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Gene silencing approaches have the potential to become a powerful curative tool for a variety of monogenic diseases caused by gain-of-function mutations. Classical osteogenesis imperfecta (OI), a dominantly inherited bone dysplasia, is characterized in its more severe forms by synthesis of structurally abnormal type I collagen, which exerts a negative effect on extracellular matrix. Specific suppression of the mutant (Mut) allele would convert severe OI forms to the mild type caused by a quantitative defect in normal collagen. Here, we describe the in vitro and ex vivo investigation of a small interfering RNA (siRNA) approach to allele-specific gene silencing using Mut Col1a1 from the Brtl mouse, a well-characterized model for classical human OI. A human embryonic kidney cell line, which expresses the firefly luciferase gene, combined with either wild-type or Mut Brtl Col1a1 exon 23 sequences, was used for the first screening. The siRNAs selected based on their specificity and the corresponding short hairpin RNAs (shRNAs) subcloned in a lentiviral vector were evaluated ex vivo in Brtl fibroblasts for their effect on collagen transcripts and protein. A preferential reduction of the Mut allele of up to 52% was associated with about 40% decrease of the Mut protein, with no alteration of cell proliferation. Interestingly, a downregulation of HSP47, a specific collagen chaperone known to be upregulated in some OI cases, was detected. Our data support further testing of shRNAs and their delivery by lentivirus as a strategy to specifically suppress the Mut allele in mesenchymal stem cells of OI patients for autologous transplantation. [ABSTRACT FROM AUTHOR]

A well-preserved, low-diversity assemblage of fossil echinoderms from the early Middle Volgian in the Slottsmoya Member (Agardhfjellet Formation) has been discovered at Janusfjellet, Sassenfjorden area, central Spitsbergen. Five species are recognised: the isocrinid Chariocrinus sp., the pedinoid Hemipedina sp., the forcipulate asteroid Asteriidae sp., the ophiacanthid Ophiacanthidae sp. and the ophiurid Ophiurinae sp. A depositional environment model reconciling autecologic, taphonomic and sedimentary evidence is presented. The Janusfjellet Lagerstatte was formed by a single, rapid burial event during a storm, entombing together autochthonous asteroids and ophiurids, and allochthonous crinoids and echinoids on a dysoxic muddy sea-floor. Comparable echinoderm material from the Boreal Late Jurassic-Early Cretaceous is scarce, outdated and usually poorly described and illustrated. The scarcity of reported occurrences probably results from a collector bias for rare complete specimens and does not reflect the true echinoderm composition of Mesozoic high-latitude communities. [ABSTRACT FROM AUTHOR]

Various Pt- and Au-based nanocatalysts prepared by water-in-oil microemulsion method were used to study CO stripping and the oxygen reduction reaction in alkaline medium. It was shown that the particle size increases with the amount of gold in the bimetallic composition, which could be explained by rapid reduction kinetic of gold salt in comparison to that observed with platinum one. This results in the faster formation of nuclei followed by a more rapid growth of the particles. Geometric effects responsible for strong adsorption of CO on high content gold–platinum nanoparticles are discussed as well as the appearing special feature of gold during CO stripping experiments. The absence of a prepeak potential on Au70Pt30/C nanoparticles could be due to a very small amount of weakly adsorbed CO on the surface. A CO-adsorbed layer seems to be so stable and compact that it does not present a formation of “holes” involving a low decrease in repulsive interactions between CO molecules and a shift of the main oxidation peak towards positive potentials. Moreover, the modification of the strength of the Pt–OH bond due to the presence of gold was described as well as the high catalytic activity of gold-based nanoparticles toward the oxygen reduction reaction in 0.1 M NaOH. [ABSTRACT FROM AUTHOR]

Clinical detection of neonatal allo-immune thrombocytopenia (NAITP) is often less than the incidence predicted in prospective studies. The aims of this study were to calculate the observed and expected incidence of NAITP in Quebec, Canada, and to evaluate the clinical outcome of infants with anti-HPA-5b NAITP. Records from 1998 to 2002 of the only PLT serology laboratory for the province of Quebec were reviewed, as were hospital charts of all HPA-5 cases. The number of expected NAITP cases was estimated with known alloantigen gene frequencies. Ninety cases of NAITP were identified. The clinical detection rate was 1 in 4100, with 9 to 30 percent of expected HPA-1a and 11 to 23 percent of expected HPA-5b NAITP cases detected. Seventy-eight percent of cases of HPA-5b NAITP were asymptomatic. Sixty-three percent of all deliveries but 94 percent of HPA-5b cases occurred in hospitals performing cord blood PLT counts. The NAITP detection rate was 25 to 50 percent of the rate reported in prospective trials. The less severe clinical presentation of NAITP owing to HPA-5b was confirmed. The frequent routine determination of cord blood PLT counts may explain increased detection of asymptomatic NAITP involving anti-HPA-5b. [ABSTRACT FROM AUTHOR]

