Abstract
Visual inspection is the primary method of interpreting functional analysis (FA) outcomes, even though it has occasionally been criticized for producing low levels of interobserver ...agreement. Researchers have addressed this issue by creating structured visual‐inspection criteria to guide visual inspection of FA outcomes (e.g., Hagopian et al., 1997,
https://doi.org/10.1901/jaba.1997.30‐313
; Roane et al., 2013,
https://doi.org/10.1002/jaba.13
). The purpose of the current study was to systematically replicate and extend Study 1 of Roane et al. (2013,
https://doi.org/10.1002/jaba.13
). We did this by evaluating the reliability and accuracy of 15 novice participants’ visual inspection of 84 FA graphs with and without the modified visual‐inspection criteria developed by Roane et al. Accuracy was markedly higher when participants used the modified visual‐inspection criteria relative to when they used traditional visual‐inspection strategies, while we observed more modest increases in reliability coefficients. Results are discussed in the context of practical and clinical implications of the modified visual‐inspection criteria and suggestions for future research.
Researchers report increasing trends in psychotropic medication use to treat problem behavior in individuals with intellectual and developmental disability, despite some controversy regarding its ...application and treatment efficacy. A substantial evidence base exists supporting behavioral intervention efficacy, however research evaluating separate and combined intervention (i.e., concurrent application of behavioral and psychopharmacological interventions) effects remains scarce. This article demonstrates how a series of analyses on clinical data collected during treatment (i.e., four case studies) may be used to retrospectively explore separate and combined intervention effects on severe problem behavior. First, we calculated individual effect sizes and corresponding confidence intervals. The results indicated larger problem behavior decreases may have coincided more often with behavioral intervention adjustments compared to medication adjustments. Second, a conditional rates analysis indicated surges in problem behavior did not reliably coincide with medication reductions. Spearman correlation analyses indicated a negative relationship between behavioral intervention phase progress and weekly episodes of problem behavior compared to a positive relationship between total medication dosage and weekly episodes of problem behavior. However, a nonparametric partial correlation analyses indicated individualized, complex relationships may exist among total medication dosage, behavioral intervention, and weekly episodes of problem behavior. We discuss potential clinical implications and encourage behavioral researchers and practitioners to consider applying creative analytic strategies to evaluate separate and combined intervention effects on problem behavior to further explore this extremely understudied topic.
Inhibiting the actions of VEGF is a new therapeutic paradigm in cancer management with antiangiogenic therapy also under intensive investigation in a range of nonmalignant diseases characterized by ...pathological angiogenesis. However, the effects of VEGF inhibition on organs that constitutively express it in adulthood, such as the kidney, are mostly unknown. Accordingly, we examined the effect of VEGF inhibition on renal structure and function under physiological conditions and in the setting of the common renal stressors: hypertension and activation of the renin-angiotensin system. When compared with normotensive Sprague-Dawley (SD) rats, glomerular VEGF mRNA was increased 2-fold in transgenic (mRen-2)27 rats that overexpress renin with spontaneously hypertensive rat (SHR) kidneys showing VEGF expression levels that were intermediate between them. Administration of either an orally active inhibitor of the type 2 VEGF receptor (VEGFR-2) tyrosine kinase or a VEGF neutralizing antibody to TGR(mRen-2)27 rats resulted in loss of glomerular endothelial cells and transformation to a malignant hypertensive phenotype with severe glomerulosclerosis. VEGFR-2 kinase inhibition treatment was well tolerated in SDs and SHRs; although even in these animals there was detectable endothelial cell loss and rise in albuminuria. Mild mesangial expansion was also noted in hypertensive SHR, but not in SD rats. These studies illustrate: (i) VEGF has a role in the maintenance of glomerular endothelial integrity under physiological circumstances, (ii) glomerular VEGF is increased in response to hypertension and activation of the renin-angiotensin system, and (iii) VEGF signaling plays a protective role in the setting of these renal stressors.
BackgroundSolid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and ...homologous vaccines in a kidney transplant population. MethodsWe undertook a single centre cohort study of 724 kidney transplant recipients prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their first dose of vaccine. Findings586/724 (80.9%) patients were infection-naïve post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001.Post-V4, 45/239 (18.8%) infection-naïve patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type. InterpretationA significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection. As such alternative strategies are required to provide protection to this vulnerable group. FundingMW/PK received study support from Oxford Immunotec.
Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the antioxidant thioredoxin, and a critical agent in the in vivo regulation of glucose. The well-described induction of TXNIP by ...high glucose may represent an important pathogenic trigger of complications arising in the diabetic environment, with sustained overexpression of TXNIP triggering the increased production of reactive oxygen species and collagen, both major contributors to the development of diabetic nephropathy (DN). To examine a possible therapeutic role for targeted TXNIP inhibition in DN, transgenic (mRen-2)27 rats were rendered diabetic with streptozotocin and then treated with 20 μM TXNIP deoxyribozyme (DNAzyme) delivered continuously over 12 weeks by an implanted osmotic mini-pump. Renal injury was measured using biochemical parameters of kidney function along with histological markers of damage. Catalytic activity of TXNIP DNAzyme was determined by TXNIP gene and peptide expression in the rat kidneys. TXNIP DNAzyme localization was demonstrated with a fluorescent-labelled TXNIP DNAzyme. A panel of markers was used to assess the extent of oxidative stress and renal fibrosis including superoxide level, nitrotyrosine staining, TGF-β1, NLRP3 and collagen IV expression. Fluorescent-labelled TXNIP DNAzyme was localized to tubulo-epithelial cells, but was not identified in glomeruli or endothelial cells. Elevated renal cortical TXNIP gene and protein expression seen in kidneys of DN animals were significantly attenuated by TXNIP DNAzyme (p < 0.05). Downstream markers of TXNIP activity, particularly oxidative stress, inflammasome signalling, tubulo-interstitial fibrosis and collagen deposition, were also attenuated in the tubulo-interstitium of DN rats treated with TXNIP DNAzyme. Consistent with the identified site of action of the DNAzyme, the effects of the TXNIP inhibition were limited to the tubulo-interstitial compartment. This study supports the role of TXNIP as an important mediator of progressive tubulo-interstitial fibrosis in DN, and also supports the notion of TXNIP inhibition as a potential new therapeutic target for DN.
Previous review articles examining functional analysis research have noted an increase in the number of child participants featured across the assessment literature. It may be reasonable to conclude ...that the same pattern may be observed in the behavioral treatment literature, although a recent review examining participant and research patterns on this topic has not been conducted. The current report examined research trends and patterns across four prominent behavior analytic journals over the last 20 years. Child participants were featured more often (78%) compared to adult participants (22%). Other research trends in the articles featuring adult participants included a heavy reliance on functional analyses, and an emphasis on evaluating reinforcement-based interventions. Finally, we observed substantial subjectivity in participant descriptors (i.e., use of the term severe). We discuss the impact these patterns may have on the: (a) evidence-base regarding adult clinical services, (b) general implications, (c) potential contributing factors, and (d) possible solutions. We conclude with a call to action by researchers and clinicians to address existing gaps.
Heart failure is a common cause of morbidity and mortality in diabetic patients that frequently manifests in the absence of impaired left ventricular systolic function. In contrast to the strong ...evidence base for the treatment of systolic heart failure, the treatment of heart failure with preserved left ventricular function is uncertain, and therapeutic targets beyond blockade of the renin-angiotensin-aldosterone and beta-adrenergic systems are being sought. One such target is the beta-isoform of protein kinase C (PKC), implicated in both the complications of diabetes and in cardiac dysfunction in the nondiabetic setting.
Using a hemodynamically validated rodent model of diabetic diastolic heart failure, the (mRen-2)27 transgenic rat, we sought to determine whether selective inhibition of PKC-beta would preserve cardiac function and reduce structural injury. Diabetic rats were randomized to receive either vehicle or the PKC-beta inhibitor, ruboxistaurin (20 mg/kg per d) and followed for 6 weeks. Compared with untreated animals, ruboxistaurin-treated diabetic rats demonstrated preserved systolic and diastolic function, as measured by the slope of preload recruitable stroke work relationship (P<0.05) and the slope of the end-diastolic pressure volume relationship (P<0.01). Collagen I deposition and cardiomyocyte hypertrophy were both reduced in diabetic animals treated with ruboxistaurin (P<0.01), as was phosphorylated-Smad2, an index of transforming growth factor-beta activity (P<0.01 for all, versus untreated diabetic rats).
