Exome sequencing in multiplex families with left-sided cardiac defects has high yield for disease gene discovery.

Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant's effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes.

Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.

BACKGROUND: Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood. METHODS: Exome sequencing was performed in a family where four members had CHD. In vitro functional analysis of the GATA6 variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay. RESULTS: A novel, heterozygous missense variant in GATA6 (c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity. CONCLUSIONS: We report a novel, familial GATA6 likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologic GATA6 variation to include intestinal abnormalities. IMPACT: Exome sequencing identified a novel heterozygous GATA6 variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life. In vitro functional assays demonstrated that GATA6 p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity. This work supports the importance of GATA6 as a causative gene for CHD and expands the phenotypic spectrum of pathogenic GATA6 variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.

scGMAI: a Gaussian mixture model for clustering single-cell RNA-Seq data based on deep autoencoder.

The rapid development of single-cell RNA sequencing (scRNA-Seq) technology provides strong technical support for accurate and efficient analyzing single-cell gene expression data. However, the analysis of scRNA-Seq is accompanied by many obstacles, including dropout events and the curse of dimensionality. Here, we propose the scGMAI, which is a new single-cell Gaussian mixture clustering method based on autoencoder networks and the fast independent component analysis (FastICA). Specifically, scGMAI utilizes autoencoder networks to reconstruct gene expression values from scRNA-Seq data and FastICA is used to reduce the dimensions of reconstructed data. The integration of these computational techniques in scGMAI leads to outperforming results compared to existing tools, including Seurat, in clustering cells from 17 public scRNA-Seq datasets. In summary, scGMAI is an effective tool for accurately clustering and identifying cell types from scRNA-Seq data and shows the great potential of its applicative power in scRNA-Seq data analysis. The source code is available at https://github.com/QUST-AIBBDRC/scGMAI/.

Failure of Noninvasive Ventilation in Acute Respiratory Failure is Associated with Higher Mortality in Patients with Solid Tumors: A Retrospective Cohort Study.

BACKGROUND: Noninvasive Ventilation (NIV) is a well-established treatment for Acute Respiratory Failure (ARF) in hematological cancer. However, the NIV impact on mortality in patients with solid tumors is unclear. OBJECTIVE: To define the factors associated with NIV failure and mortality and to describe the mortality risk of patients with solid tumors requiring NIV for ARF treatment in the intensive care unit (ICU). METHODS: A retrospective cohort study of patients with solid tumors admitted into an ICU between Jan 2016 and Dec 2017, for cancer treatment, with ARF diagnosis that had used the NIV as first-line treatment. Our primary outcome was ICU and in-hospital mortality. The secondary outcome was NIV failure. A Cox proportional hazards regression was used to identify variables associated with mortality and NIV failure. Kaplan-Meier analyses were performed to demonstrate cumulative survival. RESULTS: A total of 226 patients with solid tumors were included. The ICU and hospital mortality rates were 57.5% and 69.5%, respectively. NIV failed in 52.2% of the patients. The use of vasopressors (HR 2.48 [95% CI: 1.43-4.30] p = 0.001), baseline lactate (HR 1.20 [95% CI: 1.07-1.35] p = 0.003), baseline PaO2/FiO2 ratio (HR1.33 [1.11-1.55] p = 0.002), and NIV success (HR0.17 [95% CI: 0.10-0.27] p = 0.005) was independently associated with hospital mortality. The use of vasopressors (HR 2.58 [95% CI: 1.41-4.73] p = 0.02), NIV duration (HR 0.93 [95% CI: 0.89-0.97] p = 0.003), and baseline lactate (HR 1.13 [95% CI: 1.06-1.20] p = 0.001) was associated with NIV failure. CONCLUSIONS: NIV failure was independently associated with an increase in both ICU and hospital mortality rates. In patients with NIV therapy indication, the duration of this intervention was associated with NIV failure.

A Meta-Analysis of Group-Based Pain Management Programs: Overall Effect on Quality of Life and Other Chronic Pain Outcome Measures, with an Exploration into Moderator Variables that Influence the Efficacy of Such Interventions.

