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.

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.

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.

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.

Superior fluorescent probe for detection of cardiolipin.

Cardiolipin (CL) is a unique phospholipid found in mitochondrial inner membrane. It is a key component for mitochondrial function in both respiration and apoptosis. The level of CL is an important parameter for investigating these intracellular events and is a critical indicator of a number of diseases associated with mitochondrial respiratory functions. 10-Nonyl acridine orange (NAO) is the only fluorescent dye currently available for CL detection. However, the performance of NAO is far from satisfactory in terms of selectivity and sensitivity. In this work, we report an aggregation-induced emission-active fluorogen, TTAPE-Me, for CL detection and quantification. With improved sensitivity and excellent selectivity to CL over other major mitochondrial membrane lipids, TTAPE-Me could serve as a valuable fluorescent sensor for CL quantification. The use of TTAPE-Me for the quantification of isolated mitochondria is also demonstrated.

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.

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-adjusted and sex-adjusted standardized scores. SUMMARY OF BACKGROUND DATA: Patients with cervical spondylosis (CS) often present with pain or neurologic deficits that result in functional limitations and inactivity. However, little is known regarding the influence of CS on the 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, tumors, or 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-specific 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: Thirty CS with a mean (±SD) age of 56.0 (±13.4) y wore an Apple Watch for ≥8 hours/day in 87.1% of the days. The mean watch wear time was 15.7 (±4.2) hours/day, and the mean daily step count was 6400 (±3792). 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 36-Item Short Form Survey Physical Component Summary, EuroQol-5-dimension visual analog scale, and Patient-Reported Outcomes Measurement Information System Physical Function Subscale. Activity performance was classified into categories of "no impairment" [step count=9640 (±2,412)], "mild impairment" [6054(±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 7000 to 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.

Determining critical monitoring periods for accurate wearable step counts in patients with degenerative spine disorders.

Longitudinal physical activity monitoring is a novel and promising objective outcome measure for patients with degenerative spine disorder (DSD) that currently lacks established standards for data collection and interpretation. Here, we monitored 100 patients with DSD with the Apple Watch to establish the optimal duration and pattern of step count monitoring needed to estimate their weekly physical activity before their elective surgery. Participants were predominantly female (65.3%), had an average age of 61.5 years, and showed consistent step counts between preoperative days, as well as across weekends and weekdays. Intraclass correlations (ICC) analysis showed that a step count average over 2 days achieved an ICC of 0.92 when compared to a 7-day average before surgery, while 4 days were required for a similar agreement of 0.93 with a 14-day average. Sequential linear regression demonstrated that incorporating additional preoperative days improved the model's ability to predict 7- and 14-days step count averages. We conclude that, while daily preoperative step counts remain relatively stable, longer activity monitoring is necessary to account for the variance in step count over an increasing time frame, and the full extent of data fluctuation may only become apparent with long-term trend analysis.

A photostable AIE luminogen for specific mitochondrial imaging and tracking.

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.