A Zeolite-Templated Carbon Synthesized from Extralarge-Pore Zeolite ZEO-1.

A new member of the zeolite-templated carbon (ZTC) family with unprecedented properties has been developed using extralarge-pore zeolite ZEO-1 (JZO) as a template. The resulting ZTC-JZO exhibits strong X-ray diffraction long-range order, replicating three distinct zeolite planes with different lattice spacings. By harnessing the enhanced micropore void volume in the ZEO-1 template, we achieved the first ZTC with a bimodal micropore size distribution, resulting in superior skeleton density and thickness. The ZTC-JZO presents high electrical conductivity and demonstrates improved electrocatalytic activity in the oxygen reduction reaction.

Establishing the Foundations of Emotional Intelligence in Care Companion Robots to Mitigate Agitation Among High-Risk Patients With Dementia: Protocol for an Empathetic Patient-Robot Interaction Study.

BACKGROUND: An estimated 6.7 million persons are living with dementia in the United States, a number expected to double by 2060. Persons experiencing moderate to severe dementia are 4 to 5 times more likely to fall than those without dementia, due to agitation and unsteady gait. Socially assistive robots fail to address the changing emotional states associated with agitation, and it is unclear how emotional states change, how they impact agitation and gait over time, and how social robots can best respond by showing empathy. OBJECTIVE: This study aims to design and validate a foundational model of emotional intelligence for empathetic patient-robot interaction that mitigates agitation among those at the highest risk: persons experiencing moderate to severe dementia. METHODS: A design science approach will be adopted to (1) collect and store granular, personal, and chronological data using Personicle (an open-source software platform developed to automatically collect data from phones and other devices), incorporating real-time visual, audio, and physiological sensing technologies in a simulation laboratory and at board and care facilities; (2) develop statistical models to understand and forecast the emotional state, agitation level, and gait pattern of persons experiencing moderate to severe dementia in real time using machine learning and artificial intelligence and Personicle; (3) design and test an empathy-focused conversation model, focused on storytelling; and (4) test and evaluate this model for a care companion robot (CCR) in the community. RESULTS: The study was funded in October 2023. For aim 1, architecture development for Personicle data collection began with a search for existing open-source data in January 2024. A community advisory board was formed and met in December 2023 to provide feedback on the use of CCRs and provide personal stories. Full institutional review board approval was received in March 2024 to place cameras and CCRs at the sites. In March 2024, atomic marker development was begun. For aim 2, after a review of open-source data on patients with dementia, the development of an emotional classifier was begun. Data labeling was started in April 2024 and completed in June 2024 with ongoing validation. Moreover, the team established a baseline multimodal model trained and validated on healthy-person data sets, using transformer architecture in a semisupervised manner, and later retrained on the labeled data set of patients experiencing moderate to severe dementia. In April 2024, empathy alignment of large language models was initiated using prompt engineering and reinforcement learning. CONCLUSIONS: This innovative caregiving approach is designed to recognize the signs of agitation and, upon recognition, intervene with empathetic verbal communication. This proposal has the potential to have a significant impact on an emerging field of computational dementia science by reducing unnecessary agitation and falls of persons experiencing moderate to severe dementia, while reducing caregiver burden. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/55761.

Encapsulating Nickel-Iron Alloy Nanoparticles in a Polysilazane-Derived Microporous Si-C-O-N-Based Support to Stimulate Superior OER Activity.

