Despite documented benefits and physicians' recommendations to participate in cardiac rehabilitation (CR) programs, the average dropout rate remains between 12-56%. This study's goal was to ...demonstrate that using personalized interventions can significantly increase patient adherence. Ninety-five patients (ages 18-90) eligible for the CR program were randomly recruited and received personalized interventions using the Well-Beat system. Adherence levels were compared to those of a historical control group. The Well-Beat system provided Sheba CR Health Care Provider (HCP) guidelines for personalized patient-therapist dialogue. The system also generated ongoing personalized text messages for each patient sent twice a week and related each patient's dynamic profile to their daily behavior, creating continuity, and reinforcing the desired behavior. A significant increase in patient adherence to the CR program: Three months after initiation, 76% remained active compared to the historical average of 24% in the matched control group (log-rank p-value = 0.001). Using an Artificial Intelligence (AI)-based engine that generated recommendations and messages made it possible to improve patient adherence without increasing HCP load, benefiting all. Presenting customized patient insights to the HCP and generating personalized communications along with action motivating text messages can also be useful for remote care.
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the homeostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respiratory ...epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTR is, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitive to conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophages by affecting the lung milieu, but the mutations also appear to be directly consequential for intrinsic macrophage functions. Particular mutations can alter CFTR's folding, traffic of the protein to the membrane and function. As such, understanding the intrinsic effects of CFTR mutation requires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from the primary defect of CFTR dysfunction/absence. Investigations into CFTR's role in macrophages have exploited various models, each with their own advantages and limitations. This review summarizes these methodologic approaches, discussing their physiological correspondence and highlighting key findings. The controversy surrounding CFTR‐dependent acidification is used as a case study to highlight difficulties in commensurability across model systems. Recent work in macrophage biology, including polarization and host–pathogen interaction studies, brought into the context of CFTR research, offers potential explanations for observed discrepancies between studies. Moreover, the rapid advancement of novel gene editing technologies and new macrophage model systems makes this assessment of the field's models and methodologies timely.
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Review on “Cystic fibrosis macrophages'” a cell type that has multivalent forms because CFTR mutations' effects on macrophages can be macrophage‐intrinsic, or contingent on mutated CFTR‐induced lung epithelial dysfunction.
Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains ...poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.
Although whole‐exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising ...all OMIM‐referenced genes called “medical exome” (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non‐syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.
TruSight One global diagnostic yield in 216 consecutive patients with neurodevelopmental disorder, negative for X fragile and chromosomal microarray from 2 French clinical genetic centers (25.9%).
Objectives Despite documented benefits and physicians’ recommendations to participate in cardiac rehabilitation (CR) programs, the average dropout rate remains between 12–56%. This study’s goal was ...to demonstrate that using personalized interventions can significantly increase patient adherence. Method Ninety-five patients (ages 18–90) eligible for the CR program were randomly recruited and received personalized interventions using the Well-Beat system. Adherence levels were compared to those of a historical control group. The Well-Beat system provided Sheba CR Health Care Provider (HCP) guidelines for personalized patient-therapist dialogue. The system also generated ongoing personalized text messages for each patient sent twice a week and related each patient’s dynamic profile to their daily behavior, creating continuity, and reinforcing the desired behavior. Results A significant increase in patient adherence to the CR program: Three months after initiation, 76% remained active compared to the historical average of 24% in the matched control group (log-rank p-value = 0.001). Conclusions Using an Artificial Intelligence (AI)-based engine that generated recommendations and messages made it possible to improve patient adherence without increasing HCP load, benefiting all. Presenting customized patient insights to the HCP and generating personalized communications along with action motivating text messages can also be useful for remote care.
Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI).
To characterise in more detail ...the mutation spectrum associated with Dravet syndrome.
A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened.
SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients.
These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.
