetic kidney disease (DKD) and ASCVD risk is unclear. Methods This retrospective study enrolled 218 adult patients with type 2 diabetes mellitus and biopsy-proven DKD, and without known cardiovascular diseases. These patients were followed up at least 1 year. Baseline characteristics were obtained and the 10-year ASCVD risk score was calculated using the Pooled Cohort Equation (PCE). Renal outcome was defined as progression to end-stage renal disease (ESRD). The association between ASCVD risk and renal function and outcome was further analyzed with logistic regression and Cox proportional hazard analysis. Results Among all patients, the median 10-year ASCVD risk score was 14.1%. The median of ASCVD risk score in CKD stage 1, 2, 3, and 4 was 10.9%, 12.3%, 16.5%, and 14.8%, respectively (P = 0.268). Compared with patients with lower ASCVD risk(༜14.1%), those with higher ASCVD risk had lower eGFR, higher systolic blood pressure, and more severe renal interstitial inflammation. High ASCVD risk(> 14.1%) was an independent indicator of renal dysfunction in multivariable-adjusted logistic analysis(odds ratio [OR], 3.997; 95% confidence interval [CI], 1.385–11.530;P = 0.010). However, univariate and multivariate COX proportional hazard analysis showed the 10-year ASCVD risk score failed to be an independent risk factor for ESRD in patients with type 2 diabetes mellitus. Conclusions PCE can estimate ASCVD risk in patients with DKD, and DKD patients even in CKD stage 1 had comparable ASCVD risk score to patients in CKD stage 2, 3, and 4. Higher ASCVD risk indicated severe renal insufficiency, while no prognostic value of ASVCD risk for renal outcome was observed, which implied macroangiopathy and microangiopathy in patients with DKD were related, but relatively independent.

Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus6 ng/ml versus8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.

Background Nephrotic-range proteinuria (NRP) is associated with rapid kidney function loss and increased cardiovascular (CV) disease risk. We assessed the effects of linagliptin (LINA) on CV and kidney outcomes in people with Type 2 diabetes (T2D) with or without NRP. Methods Cardiovascular and renal microvascular outcome study with LINA randomized participants with T2D and CV disease and/or kidney disease to LINA 5 mg or placebo (PBO). The primary endpoint [time to first occurrence of 3-point major adverse cardiac events (3P-MACE)], and kidney outcomes, were evaluated by NRP status [urinary albumin:creatinine ratio (UACR) ≥2200 mg/g] at baseline (BL) in participants treated with one or more dose of study medication. Results NRP was present in 646/6979 [9.3% (LINA/PBO n = 317/n = 329); median UACR 3486 (Q1: 2746/Q3: 4941) mg/g] participants, who compared with no-NRP were younger (62.3/66.1 years) and had lower estimated glomerular filtration rate (eGFR) (39.9/56.1 mL/min/1.73 m2). Over a median of 2.2 years, 3P-MACE occurred with a 2.0-fold higher rate in NRP versus no-NRP (PBO group), with a neutral LINA effect, regardless of NRP. The composite of time to renal death, end-stage kidney disease (ESKD) or decrease of ≥40 or ≥50% in eGFR, occurred with 12.3- and 13.6-fold higher rate with NRP (PBO group); evidence of heterogeneity of effects with LINA was observed for the former [NRP yes/no: hazard ratio 0.80 (0.63–1.01)/1.25 (1.02–1.54); P-interaction 0.005], but not the latter [0.83 (0.64–1.09)/1.17 (0.91–1.51), P-interaction 0.07]. No heterogeneity was observed for renal death or ESKD [0.88 (0.64–1.21)/0.94 (0.67–1.31), P-interaction 0.79]. Glycated haemoglobin A1c (HbA1c) was significantly reduced regardless of NRP, without increasing hypoglycaemia risk. Regression to normoalbuminuria [1.20 (1.07–1.34)] and reduction of UACR ≥50% [1.15 (1.07–1.25)] from BL, occurred more frequently with LINA, regardless of NRP status (P-interactions >0.05). Conclusions Individuals with T2D and NRP have a high disease burden. LINA reduces their albuminuria burden and HbA1c, without affecting CV or kidney risk., Graphical Abstract

Supplemental Digital Content is available in the text., OBJECTIVES: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019. DESIGN: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery. SETTING: International. PATIENTS: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed. CONCLUSIONS: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.