The in situ confinement of nickel (Ni)-iron (Fe) nanoparticles (NPs) in a polymer-derived microporous silicon carboxynitride (Si-C-O-N)-based support is investigated to stimulate superior oxygen evolution reaction (OER) activity in an alkaline media. Firstly, we consider a commercial polysilazane (PSZ) and Ni and Fe chlorides to be mixed in N,N-dimethylformamide (DMF) and deliver after overnight solvent reflux a series of Ni-Fe : organosilicon coordination polymers. The latter are then heat-treated at 500 °C in flowing argon to form the title compounds. By considering a Ni : Fe ratio of 1.5, face centred cubic (fcc) NixFey alloy NPs with a size of 15-30 nm are in situ generated in a porous Si-C-O-N-based matrix displaying a specific surface area (SSA) as high as 237 m2 ⋅ g-1. Hence, encapsulated NPs are rendered accessible to promote electrocatalytic water oxidation. An OER overpotential as low as 315 mV at 10 mA ⋅ cm-2 is measured. This high catalytic performance (considering that the metal mass loading is as low as 0.24 mg cm-2) is rather stable as observed after an activation step; thus, validating our synthesis approach. This is clearly attributed to both the strong NP-matrix interaction and the confinement effect of the matrix as highlighted through post mortem microscopy observations.

A pioneering EMR-embedded digital health literacy tool reveals healthcare disparities for diverse older adults.

BACKGROUND: The COVID-19 pandemic transformed healthcare delivery with the rapid adoption of telehealth and digital technologies to access healthcare. Interventions are needed to ensure that older people in underserved communities do not face new technology-driven healthcare disparities. This article describes pioneering electronic medical record (EMR) embedded tools to assess and support each diverse patient's digital health literacy. METHODS: We designed and validated a rapid EMR-embedded Digital Health Engagement Tool (DHET) to assess each patient's digital literacy in English and Spanish. We built a separate, EMR-generated auto-scoring function to assess patient use of telehealth and healthcare navigation as recorded within the EMR. Combined, the tools created a complete digital literacy assessment for each patient. We then deployed the tools to conduct a pilot study to elucidate disparities. RESULTS: A total of 112 ethnic/racial diverse older patients were enrolled (mean age was 78, ranging from 57 to 96) years (SD = 8.04). The female participants were 72.3%. Among the participants, non-Hispanic Whites were 47.3%; Hispanic 25.0%; non-Hispanic Asian 19.6%; non-Hispanic others (including multi-race and non-Hispanic Black/African Americans) 8.0%. Digital literacy disparities were revealed for older adults, particularly those over 70 years old, female gender, and those reporting relying on a helper. CONCLUSION: New EMR-embedded tools enable healthcare systems to assess the ability of patients to navigate and utilize EMR capabilities, such as video telehealth appointments, messaging providers, reviewing labs/radiology reports, and requesting prescriptions. The study identified significant challenges for older patients in navigating EMRs and calls for healthcare systems to better support patient learning.

The Effectiveness of Language-Specific Personal Care Education on Improving the Knowledge and Skills of Vietnamese American In-Home Supportive Service Caregivers.

BACKGROUND: In-Home Supportive-Services (IHSS) caregivers provide personal care assistance to low-income older adults. According to the California Social Service Department, 20.2% of IHSS caregivers spoke Vietnamese in one county. The purpose of this project was to improve the knowledge and skills among these Vietnamese American caregivers by providing a language-specific and culturally appropriate education on personal care. METHODS: The project used a pre- and post-test design. Under the guidance of nursing faculty, four Vietnamese-speaking nursing students provided a 2-hr educational program on personal care (e.g., bathing, oral care) to registered Vietnamese IHSS caregivers. A pre- and post-survey was conducted. RESULTS: Overall, 55 caregivers completed the surveys. The surveys showed significant increases in confidence in knowledge and skills related to personal care topics (all ps < .001). CONCLUSION: The findings demonstrated that the cultural and language-specific education was effective in increasing knowledge and confidence of Vietnamese IHSS caregivers related to personal care for older adults.

Pioneering COVID-19 Pandemic Partnerships: Federally Qualified Health Centers and Geriatric Workforce Enhancement Programs Work Together to Care for Diverse Underserved Older Adults.

Background: The COVID-19 pandemic disproportionately affected populations served by Federally Qualified Health Centers (FQHCs), with high morbidity and mortality rates in ethnic minority older adults. In response to this pandemic, academic geriatric medicine teams through federally funded Geriatric Workforce Enhancement Program (GWEP) with FQHC partnership implemented new initiatives to improve the care for vulnerable older adults. Objectives: To describe how four FQHC/GWEP teams collaborated in caring for diverse communities of older adults during the pandemic. Methods: Four GWEPs have addressed pandemic response efforts with their respective FQHC partners. These collaborations to meet the increasing numbers of older adults seeking services, and the rising disparities exacerbated during the pandemic are delineated. Results: FQHC/GWEP partnerships enabled access to care, whether in-person or virtually to serve unmet needs of underserved older adults during the pandemic. Partnerships promoted COVID-19 education, testing, and vaccinations. Most FQHCs faced severe staffing shortages, and the digital divide challenged patients with barriers. GWEPs provided direct care, created educational materials, and developed telehealth programs. These partnerships addressed social determinants of health gaps caused by the pandemic. Conclusion: The findings demonstrate that strong partnerships between GWEPs and FQHCs mitigate health inequities for vulnerable ethnic minority and rural older adults during pandemic crises.

Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies.

Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, radiation dose deposition in the kidneys can become a dose-limiting factor. A good exemplar is [177Lu]Lu-DOTATATE, where patients receive a co-infusion of basic amino acids for nephroprotection. Besides peptides, there are other classes of targeting vectors like antibody fragments, antibody mimetics, peptidomimetics, and small molecules that clear through the renal pathway. In this review, we will review established and emerging strategies that can be used to mitigate radiation-induced nephrotoxicity, with a focus on the development and incorporation of cleavable linkers for radiopharmaceutical designs. Finally, we offer our perspectives on cleavable linkers for RLT, highlighting future areas of research that will help advance the technology.

A Culturally and Linguistically Appropriate Telephone Support Intervention for Diverse Family Caregivers of Persons With Dementia During the COVID-19 Pandemic.

Caregivers of persons with dementia (PWDs) were socially isolated with little support during the COVID-19 pandemic "Stay-At-Home" order in the United States. To enhance social and emotional connection for diverse caregivers, a culturally/linguistically appropriate telephone intervention provided compassionate listening, mindful breathing, and COVID-19 safety education. The study purpose was to understand caregiving challenges and to evaluate the intervention for caregivers during the early pandemic using a qualitative approach. Twenty-three caregivers participated in the intervention provided by bilingual research assistants for 3 months. Call logs were used to describe the caregivers' dialogue. Thematic analysis identified (a) the challenges, including fear of coronavirus disease, providing around-the-clock care, and forced isolation and negative emotions; and (b) caregivers' experience with the intervention, including connecting with the outside, relief from emotional stress, reliable COVID-19 information, and reinformed caregiving skills. Results suggest that the telephone support was of benefit to diverse caregivers of PWDs during the pandemic by promoting social connection and reducing emotional distress.

Trastuzumab-conjugated oxine-based ligand for [89Zr]Zr4+ immunoPET.

A new, bifunctional chelating ligand for immuno-Positron Emission Tomography (PET) was designed, synthesized, and conjugated to Trastuzumab for a proof-of-concept study with 89Zr. H4neunox was synthesized from the tris(2-aminoethyl)amine backbone, decorated with 8-hydroxyquinoline moieties, and utilizes a primary amine for functionalization. A maleimide moiety extends the chelator to create H4neunox-mal for antibody conjugation via maleimide-thiol click chemistry. Preliminary 89Zr radiolabeling of H4neunox indicated quantitative radiolabeling at 1 × 10-5 M, but improved inertness towards human serum (96% intact at 7 d) and Fe3+ (92% intact at 24 h) compared to the previously synthesized H5decaox. The chelator was successfully conjugated to the monoclonal antibody, Trastuzumab, and used in preliminary radiolabeling reactions (37 °C, 2 h) with 89Zr. Radiochemical assessments of the new H4neunox-Trastuzumab conjugate include 89Zr radiolabeling, spin filter purification, cell-binding immunoreactivity, and in vivo PET imaging and biodistribution in SKOV-3 tumour bearing nude mice, performed in comparison with the desferrioxamine B analog, DFO-Trastuzumab. The [89Zr]Zr(neunox-Trastuzumab) showed lowered inertness towards serum (76% intact at 24 h) as well as demetallation in vivo through bone uptake (21% ID/g) in PET imaging and biodistribution studies when compared to [89Zr]Zr(DFO-Trastuzumab). Although the combination of the chelator and antibody had detrimental effects on their intended purposes, nonetheless, the primary amine platform of H4neunox developed here provides an oxine-based bifunctional ligand for further derivatizations with other targeting vectors.

Development of a multi faceted platform containing a tetrazine, fluorophore and chelator: synthesis, characterization, radiolabeling, and immuno-SPECT imaging.

BACKGROUND: Combining optical (fluorescence) imaging with nuclear imaging has the potential to offer a powerful tool in personal health care, where nuclear imaging offers in vivo functional whole-body visualization, and the fluorescence modality may be used for image-guided tumor resection. Varying chemical strategies have been exploited to fuse both modalities into one molecular entity. When radiometals are employed in nuclear imaging, a chelator is typically inserted into the molecule to facilitate radiolabeling; the availability of the chelator further expands the potential use of these platforms for targeted radionuclide therapy if a therapeutic radiometal is employed. Herein, a novel mixed modality scaffold which contains a tetrazine (Tz)--for biomolecule conjugation, fluorophore-for optical imaging, and chelator-for radiometal incorporation, in one construct is presented. The novel platform was characterized for its fluorescence properties, radiolabeled with single-photon emission computed tomography (SPECT) isotope indium-111 (111In3+) and therapeutic alpha emitter actinium-225 (225Ac3+). Both radiolabels were conjugated in vitro to trans-cyclooctene (TCO)-modified trastuzumab; biodistribution and immuno-SPECT imaging of the former conjugate was assessed. RESULTS: Key to the success of the platform synthesis was incorporation of a 4,4'-dicyano-BODIPY fluorophore. The route gives access to an advanced intermediate where final chelator-incorporated compounds can be easily accessed in one step prior to radiolabeling or biomolecule conjugation. The DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugate was prepared, displayed good fluorescence properties, and was successfully radiolabeled with 111In & 225Ac in high radiochemical yield. Both complexes were then separately conjugated in vitro to TCO modified trastuzumab through an inverse electron demand Diels-Alder (IEDDA) reaction with the Tz. Pilot small animal in vivo immuno-SPECT imaging with [111In]In-DO3A-BODIPY-Tz-TCO-trastuzumab was also conducted and exhibited high tumor uptake (21.2 ± 5.6%ID/g 6 days post-injection) with low uptake in non-target tissues. CONCLUSIONS: The novel platform shows promise as a multi-modal probe for theranostic applications. In particular, access to an advanced synthetic intermediate where tailored chelators can be incorporated in the last step of synthesis expands the potential use of the scaffold to other radiometals. Future studies including validation of ex vivo fluorescence imaging and exploiting the pre-targeting approach available through the IEDDA reaction are warranted.

Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands.

