Understanding how volunteer companionship impacts those during the end of life: A realist evaluation.

Volunteers are a popular unpaid support role in end of life care yet how accompaniment influences the dying is underdeveloped. This study examined how companionship works, for whom, in what circumstances and why. Initial realist ideas were developed through participant observation (14 months), document analysis, and realist interviews with companionship trainers (n = 6). Theory testing involved volunteer interviews (n = 7), accounts from the dying, proxy accounts for the dying, and written reflections from companionship training. Companionship helps people live well until they die, prepare for death, and experience a good death. Four areas of volunteering explain these outcomes namely a loving friend, a holistic presence, a non-judgmental intermediary, and wrap around care. The four areas activate mechanisms related to reminiscing, preserving dignity/personhood, and easing suffering, contingent on specific contexts. The findings unpack how volunteering exerts its influence and what contextual factors facilitate outcomes, advancing the knowledge in this area.

An Amorphous Phase Precedes Crystallization: Unraveling the Colloidal Synthesis of Zirconium Oxide Nanocrystals.

One can nowadays readily generate monodisperse colloidal nanocrystals, but the underlying mechanism of nucleation and growth is still a matter of intense debate. Here, we combine X-ray pair distribution function (PDF) analysis, small-angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR), and transmission electron microscopy (TEM) to investigate the nucleation and growth of zirconia nanocrystals from zirconium chloride and zirconium isopropoxide at 340 °C, in the presence of surfactant (tri-n-octylphosphine oxide). Through E1 elimination, precursor conversion leads to the formation of small amorphous particles (less than 2 nm in diameter). Over the course of the reaction, the total particle concentration decreases while the concentration of nanocrystals stays constant after a sudden increase (nucleation). Kinetic modeling suggests that amorphous particles nucleate into nanocrystals through a second order process and they are also the source of nanocrystal growth. There is no evidence for a soluble monomer. The nonclassical nucleation is related to a precursor decomposition rate that is an order of magnitude higher than the observed crystallization rate. Using different zirconium precursors (e.g., ZrBr4 or Zr(OtBu)4), we can tune the precursor decomposition rate and thus control the nanocrystal size. We expect these findings to help researchers in the further development of colloidal syntheses.

Population-Based Mini-Mental State Examination Norms in Adults of Mexican Heritage in the Cameron County Hispanic Cohort.

BACKGROUND: Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings. OBJECTIVE: To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores. METHODS: Visits between 2004-2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50-85- year-old) participants with MMSE <24, a minimum MMSE cutoff most frequently used in Alzheimer's disease (AD) clinical trials. As a secondary analysis, random forest models were constructed to estimate the relative association of the MMSE with potentially relevant variables. RESULTS: The mean age of the sample set (n = 3,404) was 44.4 (SD, 16.0) years old and 64.5% female. Median MMSE was 28 (IQR, 28-29). The percentage of trial-aged participants (n = 1,267) with MMSE <24 was 18.6% overall and 54.3% among the subset with 0-4 YOE (n = 230). The five variables most associated with the MMSE in the study sample were education, age, exercise, C-reactive protein, and anxiety. CONCLUSION: The minimum MMSE cutoffs in most phase III prodromal-to-mild AD trials would exclude a significant proportion of trial-aged participants in this MA cohort, including over half of those with 0-4 YOE.

Click Chemistry-Generated Auristatin F-Linker-Benzylguanine for a SNAP-Tag-Based Recombinant Antibody-Drug Conjugate Demonstrating Selective Cytotoxicity toward EGFR-Overexpressing Tumor Cells.

Antibody-drug conjugates (ADCs) are bifunctional molecules combining the targeting potential of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs. This simple yet intelligently designed system directly addresses the lack of specificity encountered with conventional anti-cancer treatment regimes. However, despite their initial success, the generation of clinically sustainable and effective ADCs has been plagued by poor tumor penetration, undefined chemical linkages, unpredictable pharmacokinetic profiles, and heterogeneous mixtures of products. To this end, we generated a SNAP-tag-based fusion protein targeting the epidermal growth factor receptor (EGFR)-a biomarker of aggressive and drug-resistant cancers. Here, we demonstrate the use of a novel click coupling strategy to engineer a benzylguanine (BG)-linker-auristatin F (AuriF) piece that can be covalently tethered to the EGFR-targeting SNAP-tag-based fusion protein in an irreversible 1:1 stoichiometric reaction to form a homogeneous product. Furthermore, using these recombinant ADCs to target EGFR-overexpressing tumor cells, we provide a proof-of-principle for generating biologically active antimitotic therapeutic proteins capable of inducing cell death in a dose-dependent manner, thus alleviating some of the challenges of early ADC development.

Combining realist evaluation and transformative evaluation to advance research in palliative care: The case of end of life companionship.

BACKGROUND: Palliative care requires innovative methods to understand what works, for whom, in what circumstances and why. Realist evaluation has become one prominent approach due to its preoccupation with building, and testing, causal theories to explain the influence of contextual factors on outcomes. Undertaking realist evaluation is not without challenges and may amplify issues of underrepresentation, disempower those working in palliative care, and produce results with poor ecological validity. Complementary approaches are needed which mitigate these challenges, whilst producing credible findings that advances knowledge. PURPOSE: In this article it is outlined how realist evaluation provides a toolkit to advance research to explain, and empirically test, the complex contours of palliative care. Moreover, it is proposed that transformative evaluation can provide a catalyst to engage and empower those within palliative care, create the opportunity for care transformation, and produce more informed and authentic theories. DISCUSSION: Contemporary issues in palliative care pertain to the complexity of palliative care, the insufficiency of experimental designs alone, and the challenges of achieving inclusive research participation. In this article it is argued that theory led, participatory, opportunistic and naturalistic approaches can provide an antidote to the issues in the literature. The combination also mitigates many methodological critiques of the individual approaches, by increasing the transformative potential of realist evaluation, and explanatory potential of transformative evaluation.

Recommendation to update the British Society for Cutaneous Allergy corticosteroid series.

BACKGROUND: Patch testing is an important investigation when dermatitis is unresponsive to, or worsened by, topical corticosteroid treatment. There is a balance to be struck between testing too many allergens, which is expensive, time consuming and risks causing sensitization, and testing too few, which risks missing the diagnosis. The current British Society for Cutaneous Allergy (BSCA) corticosteroid series comprises eight allergens and was last updated in February 2007. AIM: To review and update the BSCA corticosteroid series. METHODS: We retrospectively analysed data from 16 patch test centres in the UK and Ireland for all patients who were patch tested to a corticosteroid series between August 2017 and July 2019. We recorded the allergens tested, the number and percentage tested to a corticosteroid series and the number of positive results for each allergen. We identified the allergens that test positive in ≥ 0.1% of selectively tested patients. RESULTS: Overall, 3531 patients were tested to a corticosteroid series in the 16 centres. The number of allergens tested ranged from 7 to 18 (mean 10). The proportion of patch test patients who were tested to a corticosteroid series ranged from 1% to 99%. Six allergens in the 2017 BSCA series tested positive in ≥ 0.1% of patients. Nine allergens not in the BSCA corticosteroid series tested positive in ≥ 0.1% of patients. CONCLUSION: This audit demonstrates the importance of regular review of recommended series and the significant variations in practice. The new BSCA corticosteroid series that we recommend contains 13 haptens, with the addition of the patient's own steroid creams as appropriate.

Chemical Insights into the Formation of Colloidal Iridium Nanoparticles from In Situ X-ray Total Scattering: Influence of Precursors and Cations on the Reaction Pathway.

