An interactive health communication application for supporting parents managing childhood long-term conditions: outcomes of a randomized controlled feasibility trial

Background: Families living with chronic or long-term conditions such as chronic kidney disease (CKD), stages 3-5, face multiple challenges and respond to these challenges in various ways. Some families adapt well while others struggle, and family response to a condition is closely related to outcome. With families and professionals, we developed a novel condition-specific interactive health communication app to improve parents’ management ability—the online parent information and support (OPIS) program. OPIS consists of a comprehensive mix of clinical caregiving and psychosocial information and support. Objective: The purpose of this study was to (1) assess feasibility of a future full-scale randomized controlled trial (RCT) of OPIS in terms of recruitment and retention, data collection procedures, and psychometric performance of the study measures in the target population, and (2) investigate trends in change in outcome measures in a small-scale RCT in parents of children with CKD stages 3-5. Methods: Parents were recruited from a pediatric nephrology clinic and randomly assigned to one of two treatment groups: usual support for home-based clinical caregiving (control) or usual support plus password-protected access to OPIS for 20 weeks (intervention). Both groups completed study measures at study entry and exit. We assessed feasibility descriptively in terms of recruitment and retention rates overall; assessed recruitment, retention, and uptake of the intervention between groups; and compared family condition management, empowerment to deliver care, and fathers’ involvement between groups. Results: We recruited 55 parents of 39 children (42% of eligible families). Of those, about three-quarters of intervention group parents (19/26, 73%) and control group parents (22/29, 76%) were retained through completion of 20-week data collection. The overall retention rate was 41/55 (75%). The 41 parents completing the trial were asked to respond to the same 10 questionnaire scales at both baseline and 20 weeks later; 10 scores were missing at baseline and nine were missing at 20 weeks. Site user statistics provided evidence that all intervention group parents accessed OPIS. Analysis found that intervention group parents showed a greater improvement in perceived competence to manage their child’s condition compared to control group parents: adjusted mean Family Management Measure (FaMM) Condition Management Ability Scale intervention group 44.5 versus control group 41.9, difference 2.6, 95% CI -1.6 to 6.7. Differences between the groups in the FaMM Family Life Difficulty Scale (39.9 vs 36.3, difference 3.7, 95% CI -4.9 to 12.2) appeared to agree with a qualitative observation that OPIS helped parents achieve understanding and maintain awareness of the impact of their child’s condition. Conclusions: A full-scale RCT of the effectiveness of OPIS is feasible. OPIS has the potential to beneficially affect self-reported outcomes, including parents’ perceived competence to manage home-based clinical care for children with CKD stage 3-5. Our design and methodology can be transferred to the management of other childhood conditions. Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 84283190; http://www.controlled-trials.com/ISRCTN84283190 (Archived by WebCite at http://www.webcitation.org/6TuPdrXTF)

Mutations underlying 3-Hydroxy-3-Methylglutaryl CoA Lyase deficiency in the Saudi population

BACKGROUND: 3-Hydroxy-3-Methylglutaric aciduria (3HMG, McKusick: 246450) is an autosomal recessive branched chain organic aciduria caused by deficiency of the enzyme 3-Hydroxy-3-Methylglutaryl CoA lyase (HL, HMGCL, EC 4.1.3.4). HL is encoded by HMGCL gene and many mutations have been reported. 3HMG is commonly observed in Saudi Arabia. METHODS: We utilized Whole Genome Amplification (WGA), PCR and direct sequencing to identify mutations underlying 3HMG in the Saudi population. Two patients from two unrelated families and thirty-four 3HMG positive dried blood spots (DBS) were included. RESULTS: We detected the common missense mutation R41Q in 89% of the tested alleles (64 alleles). 2 alleles carried the frame shift mutation F305fs (-2) and the last two alleles had a novel splice site donor IVS6+1G>A mutation which was confirmed by its absence in more than 100 chromosomes from the normal population. All mutations were present in a homozygous state, reflecting extensive consanguinity. The high frequency of R41Q is consistent with a founder effect. Together the three mutations described account for >94% of the pathogenic mutations underlying 3HMG in Saudi Arabia. CONCLUSION: Our study provides the most extensive genotype analysis on 3HMG patients from Saudi Arabia. Our findings have direct implications on rapid molecular diagnosis, prenatal and pre-implantation diagnosis and population based prevention programs directed towards 3HMG

Differential HMG-CoA lyase expression in human tissues provides clues about 3-hydroxy-3-methylglutaric aciduria

3-Hydroxy-3-methylglutaric aciduria is a rare human autosomal recessive disorder caused by deficiency of 3-hydroxy-3-methylglutaryl CoA lyase (HL). This mitochondrial enzyme catalyzes the common final step of leucine degradation and ketogenesis. Acute symptoms include vomiting, seizures and lethargy, accompanied by metabolic acidosis and hypoketotic hypoglycaemia. Such organs as the liver, brain, pancreas, and heart can also be involved. However, the pathophysiology of this disease is only partially understood. We measured mRNA levels, protein expression and enzyme activity of human HMG-CoA lyase from liver, kidney, pancreas, testis, heart, skeletal muscle, and brain. Surprisingly, the pancreas is, after the liver, the tissue with most HL activity. However, in heart and adult brain, HL activity was not detected in the mitochondrial fraction. These findings contribute to our understanding of the enzyme function and the consequences of its deficiency and suggest the need for assessment of pancreatic damage in these patients