PURPOSE: Mantle cell lymphoma (MCL) is associated with poor survival. The purpose of this study was to assess whether the C-X-C chemokine receptor type 4 (CXCR4) is a useful target for imaging and radioligand therapy of MCL, using a novel pair of radioligands, [68Ga]Ga and [177Lu]Lu-BL02. EXPERIMENTAL DESIGN: We performed a retrospective analysis of 146 patients with MCL to evaluate CXCR4 expression and its correlation with outcomes. Guided by in silico methods, we designed BL02, a new radioligand labelled with 68Ga or 177Lu for PET imaging and therapy, respectively. We performed imaging and biodistribution studies in xenograft models with varying CXCR4 expression. We evaluated [177Lu]Lu-BL02 in MCL models, and evaluated its potential for therapy in Z138 MCL xenografts. RESULTS: Phosphorylated and nonphosphorylated CXCR4 expression were correlated with poor survival in patients with MCL and characterized by unique underlying molecular signatures. [68Ga]Ga-BL02 uptake correlated with CXCR4 expression, and localized lesions in a metastatic xenograft model. [177Lu]Lu-BL02 showed high uptake in MCL xenografts. Therapy studies with a single dose in the Z138 model showed tumor regression and improved survival compared with a control group. Upon regrowth, the treated mice experienced concurrent metastasis alongside localized xenograft regrowth, and recurrent lesions showed enhanced CXCR4 signaling. CONCLUSIONS: CXCR4 is an independent factor of poor prognosis for MCL and a promising target for imaging and radioligand therapy. [68Ga]Ga-BL02 showed high contrast to visualize CXCR4-expressing xenografts for PET imaging and [177Lu]Lu-BL02 induced rapid tumor regression in a preclinical model of MCL.

Implications of physics, chemistry and biology for dosimetry calculations using theranostic pairs.

Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using radiopharmaceuticals that target identical molecular targets for both imaging (using emitted gamma rays) and radiopharmaceutical therapy (using emitted beta, alpha or Auger-electron particles) for the treatment of various diseases, such as cancer. If the therapeutic radiopharmaceutical cannot be imaged quantitatively, a "theranostic pair" imaging surrogate can be used to predict the absorbed radiation doses from the therapeutic radiopharmaceutical. However, theranostic dosimetry assumes that the pharmacokinetics and biodistributions of both radiopharmaceuticals in the pair are identical or very similar, an assumption that still requires further validation for many theranostic pairs. In this review, we consider both same-element and different-element theranostic pairs and attempt to determine if factors exist which may cause inaccurate dose extrapolations in theranostic dosimetry, either intrinsic (e.g. chemical differences) or extrinsic (e.g. injecting different amounts of each radiopharmaceutical) to the radiopharmaceuticals. We discuss the basis behind theranostic dosimetry and present common theranostic pairs and their therapeutic applications in oncology. We investigate general factors that could create alterations in the behavior of the radiopharmaceuticals or the quantitative accuracy of imaging them. Finally, we attempt to determine if there is evidence showing some specific pairs as suitable for theranostic dosimetry. We show that there are a variety of intrinsic and extrinsic factors which can significantly alter the behavior among pairs of radiopharmaceuticals, even if they belong to the same chemical element. More research is needed to determine the impact of these factors on theranostic dosimetry estimates and on patient outcomes, and how to correctly account for them.

Exercise and Stress in At-Risk Women during Pregnancy and Postpartum.

PURPOSE: We aimed to understand the relationship between exercise and stress among socioeconomically at-risk women who participated in a home visitation service during pregnancy and postpartum. METHODS: A mixed-methods design was used to support and supplement quantitative data using qualitative data. Convenience sampling was used to collect data from at-risk women via questionnaires and follow-up interviews. The Perceived Stress Scale was used to assess stress. Frequency and duration of exercise were assessed based on the American College of Obstetricians and Gynecologists exercise guidelines. Regression analyses examined the association between stress and exercise controlling for covariates. Content analysis was used to understand women's stress management experiences. RESULTS: N = 114 women completed the questionnaire and a subgroup of 11 received follow-up interviews. Greater frequency of exercise was significantly associated with lower levels of stress. Approximately one-third of women reported experiencing significant stress. Talking to their husband or partner was the most used and exercise was the least used coping strategy. Many women recognized the importance of managing stress and benefits of exercise, but were hindered by barriers such as feeling tired, preventing them from exercising. CLINICAL IMPLICATIONS: A personalized and safe exercise program has the potential to be a low-cost stress management strategy for women during pregnancy and postpartum.

"It's a horrible assignment": A qualitative study of labor and delivery nurses' experience caring for patients undergoing labor induction for fetal anomalies or fetal demise.

OBJECTIVES: This study sought to explore labor and delivery (L&D) nurses' experiences caring for women undergoing induction for intrauterine fetal demise (IUFD) or termination for fetal anomalies, and to characterize reluctance towards participation in abortion care or - conversely - the commitment to provide services. STUDY DESIGN: Researchers conducted a qualitative study that consisted of open-ended, semistructured interviews with 15 registered nurses who care for women on L&D at a large metropolitan hospital. We analyzed these data for content and themes. RESULTS: Labor and delivery nurses struggle emotionally, logistically, and morally with bereavement care, whether their patients are experiencing an IUFD or termination for fetal anomalies. The analysis generated the following themes: the emotionally intense work of perinatal loss, feelings of incompetence in bereavement care, ethical conflicts, and judgment of both termination and IUFD patients. In addition, nurses who chose to provide care for patients undergoing induction termination for fetal anomalies described a duty to care for all patients despite the increased logistic and emotional burden. CONCLUSIONS: Much of the discomfort L&D nurses reported caring for patients undergoing induction termination stems from the emotional toll, lack of skills, and bureaucratic burden of bereavement care rather than a moral objection to abortion. Instituting interventions to improve staffing, simplify paperwork, augment bereavement training, and improve support for the emotional burden of caring for these patients may therefore increase access to competent and compassionate abortion care. IMPLICATIONS: Labor and delivery nurses struggle with bereavement care whether their patients are experiencing an IUFD or termination for fetal anomalies. Instituting interventions - like interdisciplinary simulation - to support nurses in bereavement care may increase the number willing to participate in abortion care, thereby improving patient access.

225Ac-H4py4pa for Targeted Alpha Therapy.

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10-6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]- anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]- complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]- ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]- ∼ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]- = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

A Systematic Review of Molecular Imaging Agents Targeting Bradykinin B1 and B2 Receptors.

Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R is absent in normal tissues and is induced by tissue trauma or inflammation. B2R is activated by kinins, while B1R is activated by kinins that lack the C-terminal arginine residue. Perturbations of the kinin system have been implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. In general, excess activation and signaling of the kinin system lead to a pro-inflammatory state. Depending on the disease context, agonism or antagonism of the bradykinin receptors have been considered as therapeutic options. In this review, we summarize molecular imaging agents targeting these G protein-coupled receptors, including optical and radioactive probes that have been used to interrogate B1R/B2R expression at the cellular and anatomical levels, respectively. Several of these preclinical agents, described herein, have the potential to guide therapeutic interventions for these receptors.

Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of 68Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics.

High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of 68Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [68Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [68Ga]Ga-HTK01166. Our data demonstrated that derivatives of [68Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics.

Relationships within MOMS Orange County care coordinated home visitation perinatal program.

PURPOSE: The study aimed to examine how registered nurses (RNs) and paraprofessional home visitors (PHVs) work together as a team to care for underserved perinatal women in a coordinated home visitation program. DESIGN AND METHODS: Qualitative methods were used to understand the perspectives of three RNs and twenty PHVs who worked at MOMS Orange County, a community-based perinatal health program. Individual one-on-one interviews were administered with the RNs and focus groups with the PHVs. Qualitative content analysis was conducted to synthesize themes. RESULTS: RNs perceived themselves as educators, mentors, and supervisors. PHVs thought of themselves as supporters, coaches, and advocates. Interdependence and proactive communication were favorable characteristics of the relationship in which RNs trained PHVs to provide health education. The positive interactions between RNs and PHVs appeared to enhance the client-healthcare provider connection. CONCLUSIONS: Our study is one of the first to describe relationships and communication patterns among the healthcare team in a coordinated home visitation program in the United States. Future studies should examine how additional members of the team, including clients and healthcare providers, view their experiences with a home visitation program.

Osteoblasts mineralization and collagen matrix are conserved upon specific Col1a2 silencing.

Classical osteogenesis imperfecta (OI) is an inherited rare brittle bone disease caused by dominant mutations in the COL1A1 or COL1A2 genes, encoding for the α chains of collagen type I. The definitive cure for the disease will require a gene therapy approach, aimed to correct or suppress the mutant allele. Interestingly, individuals lacking α2(I) chain and synthetizing collagen α1(I)3 homotrimers do not show bone phenotype, making appealing a bone specific COL1A2 silencing approach for OI therapy. To this aim, three different Col1a2-silencing RNAs (siRNAs), -3554, -3825 and -4125, selected at the 3'-end of the murine Col1a2 transcript were tested in vitro and in vivo. In murine embryonic fibroblasts Col1a2-siRNA-3554 was able to efficiently and specifically target the Col1a2 mRNA and to strongly reduce α2(I) chain expression. Its efficiency and specificity were also demonstrated in primary murine osteoblasts, whose mineralization was preserved. The efficiency of Col1a2-siRNA-3554 was proved also in vivo. Biphasic calcium phosphate implants loaded with murine mesenchymal stem cells were intramuscularly transplanted in nude mice and injected with Col1a2-siRNA-3554 three times a week for three weeks. Collagen α2 silencing was demonstrated both at mRNA and protein level and Masson's Trichrome staining confirmed the presence of newly formed collagen matrix. Our data pave the way for further investigation of Col1a2 silencing and siRNA delivery to the bone tissue as a possible strategy for OI therapy.

Evaluation of the Tetrakis(3-Hydroxy-4-Pyridinone) Ligand THPN with Zirconium(IV): Thermodynamic Solution Studies, Bifunctionalization, and in Vivo Assessment of Macromolecular 89Zr-THPN-Conjugates.

Zirconium-89 (89Zr) is a suitable radionuclide for positron-emission tomography (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used 89Zr-chelating agent desferrioxamine B (DFO) in preclinical studies, alternative 89Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising 89Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [ZrIV(THPN)] thermodynamic stability was quantified in solution titration studies, which revealed one of the highest formation constants reported for a zirconium chelate (log ßML 50.3(1), pM = 42.8). Solution stabilities with iron(III) were also exceptionally high and can compete with some of the strongest FeIII-chelates. A first bifunctional derivative of the octadentate ligand, p-SCN-Bn-THPN, was then produced in a multistep synthesis. To assess and compare the long-term 89Zr complex stability, bifunctional THPN, as well as the literature chelators p-SCN-Phe-DFO and p-SCN-Phe-DFO*, were conjugated to the high-molecular weight (800 kDa) polymeric carrier hyperbranched polyglycerol (HPG). The functionalized HPGs were radiolabeled with 89ZrIV, and the integrity of the radioconjugates was assessed over several days in vitro and in vivo. While all three radioconjugates remained >95% intact over 5 days in human plasma, the in vivo study in healthy mice revealed higher physiologic stability of the DFO and DFO* radiochelates over bifunctional THPN conjugates. This was evidenced by increased bone uptake of osteophilic 89ZrIV for THPN. This finding contrasts with the exceptionally high thermodynamic stability of the chelate and suggests either a kinetic or metabolic lability, or may stem from coordinative changes due to the covalent conjugation of the 89Zr-THPN radiochelate as suggested by density functional theory (DFT) calculations. These important findings inform the design of next generation 3,4-HOPO chelates with the aim of improving the physiologic stability. This study furthermore demonstrates how HPG can be used as a robust carrier tool to assess and compare the long-term in vivo stability of radiochelates.