Iridium nanoparticles are important catalysts for several chemical and energy conversion reactions. Studies of iridium nanoparticles have also been a key for the development of kinetic models of nanomaterial formation. However, compared to other metals such as gold or platinum, knowledge on the nature of prenucleation species and structural insights into the resultant nanoparticles are missing, especially for nanoparticles obtained from IrxCly precursors investigated here. We use in situ X-ray total scattering (TS) experiments with pair distribution function (PDF) analysis to study a simple, surfactant-free synthesis of colloidal iridium nanoparticles. The reaction is performed in methanol at 50 °C with only a base and an iridium salt as precursor. From different precursor salts─IrCl3, IrCl4, H2IrCl6, or Na2IrCl6─colloidal nanoparticles as small as Ir∼55 are obtained as the final product. The nanoparticles do not show the bulk iridium face-centered cubic (fcc) structure but show decahedral and icosahedral structures. The formation route is highly dependent on the precursor salt used. Using IrCl3 or IrCl4, metallic iridium nanoparticles form rapidly from IrxClyn- complexes, whereas using H2IrCl6 or Na2IrCl6, the iridium nanoparticle formation follows a sudden growth after an induction period and the brief appearance of a crystalline phase. With H2IrCl6, the formation of different Irn (n = 55, 55, 85, and 116) nanoparticles depends on the nature of the cation in the base (LiOH, NaOH, KOH, or CsOH, respectively) and larger particles are obtained with larger cations. As the particles grow, the nanoparticle structure changes from partly icosahedral to decahedral. The results show that the synthesis of iridium nanoparticles from IrxCly is a valuable iridium nanoparticle model system, which can provide new compositional and structural insights into iridium nanoparticle formation and growth.

Perinatal care for women with refugee backgrounds from African countries: a qualitative study of intersections with psychological wellbeing.

BACKGROUND: Experiences with healthcare services, including perinatal healthcare services, contribute to psychological wellbeing for refugees post-resettlement. To address the paucity of literature examining the relationship between perinatal healthcare and psychological wellbeing in women with refugee backgrounds from African countries this study aimed to: (1) understand the relationship between psychological wellbeing and perinatal care amongst this population, and; (2) identify areas for improved perinatal healthcare services to ensure positive wellbeing outcomes in this population. METHODS: A total of 39 participants were included in the study. Nineteen women from seven African countries participated in interviews - seven both prior to and after having their babies, two only while pregnant and ten only after their baby had been born. In addition, interviews were conducted with 20 service providers. Interviews were thematically analysed. RESULTS: Four key themes were identified, covering continuity of care, cultural safety of care, agency in decision making, and ongoing impacts of perinatal care experiences. CONCLUSIONS: The results highlighted the need for changes to perinatal healthcare provision at the systems level, including implementing a continuity of care model, and ensuring women's access to individualised, trauma-informed perinatal services which attend to the cultural and psychosocial resettlement needs of this population. These findings informed recommendations for improving perinatal healthcare services and better psychological outcomes - and in turn broader health outcomes - for African-background refugee mothers.

Correction to "Mechanistic Insight into the Precursor Chemistry of ZrO2 and HfO2 Nanocrystals, toward Size-Tunable Syntheses".

[This corrects the article DOI: 10.1021/jacsau.1c00568.].

Mechanistic Insight into the Precursor Chemistry of ZrO2 and HfO2 Nanocrystals; towards Size-Tunable Syntheses.

One can nowadays readily generate monodisperse colloidal nanocrystals, but a retrosynthetic analysis is still not possible since the underlying chemistry is often poorly understood. Here, we provide insight into the reaction mechanism of colloidal zirconia and hafnia nanocrystals synthesized from metal chloride and metal isopropoxide. We identify the active precursor species in the reaction mixture through a combination of nuclear magnetic resonance spectroscopy (NMR), density functional theory (DFT) calculations, and pair distribution function (PDF) analysis. We gain insight into the interaction of the surfactant, tri-n-octylphosphine oxide (TOPO), and the different precursors. Interestingly, we identify a peculiar X-type ligand redistribution mechanism that can be steered by the relative amount of Lewis base (L-type). We further monitor how the reaction mixture decomposes using solution NMR and gas chromatography, and we find that ZrCl4 is formed as a by-product of the reaction, limiting the reaction yield. The reaction proceeds via two competing mechanisms: E1 elimination (dominating) and SN1 substitution (minor). Using this new mechanistic insight, we adapted the synthesis to optimize the yield and gain control over nanocrystal size. These insights will allow the rational design and synthesis of complex oxide nanocrystals.

Breaking with the Principles of Coreduction to Form Stoichiometric Intermetallic PdCu Nanoparticles.

