Expert Panel Consensus on the Effectiveness and Implementation of Models to Support Posthospitalization Care Transitions for People With Substance Use Disorders.

OBJECTIVES: Hospitals are increasingly offering treatment for substance use disorders (SUDs) during medical admissions. However, there is a lack of consensus on the best approach to facilitating a successful transition to long-term medical and SUD care after hospitalization. We aimed to establish a hierarchy of existing SUD care transition models in 2 categories-effectiveness and implementation-using an expert consensus approach. METHODS: We conducted a modified online Delphi study that convened 25 interdisciplinary clinicians with experience facilitating posthospitalization care transitions for patients with SUD. Panelists rated 10 prespecified posthospitalization care transition models according to 6 criteria concerning each model's anticipated effectiveness (eg, linkage to care, treatment retention) and implementation (eg, feasibility, acceptability). Ratings were made on a 9-point bidirectional scale. Group consensus was determined using the interpercentile range adjusted for symmetry. RESULTS: After 3 rounds of the Delphi process (96% retention across all 3 rounds), consensus was reached on all 60 rating criteria. Interdisciplinary addiction consult teams (ACTs) and in-reach from partnering outpatient clinics were rated highest for effectiveness. Interdisciplinary ACTs and bridge clinics were rated highest for implementation. Screening, brief intervention, and referral to treatment; protocol implementation; and postdischarge outreach received the lowest ratings overall. Feasibility of implementation was perceived as the largest challenge for all highly rated models. CONCLUSIONS: An expert consensus approach including diverse clinician stakeholders found that interdisciplinary ACT, in-reach from partnering outpatient clinics, and bridge clinics had the greatest potential to enhance posthospitalization care transitions for patients with SUD when considering both perceived effectiveness and implementation.

Photodynamic therapy with NIR-II probes: review on state-of-the-art tools and strategies.

In 2022 10% of the world's population was aged 65+, and by 2100 this segment is expected to hit 25%. These demographic changes place considerable pressure over healthcare systems worldwide, which results in an urgent need for accurate, inexpensive and non-invasive ways to treat cancers, a family of diseases correlated with age. Among the therapeutic tools that gained important attention in this context, photodynamic therapies (PDT), which use photosensitizers to produce cytotoxic substances for selectively destroying tumor cells and tissues under light irradiation, profile as important players for next-generation nanomedicine. However, the development of clinical applications is progressing at slow pace, due to still pending bottlenecks, such as the limited tissue penetration of the excitation light, and insufficient targeting performance of the therapeutic probes to fully avoid damage to normal cells and tissues. The penetration depth of long-wavelength near infrared (NIR) light is significantly higher than that of short-wavelength UV and visible light, and thus NIR light in the second window (NIR-II) is acknowledged as the preferred phototherapeutic means for eliminating deep-seated tumors, given the higher maximum permissible exposure, reduced phototoxicity and low autofluorescence, among others. Upon collective multidisciplinary efforts of experts in materials science, medicine and biology, multifunctional NIR-II inorganic or organic photosensitizers have been widely developed. This review overviews the current state-of-the art on NIR-II-activated photosensitizers and their applications for the treatment of deep tumors. We also place focus on recent efforts that combine NIR-II activated PDT with other complementary therapeutic routes such as photothermal therapy, chemotherapy, immunotherapy, starvation, and gas therapies. Finally, we discuss still pending challenges and problems of PDT and provide a series of perspectives that we find useful for further extending the state-of-the art on NIR-II-triggered PDT.

4f-Orbital mixing increases the magnetic susceptibility of Cp'3Eu.

Traditional models of lanthanide electronic structure suggest that bonding is predominantly ionic, and that covalent orbital mixing is not an important factor in determining magnetic properties. Here, 4f orbital mixing and its impact on the magnetic susceptibility of Cp'3Eu (Cp' = C5H4SiMe3) was analyzed experimentally using magnetometry and X-ray absorption spectroscopy (XAS) methods at the C K-, Eu M5,4-, and L3-edges. Pre-edge features in the experimental and TDDFT-calculated C K-edge XAS spectra provided unequivocal evidence of C 2p and Eu 4f orbital mixing in the π-antibonding orbital of a' symmetry. The charge-transfer configurations resulting from 4f orbital mixing were identified spectroscopically by using Eu M5,4-edge and L3-edge XAS. Modeling of variable-temperature magnetic susceptibility data showed excellent agreement with the XAS results and indicated that increased magnetic susceptibility of Cp'3Eu is due to removal of the degeneracy of the 7F1 excited state due to mixing between the ligand and Eu 4f orbitals.