Gene conversion in human rearranged immunoglobulin genes

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V<sub>H</sub> segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V<sub>H</sub> replacements with no addition of untemplated nucleotides at the V<sub>H</sub>–V<sub>H</sub> joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V<sub>H</sub> replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion

Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients

AimsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). Here, we investigate associations between plasma ACE2 and outcome of COVID-19.Methods and resultsThis analysis used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort). Comprehensive clinical data were collected on this cohort, including 28-day outcomes. The samples were run on the Olink® Explore 1536 platform which includes measurement of the ACE2 protein. High admission plasma ACE2 in COVID-19 patients was associated with increased maximal illness severity within 28 days with OR = 1.8, 95%-CI: 1.4-2.3 (P ConclusionThis study suggests that measuring plasma ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 could be a link between COVID-19 illness severity and its established risk factors hypertension, pre-existing heart disease and pre-existing kidney disease

The Longitudinal Relationship Between Satisfaction with Transitional Care and Social and Emotional Quality of Life Among Chronically Ill Adolescents

This study aimed to identify the relationship between satisfaction with transitional care and quality of life of chronically ill adolescents over time. This longitudinal study included adolescents with type I diabetes, juvenile idiopathic arthritis (JIA), and neuromuscular disorders (NMD). At baseline 138 respondents (response rate 31 %) filled in a questionnaire and 188 about 1 year later (response rate 43 %). Analysis of variance showed that adolescents with diabetes reported the highest physical quality of life, followed in order by those with NMD and JIA (p ≤ 0.01). Adolescents with diabetes reported the highest social quality of life, followed in order by those with JIA and NMD (both at p ≤ 0.001). Univariate analyses showed that satisfaction with transitional care at T0 was significantly related to emotional and physical quality of life at T1 (both at p ≤ 0.05). At T1, satisfaction with transitional care was significantly related to the emotional, physical, and social domains of quality of life (all at p ≤ 0.001). Multiple regression analyses revealed that satisfaction with transitional care at T1 was related to emotional (β -0.20; p ≤ 0.05) and social (β -0.35; p ≤ 0.01) quality of life domains over time. This indicates that lower gap scores, which measured differences between 'best care' and 'current care,' are associated with better social and emotional quality of life in this sample of adolescents. Satisfaction with transitional care and social and emotional quality of life are related over time

Scalar <i>φ</i>⁴ field theory for active-particle phase separation

Recent theories predict phase separation among orientationally disordered active particles whose propulsion speed decreases rapidly enough with density. Coarse-grained models of this process show time-reversal symmetry (detailed balance) to be restored for uniform states, but broken by gradient terms; hence detailed-balance violation is strongly coupled to interfacial phenomena. To explore the subtle generic physics resulting from such coupling we here introduce `Active Model B'. This is a scalar $\phi^4$ field theory (or phase-field model) that minimally violates detailed balance via a leading-order square-gradient term. We find that this additional term has modest effects on coarsening dynamics, but alters the static phase diagram by creating a jump in (thermodynamic) pressure across flat interfaces. Both results are surprising, since interfacial phenomena are always strongly implicated in coarsening dynamics but are, in detailed-balance systems, irrelevant for phase equilibria.Comment: 15 pages, 7 figure

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs

Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients.This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30 kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy.Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease

Analysis of nucleoside-binding proteins by ligand-specific elution from dye resin: application to Mycobacterium tuberculosis aldehyde dehydrogenases

We show that Cibacron Blue F3GA dye resin chromatography can be used to identify ligands that specifically interact with proteins from Mycobacterium tuberculosis, and that the identification of these ligands can facilitate structure determination by enhancing the quality of crystals. Four native Mtb proteins of the aldehyde dehydrogenase (ALDH) family were previously shown to be specifically eluted from a Cibacron Blue F3GA dye resin with nucleosides. In this study we characterized the nucleoside-binding specificity of one of these ALDH isozymes (recombinant Mtb Rv0223c) and compared these biochemical results with co-crystallization experiments with different Rv0223c-nucleoside pairings. We found that the strongly interacting ligands (NAD and NADH) aided formation of high-quality crystals, permitting solution of the first Mtb ALDH (Rv0223c) structure. Other nucleoside ligands (AMP, FAD, adenosine, GTP and NADP) exhibited weaker binding to Rv0223c, and produced co-crystals diffracting to lower resolution. Difference electron density maps based on crystals of Rv0223c with various nucleoside ligands show most share the binding site where the natural ligand NAD binds. From the high degree of similarity of sequence and structure compared to human mitochondrial ALDH-2 (BLAST Z-score = 53.5 and RMSD = 1.5 Å), Rv0223c appears to belong to the ALDH-2 class. An altered oligomerization domain in the Rv0223c structure seems to keep this protein as monomer whereas native human ALDH-2 is a multimer