There are limited data regarding the combined value of the pretransplant Deauville score (DS) from a positron emission tomography scan and clinical risk factors in patients with relapsed/refractory aggressive non-Hodgkin lymphoma (NHL). We performed a retrospective analysis to assess the prognostic role of pretransplant DS in patients with relapsed/refractory aggressive NHL who underwent salvage chemotherapy and autologous stem cell transplantation (ASCT). We identified 174 eligible patients between January 2013 and March 2019. In multivariable analysis, pretransplant DS, B symptoms, and secondary International Prognostic Index (sIPI) were independent risk factors for event-free survival (EFS). These variables were used to derive an integrated risk score that categorized 166 patients with available information for all risk factors into 3 groups: low (n = 92; 55.4%), intermediate (n = 48; 28.9%), and high (n = 26; 15.7%). The new prognostic index showed a strong association with EFS (low-risk vs intermediate-risk hazard ratio [HR], 3.94; 95% confidence interval [CI], 2.16-7.17; P < .001; low-risk vs high-risk HR, 10.83; 95% CI, 5.81-20.19; P < .001) and outperformed models based on clinical risk factors or DS alone. These results were validated in 60 patients from an independent external cohort (low-risk vs intermediate-risk HR, 4.04; 95% CI, 1.51-10.82; P = .005; low-risk vs high-risk HR, 10.49; 95% CI, 4.11-26.73; P < .001). We propose and validate a new prognostic index that risk-stratifies patients undergoing salvage chemotherapy followed by ASCT, thereby identifying patients at high risk for posttransplant treatment failure.

Both heart failure and diabetes are increasing in prevalence in Western communities. The interrelationship between these two conditions is well known, with conventional heart failure therapies including several newer drug classes providing benefit to subjects with diabetes. Furthermore, several of the more recently introduced medications for type 2 diabetes have resulted in significant cardiovascular morbidity and mortality benefits with a marked improvement in heart failure symptoms and hospital presentations as well as deaths. This review outlines current therapies used to treat patients with or at risk for heart failure and their particular role in subjects with diabetes. Newer therapies, including certain glucose-lowering medications and their benefits in treating heart failure patients with and without diabetes, are also discussed. Finally, heart failure is also observed in long-duration, aging patients with type 1 diabetes, but this clinical issue has not been as extensively explored as in patients with type 2 diabetes and warrants further clinical investigation.

Infection is a rare occurrence after revision anterior cruciate ligament reconstruction (rACLR). Because of the low rates of infection, it has been difficult to identify risk factors for infection in this patient population. The purpose of this study was to report the rate of infection following rACLR and assess whether infection is associated with patient- and surgeon- dependent risk factors. We reviewed two large prospective cohorts to identify patients with postoperative infections following rACLR. Age, sex, body mass index (BMI), smoking status, history of diabetes, and graft choice were recorded for each patient. The association of these factors with postoperative infection following rACLR was assessed. There were 1423 rACLR cases in the combined cohort, with 9 (0.6%) reporting post-operative infections. Allografts had a higher risk of infection than autografts (odds ratio=6.8; 95% CI: 0.9-54.5; p=0.045). Diabetes (odds ratio=28.6; 95% CI: 5.5-149.9; p=0.004) was a risk factor for infection. Patient age, sex, BMI and smoking status were not associated with risk of infection after rACLR. STATEMENT OF CLINICAL SIGNIFICANCE: While there is a low rate of infection following rACLR, use of allograft and comorbidity with diabetes are associated with a higher risk of infection following this surgery.

Rationale: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. Methods and Results: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C hi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9 , S100a8 , or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health. This has been a successful intervention in patients with isolated tears and tears associated with anterior cruciate ligament (ACL) reconstruction. However, the results of meniscal repair in the setting of revision ACL reconstruction have not been documented. Purpose: To examine the prevalence and 2-year operative success rate of meniscal repairs in the revision ACL setting. Study Design: Case-control study; Level of evidence, 3. Methods: All cases of revision ACL reconstruction with concomitant meniscal repair from a multicenter group between 2006 and 2011 were selected. Two-year follow-up was obtained by phone and email to determine whether any subsequent surgery had occurred to either knee since the initial revision ACL reconstruction. If so, operative reports were obtained, whenever possible, to verify the pathologic condition and subsequent treatment. Results: In total, 218 patients (18%) from 1205 revision ACL reconstructions underwent concurrent meniscal repairs. There were 235 repairs performed: 153 medial, 48 lateral, and 17 medial and lateral. The majority of these repairs (n = 178; 76%) were performed with all-inside techniques. Two-year surgical follow-up was obtained on 90% (197/218) of the cohort. Overall, the meniscal repair failure rate was 8.6% (17/197) at 2 years. Of the 17 failures, 15 were medial (13 all-inside, 2 inside-out) and 2 were lateral (both all-inside). Four medial failures were treated in conjunction with a subsequent repeat revision ACL reconstruction. Conclusion: Meniscal repair in the revision ACL reconstruction setting does not have a high failure rate at 2-year follow-up. Failure rates for medial and lateral repairs were both

INTRODUCTION Carbon dioxide (CO2) laser treatment is routinely used to treat hypertrophic burn scars (HBS). Although prior research has documented subjective improvement in HBS after treatment, there is little data evaluating objective changes in scar characteristics after therapy. The aim of our process improvement project was to evaluate changes to scar thickness (ST) using high-frequency ultrasound in patients with HBS undergoing CO2 laser therapy. METHODS Ultrasound measurements of ST were obtained from patients with HBS before initial and at each subsequent treatment. ST, reduction in ST per treatment, and percentage reduction in ST from baseline were tabulated. Post hoc analyses examining the effect of initial ST and scar maturity on outcome were performed. First, patients were grouped by baseline ST into thicker (group 1, initial ST ≥ median value) and thinner (group 2, initial ST < median value) scar groups. Second, patients were divided into quartiles based on time from injury to treatment. Outcomes at each time point were compared with either Mann-Whitney U or Kruskal-Wallis tests, with Bonferonni corrections performed for post hoc subgroup analyses. Significance was set at P < 0.05. RESULTS Twenty-one consecutive patients with HBS treated with CO2 laser were included. All patients completed 1 or more treatment, 48% completed 2 or more treatments, and 28% completed 3 treatments. Median initial ST was 0.71 cm (0.44-0.98 cm), and median scar maturity was 7.5 months (4.9-9.8 months). Overall, ST decreased over the treatment course (P < 0.001), with post hoc analysis demonstrating that 2 treatments were required to achieve a significant ST reduction (P < 0.01). On subgroup analysis comparing initial ST, ST decreased significantly in group 1 (thicker scars) overall (P < 0.001) but not in group 2 (P = 0.109). ST reduction was greatest after 1 treatment in group 1 (P = 0.022) and group 2 (P = 0.061). Percent reduction was greater in group 1 relative to group 2 after 1 treatment (P = 0.016). On subgroup analysis of scar maturity, there were no significant differences in either baseline ST or ST at any subsequent visit. CONCLUSIONS Fractionated ablative CO2 laser treatment improved ST after 1 to 2 treatments. Patients with thicker scars demonstrated greater ST reduction than those with thinner scars. Ultrasound adequately assessed treatment response.

The traditional model of psychiatric assessment and diagnosis can be criticised as reductive. We developed an innovative model for psychiatric assessment of adult patients referred to our adult mental health team, the Systemic Assessment Clinic, incorporating the principles and techniques of systemic family therapy and dialogical practice into standard psychiatric assessment. We conducted a service evaluation, comparing prospective use of mental health services for patients assessed either in the Systemic Assessment Clinic or in standard assessment. Patients assessed in the Systemic Assessment Clinic had more favourable outcomes than those in standard assessment: they were significantly less likely to need multiple follow-up treatment appointments with a psychiatrist and to be re-referred to mental health services once discharged, indicating reduced healthcare costs. Satisfaction rates for participants attending the systemic assessment clinic were high. Our service evaluation gives preliminary evidence that the Systemic Assessment Clinic could be a potential new model for psychiatric assessment; further evaluation is warranted in a randomised controlled trial.

Vascularized composite allotransplantation (VCA) is the most advanced reconstructive technique available to patients who suffer devastating burns to the limbs or face. However, VCA requires donor–recipient matching. Burn patients have been reported to experience sensitization, or the development of anti-human leukocyte antigen antibodies, during resuscitation and wound coverage, potentially precluding them from future VCA. This study sought to investigate the contributions of both blood and allograft to sensitization in burn patients. Four groups were compared: burn patients who received blood products and allograft (group 1), burn patients who received blood products only (group 2), trauma patients who received blood products only (group 3), and healthy volunteer controls (group 4). The average calculated panel-reactive antibody (indicating sensitization) was higher in group 1 compared to group 4 (P = .035). Additionally, the incidence of severe sensitization was higher in group 1 relative to the other groups (P = .049). When comparing groups of patients who had no sensitization, mild sensitization, moderate sensitization, and severe sensitization, there were no significant differences in age, sex, blood products received, total body surface area burned, or allograft used between groups, though severely sensitized patients tended to have greater total body surface area involvement and received more units of packed red blood cells and allograft (P = .079, P = .196, and P = .072, respectively). We therefore conclude that while burn patients who received allograft and blood demonstrated a higher incidence of anti-human leukocyte antigen sensitization relative to healthy controls, this difference cannot solely be attributed to either allograft use or transfusion.

Background Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. Methods In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β2 -microglobulin (B2M), eGFRCr-Cys , and the average of three estimates (eGFRCr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1 year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately, and all-cause mortality using Cox regression models, adjusting for established risk factors. Results Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with a > 2-fold higher risk of all clinical outcomes. Conclusions In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted. This article is protected by copyright. All rights reserved.

Aim To examine possible sex differences in the excess risk of myocardial infarction (MI) consequent to a range of conventional risk factors in a large-scale international cohort of patients with diabetes, and to quantify these potential differences both on the relative and absolute scales. Materials and methods Eleven thousand and sixty-five participants (42% women) with type 2 diabetes in the ADVANCE trial and its post-trial follow-up study, ADVANCE-ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non-fatal) by sex, and the women-to-men ratio of HRs (RHR). Results Over a median of 9.6 years of follow-up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c, total and LDL cholesterol, duration of diabetes, triglycerides, body mass index (BMI) and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men: RHRs were 1.75 (95% CI: 1.05-2.91) for current smoking, 1.53 (1.00-2.32) for former smoking, 1.18 (1.02-1.37) for SBP, and 1.13 (95% CI, 1.003-1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1000 person-years) compared with women (5.8 per 1000 person-years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. Conclusions In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex-specific approaches and early interventions in women with diabetes.