Formation of uranium disulfide from a uranium thioamidate single-source precursor.

A single-source-precursor approach was developed to synthesize uranium-based materials outside of the typically-studied oxides. This approach allows for shorter reaction times, milder reaction conditions, and control over the chemicals present in synthesis. To this end, the first homoleptic uranium thioamidate complex was synthesized as a precursor for US2 materials. Pyrolysis of the thioamidate results in decomposition via an alkene elimination pathway and formation of γ-US2, which has historically been hard to access without the need for a secondary sulfur source. Despite the oxophilicity of uranium, the method successfully forms US2 without the inclusion of oxygen in the bulk final product. These findings are supported by simultaneous thermal analysis, elemental analysis, powder X-ray diffraction, and uranium L3-edge X-ray absorption fine-structure spectroscopy. This work represents the first example of a single-source precursor approach to target and synthesize actinide materials other than the oxides.

When Average Isn't Good Enough: Identifying Meaningful Subgroups in Clinical Data.

Background: Clinical data are usually analyzed with the assumption that knowledge gathered from group averages applies to the individual. Doing so potentially obscures patients with meaningfully different trajectories of therapeutic change. Needed are "idionomic" methods that first examine idiographic patterns before nomothetic generalizations are made. The objective of this paper is to test whether such an idionomic method leads to different clinical conclusions. Methods: 51 patients completed weekly process measures and symptom severity over a period of eight weeks. Change trajectories were analyzed using a nomothetic approach and an idiographic approach with bottom-up clustering of similar individuals. The outcome was patients' well-being at post-treatment. Results: Individuals differed in the extent that underlying processes were linked to symptoms. Average trend lines did not represent the intraindividual changes well. The idionomic approach readily identified subgroups of patients that differentially predicted distal outcomes (well-being). Conclusions: Relying exclusively on average results may lead to an oversight of intraindividual pathways. Characterizing data first using idiographic approaches led to more refined conclusions, which is clinically useful, scientifically rigorous, and may help advance individualized psychotherapy approaches. Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10453-x.

Antibacterial Interactions of Ethanol-Dispersed Multiwalled Carbon Nanotubes with Staphylococcus aureus and Pseudomonas aeruginosa.

Infectious diseases are acknowledged as one of the leading causes of death worldwide. Statistics show that the annual death toll caused by bacterial infections has reached 14 million, most of which are caused by drug-resistant strains. Bacterial antibiotic resistance is currently regarded as a compelling problem with dire consequences, which motivates the urgent identification of alternative ways of fighting bacteria. Various types of nanomaterials have been reported to date as efficient antibacterial solutions. Among these, carbon-based nanomaterials, such as carbon nanodots, carbon graphene oxide, and carbon nanotubes (CNTs), have been shown to be effective in killing a wide panel of pathogenic bacteria. With this study, we aim to provide additional insights into this topic of research by investigating the antibacterial activity of a specific type of multiwalled CNTs, with diameters from 50 to 150 nm, against two representative opportunistic pathogens, i.e., the Gram-positive bacterium Staphylococcus aureus and the Gram-negative bacterium Pseudomonas aeruginosa, both included among the top antibiotic-resistant pathogens. We also test the synergistic effect of CNTs with different antibiotics commonly used in the treatment of infections caused by S. aureus and/or P. aeruginosa. Additionally, a novel approach for quantitatively analyzing bacterial aggregation in brightfield microscopy images was implemented. This method was utilized to assess the effectiveness of CNTs, either alone or in combination with antibiotics, in dispersing bacterial aggregates. Finally, atomic force microscopy coupled with a newly devised image analysis pipeline was used to examine any potential morphological changes in bacterial cells following exposure to CNTs and antibiotics.

Obesity-associated Inflammation and Alloimmunity.

