Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients

Background Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non‐depleting interleukin‐2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte‐depleting antibodies but the relative benefits and harms of the available agents are uncertain. Objectives We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients). Search methods We searched the Cochrane Kidney and Transplant's Specialised Register to 29 August 2016 through contact with the Information Specialist using search terms relevant to this review. Selection criteria Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. Data collection and analysis Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). Main results We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates. Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death‐censored graft loss was uncertain at 1 to 2 years and 5 years. In non‐CNI studies, ATG had uncertain effects on death but reduced death‐censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non‐CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all‐cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death‐censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post‐transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT). Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death‐censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD ‐13.35 mL/min, ‐23.91 to ‐2.80) and 2 years (2 studies: MD ‐12.86 mL/min, ‐23.73 to ‐2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all‐cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance. Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all‐cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD. Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo. Authors' conclusions ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non‐CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection. In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG. Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient‐centred outcomes (reduced death or lower toxicity) do not appear to be improved

Global effect of COVID-19 pandemic on physical activity, sedentary behaviour and sleep among 3- to 5-year-old children: a longitudinal study of 14 countries

Background: The restrictions associated with the 2020 COVID-19 pandemic has resulted in changes to young children’s daily routines and habits. The impact on their participation in movement behaviours (physical activity, sedentary screen time and sleep) is unknown. This international longitudinal study compared young children’s movement behaviours before and during the COVID-19 pandemic. Methods: Parents of children aged 3–5 years, from 14 countries (8 low- and middle-income countries, LMICs) completed surveys to assess changes in movement behaviours and how these changes were associated with the COVID-19 pandemic. Surveys were completed in the 12 months up to March 2020 and again between May and June 2020 (at the height of restrictions). Physical activity (PA), sedentary screen time (SST) and sleep were assessed via parent survey. At Time 2, COVID-19 factors including level of restriction, environmental conditions, and parental stress were measured. Compliance with the World Health Organizations (WHO) Global guidelines for PA (180 min/ day [≥60 min moderate- vigorous PA]), SST (≤1 h/day) and sleep (10-13 h/day) for children under 5 years of age, was determined. Results: Nine hundred- forty-eight parents completed the survey at both time points. Children from LMICs were more likely to meet the PA (Adjusted Odds Ratio [AdjOR] = 2.0, 95%Confidence Interval [CI] 1.0,3.8) and SST (AdjOR = 2.2, 95%CI 1.2,3.9) guidelines than their high-income country (HIC) counterparts. Children who could go (Continued on next page (Continued from previous page) outside during COVID-19 were more likely to meet all WHO Global guidelines (AdjOR = 3.3, 95%CI 1.1,9.8) than those who were not. Children of parents with higher compared to lower stress were less likely to meet all three guidelines (AdjOR = 0.5, 95%CI 0.3,0.9). Conclusion: PA and SST levels of children from LMICs have been less impacted by COVID-19 than in HICs. Ensuring children can access an outdoor space, and supporting parents’ mental health are important prerequisites for enabling pre-schoolers to practice healthy movement behaviours and meet the Global guidelines

Evolution and comparative analysis of the MHC Class III inflammatory region

BACKGROUND: The Major Histocompatibility Complex (MHC) is essential for immune function. Historically, it has been subdivided into three regions (Class I, II, and III), but a cluster of functionally related genes within the Class III region has also been referred to as the Class IV region or "inflammatory region". This group of genes is involved in the inflammatory response, and includes members of the tumour necrosis family. Here we report the sequencing, annotation and comparative analysis of a tammar wallaby BAC containing the inflammatory region. We also discuss the extent of sequence conservation across the entire region and identify elements conserved in evolution. RESULTS: Fourteen Class III genes from the tammar wallaby inflammatory region were characterised and compared to their orthologues in other vertebrates. The organisation and sequence of genes in the inflammatory region of both the wallaby and South American opossum are highly conserved compared to known genes from eutherian ("placental") mammals. Some minor differences separate the two marsupial species. Eight genes within the inflammatory region have remained tightly clustered for at least 360 million years, predating the divergence of the amphibian lineage. Analysis of sequence conservation identified 354 elements that are conserved. These range in size from 7 to 431 bases and cover 15.6% of the inflammatory region, representing approximately a 4-fold increase compared to the average for vertebrate genomes. About 5.5% of this conserved sequence is marsupial-specific, including three cases of marsupial-specific repeats. Highly Conserved Elements were also characterised. CONCLUSION: Using comparative analysis, we show that a cluster of MHC genes involved in inflammation, including TNF, LTA (or its putative teleost homolog TNF-N), APOM, and BAT3 have remained together for over 450 million years, predating the divergence of mammals from fish. The observed enrichment in conserved sequences within the inflammatory region suggests conservation at the transcriptional regulatory level, in addition to the functional level

