Neuropsychological and biopsychosocial evolution, therapeutic adherence and unmet care needs during paediatric transplantation: study protocol of a mixed-methods design (observational cohort study and focus groups) – the TransplantKIDS mental health project

The present article describes the protocol of a mixed-methods study (an observational cohort design and focus groups), aimed to examine neuropsychological functioning and other biopsychosocial outcomes, therapeutic adherence and unmet care needs in paediatric population undergoing solid organ or allogeneic hematopoietic transplant during the pre- and post-transplant phases. Following a multi-method/multi-source approach, neuropsychological domains will be comprehensively measured with objective tests (SDMT, K-CPT 2/CPT 3, TAVECI/TAVEC, WISC-V/WAIS-IV Vocabulary and Digit Span subtests, Verbal Fluency tests, Stroop, ROCF, and TONI-4); ecological executive functioning, affective and behavioral domains, pain intensity/interference, sleep quality and therapeutic adherence will be assessed through questionnaires (parent/legal guardians-reported: BRIEF-2 and BASC-3; and self-reported: BASC-3, BPI, PROMIS, AIQ and SMAQ); and blood levels of prescribed drugs will be taken from each patient’s medical history. These outcomes will be measured at pre-transplant and at 4-weeks and 6-months post-transplant phases. The estimated sample size was 60 patients (any type of transplant, solid organ, or hematopoietic) from La Paz University Hospital (Madrid, Spain). Finally, three focus group sessions will be organized with patients, parents/guardians, and transplant clinicians (n = 15, with 5 participants per group), in order to qualitatively identify unmet care needs during the pre-, and post-transplant stages of the process. The study protocol was registered at ClinicalTrials.gov (NCT05441436)

The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway

Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures

Worldwide Genetic Variability of the Duffy Binding Protein: Insights into Plasmodium vivax Vaccine Development

The dependence of Plasmodium vivax on invasion mediated by Duffy binding protein (DBP) makes this protein a prime candidate for development of a vaccine. However, the development of a DBP-based vaccine might be hampered by the high variability of the protein ligand (DBPII), known to bias the immune response toward a specific DBP variant. Here, the hypothesis being investigated is that the analysis of the worldwide DBPII sequences will allow us to determine the minimum number of haplotypes (MNH) to be included in a DBP-based vaccine of broad coverage. For that, all DBPII sequences available were compiled and MNH was based on the most frequent nonsynonymous single nucleotide polymorphisms, the majority mapped on B and T cell epitopes. A preliminary analysis of DBPII genetic diversity from eight malaria-endemic countries estimated that a number between two to six DBP haplotypes (17 in total) would target at least 50% of parasite population circulating in each endemic region. Aiming to avoid region-specific haplotypes, we next analyzed the MNH that broadly cover worldwide parasite population. The results demonstrated that seven haplotypes would be required to cover around 60% of DBPII sequences available. Trying to validate these selected haplotypes per country, we found that five out of the eight countries will be covered by the MNH (67% of parasite populations, range 48–84%). In addition, to identify related subgroups of DBPII sequences we used a Bayesian clustering algorithm. The algorithm grouped all DBPII sequences in six populations that were independent of geographic origin, with ancestral populations present in different proportions in each country. In conclusion, in this first attempt to undertake a global analysis about DBPII variability, the results suggest that the development of DBP-based vaccine should consider multi-haplotype strategies; otherwise a putative P. vivax vaccine may not target some parasite populations

On the Importance of Complaint Handling Design : A Multi-Level Analysis of the Impact in Specific Complaint Situations

Given the large investments required for high-quality complaint handling design, managers need practical guidance in understanding its actual importance for their particular company. However, while prior research emphasizes the general relevance of complaint handling design, it fails to provide a more differentiated perspective on this interesting issue. This study, which is based on an integrative multi-level framework and a dyadic dataset, addresses this important gap in research. Results indicate that the impact of a company’s complaint handling design varies significantly depending on the characteristics of the complaining customers with which the firm has to deal. Further, this paper shows that, contingent on these characteristics, a company’s complaint handling design can shape complainants’ fairness perceptions either considerably or only slightly. Overall, findings suggest that companies should apply an adaptive approach to complaint handling to avoid misallocation of attention, energy, and resources

The association of depression and all-cause and cause-specific mortality: an umbrella review of systematic reviews and meta-analyses

Background: Depression is a prevalent and disabling mental disorder that frequently co-occurs with a wide range of chronic conditions. Evidence has suggested that depression could be associated with excess all-cause mortality across different settings and populations, although the causality of these associations remains unclear. Methods: We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, PsycINFO, and Embase electronic databases were searched through January 20, 2018. Systematic reviews and meta-analyses that investigated associations of depression and all-cause and cause-specific mortality were selected for the review. The evidence was graded as convincing, highly suggestive, suggestive, or weak based on quantitative criteria that included an assessment of heterogeneity, 95% prediction intervals, small-study effects, and excess significance bias. Results: A total of 26 references providing 2 systematic reviews and data for 17 meta-analytic estimates met inclusion criteria (19 of them on all-cause mortality); data from 246 unique studies (N = 3,825,380) were synthesized. All 17 associations had P < 0.05 per random effects summary effects, but none of them met criteria for convincing evidence. Associations of depression and all-cause mortality in patients after acute myocardial infarction, in individuals with heart failure, in cancer patients as well as in samples from mixed settings met criteria for highly suggestive evidence. However, none of the associations remained supported by highly suggestive evidence in sensitivity analyses that considered studies employing structured diagnostic interviews. In addition, associations of depression and all-cause mortality in cancer and post-acute myocardial infarction samples were supported only by suggestive evidence when studies that tried to adjust for potential confounders were considered. Conclusions: Even though associations between depression and mortality have nominally significant results in all assessed settings and populations, the evidence becomes weaker when focusing on studies that used structured interviews and those that tried to adjust for potential confounders. A causal effect of depression on all-cause and cause-specific mortality remains unproven, and thus interventions targeting depression are not expected to result in lower mortality rates at least based on current evidence from observational studies

Association Testing Of Copy Number Variants in Schizophrenia and Autism Spectrum Disorders

Background: Autism spectrum disorders and schizophrenia have been associated with an overlapping set of copynumber variant loci, but the nature and degree of overlap in copy number variants (deletions compared toduplications) between these two disorders remains unclear.Methods: We systematically evaluated three lines of evidence: (1) the statistical bases for associations of autismspectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies;(2) data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially amongchildren, and (3) data on the extent to which the CNVs were associated with intellectual disability anddevelopmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs inautism by pooling data from seven case control studies.Results: Four of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clearstatistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors forschizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as riskfactors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal fortests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but werenot statistically associated with autism, a notable number of children with the CNVs have been diagnosed withautism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability anddevelopmental, speech, or language delays.Conclusions: These findings suggest that although CNV loci notably overlap between autism and schizophrenia,the degree of strongly statistically supported overlap in specific CNVs at these loci remains limited. These analysesalso suggest that relatively severe premorbidity to CNV-associated schizophrenia in children may sometimes bediagnosed as autism spectrum disorder

Exploring new physics frontiers through numerical relativity

The demand to obtain answers to highly complex problems within strong-field gravity has been met with significant progress in the numerical solution of Einstein's equations - along with some spectacular results - in various setups. We review techniques for solving Einstein's equations in generic spacetimes, focusing on fully nonlinear evolutions but also on how to benchmark those results with perturbative approaches. The results address problems in high-energy physics, holography, mathematical physics, fundamental physics, astrophysics and cosmology

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic