Hospital Staff Perspectives on the Drivers and Challenges in Implementing a Virtual Rehabilitation Ward: Qualitative Study.

Background: Over the past decade, the adoption of virtual wards has surged. Virtual wards aim to prevent unnecessary hospital admissions, expedite home discharge, and enhance patient satisfaction, which are particularly beneficial for the older adult population who faces risks associated with hospitalization. Consequently, substantial investments are being made in virtual rehabilitation wards (VRWs), despite evidence of varying levels of success in their implementation. However, the facilitators and barriers experienced by virtual ward staff for the rapid implementation of these innovative care models remain poorly understood. Objective: This paper presents insights from hospital staff working on an Australian VRW in response to the growing demand for programs aimed at preventing hospital admissions. We explore staff's perspectives on the facilitators and barriers of the VRW, shedding light on service setup and delivery. Methods: Qualitative interviews were conducted with 21 VRW staff using the Nonadoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework. The analysis of data was performed using framework analysis and the 7 domains of the NASSS framework. Results: The results were mapped onto the 7 domains of the NASSS framework. (1) Condition: Managing certain conditions, especially those involving comorbidities and sociocultural factors, can be challenging. (2) Technology: The VRW demonstrated suitability for technologically engaged patients without cognitive impairment, offering advantages in clinical decision-making through remote monitoring and video calls. However, interoperability issues and equipment malfunctions caused staff frustration, highlighting the importance of promptly addressing technical challenges. (3) Value proposition: The VRW empowered patients to choose their care location, extending access to care for rural communities and enabling home-based treatment for older adults. (4) Adopters and (5) organizations: Despite these benefits, the cultural shift from in-person to remote treatment introduced uncertainties in workflows, professional responsibilities, resource allocation, and intake processes. (6) Wider system and (7) embedding: As the service continues to develop to address gaps in hospital capacity, it is imperative to prioritize ongoing adaptation. This includes refining the process of smoothly transferring patients back to the hospital, addressing technical aspects, ensuring seamless continuity of care, and thoughtfully considering how the burden of care may shift to patients and their families. Conclusions: In this qualitative study exploring health care staff's experience of an innovative VRW, we identified several drivers and challenges to implementation and acceptability. The findings have implications for future services considering implementing VRWs for older adults in terms of service setup and delivery. Future work will focus on assessing patient and carer experiences of the VRW.

Standardizing Continuous Physical Activity Monitoring in Patients with Cervical Spondylosis.

STUDY DESIGN/SETTING: Prospective cohort study. OBJECTIVE: To use a commercial wearable device to measure real-life, continuous physical activity in patients with CS and to establish age- and sex-adjusted standardized scores. SUMMARY OF BACKGROUND DATA: Patients with cervical spondylosis (CS) often present with pain or neurologic deficits that results in functional limitations and inactivity. However, little is known regarding the influence of CS on patient's real-life physical activity. METHODS: This study included 100 English-speaking adult patients with cervical degenerative diseases undergoing elective spine surgery at Stanford University who owned iPhones. Patients undergoing surgery for spine infections, trauma, or tumors, or with lumbar degenerative disease were excluded. Activity two weeks before surgery was expressed as raw daily step counts. Standardized z-scores were calculated based on age- and sex-specific values of a control population. Responses to patient-reported outcome measures (PROMs) surveys assessed convergent validity. Functional impairment was categorized based on predetermined z-score cut-off values. RESULTS: 30 CS with mean(±SD) age of 56.0(±13.4) years wore an Apple Watch for ≥8 hours/day in 87.1% of the days. Mean watch wear time was 15.7(±4.2) hours/day, and mean daily step count was 6,400(±3,792). There was no significant difference in activity between 13 patients (43%) with myelopathy and 17 (57%) without myelopathy. Test-Retest reliability between wearable step count measurements was excellent (ICC ß=0.95). Physical activity showed a moderate positive correlation with SF36-PCS, EQ5D VAS, and PROMIS-PF. Activity performance was classified into categories of "no impairment" (step count=9,640(±2,412)), "mild impairment" (6,054(±816)), "moderate impairment" (3,481(±752)), and "severe impairment" (1,619(±240)). CONCLUSION: CS patients' physical activity is significantly lower than the general population, or the frequently stated goals of 7,000-10,000 steps/day. Standardized, continuous wearable physical activity monitoring in CS is a reliable, valid, and normalized outcome tool that may help characterize functional impairment before and after spinal interventions.

Standardizing Physical Activity Monitoring in Patients With Degenerative Lumbar Disorders.

BACKGROUND AND OBJECTIVES: Degenerative thoracolumbar disorders (DTDs) typically cause pain and functional impairment. However, little is known regarding the DTD impact on patient's real-life physical activity. The objective of this study is to validate a wearable measure of physical activity monitoring in patients with DTD and to create gender- and sex-specific performance thresholds that are standardized to the mean of a control population. METHODS: A commercially available smartwatch (Apple Watch) was used to monitor preoperative physical activity in patients undergoing surgery for DTD. Mean preoperative physical activity 2 weeks before the scheduled surgery was expressed as raw step count. Standardized z-scores were referenced to age- and sex-specific values of a control population from a large public database. Step counts were assessed for convergent validity with established patient-reported outcome measures, and impairment in activity was stratified into performance groups based on z-score cutoff values. RESULTS: Sixty-five patients (62% female) with a mean (±SD) age of 63.8 (±12.8) years had a mean preoperative daily step count of 5556 (±3978). Physical activity showed significant correlation with patient-reported outcome measures, including Oswestry disability index (r = -0.26, 95% CI: -0.47-0.01), 36-Item Short Form Survey Physical Component Summary score (r = 0.30, 95% CI: 0.06-0.51), and Patient-Reported Outcomes Measurement Information System Physical Function (r = 0.49, 95% CI: 0.27-0.65). "No," "Mild," "moderate," and "severe impairment" in activity performance were defined as corresponding z-scores of >0, 0 to -0.99, -1 to -1.99, and ≤-2, accounting for 22%, 34%, 40%, and 5% of the study population. Each one-step category increase in activity impairment resulted in increased subjective disability as measured by the Oswestry Disability Index, 36-Item Short Form Survey Physical Component Summary, and Patient-Reported Outcomes Measurement Information System Physical Function (all P -values <.05). CONCLUSION: We establish the first wearable objective measure of real-life physical activity for patients with DTD, with the first age- and sex-adjusted standard scores to enable clinicians and researchers to set treatment goals and directly compare activity levels between individual patients with DTD and normal controls.

DFT investigations of phenyldithiafulvene dimers at different oxidation states.

Oxidative dimerization of aryl-substituted dithiafulvenes (Ar-DTFs) presents an efficient C-C bond forming method for the preparation of diverse redox-active π-conjugated molecules and conductive polymers. Previous experimental data indicated a reaction pathway in which direct combination of two Ar-DTF radical cations is a key step. However, mechanistic details about how Ar-DTF dimers are formed under different oxidation states have not yet been clearly established prior to this work. The assembly of two Ar-DTF molecules generates a vast conformational and configurational landscape, which is quite complex but fundamentally important for understanding the dimerization mechanism. To cast a deep insight into this aspect, we have performed density functional theory (DFT) calculations at the M06-2X/Def2-SVP level of theory to thoroughly investigate the potential energy surfaces (PESs) of various dimers of a phenyl-substituted dithiafulvene (Ph-DTF) in the mixed-valence radical cation and dication states. Key stationary points in these PESs, including minimum-energy conformers (π-dimers and σ-dimers) as well as the transition states connected to them, were examined and compared. We have also calculated the binding energies of these dimers to evaluate the energetic driving forces for their formation. Based on our computational results, the roles that various Ph-DTF dimers play in different pathways of oxidative dimerization have been clarified.

Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion.

The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48 kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n = 9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUCinsulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinary-renal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.

Photocontrolled SiRNA Delivery and Biomarker-Triggered Luminogens of Aggregation-Induced Emission by Up-Conversion NaYF4:Yb3+Tm3+@SiO2 Nanoparticles for Inducing and Monitoring Stem-Cell Differentiation.

Controlling the differentiation of stem cells and monitoring cell differentiation has attracted much research interest since the discovery of stem cells. In this regard, a novel near-infrared (NIR) light-activated nanoplatform is obtained by encapsulating the photoactivatable caged compound (DMNPE/siRNA) and combining a MMP13 cleaved imaging peptide-tetrapheny-lethene (TPE) unit conjugated with the mesoporous silica-coated up-conversion nanoparticles (UCNPs) for the remote control of cell differentiation and, simultaneously, for the real-time monitoring of differentiation. Upon NIR light illumination, the photoactivated caged compound is activated, and the siRNA is released from UCNPs, allowing controlled differentiation of stem cells by light. More importantly, MMP13 enzyme triggered by osteogenic differentiation would effectively cleave the TPE probe peptide, thereby allowing the real-time monitoring of differentiation in living stem cells by aggregation-induced emission (AIE).

Increased liver AGEs induce hepatic injury mediated through an OST48 pathway.

The protein oligosaccharyltransferase-48 (OST48) is integral to protein N-glycosylation in the endoplasmic reticulum (ER) but is also postulated to act as a membrane localised clearance receptor for advanced glycation end-products (AGE). Hepatic ER stress and AGE accumulation are each implicated in liver injury. Hence the objective of this study was to increase the expression of OST48 and examine the effects on hepatic function and structure. Groups of 8 week old male mice (n = 10-12/group) over-expressing the gene for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-), were followed for 24 weeks, while randomised to diets either low or high in AGE content. By week 24 of the study, either increasing OST48 expression or consumption of high AGE diet impaired liver function and modestly increased hepatic fibrosis, but their combination significantly exacerbated liver injury in the absence of steatosis. DDOST+/- mice had increased both portal delivery and accumulation of hepatic AGEs leading to central adiposity, insulin secretory defects, shifted fuel usage to fatty and ketoacids, as well as hepatic glycogen accumulation causing hepatomegaly along with hepatic ER and oxidative stress. This study revealed a novel role of the OST48 and AGE axis in hepatic injury through ER stress, changes in fuel utilisation and glucose intolerance.

Real-time monitoring of hydrophobic aggregation reveals a critical role of cooperativity in hydrophobic effect.

The hydrophobic interaction drives nonpolar solutes to aggregate in aqueous solution, and hence plays a critical role in many fundamental processes in nature. An important property intrinsic to hydrophobic interaction is its cooperative nature, which is originated from the collective motions of water hydrogen bond networks surrounding hydrophobic solutes. This property is widely believed to enhance the formation of hydrophobic core in proteins. However, cooperativity in hydrophobic interactions has not been successfully characterized by experiments. Here, we quantify cooperativity in hydrophobic interactions by real-time monitoring the aggregation of hydrophobic solute (hexaphenylsilole, HPS) in a microfluidic mixer. We show that association of a HPS molecule to its aggregate in water occurs at sub-microsecond, and the free energy change is -5.8 to -13.6 kcal mol-1. Most strikingly, we discover that cooperativity constitutes up to 40% of this free energy. Our results provide quantitative evidence for the critical role of cooperativity in hydrophobic interactions.

Relations between symptom severity, illness perceptions, visceral sensitivity, coping strategies and well-being in irritable bowel syndrome guided by the common sense model of illness.

Irritable Bowel Syndrome (IBS) is a common condition affecting around 10-20% of the population and associated with poorer psychological well-being and quality of life. The aim of the current study was to explore the efficacy of the Common Sense Model (CSM) using Structural Equation Modelling (SEM) in an IBS cohort. One hundred and thirty-one IBS patients (29 males, 102 females, mean age 38 years) participating in the IBSclinic.org.au pre-intervention assessment were included. Measures included IBS severity (Irritable Bowel Syndrome Severity Scoring System), coping patterns (Carver Brief COPE), visceral sensitivity (Visceral Sensitivity Index), illness perceptions (Brief Illness Perceptions Questionnaire), psychological distress (Depression, Anxiety and Stress Scale), and quality of life (IBS Quality of Life scale; IBS-QoL). Using SEM, a final model with an excellent fit was identified (χ2 (8) = 11.91, p = .16, χ2/N = 1.49, CFI > .98, TLI > .96, SRMR < .05). Consistent with the CSM, Illness perceptions were significantly and directly influenced by IBS severity (ß = .90, p < .001). Illness perceptions in turn directly influenced maladaptive coping (ß = .40, p < .001) and visceral sensitivity (ß = .70, p < .001). Maladaptive coping and visceral sensitivity were significantly associated with psychological distress (ß = .55, p < .001; ß = .22, p < .01) and IBS-QoL (ß = -.28, p < .001; ß = -.62, p < .001). Based on these findings, we argue that to augment the adverse impact of IBS severity on IBS-QoL and psychological distress, psychological interventions will be best to target the mediating psychological processes including illness beliefs, visceral sensitivity and maladaptive coping.

A Phase l Study of a Tumor-targeted Systemic Nanodelivery System, SGT-94, in Genitourinary Cancers.

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.

A near-infrared AIEgen for specific imaging of lipid droplets.

A new near-infrared AIE luminogen (TPE-AC) with high specificity, good biocompatibility and excellent photostability is designed and synthesized for lipid droplet (LD) imaging in cells. TPE-AC can monitor the process of LD accumulation in cells, thus making it potential for the diagnosis of early-stage fat-related diseases.

A Lysosome-Targeting AIEgen for Autophagy Visualization.

In this work, a morpholine-functionalized aggregation-induced emission luminogen (AIEgen), AIE-LysoY, is reported for lysosomal imaging and autophagy visualization. To attain outstanding imaging contrast, AIE-LysoY is equipped with excited state intramolecular proton transfer (ESIPT) characteristic. AIE-LysoY provides a new platform for lysosome visualization with good biocompatibility, large Stokes shift, superior signal-to-noise ratio, and high photostability.

A photostable AIEgen for nucleolus and mitochondria imaging with organelle-specific emission.

Dynamic visualization of the morphology of membrane-bound organelles offers useful insights for studying various intracellular activities. Fluorescent probes with superior specificity and photostability are desirable for long-term tracking of these processes. In this work, we present the design and synthesis of an α-cyanostilbene derivative, abbreviated as ASCP, with the aggregation-induced emission (AIE) characteristic, and its application in cell imaging. ASCP can simultaneously label mitochondria and nucleolus in live cells with distinct fluorescence, which is demonstrative of a single molecule with dual-colour organelle imaging.

An AIE-based bioprobe for differentiating the early and late stages of apoptosis mediated by H2O2.

A bioprobe, TPE-Zn2BDPA, with aggregation-induced emission characteristics was designed and synthesized to differentiate the early and late stages of apoptosis mediated by H2O2. TPE-Zn2BDPA does not respond to healthy cells, but it selectively lights up the membrane of apopotic cells in both stages with brighter fluorescence in the late apoptotic stage.

Using AIE Luminogen for Long-term and Low-background Three-Photon Microscopic Functional Bioimaging.

Fluorescent probes are one of the most popularly used bioimaging markers to monitor metabolic processes of living cells. However, long-term light excitation always leads to photobleaching of fluorescent probes, unavoidable autofluorescence as well as photodamage of cells. To overcome these limitations, we synthesized a type of photostable luminogen named TPE-TPP with an aggregation induced emission (AIE) characteristic, and achieved its three-photon imaging with femtosecond laser excitation of 1020 nm. By using TPE-TPP as fluorescent probes, three-photon microscopy under 1020 nm excitation showed little photo-damage, as well as low autofluorescence to HeLa cells. Due to the AIE effect, the TPE-TPP nanoaggregates uptaken by cells were resistant to photobleaching under three-photon excitation for an extended period of time. Furthermore, we demonstrated that for the present TPE-TPP AIE the three-photon microscopy (with 1020 nm excitation) had a better signal to noise ratio than the two-photon microscopy (with 810 nm excitation) in tissue imaging.

A Luminogen with Aggregation-Induced Emission Characteristics for Wash-Free Bacterial Imaging, High-Throughput Antibiotics Screening and Bacterial Susceptibility Evaluation.

A luminogen with aggregation-induced emission characteristics is reported for bacterial imaging and antibiotics screening studies. The luminogen can light up bacteria in a wash-free manner, which simplifies the imaging process and increases its accuracy in bacterial detection. It can also be applied to high-throughput screening of antibiotics and fast evaluation of bacterial susceptibility, giving reliable results in less than 5 h.

Long-term two-photon neuroimaging with a photostable AIE luminogen.

In neuroscience, fluorescence labeled two-photon microscopy is a promising tool to visualize ex vivo and in vivo tissue morphology, and track dynamic neural activities. Specific and highly photostable fluorescent probes are required in this technology. However, most fluorescent proteins and organic fluorophores suffer from photobleaching, so they are not suitable for long-term imaging and observation. To overcome this problem, we utilize tetraphenylethene-triphenylphosphonium (TPE-TPP), which possesses aggregation-induced emission (AIE) and two-photon fluorescence characteristics, for neuroimaging. The unique AIE feature of TPE-TPP makes its nanoaggregates resistant to photobleaching, which is useful to track neural cells and brain-microglia for a long period of time. Two-photon fluorescence of TPE-TPP facilitates its application in deep in vivo neuroimaging, as demonstrated in the present paper.

Light-enhanced bacterial killing and wash-free imaging based on AIE fluorogen.

The rapid acquisition of antibiotic resistance poses difficulties in the development of effective methods to eliminate pathogenic bacteria. New bactericides, especially those do not induce the emergence of resistance, are thus in great demand. In this work, we report an aggregation-induced emission fluorogen, TPE-Bac, for bacterial imaging and elimination. TPE-Bac can be readily dissolved in aqueous solution with weak emission. The presence of bacteria can turn on its emission, and thus no washing step is required in the imaging process. Meanwhile, TPE-Bac can be applied as a bactericide for elimination of bacteria. The amphiphilic TPE-Bac bearing two long alkyl chains and two positively charged amines can intercalate into the membrane of bacteria, increase membrane permeability and lead to dark toxicity. The efficiency of bacteria killing is greatly enhanced under light irradiation. TPE-Bac can serve as a photosensitizer to induce reactive oxygen species (ROS) generation, which ensures the efficient killing of bacteria. The TPE-Bac-containing agar plates can be continuously used for bacteria killing by applying light to induce ROS generation.

Specific imaging and tracking of mitochondria in live cells by a photostable AIE luminogen.

Tracking the dynamics of mitochondrial morphology has attracted much research interest because of its involvement in early stage apoptosis and degenerative conditions. To follow this process, highly specific and photostable fluorescent probes are in demand. Commercially available mitochondria trackers, however, suffer from poor photostability. To overcome this limitation, we have designed and synthesized a fluorescent agent, tetraphenylethene-triphenylphosphonium (TPE-TPP), for mitochondrial imaging. Inherent from the mitochondrial-targeting ability of TPP groups and the aggregation-induced emission (AIE) characteristics of the TPE core, TPE-TPP possesses high specificity to mitochondria, superior photostability, and appreciable tolerance to environmental change, allowing imaging and tracking of the mitochondrial morphological changes in a long period of time.

Biosensing by luminogens with aggregation-induced emission characteristics.

Fluorescent biosensors are powerful analytical tools for studying biological events in living systems. Luminescent materials with aggregation-induced emission (AIE) attributes have attracted much research interest and have been identified as a novel class of luminogens to develop fluorescent turn-on biosensors with superior sensitivity. In this Tutorial Review, we present an overview of the AIE phenomenon and its mechanism. We summarize the structural design and working principle of AIE biosensors developed recently. Typical examples of AIE biosensors are presented.