A series of hybrid catalysts with different catalytic bed dispositions (layer bed and simple random mixture) of Cu-ZnO-Al 2 O 3 and SAPO-34 have been adopted and evaluated in syngas conversion into light C2-C4 hydrocarbons. An effect of the proximity between the two solids on the CO hydrogenation activity was demonstrated. A sphere contact quantification model was developed to estimate the concentration of contact between them for any simple random mixture. Comparing the evolution of gain of CO conversion (or hydrocarbon yield) with the theoretical results, it was shown that the density of contact was identified as the key factor for the catalytic performances (contact-activity relationship). Finally, the knowledge of the contact morphology, determined by FEG-SEM, allowed proposing the NH 3 -TPD as method characterizing the concentration of contact. [Display omitted] • The contacts between Cu-ZnO-Al 2 O 3 and SAPO-34 enhance the conversion of CO into hydrocarbons. • The CO conversion is markedly influenced by the balance between the two catalysts in simple random mixture arrangement. • A predictive model for the concentration of contacts quantification in simple random mixture was developed. • NH 3 -TPD was showed as method characterizing the concentration of contact. • Contact–activity relationship was established for layer bed and simple random mixture arrangements. [ABSTRACT FROM AUTHOR]

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) Ni x Fe y 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 m 2  ⋅ 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., (© 2024 Wiley-VCH GmbH.)

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 p s < .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.

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 89 Zr. H 4 neunox 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 H 4 neunox-mal for antibody conjugation via maleimide-thiol click chemistry. Preliminary 89 Zr radiolabeling of H 4 neunox indicated quantitative radiolabeling at 1 × 10 -5  M, but improved inertness towards human serum (96% intact at 7 d) and Fe 3+ (92% intact at 24 h) compared to the previously synthesized H 5 decaox. The chelator was successfully conjugated to the monoclonal antibody, Trastuzumab, and used in preliminary radiolabeling reactions (37 °C, 2 h) with 89 Zr. Radiochemical assessments of the new H 4 neunox-Trastuzumab conjugate include 89 Zr 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 [ 89 Zr]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 [ 89 Zr]Zr(DFO-Trastuzumab). Although the combination of the chelator and antibody had detrimental effects on their intended purposes, nonetheless, the primary amine platform of H 4 neunox developed here provides an oxine-based bifunctional ligand for further derivatizations with other targeting vectors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

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 [ 177 Lu]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.

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.

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 ( 111 In 3+ ) and therapeutic alpha emitter actinium-225 ( 225 Ac 3+ ). 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 111 In & 225 Ac 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 [ 111 In]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., (© 2022. The Author(s).)

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., (©2022 The Authors; Published by the American Association for Cancer Research.)

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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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., (Copyright © 2021. Published by Elsevier Inc.)

Herein, we present the syntheses and characterization of a new undecadendate chelator, H 4 py4pa, and its bifunctional analog H 4 py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H 4 py4pa possesses excellent affinity for 225 Ac (α, t 1/2 = 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 H 4 py4pa with large metal ions, lanthanum (La 3+ ), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225 Ac to enable a series of nonradioactive chemical studies. In line with the 1 H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)] - anion possessed a high degree of symmetry, and the La 3+ 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 H 2 macropa (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 H 4 py4pa 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.

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 68 Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [ 68 Ga]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. [ 68 Ga]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 [ 68 Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [ 68 Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [ 68 Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [ 68 Ga]Ga-HTK01166. Our data demonstrated that derivatives of [ 68 Ga]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.

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., (© 2019 Wiley Periodicals, Inc.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Zirconium-89 ( 89 Zr) 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 89 Zr-chelating agent desferrioxamine B (DFO) in preclinical studies, alternative 89 Zr-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 89 Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [Zr IV (THPN)] thermodynamic stability was quantified in solution titration studies, which revealed one of the highest formation constants reported for a zirconium chelate (log β ML 50.3(1), pM = 42.8). Solution stabilities with iron(III) were also exceptionally high and can compete with some of the strongest Fe III -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 89 Zr 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 89 Zr IV , 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 89 Zr IV 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 89 Zr-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.

An Emotional Health Curriculum (EHC) was developed to promote positive mental health in primarily Hispanic elementary school-aged children. In order to further expand the EHC, the mothers' experiences with the curriculum were examined. Eighteen mothers participated in two focus groups. Mothers reported that they valued this curriculum as a preventive program. Importantly, all mothers wished to extend their involvement to not only assisting their child in completing the curriculum homework but also attending a proposed parenting program. This study provides preliminary evidence that mothers embraced the EHC as an accessible community mental health service for their children and sought greater involvement.

High rates of mental health problems in adolescents have been well documented; less is known about elementary school children in disadvantaged communities. We examined emotional and behavioral health needs in 202 third and fourth graders enrolled in a charter school in a largely Hispanic community. The child-reported Revised Child Anxiety and Depression Scale-25 and Teacher's Report Form were used to evaluate mental health needs as perceived by these children and their teachers. The prevalence of teacher-reported depression and child self-reported anxiety was 7.0% and 6.67%, respectively. Living in a single parent household was found to be a specific risk factor in that those children had higher rates of emotional and behavioral problems than children living with both parents. Evidence of higher depression and anxiety identified in this sample compared to national representative data suggests the need for development of culturally sensitive early prevention and intervention in this underserved community.

Potentially nonadentate (N 5 O 4 ) bifunctional chelator p-SCN-Bn-H 4 neunpa and its immunoconjugate H 4 neunpa-trastuzumab for 111 In radiolabeling are synthesized. The ability of p-SCN-Bn-H 4 neunpa and H 4 neunpa-trastuzumab to quantitatively radiolabel 111 InCl 3 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In 3+ , Bi 3+ , and La 3+ resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both 111 In complexes to have high stability over 5 days. Mouse biodistribution of [ 111 In][In(p-NO 2 -Bn-neunpa)] - , compared to that of [ 111 In][In(p-NH 2 -Bn-CHX-A″-diethylenetriamine pentaacetic acid (DTPA))] 2- , at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates 111 In-neunpa-trastuzumab and 111 In-CHX-A″-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of 111 In-neunpa-trastuzumab compared to that of 111 In-CHX-A″-DTPA-trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN-Bn-H 4 neunpa to be a promising chelator for 111 In (and other radiometals) with high in vitro stability and also show H 4 neunpa-trastuzumab to be an excellent 111 In chelator with promising biodistribution in mice.

Problem: Hispanic children have greater mental health challenges but fewer received mental health services than other ethnic groups. A classroom-based Emotional Health Curriculum (EHC) was developed to address mental health disparities in an underserved Hispanic community., Methods: A quasi-experimental design with one group pre- and post-intervention was used to test the feasibility of an 8-week EHC for one hundred 3rd and 4th grade children in a dual-immersion Spanish-English elementary school. Limited efficacy was measured by changes in depression and anxiety scores reported by children and teachers. Acceptance was evaluated by a child-reported satisfaction survey and a focus group in which the four teachers shared their experiences. Implementation was measured by participation, retention, and fidelity rates., Findings: The child-reported depression and anxiety and teacher-reported depression were significantly decreased in at-risk children with the effect size ranging from 0.60 to 1.16 (ps < 0.05). The majority of children (89.7%) enjoyed the EHC and teachers observed that children had acquired skills to manage their emotional distress. The participation, retention, and fidelity rates were 98%, 94%, and 99.13%, respectively., Conclusions: The results provide promising evidence that the EHC has the potential to improve depression and anxiety symptoms in at-risk children., (© 2018 Wiley Periodicals, Inc.)

The aim of this work was to obtain an in-depth understanding of the U(VI) adsorption mechanism over amino-functionalized mesoporous silica SBA-15 and highlights its high efficiency in aqueous media for U(VI) removal and preconcentration. The samples were synthesized and functionalized by both grafting and co-condensation methods, using different alkyl-substituted amine groups and were characterized using X-ray diffraction, N 2 physisorption, Fourier transform infrared spectroscopy, and elemental C-H-N-S analyses. The properties for U(VI) adsorption were evaluated under discontinuous conditions, with the determination of the effect of several parameters (initial pH, contact time, initial U(VI) concentration, functionalization method, and organic moiety composition). U(VI) adsorption over grafted materials reached equilibrium at around 30 min, with a maximum adsorption capacity of 573 mg U ·g ads -1 for the most efficient material at its optimal adsorption pH (equal to 6) at 20 °C. Functionalized materials by grafting exhibit better adsorption capacities than co-condensed samples because of higher function surface density and function availability. U(VI) adsorption mechanisms were also studied by measuring the electrophoretic mobilities of the particles, aqueous U(VI) speciation, in situ attenuated total reflection infrared and Raman spectroscopies, and transmission electron microscopy analysis. U(VI) adsorption occurred through the formation of an inner sphere complex. The localization of adsorbed U(VI) has also been determined inside of the mesopores, with the formation of several particles on the nanometer scale, in the size of U-hydroxy phases. Besides, the study of the reusability of amino-functionalized SBA-15 by applying adsorption-desorption cycles was also conducted. The adsorption capacity of the material remains stable for at least four adsorption-desorption cycles without any noticeable capacity decrease.

Background: The somatostatin receptor subtype 2 (sstr2) is expressed on a majority of luminal breast cancers, however SPECT and scintigraphy imaging with agonistic sstr2 probes has been sub-optimal. High affinity antagonists can access more binding sites on the cell surface, resulting in higher tumor uptake and improved sensitivity. We compared the tumor uptake and biodistribution of the antagonist 68 Ga-NODAGA-JR11 with two agonists 68 Ga-DOTA-Tyr 3 -octreotide ( 68 Ga-DOTATOC) and 68 Ga-DOTA-Tyr 3 -octreotate ( 68 Ga-DOTATATE), in the human, sstr2-positive, luminal breast cancer model: ZR-75-1., Results: Peptides were assayed for binding affinity using a filtration-based competitive assay to sstr2. nat Ga-DOTATOC and nat Ga-DOTATATE had excellent affinity (inhibition constant K i : 0.9 ± 0.1 nM and 1.4 ± 0.3 nM respectively) compared to nat Ga-NODAGA-JR11 (25.9 ± 0.2 nM). The number of binding sites on ZR-75-1 cells was determined in vitro by saturation assays. Agonist 67/nat Ga-DOTATOC bound to 6.64 ± 0.39 × 10 4 sites/cells, which was 1.5-fold higher than 67/nat Ga-NODAGA-JR11 and 2.3-fold higher than 67/nat Ga-DOTATATE. All three 68 Ga-labeled peptides were obtained in good decay-corrected radiochemical yield (61-68%) and were purified by high performance liquid chromatography to ensure high specific activity (137 - 281 MBq/nmol at the end of synthesis). NOD scid gamma mice bearing ZR-75-1 tumors were injected intravenously with the labeled peptides and used for PET/CT imaging and biodistribution at 1 h post-injection. We found that 68 Ga-DOTATOC had the highest tumor uptake (18.4 ± 2.9%ID/g), followed by 68 Ga-DOTATATE (15.2 ± 2.2%ID/g) and 68 Ga-NODAGA-JR11 (12.2 ± 0.8%ID/g). Tumor-to-blood and tumor-to-muscle ratios were also higher for the agonists (>40 and >150 respectively), compared to the antagonist (15.6 ± 2.2 and 45.2 ± 11.6 respectively)., Conclusions: The antagonist 68 Ga-NODAGA-JR11 had the lowest tumor uptake and contrast compared to agonists 68 Ga-DOTATOC and 68 Ga-DOTATATE in ZR-75-1 xenografts.The main contributing factor to this result could be the use of an endogenously expressing cell line, which may differ from previously published transfected models in the number of low-affinity, antagonist-specific binding sites. The relative merit of agonists versus antagonists for sstr2 breast cancer imaging warrants further investigation, first in preclinical models with other sstr2-positive breast cancer xenografts, and ultimately in luminal breast cancer patients.

Background: MOMS Orange County is a coordinated home visitation program in which trained paraprofessional home visitors work under the close supervision of registered nurses. This model was developed to address health disparities in birth outcomes in a Hispanic community in Orange County, CA., Purpose: The primary objective was to test the impact of MOMS Orange County on birth outcomes. The second objective was to examine the breadth of prenatal health education topics as a mediator of the relationship between home visits and birth outcomes., Methods: A retrospective cohort design was used. Paraprofessional home visitors collected prenatal and postnatal data during home visits. Only those whose birth outcomes were obtained were included in the analysis (N = 2,027 participants). Regression models were conducted to test the associations between prenatal home visits and birth outcomes, adjusting for 10 covariates., Results: Number of prenatal home visits predicted higher birthweight and greater gestational age at birth. Breadth of health education topics partially mediated the associations between home visits and birthweight. The same mediation was revealed with gestational age at birth., Clinical Implications: The MOMS Orange County prenatal home visitation program may be a promising approach to decrease adverse birth outcomes in disadvantaged communities. Rigorously designed studies are needed to further test this model.

Interleukin 1 (IL1) may play an important role in endometriosis-associated pelvic inflammation, and natural specific inhibitors, including soluble IL1 receptor accessory protein (sIL1RAcP) and soluble IL1 receptor type 2 (sIL1R2), are critical for counterbalancing the pleiotropic effects of IL1. The objective of this study was to evaluate the levels of sIL1RAcP, together with those of sIL1R2 and IL1β, in the peritoneal fluid of women with and without endometriosis. Peritoneal fluid samples were obtained at laparoscopy and assessed by ELISA. sIL1RAcP concentrations were reduced in endometriosis stages I-II and III-IV. sIL1R2 concentrations were decreased, and those of IL1β were significantly increased in endometriosis stages I-II. sIL1RAcP and sIL1R2 concentrations were significantly decreased in the secretory phase of the menstrual cycle, and IL1β concentrations were elevated in the proliferative and the secretory phases. sIL1RAcP and sIL1R2 concentrations were reduced in women with endometriosis who were infertile, fertile, suffering from pelvic pain or pain-free. However, IL1β concentrations were significantly reduced in women with endometriosis who were infertile or had pelvic pain. These changes may exacerbate the local peritoneal inflammatory reaction observed in women with endometriosis and contribute to endometriosis pathophysiology and the major symptoms of this disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Tumor cells alter the balanced process of bone formation and bone resorption mediated respectively by osteoblasts and osteoclasts, leading to the disruption of the normal equilibrium and resulting in a spectrum of osteolytic to osteoblastic lesions. This review will summarize research on molecules that play direct and essential roles in the differentiation and activity of osteoclasts, and the role of these molecules in bone destruction caused by cancer. Results from experimental models suggest that the Receptor Activator of NF-kB Ligand (RANKL), a member of the TNF superfamily is a common effector of bony lesions in osteolysis caused by primary and secondary bone tumors. Therefore, osteoclast represents an attractive target across a broad range of tumors that develop in bone. Elucidation of the mechanisms of RANKL interactions with its activator (RANK) and decoy (osteoprotegerin: OPG) receptors has enable the development of pharmacological inhibitors of RANKL (and of its signalling pathway) which have been recently patented, with potential for the treatment of cancer-induced bone disease. Blocking bone resorption by specific other drugs such as bisphosphonates, inhibitors of cathepsin K (the main enzyme involved in bone resorption mechanisms) or signalling pathways regulating osteoclast differentiation and activation is also a promising target for the treatment of osteolysis associated to bone tumors.

Osteosarcoma is the most frequent primary bone tumor that develops mainly during youth, the median age of diagnosis being 18 years. Despite improvement in osteosarcoma treatment, survival rate is only 30% after 5 years for patients with pulmonary metastases at diagnosis. This warrants exploration of new therapeutic options. The anti-bone resorption molecule receptor activator of NF-kappaB (RANK) is very promising, as it may block the vicious cycle between bone resorption and tumor proliferation that takes place during tumor development in bone site. The cDNA encoding murine RANK-Fc (mRANK-Fc) was administered by gene transfer using an amphiphilic polymer in a mouse model of osteolytic osteosarcoma. Clinical and bone microarchitecture variables were assessed by radiography and micro-CT analyses. In vitro experiments were designed to determine the mechanism of action of RANK-Fc on tumor cell proliferation (XTT assays), apoptosis (caspase activation), cell cycle distribution (fluorescence-activated cell sorting analysis), or gene expression (reverse transcription-PCR). RANK-Fc was effective in preventing the formation of osteolytic lesions associated with osteosarcoma development and in reducing the tumor incidence, the local tumor growth, and the lung metastases dissemination leading to a 3.9-fold augmentation of mice survival 28 days after implantation. On the contrary, mRANK-Fc did not prevent the development of nonosseous tumor nodules, suggesting that bone environment is necessary for mRANK-Fc therapeutic efficacy. Furthermore, mRANK-Fc has no direct activity on osteosarcoma cells in vitro. mRANK-Fc exerts an indirect inhibitory effect on osteosarcoma progression through inhibition of bone resorption.