PKC-ss inhibition attenuated diastolic dysfunction, myocyte hypertrophy, and collagen deposition and preserved cardiac contractility. PKC-beta inhibition may represent a novel therapeutic strategy for the prevention of diabetes-associated cardiac dysfunction.
Aims
Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a ...potential therapeutic target. We tested this hypothesis using a new anti‐fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren‐2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans.
Methods and results
Homozygous Ren‐2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm2; P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope‐mmHg; P < 0.05), and reduced end‐diastolic pressure–volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope‐mmHg/μL; P < 0.05).
Conclusions
A direct anti‐fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.
Aim: Early renal enlargement may predict the future development of nephropathy in patients with diabetes. The epidermal growth factor (EGF)‐EGF receptor (EGFR) system plays a pivotal role in ...mediating renal hypertrophy, where it may act to regulate cell growth and proliferation and also to mediate the actions of angiotensin II through transactivation of the EGFR. In the present study we sought to investigate the effects of long‐term inhibition of the EGFR tyrosine kinase in an experimental model of diabetes that is characterized by angiotensin II dependent hypertension.
Methods: Female heterozygous streptozotocin‐diabetic TGR(mRen‐2)27 rats were treated with the EGFR inhibitor PKI 166 by daily oral dosing for 16 weeks.
Results: Treatment of TGR(mRen‐2)27 rats with PKI 166 attenuated the increase in kidney size, glomerular hypertrophy and albuminuria that occurred with diabetes. The reduction in albuminuria, with EGFR inhibition in diabetic TGR(mRen‐2)27 rats, was associated with preservation of the number of glomerular cells staining positively for the podocyte nuclear marker, WT1. Immunostaining for WT1 inversely correlated with glomerular volume in diabetic rats. In contrast to agents that block the renin‐angiotensin system (RAS), EGFR inhibition had no effect on either the quantity of mesangial matrix or the magnitude of tubular injury in diabetic animals.
Conclusion: These observations indicate that inhibition of the tyrosine kinase activity of the EGFR attenuates kidney and glomerular enlargement in association with podocyte preservation and reduction in albuminuria in diabetes. Accordingly, targeting the EGF‐EGFR pathway may represent a therapeutic strategy for patients who continue to progress despite RAS‐blockade.
This study shows that long‐term administration of an epidermal growth factor‐receptor kinase inhibitor preserves podocytes and suppresses albuminuria in the transgenic (mRen‐2)27 rat model of diabetic nephropathy, although mesangial matrix expansion, tubular injury and hypertension were unaffected. This strategy could potentially help those patients who fail to respond to angiotensin blockade.
People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical ...effectiveness of BNT162B2 versus ChAdOx1 in haemodialysis patients.
In this observational cohort study, 1021 patients were followed-up from time of vaccination until December 2021. All patients underwent weekly RT-PCR screening. Patients were assessed for nucleocapsid(anti-NP) and spike(anti-S) antibodies at timepoints after second(V2) and third(V3) vaccinations. 191 patients were investigated for T-cell responses. Vaccine effectiveness (VE) for prevention of infection, hospitalisation and mortality was evaluated using the formula VE=(1-adjustedHR)x100.
45.7% (467/1021) had evidence of prior infection. There was no difference in the proportion of infection-naïve patients who seroconverted by vaccine type, but median anti-S antibody titres were higher post-BNT162b2 compared with ChAdOx1; 462(152-1171) and 78(20-213) BAU/ml respectively, p<0.001. Concomitant immunosuppressant use was a risk factor for non-response, OR 0.1295% CI 0.05–0.25 p<0.001. Post-V3 (all BNT162b2), median anti-S antibody titres remained higher in those receiving BNT162b2 versus ChAdOx1 as primary doses; 2756(187–1246) and 1250(439–2635) BAU/ml respectively, p=0.003.
Anti-S antibodies waned over time. Hierarchical levels of anti-S post-V2 predicted risk of infection; patients with no/low anti-S being at highest risk. VE for preventing infection, hospitalisation and death was 53% (95% CI 6–75), 77% (95% CI 30–92) and 93% (95% CI 59–99) respectively, with no difference seen by vaccine type.
Serum anti-S concentrations predict risk of breakthrough infection. Anti-S responses vary dependent upon clinical features, infection history and vaccine type. Monitoring of serological responses may enable individualised approaches to vaccine boosters in at risk populations.
National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.
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