Intermetallic nanoparticles (NPs) have shown enhanced catalytic properties as compared to their disordered alloy counterparts. To advance their use in green energy, it is crucial to understand what controls the formation of intermetallic NPs over alloy structures. By carefully selecting the additives used in NP synthesis, it is here shown that monodisperse, intermetallic PdCu NPs can be synthesized in a controllable manner. Introducing the additives iron(III) chloride and ascorbic acid, both morphological and structural control can be achieved. Combined, these additives provide a synergetic effect resulting in precursor reduction and defect-free growth; ultimately leading to monodisperse, single-crystalline, intermetallic PdCu NPs. Using in situ X-ray total scattering, a hitherto unknown transformation pathway is reported that diverges from the commonly reported coreduction disorder-order transformation. A Cu-rich structure initially forms, which upon the incorporation of Pd(0) and atomic ordering forms intermetallic PdCu NPs. These findings underpin that formation of stoichiometric intermetallic NPs is not limited by standard reduction potential matching and coreduction mechanisms, but is instead driven by changes in the local chemistry. Ultimately, using the local chemistry as a handle to tune the NP structure might open new opportunities to expand the library of intermetallic NPs by exploiting synthesis by design.

Surfactant-free syntheses and pair distribution function analysis of osmium nanoparticles.

A surfactant-free synthesis of precious metal nanoparticles (NPs) performed in alkaline low-boiling-point solvents has been recently reported. Monoalcohols are here investigated as solvents and reducing agents to obtain colloidal Os nanoparticles by using low-temperature (<100 °C) surfactant-free syntheses. The effect of the precursor (OsCl3 or H2OsCl6), precursor concentration (up to 100 mM), solvent (methanol or ethanol), presence or absence of a base (NaOH), and addition of water (0 to 100 vol %) on the resulting nanomaterials is discussed. It is found that no base is required to obtain Os nanoparticles as opposed to the case of Pt or Ir NPs. The robustness of the synthesis for a precursor concentration up to 100 mM allows for the performance of X-ray total scattering with pair distribution function (PDF) analysis, which shows that 1-2 nm hexagonal close packed (hcp) NPs are formed from chain-like [OsO x Cl y ] complexes.

Simple Setup Miniaturization with Multiple Benefits for Green Chemistry in Nanoparticle Synthesis.

The development of nanomaterials often relies on wet-chemical synthesis performed in reflux setups using round-bottom flasks. Here, an alternative approach to synthesize nanomaterials is presented that uses glass tubes designed for NMR analysis as reactors. This approach uses less solvent and energy, generates less waste, provides safer conditions, is less prone to contamination, and is compatible with high-throughput screening. The benefits of this approach are illustrated by an in breadth study with the synthesis of gold, iridium, osmium, and copper sulfide nanoparticles.

European patch test results with audit allergens as candidates for inclusion in the European Baseline Series, 2019/20: Joint results of the ESSCAA and the EBSB working groups of the ESCD, and the GEIDACC.

BACKGROUND: In 2019, a number of allergens (haptens), henceforth, "the audit allergens," were considered as potential additions to the European Baseline Series (EBS), namely, sodium metabisulfite, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, imidazolidinyl urea, Compositae mix II (2.5% or 5% pet), linalool hydroperoxides (lin-OOH), limonene hydroperoxides (lim-OOH), benzisothiazolinone (BIT), octylisothiazolinone (OIT), decyl glucoside, and lauryl glucoside; Evernia furfuracea (tree moss), was additionally tested by some departments as well. OBJECTIVES: To collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe. METHODS: Patch test data covering the audit allergens in 2019 and 2020 were collected by those departments of the European Surveillance System on Contact Allergies testing these, as well as further collaborators from the EBS working group of the European Society of Contact Dermatitis (ESCD), and the Spanish Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea. As patch test outcome, reactions between day (D) 3 and D5 were considered. RESULTS: Altogether n = 12 403 patients were tested with any of the audit allergen. Positive reactions were most common to lin-OOH 1% pet. (8.74% [95%CI: 8.14-9.37%]), followed by lin-OOH 0.5% pet., and lim-OOH 0.3% pet (5.41% [95% CI: 4.95-5.89%]). Beyond these terpene hydroperoxides, BIT 0.1% pet. was the second most common allergen with 4.72% (95% CI: 4.2-5.28%), followed by sodium metabisulfite 1% pet. (3.75% [95%CI: 3.32-4.23%]) and Compositae mix 5% pet. (2.31% [95% CI: 1.84-2.87%]). For some allergens, clinical relevance was frequently difficult to ascertain. CONCLUSIONS: Despite many positive patch test reactions, it remains controversial whether lin- and lim-OOH should be tested routinely, while at least the two preservatives BIT and sodium metabisulfite appear suitable. The present results are a basis for further discussion and ultimately decision on their implementation into routine testing among the ESCD members.