OBJECTIVES: Group-based pain management programs (GPMPs) have been found to significantly improve quality of life and other pain outcome measures in patients with chronic musculoskeletal pain. The aims of this meta-analysis were to reevaluate the overall effect of GPMPs on various pain outcomes for individuals experiencing chronic musculoskeletal conditions and to explore moderator variables that potentially contribute to the overall efficacy of GPMPs. METHODS: Using the R package called metaphor and RevMan, we estimated the overall effectiveness of GPMPs on various pain outcome measures. The differential effectiveness of GPMPs was examined by conducting a mixed-effects meta-analytic model using various study-level characteristics. Moderator analyses included three content moderator variables and seven format moderator variables. Receiver operating characteristic curves investigated optimal points in some of the moderator variable analysis results. RESULTS: Significant overall main effects of GPMPs were found on all the explored outcome measures in this study (P < 0.05). In moderator analyses, it was found that the structure of GPMPs, rather than the content, significantly improved outcomes (P < 0.05). Receiver operating characteristic curve analyses identified the optimal number of GPMP sessions and number of participants per group. DISCUSSION AND CLINICAL RELEVANCE: GPMPs have a statistically significant overall effect on all explored pain outcome measures. The investigation into content and structural moderators suggests that certain GPMP design factors have a greater effect on pain outcomes than do content factors. Therefore, GPMP structural designs appear to be important in reducing pain and improving quality of life for patients with chronic pain and warrant further investigation.

Ventilatory Impairments Associated with Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: The peripheral and central repercussions of Parkinson's disease (PD) affect the neuromuscular system producing a loss of muscle strength that can influence the respiratory system. Although several studies have examined various respiratory aspects of PD, to the best of our knowledge no study to date has systematically reviewed the existing data. OBJECTIVES: To examine the available literature related to the respiratory impairment in PD patients. METHODS: We used PRISMA guidelines when reporting this review. We searched Pubmed, Cinhal, SciELO, and Cochrane Library, from inception until August 2018. Main variables assessed were forced vital capacity percent predicted (FVC%) and forced expiratory volume in 1 s percent predicted (FEV1%) for PD patients. RESULTS: Six studies were included in this systematic review and meta-analysis. The obtained results concluded that PD patients present poorer pulmonary function when compared to healthy controls. When PD patients were compared between ON and OFF states, the results reviewed are in favour of the ON state. In the meta-analysis performed for FVC% and FEV1%, the results fail to find significant differences between PD patients and controls (p = 0.336 and p = 0.281, respectively), and between PD ON and OFF states (p = 0.109 and p = 0.059, respectively). CONCLUSIONS: We conclude that PD patients have impaired respiratory capacities that are related to the PD severity, time since diagnosis, and OFF state. Adequate follow-up of the respiratory function and studies focused on PD phenotypes have to be considered in future studies.

Acute and Time-Course Effects of Osteopathic Manipulative Treatment on Vascular and Autonomic Function in Patients With Heart Failure: A Randomized Trial.

OBJECTIVE: The purposed of this study was to valuate the effect of osteopathic manipulative treatment (OMT) on flow-mediated dilation and heart rate variability of patients with heart failure. BACKGROUND: Osteopathic manipulative treatment modulates both the vascular and autonomic nervous system (ANS) in healthy volunteers. However, the acute and time-course effects of the OMT on patients with an overactive ANS remain unclear. METHODS: This randomized controlled trial study included 20 patients with heart failure aged 50 to 60 years, allocated to a single session of OMT (base of the skull, retromaxillary region, heart, and thoracic duct) or sham. Flow-mediated dilation (FMD) at the brachial artery, hemodynamic measures, and heart rate variability were assessed in 3 periods (baseline, immediately after the intervention, and after 15 minutes). Multivariate analysis of variance procedure was used to compare intervention and periods. RESULTS: The OMT group had a greater FMD modulation compared with the sham (FMD,% =  9.5 vs. -5.6, 95% confidence interval (CI): [6.6, -12.35] vs. [-14.25, 2.8]; p = 0.001) and grater peak diameter (PD, mm =  0.77 vs -0.16 mm, 95% CI: [0.31,-1.24] vs [-0.63, 0.29]; P =  0.001), suggesting an important acute and time-course vascular effect from OMT. We also found some relevant heart rate variability modulation after 15 minutes from OMT: high frequency (HF, ms2 = 295 vs -354, 95% CI: [144.2, -769]; P = .001) and low frequency (LF, ms2) = 670 vs 775, 95% CI: [-98, 3591]; P = .001), suggesting a time-course ANS modulation after OMT. CONCLUSIONS: Osteopathic manipulative treatment was effective at increasing brachial blood flow and stimulating the vagal system in patients with heart failure. Moreover, vascular changes seem to precede the autonomic modulation.