Background The investigational medicinal product GKT137831 is a selective inhibitor of NOX 1 and 4 isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes, which has the potential to ameliorate diabetic kidney disease. An investigator-initiated, double-blind, randomised, placebo-controlled, multicentre phase 2 clinical trial started recruitment in December 2017, with the aim of evaluating the efficacy and safety of GKT13783, in adults with type 1 diabetes mellitus and persistently elevated urinary albumin excretion over a period of 48 weeks. Methods/design The trial is currently recruiting in Australia and New Zealand, with recruitment expected to end on 30 June 2020. The primary outcome measure of the trial is the urinary albumin excretion level measured at 48 weeks of treatment. This statistical analysis plan presents an update to the published trial protocol and provides a comprehensive description of the statistical methods that will be used for the analysis of the data from this trial. In doing so, we follow the “Guidelines for the content of statistical analysis plans in clinical trials” to support transparency and reproducibility of the trial findings. Discussion With the use of this prior statistical analysis plan, we aim to minimise bias in the reporting of the findings of this trial, which evaluates the investigational medicinal product GKT137831. The results of the trial are expected to be published in 2022. Trial registration ANZCTR registry: ACTRN12617001187336. Registered on 14 July 2017. Universal Trial Number: U1111-1187-2609; Protocol number: T1DGKT137831; Genkyotex trial number: GSN000241.

A third of patients receiving Interferon-α (IFN-α) treatment for Hepatitis-C develop major depressive disorder (MDD). Conversely, anti-Tumor Necrosis Factor (TNF) therapies improve depression providing key empirical support for the “inflammatory theory” of depression. Heightened amygdala reactivity (particularly to negatively valanced stimuli) is a consistent finding within MDD; can predict treatment efficacy and reverses following successful treatment. However, whether IFN-α and anti-TNF enhance/attenuate depressive symptoms through modulation of amygdala emotional reactivity is unknown. Utilizing a prospective study design, we recruited 30 patients (mean 48.0 ± 10.5 years, 21 male) initiating IFN-α treatment for Hepatitis-C and 30 (mean 50.4 ± 15.7 years, 10 male) anti-TNF therapy for inflammatory arthritis. All completed an emotional face-processing task during fMRI and blood sampling before and after their first IFN-α (4-h) or anti-TNF (24-h) injection and follow-up psychiatric assessments for 3 months of treatment. IFN-α significantly increased depression symptoms (Hamilton Depression Rating Scale HAM-D) at 4 weeks (p p > 0.1). Conversely, anti-TNF significantly improved depressive symptoms (Hospital Anxiety and Depression Rating Scale HADS) at both 24-h (P = 0.015) and 12 weeks (p = 0.018). In support of our a-priori hypothesis, both IFN-α and anti-TNF significantly modulated amygdala reactivity with IFN-α acutelyenhancingright amygdala responses to sad (compared with neutral) faces (p = 0.032) and anti-TNF converselydecreasingright amygdala reactivity (across emotional valence) (p = 0.033). Furthermore, these changes predicted IFN-induced increases in HAM-D 4 weeks later (R2 = 0.17,p = 0.022) and anti-TNF-associated decreases in HADS at 24-h (R2 = 0.23,p = 0.01) suggesting that actions of systemic inflammation on amygdala emotional reactivity play a mechanistic role in inflammation-associated depressive symptoms.

Hypertension is a risk factor for the vascular permeability and neovascularization that threatens vision in diabetic retinopathy. Excess reactive oxygen species derived from the Nox (NADPH oxidase) isoforms, Nox1 and Nox4, contributes to vasculopathy in diabetic retinopathy; however, if Nox1/4 inhibition is beneficial in hypertensive diabetic retinopathy is unknown. Here, we determined that diabetic spontaneously hypertensive rats had exacerbated retinal vascular permeability and expression of angiogenic and inflammatory factors, compared with normotensive diabetic Wistar Kyoto rats. GKT136901, a specific dual inhibitor of Nox1 and Nox4, prevented these events in diabetic Wistar Kyoto rats and spontaneously hypertensive rats. Retinal neovascularization does not develop in diabetic rodents, and therefore, the oxygen-induced retinopathy model is used to evaluate this pathology. We previously demonstrated that Nox1/4 inhibition reduced retinal neovascularization in oxygen-induced retinopathy. However, although Nox5 is expressed in human retina, its contribution to retinopathy has not been studied in vivo, largely due to its absence from the rodent genome. We generated transgenic mice with inducible human Nox5 expressed in endothelial cells (vascular endothelial-cadherin + Nox5 + mice). In vascular endothelial-cadherin + Nox5 + mice with oxygen-induced retinopathy, retinal vascular permeability and neovascularization, as well as the expression of angiogenic and inflammatory factors, were increased compared with wild-type littermates. In bovine retinal endothelial cells, which express Nox1, Nox4, and Nox5, Nox1/4 inhibition, as well as Nox5 silencing RNA, reduced the high glucose–induced upregulation of oxidative stress, angiogenic, and inflammatory factors. Collectively, these data indicate the potential of Nox1, Nox4, and Nox5 inhibition to reduce vision-threatening damage to the retinal vasculature.

Objective: To characterize the relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in Chinese patients and to determine whether the severity of DR predicts end-stage renal disease (ESRD). Methods: Bilateral fundic photographs of 91 Chinese type 2 diabetic patients with biopsy-confirmed DN, not in ESRD stage, were obtained at the time of renal biopsy in this longitudinal study. The baseline severity of DR was determined using the Lesion-aware Deep Learning System (RetinalNET) in an open framework for deep learning and was graded using the Early Treatment Diabetic Retinopathy Study severity scale. Cox proportional hazard models were used to estimate the hazard ratio (HR) for the effect of the severity of diabetic retinopathy on ESRD. Results: During a median follow-up of 15 months, 25 patients progressed to ESRD. The severity of retinopathy at the time of biopsy was a prognostic factor for progression to ESRD (HR 2.18, 95% confidence interval 1.05 to 4.53, P = .04). At baseline, more severe retinopathy was associated with poor renal function, and more severe glomerular lesions. However, 30% of patients with mild retinopathy and severe glomerular lesions had higher low-density lipo-protein-cholesterol and more severe proteinuria than those with mild glomerular lesions. Additionally, 3% of patients with severe retinopathy and mild glomerular changes were more likely to have had diabetes a long time than those with severe glomerular lesions. Conclusion: Although the severity of DR predicted diabetic ESRD in patients with type 2 diabetes mellitus and DN, the severities of DR and DN were not always consistent, especially in patients with mild retinopathy or microalbuminuria. Abbreviations: CI = confidence interval; DM = diabetic mellitus; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = hemoglobin A1c; HR = hazard ratio; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; VEGF = vascular endothelial growth factor.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two-by-two factorial design. In the blood pressure-lowering arm, patients were treated using a fixed combination of the ACE-inhibitor, perindopril, and the thiazide-like diuretic, indapamide, or placebo, whereas in the glucose-lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose-lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end-points were major macro- and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow-up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment.

OBJECTIVE To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline. RESEARCH DESIGN AND METHODS We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. RESULTS During 5 years’ follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83–0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41–2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively). CONCLUSIONS The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.

Aims In CARMELINA®, linagliptin demonstrated cardiovascular and renal safety in patients with type 2 diabetes (T2D) with high renal and cardiovascular disease (CVD) risk. We investigated safety and efficacy of this dipeptidyl peptidase‐4 inhibitor in older participants. Materials and methods Subjects aged ≥18 years with T2D and established CVD with urinary albumin‐to‐creatinine ratio (UACR) >30 mg/g, and/or prevalent kidney disease, were randomized to linagliptin or placebo added to usual care. The primary endpoint (time to first occurrence of 3P‐MACE: cardiovascular death, non‐fatal myocardial infarction or non‐fatal stroke) and other outcomes were evaluated across age groups

Advances in immunosuppressive therapy have drastically improved acute rejection rates in kidney transplant recipients over the past five decades. Nevertheless, it should remain high on any differential diagnosis of unexplained graft dysfunction because of the potential negative effect on graft longevity. Understanding the pre- and post-transplant risk factors for acute rejection can help estimate the probability of immunologic graft damage, and accurate identification of the type and severity of acute rejection will guide appropriate treatment. Tissue biopsy remains the gold standard for evaluating immunologic graft damage, and the histologic definition of acute rejection has evolved in recent years. Intravenous steroids and T cell depletion remain the standard therapy for T cell-mediated rejection and are effective in reversing most cases. Plasma exchange and intravenous Ig, with or without rituximab, are most commonly used for the treatment of antibody-mediated rejection and several newer agents have recently been investigated for severe cases. This review aims to provide the general nephrologist caring for transplant recipients with an approach to immunologic risk assessment and a summary of recent advances in the diagnosis and treatment of acute graft rejection.

The UK’s National Institute for Health and Care Excellence (NICE) is in the process of writing guidelines for “Medicines Associated with Dependence or Withdrawal Symptoms: Safe Prescribing ...

Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif−/−) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif−/− mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif−/− as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.