Obesity is a worldwide health problem with a rapidly rising incidence. In organ transplantation, increasing numbers of patients with obesity accumulate on waiting lists and undergo surgery. Obesity is in general conceptualized as a chronic inflammatory disease, potentially impacting alloimmune response and graft function. Here, we summarize our current understanding of cellular and molecular mechanisms that control obesity-associated adipose tissue inflammation and provide insights into mechanisms affecting transplant outcomes, emphasizing on the beneficial effects of weight loss on alloimmune responses.

Identification of novel and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries.

In vitro screening of large compound libraries with automated high-throughput screening is expensive and time-consuming and requires dedicated infrastructures. Conversely, the selection of DNA-encoded chemical libraries (DECLs) can be rapidly performed with routine equipment available in most laboratories. In this study, we identified novel inhibitors of SARS-CoV-2 main protease (Mpro) through the affinity-based selection of the DELopen library (open access for academics), containing 4.2 billion compounds. The identified inhibitors were peptide-like compounds containing an N-terminal electrophilic group able to form a covalent bond with the nucleophilic Cys145 of Mpro, as confirmed by x-ray crystallography. This DECL selection campaign enabled the discovery of the unoptimized compound SLL11 (IC50 = 30 nM), proving that the rapid exploration of large chemical spaces enabled by DECL technology allows for the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. As demonstrated further by x-ray crystallography, SLL11 was found to adopt a highly unique U-shaped binding conformation, which allows the N-terminal electrophilic group to loop back to the S1' subsite while the C-terminal amino acid sits in the S1 subsite. MP1, a close analog of SLL11, showed antiviral activity against SARS-CoV-2 in the low micromolar range when tested in Caco-2 and Calu-3 (EC50 = 2.3 µM) cell lines. As peptide-like compounds can suffer from low cell permeability and metabolic stability, the cyclization of the compounds will be explored in the future to improve their antiviral activity.

Analyzing the Intensities of K-Edge Transitions in X2 Molecules (X = F, Cl, Br) for Use in Ligand K-Edge X-ray Absorption Spectroscopy.

Ligand K-edge X-ray absorption spectroscopy (XAS) is regularly used to determine the ligand contribution to metal-ligand bonds. For quantitative studies, the pre-edge transition intensities must be referenced to an intensity standard, and pre-edge intensities obtained from different ligand atoms cannot be compared without standardization due to different cross sections at each absorption edge. In this work, the intensities of the 1s → σ* transitions in F2, Cl2, and Br2 are analyzed for their use as references for ligand K-edge XAS. We show that the intensities of these transitions are equal to the intensities of the 1s → np transitions in the unbound halogens. This finding is supported by a comparison between the normalized experimental intensities for the molecules and the calculated oscillator strengths for the atoms. These results highlight the potential for these molecules to be used as intensity standards in F, Cl, and Br K-edge XAS experiments.

Organizational and patient factors associated with positive primary care experiences for veterans with current or recent homelessness.

OBJECTIVE: To identify organizational service features associated with positive patient ratings of primary care within primary care clinics tailored to accommodate persons with ongoing and recent experiences of homelessness (PEH). DATA SOURCES AND STUDY SETTING: PEH receiving primary care in 29 United States Veterans Health Administration homeless-tailored clinics were surveyed about their primary care experience using the validated Primary Care Quality-Homeless (PCQ-H) survey. Characteristics of the clinics were assessed through surveys of clinic staff using a new organizational survey developed through literature review, site visits, statistical analysis, and consensus deliberation. STUDY DESIGN: Cross-sectional examination of patients' ratings of care based on surveys of patients, and of clinic characteristics, analyzed with Classification and Regression Tree (CART) analysis, a form of machine learning. DATA COLLECTION METHODS: Patient surveys (n = 3394) were obtained from a random sample of enrolled patients by both mail and telephone by an external survey contractor. Staff (n = 52 from 29 clinics) were interviewed by telephone. PRINCIPAL FINDINGS: This analysis identified service features that impact patient experience favorably, including aspects of patient-centeredness, team identity, strong external leadership support, and service that reach beyond traditional primary care clinic confines. Results varied according to the patient experience scale analyzed. Individual characteristics of PEH, such as degree of social support, general health, and unsheltered status, were also correlated with how they rate care. CONCLUSIONS: Organizational characteristics correlate with ratings of primary care from patients with recent and ongoing homelessness. Primary care programs serving homeless individuals can assure better care based on who they hire, how they foster team identity, what services they provide, and the strength of leadership support to protect a homeless-focused mission.

Changes in mindfulness facets across yoga, CBT and stress education in individuals with generalized anxiety disorder.

Improving mindfulness is an important treatment target for generalized anxiety disorder (GAD). However, less is known about how different treatments impact specific aspects of mindfulness. In a clinical trial (Simon et al., 2021), 226 individuals with GAD were randomized to 12 weeks of Kundalini Yoga (KY), cognitive behavioral therapy (CBT) or stress education (SE). To examine whether specific facets of mindfulness, as measured by the Five Facet Mindfulness Questionnaire (FFMQ) change more than others across treatment and between treatments, we ran a multi-variate multilevel growth curve model (MMLM). Results indicated that while the Non-judge, Act with Awareness, and Non-react facets increased significantly during treatment, the Observe and Describe facets did not. Improvement in the Acting with Awareness facet during treatment was significantly greater for KY than CBT. These findings reveal the need to better understand how behavioral treatments can influence specific components of mindfulness for those with anxiety.

Technical note: Phantom-based evaluation of CBCT dose calculation accuracy for use in adaptive radiotherapy.

BACKGROUND: High-quality 3D-anatomy of the day is needed for treatment plan adaptation in radiotherapy. For online x-ray-based CBCT workflows, one approach is to create a synthetic CT or to utilize a fan-beam CT with corresponding registrations. The former potentially introduces uncertainties in the dose calculation if deformable image registration is used. The latter can introduce burden and complexity to the process, the facility, and the patient. PURPOSE: Using the CBCT of the day, acquired on the treatment device, for direct dose calculation and plan adaptation can overcome these limitations. This study aims to assess the accuracy of the calculated dose on the CBCT scans acquired on a Halcyon linear accelerator equipped with HyperSight. METHODS: HyperSight's new CBCT reconstruction algorithm includes improvements in scatter correction, HU calibration of the imager, and beam shape adaptation. Furthermore, HyperSight introduced a new x-ray detector. To show the effect of the implemented improvements, gamma comparisons of 2%/2 mm, 2%/1 mm, and 1%/1 mm were made between the dose distribution in phantoms calculated on the CBCT reconstructions and the simulation CT scans, considering this the standard of care. The resulting gamma passing rates were compared to those obtained with the Halcyon 3.0 reconstruction and hardware without HyperSight's technologies. Various anatomical phantoms for dosimetric evaluations on brain, head and neck, lung, breast, and prostate cases have been used in this study. RESULTS: The overall results demonstrated that HyperSight outperformed the Halcyon 3.0 version. Based on the gamma analysis, the calculated dose using HyperSight was closer to the CT scan-based doses than the calculated dose using iCBCT Halcyon 3.0 for most cases. Over all plans and gamma criteria, Halcyon 3.0 achieved an average passing rate of 92.9%, whereas HyperSight achieved 98.1%. CONCLUSION: Using HyperSight CBCT images for direct dose calculation, for example, in (online) plan adaptation, seems feasible for the investigated cases.

A Process-Based Approach to Transtheoretical Clinical Research and Training.

Background: The science and practice of psychopathology and psychological intervention of today is more like an island archipelago than it is a single land mass, and connections between different traditions are both limited and fraught with misunderstanding. Method: Our analysis and solution to the problem is process-based therapy (PBT). PBT defines psychopathology as failed adaptation processes to a given context. Therapy involves adaptation through context-dependent or context-altering applications of biopsychosocial strategies that allows a goal to be met. Results: This coherent approach to more transtheoretical and integrative concepts of clinical training and practice provides a firm foundation by targeting biopsychosocial processes of change, analyzing these processes using an idiographic complex network analytic approach, and organizing findings on the intellectual agora of multi-dimensional and multi-level evolutionary science. Conclusion: PBT is a new empirical form of functional analysis, resulting in interventions and trainings that are built on elements or kernels of direct relevance to client's specific needs. In PBT, case formulation continues as long as treatment persists.

A peptide strategy for inhibiting different protein aggregation pathways.

Protein aggregation correlates with many human diseases. Protein aggregates differ in structure and shape. Strategies to develop effective aggregation inhibitors that reach the clinic failed so far. Here, we developed a family of peptides targeting early aggregation stages for both amorphous and fibrillar aggregates of proteins unrelated in sequence and structure. They act on dynamic precursors before mechanistic differentiation takes place. Using peptide arrays, we first identified peptides inhibiting the amorphous aggregation of a molten globular, aggregation-prone mutant of the Axin tumor suppressor. Optimization revealed that the peptides activity did not depend on their sequences but rather on their molecular determinants: a composition of 20-30% flexible, 30-40% aliphatic and 20-30% aromatic residues, a hydrophobicity/hydrophilicity ratio close to 1, and an even distribution of residues of different nature throughout the sequence. The peptides also suppressed fibrillation of Tau, a disordered protein that forms amyloids in Alzheimer's disease, and slowed down that of Huntingtin Exon1, an amyloidogenic protein in Huntington's disease, both entirely unrelated to Axin. Our compounds thus target early aggregation stages of different aggregation mechanisms, inhibiting both amorphous and amyloid aggregation. Such cross-mechanistic, multi-targeting aggregation inhibitors may be lead compounds for developing drug candidates against various protein aggregation diseases.

Relationship between outcomes and processes in patients with chronic low back pain plus depressive symptoms: idiographic analyses within a randomized controlled trial.

OBJECTIVE: This study explored the extent to which within-patient changes in processes targeted in Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD) are associated with changes within-patient in pain intensity and depressed mood and evaluated the extent that process-outcome relationships differed between patients. METHODS: An idiographic analysis embedded within a randomized controlled trial comparing ACT, BATD, and treatment-as-usual (TAU) was conducted to examine the strength of the relationship between outcomes and process variables in patients with chronic low back pain (CLBP) plus depressive symptoms. Based on data from ecological momentary assessment in patients (n = 82), the level of heterogeneity and the pooled effects of these relationships during the intervention period (70 days) were explored. RESULTS: Overall, a high level of heterogeneity was identified in the relationship between pain intensity or depressed mood and psychological inflexibility or behavioral activation. Individual differences in the relationships between outcomes and process variables were identified in individual people during the intervention period. These individual differences appear independent of the group (ACT, BATD, and TAU) and other definable differences (responders/non-responders, completers/non-completers, and clinical depression/non-clinical depression). CONCLUSIONS: These findings suggest the potential utility of personalizing psychological interventions according to the therapeutic needs of these patients.

Physicochemical and structural insights into lyophilized mRNA-LNP from lyoprotectant and buffer screenings.

The surge in RNA therapeutics has revolutionized treatments for infectious diseases like COVID-19 and shows the potential to expand into other therapeutic areas. However, the typical requirement for ultra-cold storage of mRNA-LNP formulations poses significant logistical challenges for global distribution. Lyophilization serves as a potential strategy to extend mRNA-LNP stability while eliminating the need for ultra-cold supply chain logistics. Although recent advancements have demonstrated the promise of lyophilization, the choice of lyoprotectant is predominately focused on sucrose, and there remains a gap in comprehensive evaluation and comparison of lyoprotectants and buffers. Here, we aim to systematically investigate the impact of a diverse range of excipients including oligosaccharides, polymers, amino acids, and various buffers, on the quality and performance of lyophilized mRNA-LNPs. From the screening of 45 mRNA-LNP formulations under various lyoprotectant and buffer conditions for lyophilization, we identified previously unexplored formulation compositions, e.g., polyvinylpyrrolidone (PVP) in Tris or acetate buffers, as promising alternatives to the commonly used oligosaccharides to maintain the physicochemical stability of lyophilized mRNA-LNPs. Further, we delved into how physicochemical and structural properties influence the functionality of lyophilized mRNA-LNPs. Leveraging high-throughput small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM), we showed that there is complex interplay between mRNA-LNP structural features and cellular translation efficacy. We also assessed innate immune responses of the screened mRNA-LNPs in human peripheral blood mononuclear cells (PBMCs), and showed minimal alterations of cytokine secretion profiles induced by lyophilized formulations. Our results provide valuable insights into the structure-activity relationship of lyophilized formulations of mRNA-LNP therapeutics, paving the way for rational design of these formulations. This work creates a foundation for a comprehensive understanding of mRNA-LNP properties and in vitro performance change resulting from lyophilization.

Actinium chelation and crystallization in a macromolecular scaffold.

Targeted alpha therapy (TAT) pairs the specificity of antigen targeting with the lethality of alpha particles to eradicate cancerous cells. Actinium-225 [225Ac; t1/2 = 9.920(3) days] is an alpha-emitting radioisotope driving the next generation of TAT radiopharmaceuticals. Despite promising clinical results, a fundamental understanding of Ac coordination chemistry lags behind the rest of the Periodic Table due to its limited availability, lack of stable isotopes, and inadequate systems poised to probe the chemical behavior of this radionuclide. In this work, we demonstrate a platform that combines an 8-coordinate synthetic ligand and a mammalian protein to characterize the solution and solid-state behavior of the longest-lived Ac isotope, 227Ac [t1/2 = 21.772(3) years]. We expect these results to direct renewed efforts for 225Ac-TAT development, aid in understanding Ac coordination behavior relative to other +3 lanthanides and actinides, and more broadly inform this element's position on the Periodic Table.

A Randomized Trial of Electrographic Flow-Guided Redo Ablation for Nonparoxysmal Atrial Fibrillation (FLOW-AF).

BACKGROUND: Electrographic flow (EGF) mapping enables full spatiotemporal reconstruction of organized wavefront propagation to identify extrapulmonary vein sources of atrial fibrillation (AF). OBJECTIVES: FLOW-AF (A Randomized Controlled Study to Evaluate the Reliability of the Ablacon Electrographic FLOW [EGF] Algorithm Technology [Ablamap Software] to Identify AF Sources and Guide Ablation Therapy in Patients With Persistent Atrial Fibrillation) was multicenter, randomized controlled study of EGF mapping to: 1) stratify a nonparoxysmal AF population undergoing redo ablation; 2) guide ablation of these extrapulmonary vein AF sources; and 3) improve AF recurrence outcomes. METHODS: FLOW-AF enrolled persistent atrial fibrillation (PerAF)/long-standing PerAF patients undergoing redo ablation at 4 centers. One-minute EGF maps were recorded from standardized biatrial basket positions. Patients with source activity ≥26.5% were randomized 1:1 to PVI + EGF-guided ablation vs PVI only; patients without sources ≥26.5% threshold were not randomized. Follow-up and electrocardiographic monitoring occurred at 3, 6, and 12 months. RESULTS: We enrolled 85 patients (age 65.6 ± 9.3 years, 37% female, 24% long-standing PerAF). Thirty-four (40%) patients had no sources greater than threshold; at least 1 source greater than threshold was present in 46 (60%) (EGF-guided ablation, n = 22; control group, n = 26). Patients with sources were older (68.2 vs 62.6 years; P = 0.005) with higher CHA2DS2-VASc scores (2.8 vs 1.9; P = 0.001). The freedom from safety events was 97.2%, and 95% of EGF-identified sources were successfully ablated. In randomized patients, AF-free survival at 12 months was 68% for EGF-guided ablation vs 17% for the control group (P = 0.042); freedom from AF/atrial tachycardia/atrial flutter at 12 months was 51% vs 14% (P = 0.103), respectively. CONCLUSIONS: In nonparoxysmal AF patients undergoing redo ablation, EGF mapping identified AF sources in 60% of patients, and could be successfully ablated in 95%. Compared with PVI alone, PVI + source ablation improved AF-free survival by 51% on an absolute basis. (FLOW-AF: A Study to Evaluate the Ablacon Electrographic FLOW EGF Technology [A Randomized Controlled Study to Evaluate the Reliability of the Ablacon Electrographic FLOW (EGF) Algorithm Technology (Ablamap Software) to Identify AF Sources and Guide Ablation Therapy in Patients With Persistent Atrial Fibrillation]; NCT04473963).