24 hour movement behaviours and the health and development of pre-school children from Zimbabwean settings: the SUNRISE pilot study

Background: In 2019, the World Health Organization (WHO) released global guidelines for physical activity, sedentary behaviour and sleep for the early years. The International Study of Movement Behaviours in the Early Years, SUNRISE, aimed to assess the extent to which children aged three and four years meet the WHO global guidelines and its association with health and development. Objectives: To assess movement behaviours in pre-school children from low-income settings in Zimbabwe and to establish associations between these movement behaviours and adiposity, motor skills and executive function.Methods: Pre-school children/caregivers were recruited from two urban and two rural public schools respectively in Zimbabwe. The caregivers answered questions on the children’s physical activity, screen time, sedentary behaviour and sleep patterns. Children’s movement behaviours were objectively measured using accelerometers. Gross and fine motor skills and executive function were assessed using the Ages and Stages Questionnaire-3 and Early Years Toolbox, respectively. Focus group discussions were carried out with caregivers and teachers on the acceptability and feasibility of the study. Results: Eighty-one children participated in the study. The proportions of children meeting the guidelines were physical activity 92%, sedentary behaviour 70%, and sleep 86%, and all guidelines combined 24%. Boys and girls were similar (p>0.05 for all variables) for all executive function variables, but rural children had significantly lower inhibition scores (p=0.026) than urban children. Conclusion: The study adds to the growing literature on movement behaviours and associated risk factors in low-resourced settings. Further investigations of movement behaviours in this age group in Zimbabwe are recommended

Decision regret in men living with and beyond nonmetastatic prostate cancer in the United Kingdom: A population‐based patient‐reported outcome study

Objective: Clinical options for managing nonmetastatic prostate cancer (PCa) vary. Each option has side effects associated with it, leading to difficulty in decision‐making. This study aimed to assess the relationship between patient involvement in treatment decision‐making and subsequent decision regret (DR), and quantify the impact of health‐related quality of life (HRQL) outcomes on DR. Methods: Men living in the United Kingdom, 18 to 42 months after diagnosis of PCa, were identified from cancer registration data and sent a questionnaire. Measures included the Decision Regret Scale (DRS), Expanded Prostate cancer Index Composite short form (EPIC‐26), EQ‐5D‐5L, and an item on involvement in treatment decision‐making. Multivariable ordinal regression was utilized, with DR categorized as none, mild, or moderate/severe regret. Results: A total of 17 193 men with stage I‐III PCa completed the DRS: 36.6% reported no regret, 43.3% mild regret, and 20.0% moderate/severe regret. The odds of reporting DR were greater if men indicated their views were not taken into account odds ratio ([OR] = 6.42, 95% CI: 5.39‐7.64) or were involved “to some extent” in decision‐making (OR = 4.63, 95% CI: 4.27‐5.02), compared with men who were “definitely” involved. After adjustment, including for involvement, men reporting moderate/big problems with urinary, bowel, or sexual function were more likely to experience regret compared with men with no/small problems. Better HRQL scores were associated with lower levels of DR. Conclusions: This large‐scale study demonstrates the benefit of patient involvement in treatment decision‐making for nonmetastatic PCa. However, men experiencing side effects and poorer HRQL report greater DR. Promoting engagement in clinical decision‐making represents good practice and may reduce the risk of subsequent regret

Accuracy of the no-biopsy approach for the diagnosis of coeliac disease in adults: a systematic review and meta-analysis

BACKGROUND & AIMS: Current international guidelines recommend duodenal biopsies to confirm the diagnosis of coeliac disease in adult patients. However, growing evidence suggests that IgA anti-tissue transglutaminase (tTg) antibody levels ≥10 times the upper limit of normal (ULN) can accurately predict coeliac disease, eliminating the need for biopsy. We performed a systematic review and meta-analysis to evaluate the accuracy of the no-biopsy approach to confirm the diagnosis of coeliac disease in adults. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library and Web of Science from January 1998 to October 2023 for studies reporting the sensitivity and specificity of IgA-tTG ≥10×ULN against duodenal biopsies (Marsh grade ≥2) in adults with suspected coeliac disease. We used a bivariate random-effects model to calculate the summary estimates of sensitivity, specificity, positive and negative likelihood ratios. The positive and negative likelihood ratios were used to calculate the positive predictive value (PPV) of the no-biopsy approach across different pre-test probabilities of coeliac disease. The methodological quality of the included studies was evaluated using the QUADAS-2 tool. This study was registered with PROSPERO, number CRD42023398812. RESULTS: A total of 18 studies comprising 12,103 participants from 15 countries were included. The pooled prevalence of biopsy-proven coeliac disease in the included studies was 62% (95% CI, 40% - 83%). The proportion of patients with IgA-tTG ≥10×ULN was 32% (95% CI, 24% - 40%). The summary sensitivity of IgA-tTG ≥10×ULN was 51% (95% CI, 42% - 60%), and the summary specificity was 100% (95% CI, 98% - 100%). The area under the summary receiver operating characteristic curve was 0.83 (95% CI, 0.77 - 0.89). The PPV of the no-biopsy approach to identify patients with coeliac disease was 65%, 88%, 95%, and 99% if coeliac disease prevalence was 1%, 4%, 10% and 40%, respectively. Between-study heterogeneity was moderate (I2 =30.3%), and additional sensitivity analyses did not significantly alter our findings. Only one study had a low risk of bias across all domains. CONCLUSION: The results of this meta-analysis suggest that selected adult patients with IgA-tTG ≥10×ULN and a moderate to high pre-test probability of coeliac disease could be diagnosed without undergoing invasive endoscopy and duodenal biopsy

Increasing physical activity among young children from disadvantaged communities: Study protocol of a group randomised controlled effectiveness trial

Background: Participation in regular physical activity (PA) during the early years helps children achieve healthy body weight and can substantially improve motor development, bone health, psychosocial health and cognitive development. Despite common assumptions that young children are naturally active, evidence shows that they are insufficiently active for health and developmental benefits. Exploring strategies to increase physical activity in young children is a public health and research priority. Methods: Jump Start is a multi-component, multi-setting PA and gross motor skill intervention for young children aged 3–5 years in disadvantaged areas of New South Wales, Australia. The intervention will be evaluated using a two-arm, parallel group, randomised cluster trial. The Jump Start protocol was based on Social Cognitive Theory and includes five components: a structured gross motor skill lesson (Jump In); unstructured outdoor PA and gross motor skill time (Jump Out); energy breaks (Jump Up); activities connecting movement to learning experiences (Jump Through); and a home-based family component to promote PA and gross motor skill (Jump Home). Early childhood education and care centres will be demographically matched and randomised to Jump Start (intervention) or usual practice (comparison) group. The intervention group receive Jump Start professional development, program resources, monthly newsletters and ongoing intervention support. Outcomes include change in total PA (accelerometers) within centre hours, gross motor skill development (Test of Gross Motor Development-2), weight status (body mass index), bone strength (Sunlight MiniOmni Ultrasound Bone Sonometer), self-regulation (Heads-Toes-Knees-Shoulders, executive function tasks, and proxy-report Temperament and Approaches to learning scales), and educator and parent self-efficacy. Extensive quantitative and qualitative process evaluation and a cost-effectiveness evaluation will be conducted. Discussion: The Jump Start intervention is a unique program to address low levels of PA and gross motor skill proficiency, and support healthy lifestyle behaviours among young children in disadvantaged communities. If shown to be efficacious, the Jump Start approach can be expected to have implications for early childhood education and care policies and practices, and ultimately a positive effect on the health and development across the life course

Comparison of coronary heart disease genetic assessment with conventional cardiovascular risk assessment in primary care: reflections on a feasibility study

This study assesses the feasibility of collecting genetic samples and self-reported outcome measures after cardiovascular risk assessment, and presenting the genetic test results to participants. Coronary heart disease (CHD) genetic tests are increasingly available through direct-to-consumer marketing, but their potential clinical impact on cardiovascular risk assessment is unclear. Observational study in 10 British general practices in Central England. A total of 320 individuals, who had completed conventional cardiovascular risk assessment, were offered CHD genetic test, with follow-up outcome questionnaire at eight months for lifestyle change and State-Trait Anxiety. A total of 119 (37%) participants returned genetic test specimens, with over a third reporting family history of CHD in a specified relative; 79 (66.4%) were categorized above-average risk on conventional cardiovascular risk assessment, 65 of whom (82.3%) were only average risk on genetic assessment. The dietary fat questionnaire was poorly completed while study participation was not associated with increased anxiety (mean increase in anxiety score=2.1; 95% CI −0.1–4.3; P=0.06). As a feasibility study, over a third of individuals offered genetic testing in primary care, as part of CVD risk assessment, took up the offer. Although intervention did not appear to increase anxiety, this needs further evaluation. To improve generalizability and effect size, future studies should actively engage individuals from wider socio-economic backgrounds who may not have already contemplated lifestyle change. The current research suggests general practitioners will face the clinical challenge of patients presenting with direct-to-consumer genetic results that are inconsistent with conventional cardiovascular risk assessment

\u27Jump start\u27 childcare-based intervention to promote physical activity in pre-schoolers: six-month findings from a cluster randomised trial

BACKGROUND: Participation in adequate levels of physical activity during the early years is important for health and development. We report the 6-month effects of an 18-month multicomponent intervention on physical activity in early childhood education and care (ECEC) settings in low-income communities. METHODS: A cluster randomised controlled trial was conducted in 43 ECEC settings in disadvantaged areas of New South Wales, Australia. Three-year-old children were recruited and assessed in the first half of 2015 with follow-up 6 months later. The intervention was guided by Social Cognitive Theory and included five components. The primary outcome was minutes per hour in total physical activity during ECEC hours measured using Actigraph accelerometers. Intention-to-treat analysis of the primary outcome was conducted using a generalized linear mixed model. RESULTS: A total of 658 children were assessed at baseline. Of these, 558 (85%) had valid accelerometer data (mean age 3.38y, 52% boys) and 508 (77%) had valid accelerometry data at 6-month follow-up. Implementation of the intervention components ranged from 38 to 72%. There were no significant intervention effects on mins/hr. spent in physical activity (adjusted difference = - 0.17 mins/hr., 95% CI (- 1.30 to 0.97), p = 0.78). A priori sub-group analyses showed a greater effect among overweight/obese children in the control group compared with the intervention group for mins/hr. of physical activity (2.35mins/hr., [0.28 to 4.43], p = 0.036). CONCLUSIONS: After six-months the Jump Start intervention had no effect on physical activity levels during ECEC. This was largely due to low levels of implementation. Increasing fidelity may result in higher levels of physical activity when outcomes are assessed at 18-months

Imagining the highway:Anticipating infrastructural and environmental change in Belize

This article examines the social and political, as well physical, construction of infrastructure, by attending to the implications of a highway yet to be built. In southern Belize, where the development of rural road networks figures strongly in historical narratives of political and environmental change, the recent paving of a major domestic highway has had distinctive implications for livelihoods and land rights among the predominantly Maya population of rural Toledo district. At the time of research, a plan for a new paved highway to the Guatemalan border animated longstanding debates over territoriality, environment and development, even as the details remained elusive. Bringing political ecology into conversation with attention to the perception of sensory environments, and the affective power of anticipation, I argue for extending anthropological conversations about infrastructure to encompass the meanings and consequences of imagined infrastructures for the ways people encounter, experience and enact social and environmental change