Chronic pain in childhood is an international public health problem. We conducted a systematic review and meta-analysis to provide a summary of the published evidence of pharmacological, physical, and psychological therapies for children with chronic pain conditions. We searched CENTRAL, MEDLINE, EMBASE, and PsycINFO from inception to April 2020; clinical trial registries; and other sources for randomised controlled trials or comparative observational trials. We extracted critical outcomes of pain intensity, quality of life, physical functioning, role functioning, emotional functioning, sleep, and adverse events. We assessed studies for risk of bias and certainty of the evidence using GRADE. We included 34 pharmacological (4091 participants), 25 physical therapy (1470 participants), and 63 psychological trials (5025 participants). Participants reported a range of chronic pain conditions. Most studies were assessed to have unclear or high risk of bias across multiple domains. Pharmacological, physical, and psychological therapies showed some benefit for reducing pain, posttreatment, but only physical and psychological therapies improved physical functioning. We found no benefit of any treatment modality for health-related quality of life, role functioning, emotional functioning, or sleep. Adverse events were poorly reported, particularly for psychological and physical interventions. The largest evidence base for the management of chronic pain in children supports the use of psychological therapies, followed by pharmacological and physical therapies. However, we rated most outcomes as low or very low certainty, meaning further evidence is likely to change our confidence in the estimates of effects. This protocol was registered on PROSPERO (CRD42020172451).

Background Gastro-intestinal (GI) intolerance is a frequently reported outcome in patients with kidney failure receiving maintenance dialysis and those who have received kidney transplants. Symptoms of GI intolerance (diarrhoea, constipation, bloating, abdominal pain, heart burn, and reflux) are associated with significant reduction in quality of life, morbidity, and increased used of healthcare resources. Having chronic kidney disease (CKD), together with related changes in diet and medication, may alter the gut microbiota and the microbial-derived uraemic metabolites that accumulate in kidney failure, and contribute to various complications including chronic diarrhoea, opportunistic infections, and drug-related colitis. Despite the high disease burden among patients with kidney replacement therapies, GI symptoms are often under-recognised and, consequently limited resources and strategies are devoted to the management of gastrointestinal complications in patients with CKD. Methods The CKD Bowel Health Study is a multi-centre mixed-methods observational longitudinal study to better understand the bowel health and GI symptom management in patients with CKD. The program comprises of a longitudinal study that will assess the burden and risk factors of GI intolerance in patients treated with maintenance dialysis; a semi-structured interview study that will describe experiences of GI intolerance (including symptoms, treatment, self-management) in transplant candidates and recipients; and a discrete choice experience to elicit patient preferences regarding their experiences and perspectives of various intervention strategies for the management of GI symptoms after kidney transplantation. Discussion This proposed program of work aims to define the burden the GI intolerance in patients with kidney failure and generate evidence on the patients’ experiences of GI intolerance and their perspectives on their clinical and own management strategies of these symptoms, ensuring a patient-centred approach to guide clinical decision making and to inform the best study design for intervention trials. Trial registration This study is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000548831. This study has been approved by the Western Sydney Local Health District Human Research Ethics Committee of New South Wales Health (HREC ETH03007). This study is supported by a National Health and Medical Research Council (NHMRC) Australia Investigator Grant (APP1195414), and an NHMRC Australia Postgraduate Scholarship (APP2005244).

OBJECTIVE To compare intraocular pressures (IOPs) estimated by rebound and applanation tonometry for dogs with lens instability. ANIMALS 66 dogs. PROCEDURES Medical records of dogs examined between September 2012 and July 2018 were reviewed for diagnoses of anterior (ALL) or posterior (PLL) lens luxation or lens subluxation. RESULTS Estimates of IOP obtained with rebound and applanation tonometry significantly differed from each other for all types of lens instability considered collectively (mean ± SE difference between tonometric readings, 8.1 ± 1.3 mm Hg) and specific types of lens instability considered individually (mean ± SE difference between tonometric readings: ALL, 12.8 ± 2.5 mm Hg; PLL, 5.9 ± 1.7 mm Hg; subluxation, 2.8 ± 0.8 mm Hg). Median (range) differences between rebound and applanation tonometer readings for dogs with ALL was 5 mm Hg (–9 to 76 mm Hg), with PLL was 3 mm Hg (–1 to 19 mm Hg), and with lens subluxation was 3 mm Hg (–9 to 18 mm Hg). In eyes with ALL, rebound tonometer readings exceeded applanation tonometer readings on 44 of 60 (73%) occasions. CONCLUSIONS AND CLINICAL RELEVANCE Rebound tonometry yielded higher estimates of IOP than did applanation tonometry in eyes with ALL and with all types of lens luxation considered collectively. Estimates of IOP in eyes with lens instability should ideally be obtained with both rebound and applanation tonometers. Veterinarians with only one type of tonometer should interpret results for dogs with lens instability concurrent with physical examination findings.