Nesting birds must often cope with harassment from biting insects, but it is difficult to ascertain what effect such pests might have on breeding success and population dynamics. We tested the ...hypothesis that a black fly (Simulium annulus) that feeds on the blood of nesting Common Loons (Gavia immer) causes nest abandonment in this charismatic diving bird. In addition, we measured effects of fly-induced abandonment on a loon population, and examined potential predictors of fly abundance and nest abandonment. We also tested a second hypothesis, which holds that loon pairs that abandon a nest owing to flies should often remain at the site for their subsequent nesting attempt, since fly outbreaks last only 1–2 weeks. All predictions of the fly-induced abandonment hypothesis were supported, including strong correlations between fly counts and rate of abandonment, reduced incubation during severe fly years, and increased abandonment during cool springs, which promote longevity of the flies. The correlation between nest abandonment and population breeding success suggests that S. annulus reduced the chick fledging rate by as much as 23% in a year of severe infestation. Fly numbers on loons and their nests were highest when temperatures were high and winds were light. Surprisingly, however, exposure to the prevailing wind increased, not decreased, nest abandonment, perhaps because of wave action. Lake size was inversely and female age directly correlated with abandonment rate, possibly due to food limitation in small lakes and senescence of females, respectively. Finally, pairs that abandoned a first nest renested at the same site with much greater frequency than did pairs that lost eggs to a predator, indicating that loons are capable of responding adaptively to a cause of nest failure that is time- but not space-dependent.
Human myeloid-derived growth factor (MYDGF; also known as C19orf10) is named based on its identification as a secreted monocyte/macrophage–derived mediator of cardiac repair following myocardial ...infarction in mice. Homologs of MYDGF, however, are present in organisms throughout and outside of the animal kingdom, some of which lack hematopoietic and circulatory systems. Moreover, the UPF0556 protein domain, which defines these homologs, lacks a known structure. As a result, the functions and properties of MYDGF are unclear. Our current work was initiated to test whether MYDGF is present in secretory vesicles of eosinophils as it was recently reported to be abundant in these cells. However, we could not demonstrate secretion and unexpectedly discovered that MYDGF colocalizes with P4HB in the nuclear envelope, which comprises the bulk of endoplasmic reticulum (ER) in eosinophils, and with P4HB and RCAS1 in Golgi. We noted a ubiquitous C-terminal sequence, BXEL (B, basic; X, variable residue; E, Glu; L, Leu), that has the potential to retain human MYDGF and its homologs in the ER. To test the functionality of this sequence, we expressed full-length human MYDGF or MYDGF lacking the C-terminal Glu-Leu residues in monolayers of human embryonic kidney 293 (HEK293) cells. Full-length MYDGF accumulated in cells, whereas truncated MYDGF appeared in the medium. These observations reveal that MYDGF resides in the ER and Golgi and provide a new framework for investigating and understanding this intriguing protein.
Signal transducer and activator of transcription 3 (STAT3) is a key mediator of leukocyte differentiation and proliferation. The 3' end of STAT3 transcripts is subject to two alternative splicing ...events. One results in either full-length STAT3α or in STAT3β, which lacks part of the C-terminal transactivation domain. The other is at a tandem donor (5') splice site and results in the codon for Ser-701 being included (S) or excluded (ΔS). Despite the proximity of Ser-701 to the site of activating phosphorylation at Tyr-705, ΔS/S splicing has barely been studied. Sequencing of cDNA from purified eosinophils revealed the presence of four transcripts (S-α, ΔS-α, S-β, and ΔS-β) rather than the three reported in publically available databases from which ΔS-β is missing. To gain insight into regulation of the two alternative splicing events, we developed a quantitative(q) PCR protocol to compare transcript ratios in eosinophils in which STAT3 is upregulated by cytokines, activated B cell diffuse large B cell Lymphoma (DLBCL) cells in which STAT3 is dysregulated, and in germinal center B cell-like DLBCL cells in which it is not. With the exception of one line of activated B cell DLCBL cells, the four variants were found in roughly the same ratios despite differences in total levels of STAT3 transcripts. S-α was the most abundant, followed by S-β. ΔS-α and ΔS-β together comprised 15.6 ± 4.0 % (mean ± SD, n = 21) of the total. The percentage of STAT3β variants that were ΔS was 1.5-fold greater than of STAT3α variants that were ΔS. Inspection of Illumina's "BodyMap" RNA-Seq database revealed that the ΔS variant accounts for 10-26 % of STAT3 transcripts across 16 human tissues, with less variation than three other genes with the identical tandem donor splice site sequence. Thus, it seems likely that all cells contain the S-α, ΔS-α, S-β, and ΔS-β variants of STAT3.
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