A Meta-Analysis of Therapeutic Pain Neuroscience Education, Using Dosage and Treatment Format as Moderator Variables.

OBJECTIVES: This meta-analysis aimed to assess the overall effect of therapeutic pain neuroscience education (TPNE) on chronic musculoskeletal pain and to further assess whether such an effect differs by TPNE dosage as well as other treatment format components. Dosage included the number of TPNE sessions provided as well as the amount of time per TPNE session. Structural components included TPNE provided alone as treatment or combined with other pain management modalities, as well as the inclusion of group-based treatment sessions. METHODS: Electronic databases were utilized to search for randomized controlled trials that included TPNE. The overall effectiveness of TPNE was estimated on 4 pain outcome measures, including kinesiophobia, pain intensity, pain disability, and pain catastrophizing. The differential effectiveness of TPNE was examined using a mixed-methods moderator analysis on various study-level characteristics to identify potential moderators affecting the overall results. RESULTS: Significant effects of TPNE were found on all the outcome measures. The only moderator that displayed a significant effect was group-based treatment on kinesiophobia (z = -2.23, P < 0.05, 95% confidence interval [CI] -2.70 to -0.20). Between-group analysis revealed that only interventions that included group sessions were found to be statistically significant (z = 2.20, P < 0.05) and displayed a large effect size (d = 0.80, 95% CI 0.09 to 1.50). DISCUSSION: Therapeutic pain neuroscience education had a statistically significant impact on all the explored pain outcome measures. However, when investigating the treatment dosage and format moderator variables, they appeared to not have a statistically significant effect except for group-based interventions on kinesiophobia levels. CONCLUSION: This meta-analysis examined the efficacy of TPNE for patients with chronic pain. It assessed various pain outcome measures following intervention. In addition, this research identified that various moderator variables do not have and do have an impact on the treatment modality of TPNE.

Strategies in scheduling marine protected area establishment in a network system.

Instantaneous implementation of systematic conservation plans at regional scales is rare. More typically, planned actions are applied incrementally over periods of years or decades. During protracted implementation, the character of the connected ecological system will change as a function of external anthropogenic pressures, local metapopulation processes, and environmental fluctuations. For heavily exploited systems, habitat quality will deteriorate as the plan is implemented, potentially influencing the schedule of protected area implementation necessary to achieve conservation objectives. Understanding the best strategy to adopt for applying management within a connected environment is desirable, especially given limited conservation resources. Here, we model the sequential application of no-take marine protected areas (MPAs) in the central Philippines within a metapopulation framework, using a range of network-based decision rules. The model was based on selecting 33 sites for protection from 101 possible sites over a 35-yr period. The graph-theoretic network criteria to select sites for protection included PageRank, maximum degree, closeness centrality, betweenness centrality, minimum degree, random, and historical events. We also included a dynamic strategy called colonization-extinction rate that was updated every year based on the changing capacity of each site to produce and absorb larvae. Each rule was evaluated in the context of achieving the maximum metapopulation mean lifetime at the conclusion of the implementation phase. MPAs were designated through the alteration of the extinction risk parameter. The highest ranked criteria were PageRank while the actual implementation from historical records ranked lowest. Our results indicate that protecting the sites ranked highest with regard to larval supply is likely to yield the highest benefit for fish abundance and fish metapopulation persistence. Model results highlighted the benefits of including network processes in conservation planning.

Effect of electrical stimulation on muscle atrophy and spasticity in patients with spinal cord injury - a systematic review with meta-analysis.

STUDY DESIGN: This work is a systematic review with meta-analysis OBJECTIVE: Evaluate the effect of electrical stimulation (ES) on skeletal muscle volume and spasticity in individuals with spinal cord injury (SCI). SETTING: University of Brasilia, Brazil METHODS: Searches were conducted of the Cochrane Library, MEDLINE, CINAHL, PEDro, PsycINFO and EMBASE electronic databases for relevant articles published up to June 2018. No restrictions were imposed regarding the year of publication. The inclusion criteria were randomized controlled trials involving adults with SCI comparing ES to an active or passive control. Two independent reviewers extracted the data from the selected studies and methodological quality was assessed using the PEDro scale. RESULTS: The initial search led to the retrieval of 164 studies, seven of which met the eligibility criteria, but only six were included in the meta-analysis. The six studies comprised 104 patients with complete or incomplete SCI. In the two studies that investigated the use of ES on muscle volume of the lower limbs, the overall effect was statistically significant in patients with acute SCI (mean difference: 0.86; 95% CI: 0.04 to 1.69; p < 0.04). Among the four studies that examined the use of ES for spasticity of the lower limb, the overall effect was non-significant (mean difference: 0.55; 95% CI: -0.31 to 1.41; p = 0.21). CONCLUSIONS: Electrical stimulation was found to be an effective method for increasing muscle volume in SCI patients, but had no effect on spasticity. Further investigation of the effect of ES on spasticity in SCI is needed.

HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells.

Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin ß6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin ß6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin ß6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin αvß6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin ß6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction.

Pediatric cardiothoracic program in Malaysia: a study based on the outcome of the program.

Vulnerable communities in Malaysia have been facing issues of accessibility and availability for pediatric cardiac services for years due to long waiting times, high costs and a lack of pediatric cardiothoracic surgeons. To ease this situation, the government has allocated a certain amount of funds, introduced through the Pediatric Cardiothoracic Program (PCP), in which the patients are transported to the Narayana Health Institute of Cardiac Science (NH) in India to receive a heart operation following an eligibility check at MediAssist4U Sdn Bhd in Selangor, Malaysia, a facility appointed by the NH. This study aimed to determine the demographic incidence of congenital heart diseases of patients in this program and to evaluate the outcome of the program in association with post-operative mortality rate and the beneficial factors of the program. In this study, 241 patients who participated in this program from August 2008 to September 2012 were reviewed. Fisher's exact tests were applied to calculate p-values of categorical data. Out of 241, 11 patients were rejected because of their poor health condition for flight transportation to India, leaving 230 patients for analysis. The majority of patients were 1 to 4 years of age (57.8%), Malays (61.7%), from families of monthly household income less than RM 1,500 (86.5%) and with primary school-educated parents (86.5%). Patients could apply from any government hospital in Malaysia, but 34.8% of the patients were from the state of Johor. The region (Peninsular Malaysia and East Malaysia) of patients seeking pediatric cardiac services was significantly associated with race (p<0.001), low household income (p<0.001) and low education background of parents (p=0.004). The associations between the age group and diagnosis group (p=0.010) and between duration of hospitalization and outcome of medical management (p=0.013) were significant. Post-operative mortality rate was 1.7% (95% confidence interval, 0.5-4.4). In conclusion, the patients and the government were considered to have benefited from the PCP.

Ionically cross-linked poly(allylamine) as a stimulus-responsive underwater adhesive: ionic strength and pH effects.

Gel-like coacervates that adhere to both hydrophilic and hydrophobic substrates under water have recently been prepared by ionically cross-linking poly(allylamine) (PAH) with pyrophosphate (PPi) and tripolyphosphate (TPP). Among the many advantages of these underwater adhesives (which include their simple preparation and low cost) is their ability to dissolve on demand when exposed to high or low pH. To further analyze their stimulus-responsive properties, we have investigated the pH and ionic strength effects on the formation, rheology and adhesion of PAH/PPi and PAH/TPP complexes. The ionic cross-linker concentrations needed to form these adhesives decreased with increasing pH and ionic strength (although the complexes ceased to form when the parent solution pH exceeded ca. 8.5; i.e., the effective pKa of PAH). Once formed, their ionic cross-links were most stable (as inferred from their relaxation times) at near-neutral or slightly alkaline pH values (of roughly 6.5-9) and at low ionic strengths. The decrease in ionic cross-link stability within complexes prepared at other pH values and at elevated (150-300 mM) NaCl concentrations diminished both the strength and longevity of adhesion (although, under most conditions tested, the short-term tensile adhesion strengths remained above 10(5) Pa). Additionally, the sensitivity of PAH/PPi and PAH/TPP complexes to ionic strength was demonstrated as a potential route to injectable adhesive design (where spontaneous adhesive formation was triggered via injection of low-viscosity, colloidal PAH/TPP dispersions into phosphate buffered saline). Thus, while the sensitivity of ionically cross-linked PAH networks to pH and ionic strength can weaken their adhesion, it can also impart them with additional functionality, such as minimally invasive, injectable delivery, and ability to form and dissolve their bonds on demand.

Self-assembly of stiff, adhesive and self-healing gels from common polyelectrolytes.

Underwater adhesion has numerous potential medical, household, and industrial applications. It is typically achieved through covalent polymerization and cross-linking reactions and/or the use of highly specialized biological or biomimetic polymers. As a simpler alternative to these covalent and biomimetic strategies, this article shows that stiff, gel-like complexes that adhere to various substrates under water can also be prepared through the ionic cross-linking of common, commercial polyelectrolytes. The gels form spontaneously when synthetic polycations, such as poly(allylamine) (PAH), are mixed with strongly binding multivalent anions, pyrophosphate (PPi) and tripolyphosphate (TPP). The PAH/PPi and PAH/TPP gels exhibit very high storage moduli (G∞' ≈ 400 kPa), self-heal when torn, and adhere to both hydrophilic and hydrophobic substrates under water (with short-term tensile adhesion strengths of 350­450 kPa). Furthermore, these gels can be dissolved on demand (if adhesion needs to be reversed) by changing the ambient pH, which controls the ionization state of the polyelectrolyte and ionic cross-linker. These properties suggest that synthetic polycations cross-linked with PPi and TPP ions could provide a simple, inexpensive, and scalable platform for underwater adhesion.

Enhancing drug and cell line representations via contrastive learning for improved anti-cancer drug prioritization.

Due to cancer's complex nature and variable response to therapy, precision oncology informed by omics sequence analysis has become the current standard of care. However, the amount of data produced for each patient makes it difficult to quickly identify the best treatment regimen. Moreover, limited data availability has hindered computational methods' abilities to learn patterns associated with effective drug-cell line pairs. In this work, we propose the use of contrastive learning to improve learned drug and cell line representations by preserving relationship structures associated with drug mechanisms of action and cell line cancer types. In addition to achieving enhanced performance relative to a state-of-the-art method, we find that classifiers using our learned representations exhibit a more balanced reliance on drug- and cell line-derived features when making predictions. This facilitates more personalized drug prioritizations that are informed by signals related to drug resistance.

Modeling Path Importance for Effective Alzheimer's Disease Drug Repurposing.

Recently, drug repurposing has emerged as an effective and resource-efficient paradigm for AD drug discovery. Among various methods for drug repurposing, network-based methods have shown promising results as they are capable of leveraging complex networks that integrate multiple interaction types, such as protein-protein interactions, to more effectively identify candidate drugs. However, existing approaches typically assume paths of the same length in the network have equal importance in identifying the therapeutic effect of drugs. Other domains have found that same length paths do not necessarily have the same importance. Thus, relying on this assumption may be deleterious to drug repurposing attempts. In this work, we propose MPI (Modeling Path Importance), a novel network-based method for AD drug repurposing. MPI is unique in that it prioritizes important paths via learned node embeddings, which can effectively capture a network's rich structural information. Thus, leveraging learned embeddings allows MPI to effectively differentiate the importance among paths. We evaluate MPI against a commonly used baseline method that identifies anti-AD drug candidates primarily based on the shortest paths between drugs and AD in the network. We observe that among the top-50 ranked drugs, MPI prioritizes 20.0% more drugs with anti-AD evidence compared to the baseline. Finally, Cox proportional-hazard models produced from insurance claims data aid us in identifying the use of etodolac, nicotine, and BBB-crossing ACE-INHs as having a reduced risk of AD, suggesting such drugs may be viable candidates for repurposing and should be explored further in future studies.

Diaphragm thickness and mobility elicited by two different modalities of inspiratory muscle loading in heart failure participants: A randomized crossover study.

OBJECTIVES: To analyze diaphragmatic thickness, at end-inspiration and end-expiration, diaphragmatic thickening index and mobility via US under two different modalities of inspiratory muscle loading, in two different modalities of inspiratory muscle loading and different load intensities at full-vital capacity maneuvers and the relationship between diaphragmatic thickness with pulmonary function tests in participants with HF. METHODS: This randomized crossover trial, enrolled with 17 HF subjects, evaluated diaphragm thickness (Tdi, mm), fractional thickness (TFdi, %), and mobility (mm) US during low and high intensities (30% and 60% of maximal inspiratory pressure-MIP) with two modalities of inspiratory muscle loading mechanical threshold loading (MTL) and tapered flow-resistive loading (TFRL). RESULTS: Both MTL and TFRL produced a increase in Tdi, but only with high intensity loading compared to baseline-2.21 (0.26) vs. 2.68 (0.33) and 2.73 (0.44) mm; p = .01. TFdi was greater than baseline under all conditions, except during low intensity of TFRL. Diaphragm mobility was greater than baseline under all conditions, and high intensity of TFRL elicited greater mobility compared to all other conditions. Additionally, baseline Tdi was moderately correlated with pulmonary function tests. CONCLUSIONS: MTL and TFRL modalities elicit similar increases in diaphragm thickness at loads, but only during high intensity loading it was greater than baseline. Diaphragm mobility was significantly greater than baseline under both loads and devices, and at high intensity compared to low intensity, although TFRL produced greater mobility compared to modalities of inspiratory muscle loading. There is an association between diaphragm thickness and pulmonary function tests.

Modeling Path Importance for Effective Alzheimer's Disease Drug Repurposing.

Recently, drug repurposing has emerged as an effective and resource-efficient paradigm for AD drug discovery. Among various methods for drug repurposing, network-based methods have shown promising results as they are capable of leveraging complex networks that integrate multiple interaction types, such as protein-protein interactions, to more effectively identify candidate drugs. However, existing approaches typically assume paths of the same length in the network have equal importance in identifying the therapeutic effect of drugs. Other domains have found that same length paths do not necessarily have the same importance. Thus, relying on this assumption may be deleterious to drug repurposing attempts. In this work, we propose MPI (Modeling Path Importance), a novel network-based method for AD drug repurposing. MPI is unique in that it prioritizes important paths via learned node embeddings, which can effectively capture a network's rich structural information. Thus, leveraging learned embeddings allows MPI to effectively differentiate the importance among paths. We evaluate MPI against a commonly used baseline method that identifies anti-AD drug candidates primarily based on the shortest paths between drugs and AD in the network. We observe that among the top-50 ranked drugs, MPI prioritizes 20.0% more drugs with anti-AD evidence compared to the baseline. Finally, Cox proportional-hazard models produced from insurance claims data aid us in identifying the use of etodolac, nicotine, and BBB-crossing ACE-INHs as having a reduced risk of AD, suggesting such drugs may be viable candidates for repurposing and should be explored further in future studies.

Health outcomes and service use patterns associated with co-located outpatient mental health care and alcohol and other drug specialist treatment: A systematic review.

ISSUES: Despite long-standing recommendations to integrate mental health care and alcohol and other drug (AOD) treatment, no prior study has synthesised evidence on the impact of physically co-locating these specialist services on health outcomes. APPROACH: We searched Medline, PsycINFO, Embase, Web of Science and CINAHL for studies examining health outcomes associated with co-located outpatient mental health care and AOD specialist treatment for adults with a dual diagnosis of substance use disorder and mental illness. Due to diversity in study designs, patient populations and outcome measures among the included studies, we conducted a narrative synthesis. Risk of bias was assessed using the MASTER scale. KEY FINDINGS: Twenty-eight studies met our inclusion criteria. We found provisional evidence that integrated care that includes co-located mental health care and AOD specialist treatment is associated with reductions in substance use and related harms and mental health symptom severity, improved quality of life, decreased emergency department presentations/hospital admissions and reduced health system expenditure. Many studies had a relatively high risk of bias and it was not possible to disaggregate the independent effect of physical co-location from other common aspects of integrated care models such as care coordination and the integration of service processes. IMPLICATIONS: There are few high-quality, peer-reviewed studies establishing the impact of co-located mental health care and AOD specialist treatment on health outcomes. Further research is required to inform policy, guide implementation and optimise practice. CONCLUSION: Integrated care that includes the co-location of mental health care and AOD specialist treatment may yield health and economic benefits.