— Epidermotropic cutaneous T-cell lymphoma was diagnosed in six Syrian hamsters (Mesocricetus auratus) with a generalised dermatosis characterised by pruritus, alopecia and exfoliative erythroderma. Plaques and nodules were evident in one animal. Clinical and histopathological findings were suggestive of mycosis fungoides and electron microscopical investigations in one case were supportive. Immuno-histochemical stains for CD3 antigen were strongly positive in all cases. Resume— Un lyphome T cutane a ete diagnostique chez six hamsters de Siberie (Mesocricetus auratus) avec une dermatose generalisee, caracterisee par un prurit, une alopecle et une erythrodermie exfoliative. Des plaques et des nodules ont ete observees sur un animal. Les donnees cliniques et histopathologiques etaient evocatrices d'un mycosis fungoides et les examens en microscopie electronique etaient compatibles dans un cas. Les marquages immuno-histochimiques de l'antigene CD3 etaient tres positifs dans tous les cas. Zusammenfassung— Bei sechs Syrischen Goldhamstern (Mesocricetus auratus) wurde ein epidermotropes kutanes T-Zell-Lymphom mit einer generalisierten Dermatose diagnostiziert, die durch Pruritus, Alopezie und eine exfoliative Erythrodermie gekennzeichnet war. Bei einem Tier traten auch Plagues und Knoten auf. Die klinischen und histopathologischen Befunde deuteten auf Mycosis fungoides hin. Elektronenmikroskopische Untersuchungen unterstutzten diesen Verdacht in einem Fall. Immunhistochemische Farbungen auf CD3-Antigen waren bei alien Fallen stark positiv. Resumen En un grupo de seis hamsters de siria, (Mesocricetus auratus), se diagnostico limfoma epidermotropico cutaneo de linfocitos T, presentando una dermatosis generalizada de tipo pruriginoso, acompanada de alopecia y eritroderma exfoliativo. Las placas y nodulos fueron evidentes en uno de los animales. Los estudios clinicos e histopatologicos indicaron una micosis fungoide, y las investigaciones de microscopia, en uno de los caseos, parecio indicar lo mismo. La tintura inmuno-histoquimica para el antigeno CD3 resulto claramente positiva en todod los casos.

Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.

Key Points Question Does preemptive intervention compared with usual care reduce the severity of autism symptoms and the likelihood of an autism spectrum disorder (ASD) diagnosis in infants showing early signs of ASD? Findings In this randomized clinical trial of 103 infants showing early behavioral signs of ASD, preemptive intervention led to a statistically significant reduction in the severity of ASD behaviors across early childhood. Infants who received the preemptive intervention had lower odds of meeting diagnostic criteria for ASD (7%) than those who received usual care (21%) at age 3 years, with a number needed to treat of 7 participants. Meaning This study found that a preemptive intervention reduced ASD diagnostic behaviors when used at the time atypical development first emerges during infancy., Importance Intervention for individuals with autism spectrum disorder (ASD) typically commences after diagnosis. No trial of an intervention administered to infants before diagnosis has shown an effect on diagnostic outcomes to date. Objective To determine the efficacy of a preemptive intervention for ASD beginning during the prodromal period. Design, Setting, and Participants This 2-site, single rater–blinded randomized clinical trial of a preemptive intervention vs usual care was conducted at 2 Australian research centers (Perth, Melbourne). Community sampling was used to recruit 104 infants aged 9 to 14 months showing early behaviors associated with later ASD, as measured by the Social Attention and Communication Surveillance–Revised. Recruitment occurred from June 9, 2016, to March 30, 2018. Final follow-up data were collected on April 15, 2020. Interventions Infants were randomized on a 1:1 ratio to receive either a preemptive intervention plus usual care or usual care only over a 5-month period. The preemptive intervention group received a 10-session social communication intervention, iBASIS–Video Interaction to Promote Positive Parenting (iBASIS-VIPP). Usual care comprised services delivered by community clinicians. Main Outcomes and Measures Infants were assessed at baseline (approximate age, 12 months), treatment end point (approximate age, 18 months), age 2 years, and age 3 years. Primary outcome was the combined blinded measure of ASD behavior severity (the Autism Observation Scale for Infants and the Autism Diagnostic Observation Schedule, second edition) across the 4 assessment points. Secondary outcomes were an independent blinded clinical ASD diagnosis at age 3 years and measures of child development. Analyses were preregistered and comprised 1-tailed tests with an α level of .05. Results Of 171 infants assessed for eligibility, 104 were randomized; 50 infants (mean [SD] chronological age, 12.40 [1.93] months; 38 boys [76.0%]) received the iBASIS-VIPP preemptive intervention plus usual care (1 infant was excluded after randomization), and 53 infants (mean [SD] age, 12.38 [2.02] months; 32 boys [60.4%]) received usual care only. A total of 89 participants (45 in the iBASIS-VIPP group and 44 in the usual care group) were reassessed at age 3 years. The iBASIS-VIPP intervention led to a reduction in ASD symptom severity (area between curves, −5.53; 95% CI, −∞ to −0.28; P = .04). Reduced odds of ASD classification at age 3 years was found in the iBASIS-VIPP group (3 of 45 participants [6.7%]) vs the usual care group (9 of 44 participants [20.5%]; odds ratio, 0.18; 95% CI, 0-0.68; P = .02). Number needed to treat to reduce ASD classification was 7.2 participants. Improvements in caregiver responsiveness and language outcomes were also observed in the iBASIS-VIPP group. Conclusions and Relevance Receipt of a preemptive intervention for ASD from age 9 months among a sample of infants showing early signs of ASD led to reduced ASD symptom severity across early childhood and reduced the odds of an ASD diagnosis at age 3 years. Trial Registration http://anzctr.org.au identifier: ACTRN12616000819426., This randomized clinical trial examines whether preemptive intervention compared with usual care reduces the severity of autism symptoms and the odds of an autism spectrum disorder diagnosis among infants showing early signs of autism.

BACKGROUND AND AIM OF THE STUDY Long-term laryngotracheal complications have not been described in adult patients undergoing cardiac surgery. The purpose of this study was to determine the incidence of and risk factors for laryngotracheal complications following cardiac surgery. METHODS A retrospective chart review of patients at high risk for laryngotracheal complications following cardiac surgery between 2006 and 2016 was performed. High-risk patients were reviewed to determine the presence of laryngotracheal complications including laryngotracheal stenosis, keyhole deformity, or vocal cord immobility. Logistic regression was used to identify predictors of long-term laryngotracheal complications. RESULTS Of 11,417 patients who underwent cardiac surgery, 1099 were identified as at high risk. Of these, 24 (2.2%) developed laryngotracheal complications following their surgery and intensive care unit (ICU) stay. Laryngotracheal stenosis and keyhole deformity were present in 13 (1.2%) and 6 (0.5%) patients, respectively. Logistic regression demonstrated older age (age ≥ 70 odds ratio [OR] 0.31, 95% confidence interval [CI] 0.12-0.83) was protective, while readmission to ICU for ventilation (OR 3.11, 95% CI 1.17-8.25) and receiving a tracheostomy (OR 7.83, 95% CI 2.22-27.6) were associated with laryngotracheal complications. CONCLUSIONS The incidence of long-term laryngotracheal complications following cardiac surgery was 2.2%. Readmission to ICU for ventilation and having a tracheostomy performed were associated with laryngotracheal complications.

Aims: The association between diabetes and cognitive decline (CD) and dementia has been well-documented. This study estimated the associations between risk factors and CD/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death.\ud \ud Materials and methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with type 2 diabetes was used to estimate the odds of CD/dementia using multinomial logistic regression.\ud \ud Results: During a median five-year follow-up, 1,827 participants (43.2% women) had CD/dementia (1,718 with CD only; 21 with dementia only; 88 with CD and dementia), and 929 (31.0% women) died without CD/dementia. Women had a lower odds of CD/dementia than men (Odds Ratio (OR) (95% confidence interval), 0.88 (0.77, 1.00)); older age, higher total cholesterol, HbA1c , waist circumference, waist-to-height ratio, moderately increased ACR (Albumin-Creatinine Ratio), stroke/transient ischemic attack and retinal disease were each associated with greater odds of CD/dementia; higher years at education completion, baseline cognitive function, taller stature and current alcohol use were inversely associated. Higher waist circumference (women-to-men Ratio of Odds Ratios (ROR), 1.05 (1.00, 1.10) per 5 cm) and presence of anxiety/depression (ROR, 1.28 (1.01, 1.63)) were associated with greater OR for CD/dementia in women than men.\ud \ud Conclusions: Several risk factors were associated with CD/dementia. Higher waist circumference and mental health symptoms were more strongly associated with CD/dementia in women than men. Further studies should examine the mechanisms which underlie these sex differences. This article is protected by copyright. All rights reserved.

Insulin and insulin-like growth factor stimulate protein synthesis and cardioprotection in the heart, acting through their receptors (INSRs, IGF1Rs) and signalling via protein kinase B (PKB, also known as Akt). Protein synthesis is increased in hearts perfused at alkaline pHo to the same extent as with insulin. Moreover, α1-adrenergic receptor (α1-AR) agonists (e.g. phenylephrine) increase protein synthesis in cardiomyocytes, activating PKB/Akt. In both cases, the mechanisms are not understood. Our aim was to determine if insulin receptor-related receptors (INSRRs, activated in kidney by alkaline pH) may account for the effects of alkaline pHo on cardiac protein synthesis, and establish if α1-ARs signal through the insulin receptor family. Alkaline pHo activated PKB/Akt signalling to the same degree as insulin in perfused adult male rat hearts. INSRRs were expressed in rat hearts and, by immunoblotting for phosphorylation (activation) of INSRRs/INSRs/IGF1Rs, we established that INSRRs, together with INSRs/IGF1Rs, are activated by alkaline pHo. The INSRR/INSR/IGF1R kinase inhibitor, linsitinib, prevented PKB/Akt activation by alkaline pHo, indicating that INSRRs/INSRs/IGF1Rs are required. Activation of PKB/Akt in cardiomyocytes by α1-AR agonists was also inhibited by linsitinib. Furthermore, linsitinib inhibited cardiomyocyte hypertrophy induced by α1-ARs in cultured cells, reduced the initial cardiac adaptation (24 h) to phenylephrine in vivo (assessed by echocardiography) and increased cardiac fibrosis over 4 days. We conclude that INSRRs are expressed in the heart and, together with INSRs/IGF1Rs, the insulin receptor family provide a potent system for promoting protein synthesis and cardioprotection. Moreover, this system is required for adaptive hypertrophy induced by α1-ARs.