A meta-analysis of the neuropsychological sequelae of chemotherapy-only treatment for pediatric acute lymphoblastic leukemia

Background Mixed findings on the neuropsychological sequelae of chemotherapy-only treatment for pediatric acute lymphoblastic leukemia (ALL), without radiation, indicate the need for a comprehensive meta-analytic review. The purpose of the current study was to conduct a meta-analysis assessing neuropsychological and academic functioning differences between children with ALL treated solely with chemotherapy and comparison groups. Procedure Thirteen articles met inclusion criteria for the meta-analysis and were analyzed using a random effects model, weighted least squares methods. Results Mean effect sizes were significantly different from zero for multiple domains of intelligence and academic achievement; processing speed; verbal memory; and some aspects of executive functioning and fine motor skills, indicating worse functioning in ALL survivors. Effect sizes for visual-motor skills and visual memory were not significantly different from zero. Conclusions Results support the presence of neuropsychological and academic sequelae for ALL survivors treated solely with chemotherapy and highlight the need for ongoing follow-up of children with ALL using a standardized neuropsychological test battery and research methodology. Pediatr Blood Cancer 2008;51:99–104. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58651/1/21544_ftp.pd

Internal migration dynamics in Spain: Winners and losers from the recent economic recession

This paper analyses the impact of the 2008 economic crisis on the spatial distribution of interprovincial migration in Spain, with a particular focus on changes in provinces' relative attractiveness. First, the paper examines the distribution of the net migration rate across provinces over the period 2002-2013. Next, by comparing the precrisis (2002-2007) and crisis (2008-2013) periods, the paper investigates which provinces became more attractive locations for migrants during the crisis and explores some of the factors behind it. The empirical evidence unveils two key results. First, major changes took place in spatial patterns of migration flows in Spain in the wake of the 2008 recession. Second, the rich provinces that best weathered the economic downturn, especially those with a relatively small construction sector and a good performance of industry and services, became appealing destinations during the crisis

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

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The effects of N-length and ITI on resistance to extinction in a free-operant situation

The prediction of Capaldi\u27s sequential learning theory (i966, 1967, 1970) that resistance to extinction (Rn) increases as a function of the number of successive nonrewarded trials (N-length) conditioned to the instrumental response has recently been supported in a discrete-trials leverpress situation but not in a free-operant leverpress situation (Wolach & Ferraro, 1971). To investigate this discrepancy, 32 male albino rats were trained to leverpress in the presence of a visual sD under one of two N-length conditions (8 or 16) and one of four intertrial interval (ITI) conditions (5, 10, 15, or 30 sec.), the lowest of which corresponded to a freeoperant interresponse time. A subsequent extinction phase revealed that the 16 N-length group displayed greater Rn than the 8 N-length group at each ITI investigated on the dependent measures of extinction speed (p is less than .01) and trials to extinction criterion (p is less than .05). The results were interpreted as supporting the applicability of sequential theory to both discrete-trials and free-operant methodologies