Cardiopulmonary Exercise Testing in Post-COVID-19 Patients: Where Does Exercise Intolerance Come From? / Teste Cardiopulmonar em Pacientes Pós-COVID-19: De Onde vem a Intolerância ao Exercício?

BACKGROUND: Post-COVID-19 exercise intolerance is poorly understood. Cardiopulmonary exercise testing (CPET) can identify the underlying exercise limitations. OBJECTIVES: To evaluate the source and magnitude of exercise intolerance in post-COVID-19 subjects. METHODS: Cohort study assessing subjects with different COVID-19 illness severities and a control group selected by propensity score matching. In a selected sample with CPET prior to viral infection, before and after comparisons were performed. Level of significance was 5% in the entire analysis. RESULTS: One hundred forty-four subjects with COVID-19 were assessed (median age: 43.0 years, 57% male), with different illness severities (60% mild, 21% moderate, 19% severe). CPET was performed 11.5 (7.0, 21.2) weeks after disease onset, with exercise limitations being attributed to the peripheral muscle (92%), and the pulmonary (6%), and cardiovascular (2%) systems. Lower median percent-predicted peak oxygen uptake was observed in the severe subgroup (72.2%) as compared to the controls (91.6%). Oxygen uptake differed among illness severities and controls at peak and ventilatory thresholds. Conversely, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse were similar. Subgroup analysis of 42 subjects with prior CPET revealed significant reduction in only peak treadmill speed in the mild subgroup and in oxygen uptake at peak and ventilatory thresholds in the moderate/severe subgroup. By contrast, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse did not change significantly. CONCLUSIONS: Peripheral muscle fatigue was the most common exercise limitation etiology in post-COVID-19 patients regardless of the illness severity. Data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components.

FUNDAMENTO: A intolerância ao exercício pós-COVID-19 não é bem entendida. O teste de esforço cardiopulmonar (TECP) pode identificar as limitações ao exercício subjacentes. OBJETIVOS: Avaliar a etiologia e a magnitude da intolerância ao exercício em sujeitos pós-COVID-19. MÉTODOS: Estudo de coorte que avaliou sujeitos com níveis de gravidades diferentes da doença COVID-19 e um grupo de controle selecionado por pareamento por escores de propensão. Em uma amostra seleta com TECP anterior à infecção viral disponível, foram realizadas comparações antes e depois. O nível de significância foi de 5% em toda a análise. RESULTADOS: Foram avaliados cento e quarenta e dois sujeitos com COVID-19 (idade mediana: 43 anos, 57% do sexo masculino), com níveis de gravidade de doença diferentes (60% leve, 21% moderada, 19% grave). O TECP foi realizado 11,5 (7,0, 21,2) semanas após o aparecimento da doença, com as limitações ao exercício sendo atribuídas aos sistemas muscular periférico (92%), pulmonar (6%), e cardiovascular (2%). Menor valor mediano do consumo de oxigênio pico percentual foi observado no subgrupo com níveis graves de doença (72,2%) em comparação com os controles (91,6%). O consumo de oxigênio foi diferente entre os grupos com diferentes níveis de gravidade de doença e o controle no pico e nos limiares ventilatórios. Inversamente, os equivalentes ventilatórios, a inclinação da eficiência do consumo de oxigênio, e o pico do pulso de oxigênio foram semelhantes. A análise do subgrupo de 42 sujeitos com TECP prévio revelou uma redução significativa no pico de velocidade da esteira no subgrupo com nível leve de doença, e no consumo de oxigênio no pico e nos limiares ventilatórios nos subgrupos com níveis moderado/grave. Por outro lado, os equivalentes ventilatórios, a inclinação da eficiência do consumo de oxigênio e o pico do pulso de oxigênio não apresentaram alterações significativas. CONCLUSÕES: A fadiga do músculo periférico foi a etiologia de limitação de exercício mais comum em pacientes pós-COVID-19 independentemente da gravidade da doença. Os dados sugerem que o tratamento deve enfatizar programas de reabilitação abrangentes, incluindo componentes aeróbicos e de fortalecimento muscular.