Rehabilitation clinicians' use of mainstream wireless technologies in practice: a scoping review.

PURPOSE: This scoping review was conducted to understand the barriers, facilitators, and education and training needs of rehabilitation clinicians in their use of mainstream wireless technologies (MWT) to support people with disabilities and older adults. It was also conducted to understand the functional skills of clients that were targeted with MWT use. MATERIALS AND METHODS: This scoping review was reported using PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) and the Population (or Participants)/Concept/Context) framework. We searched PubMed; ProQuest to access APA PsycINFO; Web of Science Core Collection; and EBSCOhost to access Cumulated Index to Nursing and Allied Health Literature (CINAHL), Ovid MEDLINE ALL, and Education Resources Information Center (ERIC). Articles published between 2015-2022 were retrieved. RESULTS: A total of 90 articles were included. Most interventions were apps, smartphones, and tablets; were geared toward adults; and targeted motor, cognitive and speech skills. An infographic on barriers and facilitators was generated as a decision support tool for clinicians when implementing MWT. The topic, format, timing, and source of information clinicians need are also delineated. CONCLUSION: MWT such as apps, smartphones and tablets are being used by rehabilitation clinicians to address motor, cognitive, and speech skills, most commonly in adults. Clinicians voice a need for more education and training. Barriers and facilitators exist at the clinician-, technology-, client-, institution-, and policy levels.Implications For RehabilitationA total of 90 articles from 2015-2022 were included in this scoping reviewMost interventions were apps, smartphones, and tablets; were geared toward adults; and targeted motor, cognitive and speech skills.An infographic was generated as a decision support tool for clinicians when implementing mainstream wireless technologies in clinical practice.Clinicians' education and training needs with regard to mainstream wireless technologies are broad. Materials on a variety of topics, in different formats, from multiple sources are needed.This review also discusses implications of findings on policy, technology development, and future research.

Providing mainstream smart home technology as assistive technology for persons with disabilities: a qualitative study with professionals.

PURPOSE: Mainstream smart home technology (MSHT) is becoming increasingly powerful, affordable, and relevant to improving environment control, independence, and participation of people with disabilities. This study examined how MSHT is delivered as assistive technology (AT) by practitioners of various disciplines and roles and collected their perspectives on the challenges and important considerations during the delivery process. METHODS: Practitioners with at least 1 year of experience providing MSHT as AT were interviewed individually or in small groups of 2-3 participants. Researchers developed guiding questions based on the AT service delivery process and applied an inductive qualitative analysis to generate common themes from the data. RESULTS: While all 15 participants confirmed the potential benefits of MSHT to people with disabilities, most followed an informal service delivery process and encountered various challenges, including challenges related to technology updates and compatibility, difficulty in keeping up with technology changes and advancement, funding for MSHT and services, client Wi-Fi/Internet access and quality, and security and privacy concerns. Participants also emphasised the importance of assessment and technology trialling during the delivery process and shared strategies for device customisation and client training. CONCLUSIONS: This study provides first-hand information about the current practice of MSHT service delivery, as well as insights into areas where support is likely needed. The results could inform the development of new tools and resources to support MSHT service delivery. More research is required to develop and evaluate viable service delivery models for mainstream technologies to be used as AT.IMPLICATIONS FOR REHABILITATIONPractitioners who have experience delivering MSHT as AT confirmed the benefits of MSHT for improving independence, safety, and social connection of people with disabilities.Practitioners emphasised the importance of assessment prior to device selection even though MSHT can be readily purchased off the shelf.Practitioners need support for device trialling, installation, troubleshooting, and keeping up with constantly evolving MSHT.More research is needed to develop and evaluate service delivery models for mainstream technologies as AT for people with disabilities.

Early versus late awake prone positioning in non-intubated patients with COVID-19.

BACKGROUND: Awake prone positioning (APP) is widely used in the management of patients with coronavirus disease (COVID-19). The primary objective of this study was to compare the outcome of COVID-19 patients who received early versus late APP. METHODS: Post hoc analysis of data collected for a randomized controlled trial (ClinicalTrials.gov NCT04325906). Adult patients with acute hypoxemic respiratory failure secondary to COVID-19 who received APP for at least one hour were included. Early prone positioning was defined as APP initiated within 24 h of high-flow nasal cannula (HFNC) start. Primary outcomes were 28-day mortality and intubation rate. RESULTS: We included 125 patients (79 male) with a mean age of 62 years. Of them, 92 (73.6%) received early APP and 33 (26.4%) received late APP. Median time from HFNC initiation to APP was 2.25 (0.8-12.82) vs 36.35 (30.2-75.23) hours in the early and late APP group (p < 0.0001), respectively. Average APP duration was 5.07 (2.0-9.05) and 3.0 (1.09-5.64) hours per day in early and late APP group (p < 0.0001), respectively. The early APP group had lower mortality compared to the late APP group (26% vs 45%, p = 0.039), but no difference was found in intubation rate. Advanced age (OR 1.12 [95% CI 1.0-1.95], p = 0.001), intubation (OR 10.65 [95% CI 2.77-40.91], p = 0.001), longer time to initiate APP (OR 1.02 [95% CI 1.0-1.04], p = 0.047) and hydrocortisone use (OR 6.2 [95% CI 1.23-31.1], p = 0.027) were associated with increased mortality. CONCLUSIONS: Early initiation (< 24 h of HFNC use) of APP in acute hypoxemic respiratory failure secondary to COVID-19 improves 28-day survival. Trial registration ClinicalTrials.gov NCT04325906.

User Preferences for the Design of a Mobile Health System to Support Transition-Age Youth With Epilepsy.

BACKGROUND: Transition-age youth with epilepsy (TAYWE) experience poor self management and adverse health outcomes. The purpose of this study was to gain the perspectives of TAYWE, their caregivers, and clinicians to inform the design of a mobile health (mHealth) system to support the self-management needs of TAYWE. METHODS: Individual semi-structured interviews and focus groups were conducted with TAYWE, their caregivers, and clinicians who manage their care. RESULTS: Sixteen TAYWE and seven caregivers participated in focus group sessions, and four clinicians were interviewed. Participants expressed the need for an mHealth system that addressed privacy, supervision of caregiver involvement, a user-friendly system design, and motivation to sustain ongoing use. Three themes evolved: current mobile app use, mHealth systems features and functions, and implementation concerns. DISCUSSION: Data from this study informs the design of an mHealth system to support self-management in TAYWE and identifies important areas for practitioners to address when providing health care to TAYWE.

Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation.

Physiologic microbe-host interactions in the intestine require the maintenance of the microbiota in a luminal compartment through a complex interplay between epithelial and immune cells. However, the roles of mucosal myeloid cells in this process remain incompletely understood. In this study, we identified that decreased myeloid cell phagocytic activity promotes colon tumorigenesis. We show that this is due to bacterial accumulation in the lamina propria and present evidence that the underlying mechanism is bacterial induction of prostaglandin production by myeloid cells. Moreover, we show that similar events in the normal colonic mucosa lead to reductions in Tuft cells, goblet cells, and the mucus barrier of the colonic epithelium. These alterations are again linked to the induction of prostaglandin production in response to bacterial penetration of the mucosa. Altogether, our work highlights immune cell-epithelial cell interactions triggered by the microbiota that control intestinal immunity, epithelial differentiation, and carcinogenesis.

Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling.

Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5ß1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

Membrane Extraction of HMG CoA Reductase as Determined by Susceptibility of Lumenal Epitope to In Vitro Protease Digestion.

Although many aspects of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway have been elucidated, methods to detect and examine intermediate steps in the process are lacking. Here, we describe the use of a protease protection assay to study the metabolically regulated ERAD substrate HMG CoA reductase. Studies utilizing this assay reveal that ubiquitinated reductase becomes extracted across the ER membrane prior to its cytosolic release and proteasomal degradation through reactions mediated by distinct AAA-ATPases. A similar approach could be applied to other substrates to determine whether membrane extraction is an intermediate step in their ERAD.

Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling.

Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the endolysosomal system is critical in its regulation. In this study we report that Notch recycling to the cell surface is dependent on the COMMD-CCDC22-CCDC93 (CCC) complex, a recently identified regulator of endosomal trafficking. Disruption in this system leads to intracellular accumulation of Notch2 and concomitant reduction in Notch signaling. Interestingly, among the 10 copper metabolism MURR1 domain containing (COMMD) family members that can associate with the CCC complex, only COMMD9 and its binding partner, COMMD5, have substantial effects on Notch. Furthermore, Commd9 deletion in mice leads to embryonic lethality and complex cardiovascular alterations that bear hallmarks of Notch deficiency. Altogether, these studies highlight that the CCC complex controls Notch activation by modulating its intracellular trafficking and demonstrate cargo-specific effects for members of the COMMD protein family.

Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM).

A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective and CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, and (S)-9b alone was effective in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy.

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity.

Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person's microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders.

Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone.

Type 1 diabetes mellitus (T1D) is associated with decreased bone mineral density, a deficit in bone structure, and subsequently an increased risk of fragility fracture. These clinical observations, paralleled by animal models of T1D, suggest that the insulinopenia of T1D has a deleterious effect on bone. To further examine the action of insulin signaling on bone development, we generated mice with an osteoprogenitor-selective (osterix-Cre) ablation of the insulin receptor (IR), designated OIRKO. OIRKO mice exhibited an 80% decrease in IR in osteoblasts. Prenatal elimination of IR did not affect fetal survival or gross morphology. However, loss of IR in mouse osteoblasts resulted in a postnatal growth-constricted phenotype. By 10-12 weeks of age, femurs of OIRKO mice were more slender, with a thinner diaphyseal cortex and, consequently, a decrease in whole bone strength when subjected to bending. In male mice alone, decreased metaphyseal trabecular bone, with thinner and more rodlike trabeculae, was also observed. OIRKO mice did not, however, exhibit abnormal glucose tolerance. The skeletal phenotype of the OIRKO mouse appeared more severe than that of previously reported bone-specific IR knockdown models, and confirms that insulin receptor expression in osteoblasts is critically important for proper bone development and maintenance of structural integrity.

Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis.

Insulin signaling in the central nervous system (CNS) regulates energy balance and peripheral glucose homeostasis. Rictor is a key regulatory/structural subunit of the mTORC2 complex and is required for hydrophobic motif site phosphorylation of Akt at serine 473. To examine the contribution of neuronal Rictor/mTORC2 signaling to CNS regulation of energy and glucose homeostasis, we utilized Cre-LoxP technology to generate mice lacking Rictor in all neurons, or in either POMC or AgRP expressing neurons. Rictor deletion in all neurons led to increased fat mass and adiposity, glucose intolerance and behavioral leptin resistance. Disrupting Rictor in POMC neurons also caused obesity and hyperphagia, fasting hyperglycemia and pronounced glucose intolerance. AgRP neuron specific deletion did not impact energy balance but led to mild glucose intolerance. Collectively, we show that Rictor/mTORC2 signaling, especially in POMC-expressing neurons, is important for central regulation of energy and glucose homeostasis.

Sequential actions of the AAA-ATPase valosin-containing protein (VCP)/p97 and the proteasome 19 S regulatory particle in sterol-accelerated, endoplasmic reticulum (ER)-associated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase results from its sterol-induced binding to ER membrane proteins called Insig-1 and Insig-2. This binding allows for subsequent ubiquitination of reductase by Insig-associated ubiquitin ligases. Once ubiquitinated, reductase becomes dislocated from ER membranes into the cytosol for degradation by 26 S proteasomes through poorly defined reactions mediated by the AAA-ATPase valosin-containing protein (VCP)/p97 and augmented by the nonsterol isoprenoid geranylgeraniol. Here, we report that the oxysterol 25-hydroxycholesterol and geranylgeraniol combine to trigger extraction of reductase across ER membranes prior to its cytosolic release. This conclusion was drawn from studies utilizing a novel assay that measures membrane extraction of reductase by determining susceptibility of a lumenal epitope in the enzyme to in vitro protease digestion. Susceptibility of the lumenal epitope to protease digestion and thus membrane extraction of reductase were tightly regulated by 25-hydroxycholesterol and geranylgeraniol. The reaction was inhibited by RNA interference-mediated knockdown of either Insigs or VCP/p97. In contrast, reductase continued to become membrane-extracted, but not cytosolically dislocated, in cells deficient for AAA-ATPases of the proteasome 19 S regulatory particle. These findings establish sequential roles for VCP/p97 and the 19 S regulatory particle in the sterol-accelerated ERAD of reductase that may be applicable to the ERAD of other substrates.

A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors.

Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.

Geranylgeraniol suppresses the viability of human DU145 prostate carcinoma cells and the level of HMG CoA reductase.

The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor receptors. The diterpene geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50=80±18 µmol/L, n=5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, geranylgeraniol may have potential in the chemoprevention and/or therapy of human prostate cancer.

Osteo-promoting effects of insulin-like growth factor I (IGF-I) in a mouse model of type 1 diabetes.

OBJECTIVE: Using a streptozotocin (STZ)-induced mouse model of type 1 diabetes (T1D), we have previously demonstrated that long-term diabetes inhibits regenerative bone formation during tibial distraction osteogenesis (DO) and perturbs skeletal integrity by decreasing cortical thickness, bone mineral density and bone's resistance to fracture. Because long-standing T1D is also associated with a deficiency of insulin-like growth factor I (IGF-I), we examined the effects of systemic IGF-I treatment on skeletal microarchitecture and strength, as well as on bone formation in diabetic mice. RESEARCH DESIGN AND METHODS: Streptozotocin-induced diabetic or control mice were treated with recombinant human IGF-I (rhIGF-I, 1.5mg/kg/day as subcutaneous infusion) or vehicle throughout a 14day DO procedure. Thereafter, trunk blood was assayed for glucose, insulin, rhIGF-I, mouse IGF-I and leptin. Bone formation in distracted tibiae was quantified. Effects on cortical bone strength and trabecular bone architecture were assessed by µCT analysis and three-point bend testing of contralateral femurs. RESULTS: New bone formation during DO was reduced in diabetic mice but significantly improved with rhIGF-I treatment. The contralateral femurs of diabetic mice demonstrated significant reductions in trabecular thickness, yield strength and peak force of cortical bone, which were improved with rhIGF-I treatment. rhIGF-I also reduced intracortical porosity in control mice. However, treatment with rhIGF-I did not normalize serum glucose, or correct concurrent deficiencies of insulin or leptin seen in diabetes. CONCLUSIONS: These findings demonstrate that despite persistent hyperglycemia, rhIGF-I promoted new bone formation and improved biomechanical properties of bone in a model of T1D, suggesting that it may be useful as a fracture preventative in this disease.