Establishment of a Patient-Derived, Magnetic Levitation-Based, Three-Dimensional Spheroid Granuloma Model for Human Tuberculosis.

Tuberculous granulomas that develop in response to Mycobacterium tuberculosis (M. tuberculosis) infection are highly dynamic entities shaped by the host immune response and disease kinetics. Within this microenvironment, immune cell recruitment, polarization, and activation are driven not only by coexisting cell types and multicellular interactions but also by M. tuberculosis-mediated changes involving metabolic heterogeneity, epigenetic reprogramming, and rewiring of the transcriptional landscape of host cells. There is an increased appreciation of the in vivo complexity, versatility, and heterogeneity of the cellular compartment that constitutes the tuberculosis (TB) granuloma and the difficulty in translating findings from animal models to human disease. Here, we describe a novel biomimetic in vitro three-dimensional (3D) human lung spheroid granuloma model, resembling early "innate" and "adaptive" stages of the TB granuloma spectrum, and present results of histological architecture, host transcriptional characterization, mycobacteriological features, cytokine profiles, and spatial distribution of key immune cells. A range of manipulations of immune cell populations in these spheroid granulomas will allow the study of host/pathogen pathways involved in the outcome of infection, as well as pharmacological interventions. IMPORTANCE TB is a highly infectious disease, with granulomas as its hallmark. Granulomas play an important role in the control of M. tuberculosis infection and as such are crucial indicators for our understanding of host resistance to TB. Correlates of risk and protection to M. tuberculosis are still elusive, and the granuloma provides the perfect environment in which to study the immune response to infection and broaden our understanding thereof; however, human granulomas are difficult to obtain, and animal models are costly and do not always faithfully mimic human immunity. In fact, most TB research is conducted in vitro on immortalized or primary immune cells and cultured in two dimensions on flat, rigid plastic, which does not reflect in vivo characteristics. We have therefore conceived a 3D, human in vitro spheroid granuloma model which allows researchers to study features of granuloma-forming diseases in a 3D structural environment resembling in vivo granuloma architecture and cellular orientation.

Patch test results with the European baseline series and additions thereof in the ESSCA network, 2015-2018.

BACKGROUND: Clinical surveillance of the prevalence of contact allergy in consecutively patch tested patients is a proven instrument to continually assess the importance of contact allergens (haptens) assembled in a baseline series. OBJECTIVES: To present current results from the European Surveillance System on Contact Allergies, including 13 countries represented by 1 to 11 departments. METHODS: Anonymized or pseudonymized patch test and clinical data from various data capture systems used locally or nationally as transferred to the Erlangen data centre were pooled and descriptively analysed after quality control. RESULTS: In the 4 years (2015-2018), data from 51 914 patients patch tested with the European baseline series (EBS) of contact allergens were analysed. Contact allergy to nickel was most frequent (17.6% positive), followed by contact allergy to fragrance mix I (6.9%), methylisothiazolinone (MI; 6.2%), and Myroxylon pereirae resin (balsam of Peru; 5.8%). CONCLUSIONS: While the prevalence of MI contact allergy decreased substantially following regulatory intervention, the persistently high levels of allergy to metals, fragrances, other preservatives, and rubber chemicals point to problems needing further research and, potentially, preventive efforts. Results with national additions to the baseline series provide important information on substances possibly to be considered for inclusion in the EBS.

Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers- results of the ESSCA network, 2015-2018.

BACKGROUND: Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq. OBJECTIVES: To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS. MATERIALS AND METHODS: A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs. RESULTS: A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] -0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance. CONCLUSIONS: Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen.