End-of-life doulas: A systematic integrative review and redirection.

BACKGROUND AND OBJECTIVES: End-of-life doulas (EOLD) are an emerging role providing non-medical support and advocacy for the dying and their families. Research about EOLD is new and currently highlights a need for more clarity in role definition and application. This review aims to comprehensively analyze existing knowledge regarding EOLD and their role in end-of-life care. RESEARCH DESIGN AND METHODS: A systematic and comprehensive search of nine bibliographic databases identified all published academic articles related to EOLD (as named, self-identified, and/or trained) research from inception to June 2023. This review utilized an integrative approach and textual narrative synthesis to summarize the existing body of research findings related to EOLD. RESULTS: Twenty-five articles were identified, representing multiple disciplines including health and medicine, public health, social/behavioral sciences, and humanities. Research on EOLD has rapidly increased in recent years and is showing signs of maturation. The review focuses specifically on summarizing the breadth and depth of identified research on EOLD and critically analyzes emergent themes from the review: Application, Perception, Identity, and Future Research Directions. DISCUSSION AND IMPLICATIONS: This review provides the most comprehensive review of the research literature on EOLD to date. Thematic findings for future research directions have provided the basis of a redirected research agenda to guide the field going forward. There is still a need to clarify who EOLD are and how they are being conceptualized by multiple stakeholders. Future research must address these missing voices to fully grasp the value and unique role that EOLD contribute to EOL care.

Stimuli-responsive anion transport utilising caged hydrazone-based anionophores.

Ion transport across biological membranes, facilitated by naturally occurring ion channels and pumps, plays a crucial role in biological processes. Gating is an important aspect of these systems, whereby transport is regulated by a range of external stimuli such as light, ligands and membrane potential. While synthetic ion transport systems, especially those with gating mechanisms, are rare, they have garnered significant attention due to their potential applications in targeted therapeutics as anticancer agents or to treat channelopathies. In this work, we report stimuli-responsive anion transporters based on dynamic hydrogen bonding interactions of hydroxyl-functionalised hydrazone anionophores. Caging of the hydroxyl groups with moities that are responsive to light and H2S locks the hydrazone protons through intramolecular hydrogen bonding, rendering them unavailable for anion binding and transport. Upon decaging with light or H2S, the hydrogen bonding pattern is reversed, rendering the hydrazone protons available for anion binding, and leading to efficient switch-on of ion transport across the lipid bilayer membrane.

Effect of Ventilator Mode on Ventilator-Free Days in Critically Ill Adults: A Randomized Trial.

Rationale: For critically ill adults receiving invasive mechanical ventilation, the ventilator mode determines how breaths are delivered. Whether the choice of ventilator mode affects outcomes for critically ill patients is unknown. To compare the effects of three common ventilator modes (volume control, pressure control, and adaptive pressure control) on death and duration of mechanical ventilation. Methods: We conducted a pragmatic, cluster-randomized, crossover trial among adults receiving invasive mechanical ventilation in a medical ICU between November 1, 2022 and July 31, 2023. Each month, patients in the participating unit were assigned to receive volume control, pressure control, or adaptive pressure control during continuous mandatory ventilation. The primary outcome was ventilator-free days through 28 days. Results: Among 566 patients included in the primary analysis, the median number of ventilator-free days was 23 [IQR, 0-26] in the volume control group, 22 [0-26] in the pressure control group, and 24 [0-26] in the adaptive pressure control group (P=0.60). The median tidal volume was similar in the three groups, but the percentage of breaths larger than 8mL/kg of predicted body weight differed between volume control (median, 4.0%; IQR, 0.0-14.1), pressure control (10.6%; 0.0-31.5), and adaptive pressure control (4.7%; 0.0-19.2). Incidences of hypoxemia, acidemia, and barotrauma were similar in the three groups. Conclusions: Among critically ill adults receiving invasive mechanical ventilation, the use of volume control, pressure control, or adaptive pressure control did not affect the number of ventilator-free days, however, confidence intervals included differences that may be clinically meaningful.

Evaluating the Efficacy of Time for Living and Caring: An Online Intervention to Support Dementia Caregivers' Use of Respite.

Background and Objectives: Respite, defined as time away from caregiving, is the most requested type of caregiver support. Time for Living and Caring (TLC) is a virtual coaching "app" that helps caregivers schedule and plan their respite time-use. The objectives of this analysis are: (1) to assess the efficacy of the TLC intervention on respite time-use and on caregiver well-being and (2) to identify the key features of the intervention that serve as the likely mechanism of action. Research Design and Methods: A sample of dementia caregivers (n = 163, 79% female, 84% White, 6% Hispanic, average age 62) were randomized into one of two intervention delivery methods. Intervention efficacy was evaluated using pre/post-comparisons of respite time-use and an additive "dosing" model that estimated unique parameters associated with the exposure to each specific intervention component. Results: Both immediate and delayed-attention groups reported increased respite time. They also improved in their ability to plan and perceive benefit from their respite time-use over the 16-week intervention period. At 8 weeks, the immediate group did not change in anxiety, whereas the delayed group worsened (p < .001). At 16 weeks, the groups were similar in their anxiety levels. By the 20-week follow-up period, when neither group had access to TLC, both experienced an increase in anxiety. Discussion and Implications: TLC is a promising intervention that may support caregivers' well-being, by helping them schedule and plan their respite to maximize its benefit. The provision of weekly coaching seems to be the intervention component (mechanism) associated with caregiver outcomes. Clinical Trial Registration: NCT03689179.

Protocol and Statistical Analysis Plan for the Mode of Ventilation During Critical Illness (MODE) Trial.

BACKGROUND: For every critically ill adult receiving invasive mechanical ventilation, clinicians must select a mode of ventilation. The mode of ventilation determines whether the ventilator directly controls the tidal volume or the inspiratory pressure. Newer hybrid modes allow clinicians to set a target tidal volume; the ventilator controls and adjusts the inspiratory pressure. A strategy of low tidal volumes and low plateau pressure improves outcomes, but the optimal mode to achieve these targets is not known. RESEARCH QUESTION: Can a cluster-randomized trial design be used to assess whether the mode of mandatory ventilation affects the number of days alive and free of invasive mechanical ventilation among critically ill adults? STUDY DESIGN AND METHODS: The Mode of Ventilation During Critical Illness (MODE) trial is a cluster-randomized, multiple-crossover pilot trial being conducted in the medical ICU at an academic center. The MODE trial compares the use of volume control, pressure control, and adaptive pressure control. The study ICU is assigned to a single-ventilator mode (volume control vs pressure control vs adaptive pressure control) for continuous mandatory ventilation during each 1-month study block. The assigned mode switches every month in a randomly generated sequence. The primary outcome is ventilator-free days to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of mechanical ventilation to 28 days after enrollment. Enrollment began November 1, 2022, and will end on July 31, 2023. RESULTS: This manuscript describes the protocol and statistical analysis plan for the MODE trial of ventilator modes comparing volume control, pressure control, and adaptive pressure control. INTERPRETATION: Prespecifying the full statistical analysis plan prior to completion of enrollment increases rigor, reproducibility, and transparency of the trial results. CLINICAL TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov on October 3, 2022, before initiation of patient enrollment on November 1, 2022 (ClinicalTrials.gov identifier: NCT05563779).

The Impact of Infant Bacille Calmette-Guérin Vaccination on the Immunogenicity of Other Vaccines: A Randomized Exploratory Study.

The effect of the Bacille Calmette-Guérin (BCG) vaccine on the immunogenicity of separately administered serogroup C meningococcal vaccine and other vaccinations was examined in 28 infants randomized to receive BCG at age ≤7 days, at 3 months or after study completion. Immunogenicity of the serogroup C meningococcal vaccine and other routine vaccines might be improved when BCG is administered in early infancy.

Comparison of recruitment methodologies for clinical trials: Results from the time for living and caring (TLC) intervention study.

BACKGROUND: Recruiting participants for research studies is a critical yet challenging task. Community-engaged recruitment strategies have gained prominence as effective means to engage diverse populations and ensure the representativeness of study samples. This case study aims to investigate the cost and effectiveness of various recruitment methods in enhancing research participation. METHODS: A comparative approach was employed to assess the outcomes of five different recruitment strategies used in the Time for Living & Caring (TLC) research study. Data on recruitment success, participant demographics, and retention rates were collected and analyzed using descriptive statistics, including ANOVA and Chi-squares, to statistically compare the outcomes associated with 5 different recruitment methodologies. The recruitment methodologies included two community-engaged strategies (community partner referral and community-based recruiters), a clinical database, social media, and word-of-mouth referral. CONCLUSION: The meta-data used to build this methodological case study describe different recruitment methodologies that may be used for clinical trials. This data-driven evaluation provides examples and considerations for researchers when developing budgets and proposals for future clinical trials. The primary finding is that there are tradeoffs in terms of cost, time, labor, and ultimately the representativeness of the sample, based on the type of recruitment methodology chosen.

Using Digital Inequality Framework to Evaluate a Technology-Delivered Intervention for Caregivers: Age, Education, and Computer Proficiency.

Objectives: Using "digital inequality" as a conceptual framework, this study evaluates the feasibility and usability of a technology-delivered intervention (an "app") for Alzheimer's and related dementia family caregivers. Time for Living and Caring (TLC) is an on-line intervention that provides virtual coaching and self-administered education and resources. Methods: A sample of family caregivers (n = 163) used the tool for 16 weeks, which included completing the Computer Proficiency Questionnaire (CPQ-12) at baseline. Analyses investigate the relationship between age, CPQ scores, intervention use, appraisal, and caregiver outcomes. Results: Age was inversely associated with CPQ; however, CPQ scores did not have a significant relationship with participant's self-perceived benefits or intervention appraisal. Computer Proficiency Questionnaire scores provided insight regarding research feasibility, with lower scores associated with greater odds of discontinuing engagement. Discussion: CPQ-12 scores can be used as a screening tool to identify those who may need additional support to engage with and benefit from technology-delivered interventions.

Masked alkynes for synthesis of threaded carbon chains.

Polyynes are chains of sp1 carbon atoms with alternating single and triple bonds. As they become longer, they evolve towards carbyne, the 1D allotrope of carbon, and they become increasingly unstable. It has been anticipated that long polyynes could be stabilized by supramolecular encapsulation, by threading them through macrocycles to form polyrotaxanes-but, until now, polyyne polyrotaxanes with many threaded macrocycles have been synthetically inaccessible. Here we show that masked alkynes, in which the C≡C triple bond is temporarily coordinated to cobalt, can be used to synthesize polyrotaxanes, up to the C68 [5]rotaxane with 34 contiguous triple bonds and four threaded macrocycles. This is the length regime at which the electronic properties of polyynes converge to those of carbyne. Cyclocarbons constitute a related family of molecular carbon allotropes, and cobalt-masked alkynes also provide a route to [3]catenanes and [5]catenanes built around cobalt complexes of cyclo[40]carbon and cyclo[80]carbon, respectively.

Protocol and statistical analysis plan for the Mode of Ventilation During Critical IllnEss (MODE) trial.

Introduction: For every critically ill adult receiving invasive mechanical ventilation, clinicians must select a mode of ventilation. The mode of ventilation determines whether the ventilator directly controls the tidal volume or the inspiratory pressure. Newer hybrid modes allow clinicians to set a target tidal volume, for which the ventilator controls and adjusts the inspiratory pressure. A strategy of low tidal volumes and low plateau pressure improves outcomes, but the optimal mode to achieve these targets is not known. Methods and analysis: The Mode of Ventilation During Critical Illness (MODE) trial is a cluster-randomized, multiple-crossover pilot trial being conducted in the medical intensive care unit (ICU) at an academic center. The MODE trial compares the use of volume control, pressure control, and adaptive pressure control. The study ICU is assigned to a single ventilator mode (volume control versus pressure control versus adaptive pressure control) for continuous mandatory ventilation during each 1-month study block. The assigned mode switches every month in a randomly generated sequence. The primary outcome is ventilator-free days (VFDs) to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of mechanical ventilation to 28 days after enrollment. Enrollment began November 1, 2022 and will end on July 31, 2023. Ethics and dissemination: The trial was approved by the Vanderbilt University Medical Center institutional review board (IRB# 220446). Results of this study will be submitted to a peer-reviewed journal and presented at scientific conferences. Trial registration number: The trial was registered with clinicaltrials.gov on October 3, 2022, prior to initiation of patient enrollment on November 1, 2022 (ClinicalTrials.gov identifier: NCT05563779).

Hydrogen atoms in supramolecular chemistry: a structural perspective. Where are they, and why does it matter?

Hydrogen bonding interactions are ubiquitous across the biochemical and chemical sciences, and are of particular interest to supramolecular chemists. They have been used to assemble hydrogen bonded polymers, cages and frameworks, and are the functional motif in many host-guest systems. Single crystal X-ray diffraction studies are often used as a key support for proposed structures, although this presents challenges as hydrogen atoms interact only weakly with X-rays. In this Tutorial Review, we discuss the information that can be gleaned about hydrogen bonding interactions through crystallographic experiments, key limitations of the data, and emerging techniques to overcome these limitations.

Memory-like innate response to booster vaccination with MF-59 adjuvanted influenza vaccine in children.

The pediatric population receives the majority of vaccines globally, yet there is a paucity of studies on the transcriptional response induced by immunization in this special population. In this study, we performed a systems-level analysis of immune responses to the trivalent inactivated influenza vaccine adjuvanted with MF-59 in children (15-24 months old) and in young, healthy adults. We analyzed transcriptional responses elicited by vaccination in peripheral blood, as well as cellular and antibody responses following primary and booster vaccinations. Our analysis revealed that primary vaccination induced a persistent transcriptional signature of innate immunity; booster vaccination induced a transcriptional signature of an enhanced memory-like innate response, which was consistent with enhanced activation of myeloid cells assessed by flow cytometry. Furthermore, we identified a transcriptional signature of type 1 interferon response post-booster vaccination and at baseline that was correlated with the local reactogenicity to vaccination and defined an early signature that correlated with the hemagglutinin antibody titers. These results highlight an adaptive behavior of the innate immune system in evoking a memory-like response to secondary vaccination and define molecular correlates of reactogenicity and immunogenicity in infants.

ß,ß-Directly Linked Porphyrin Rings: Synthesis, Photophysical Properties, and Fullerene Binding.

Cyclic porphyrin oligomers have been studied as models for photosynthetic light-harvesting antenna complexes and as potential receptors for supramolecular chemistry. Here, we report the synthesis of unprecedented ß,ß-directly linked cyclic zinc porphyrin oligomers, the trimer (CP3) and tetramer (CP4), by Yamamoto coupling of a 2,3-dibromoporphyrin precursor. Their three-dimensional structures were confirmed by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray diffraction analyses. The minimum-energy geometries of CP3 and CP4 have propeller and saddle shapes, respectively, as calculated using density functional theory. Their different geometries result in distinct photophysical and electrochemical properties. The smaller dihedral angles between the porphyrin units in CP3, compared with CP4, result in stronger π-conjugation, splitting the ultraviolet-vis absorption bands and shifting them to longer wavelengths. Analysis of the crystallographic bond lengths indicates that the central benzene ring of the CP3 is partially aromatic [harmonic oscillator model of aromaticity (HOMA) 0.52], whereas the central cyclooctatetraene ring of the CP4 is non-aromatic (HOMA -0.02). The saddle-shaped structure of CP4 makes it a ditopic receptor for fullerenes, with affinity constants of (1.1 ± 0.4) × 105 M-1 for C70 and (2.2 ± 0.1) × 104 M-1 for C60, respectively, in toluene solution at 298 K. The formation of a 1:2 complex with C60 is confirmed by NMR titration and single-crystal X-ray diffraction.

Halogen-Bonding Heteroditopic [2]Catenanes for Recognition of Alkali Metal/Halide Ion Pairs.

The first examples of halogen bonding (XB) heteroditopic homo[2]catenanes were prepared by discrete Na+ template-directed assembly of oligo(ethylene glycol) units derived from XB donor-containing macrocycles and acyclic bis-azide precursors, followed by a CuI -mediated azide-alkyne cycloaddition macrocyclisation reaction. Extensive 1 H NMR spectroscopic studies show the [2]catenane hosts exhibit positive cooperative ion-pair recognition behaviour, wherein XB-mediated halide recognition is enhanced by alkali metal cation pre-complexation. Notably, subtle changes in the catenanes' oligo(ethylene glycol) chain length dramatically alters their ion-binding affinity, stoichiometry, complexation mode, and conformational dynamics. Solution-phase and single-crystal X-ray diffraction studies provide evidence for competing host-separated and direct-contact ion-pair binding modes. We further demonstrate the [2]catenanes are capable of extracting solid alkali-metal halide salts into organic media.

Online interventions to support family caregivers: The value of community-engaged research practices.

Family members provide significant amounts of unpaid care to aging, chronically ill, and disabled persons in their homes. They often do this with little education or support and commonly report feeling overwhelmed and stressed. Providing education and support to family caregivers has demonstrated benefit on the health and well-being of the caregiver and care-receiver. However, because "caregiver" is not a reimbursable category in health care, caregiver interventions need to be delivered in a cost-efficient way. Technology-delivered and self-administered intervention models are increasingly being recommended as a pragmatic way to support aging families in our communities. This paper outlines the redevelopment of two behavioral interventions to an exclusively online delivery. This case-study analysis presents a model for community-engaged intervention research practices, which have the potential to create interventions that are more sustainable and more likely to be implemented than those designed and tested with more traditional research methodology.

Rapid and Scalable Halosulfonylation of Strain-Release Reagents.

Sulfonylated aromatics are commonplace motifs in drugs and agrochemicals. However, methods for the direct synthesis of sulfonylated non-classical arene bioisosteres, which could improve the physicochemical properties of drug and agrochemical candidates, are limited. Here we report a solution to this challenge: a one-pot halosulfonylation of [1.1.1]propellane, [3.1.1]propellane and bicyclo[1.1.0]butanes that proceeds under practical, scalable and mild conditions. The sulfonyl halides used in this chemistry feature aryl, heteroaryl and alkyl substituents, and are conveniently generated in situ from readily available sulfinate salts and halogen atom sources. This methodology enables the synthesis of an array of pharmaceutically and agrochemically relevant halogen/sulfonyl-substituted bioisosteres and cyclobutanes, on up to multidecagram scale.

Maximizing the Benefit of Respite for Dementia Caregivers: A Study Protocol Describing the Development & Evaluation of the Time for Living & Caring (TLC) Intervention.

Dementia caregivers are susceptible to adverse physical and mental health outcomes, given the often prolonged and challenging care and support they provide to family members with Alzheimer's Disease and Related Dementias (ADRD). This report describes a community-engaged implementation of a novel behavioral intervention - an "app" (interactive website) called TLC (Time for Living and Caring) that coaches caregivers on how to maximize the benefits associated with respite time. The rationale and features of the TLC intervention and the full research protocol used to develop and then evaluate its feasibility, acceptability, and initial efficacy are described here.

Variability in X-ray induced effects in [Rh(COD)Cl]2 with changing experimental parameters.

X-ray characterisation methods have undoubtedly enabled cutting-edge advances in all aspects of materials research. Despite the enormous breadth of information that can be extracted from these techniques, the challenge of radiation-induced sample change and damage remains prevalent. This is largely due to the emergence of modern, high-intensity X-ray source technologies and the growing potential to carry out more complex, longer duration in situ or in operando studies. The tunability of synchrotron beamlines enables the routine application of photon energy-dependent experiments. This work explores the structural stability of [Rh(COD)Cl]2, a widely used catalyst and precursor in the chemical industry, across a range of beamline parameters that target X-ray energies of 8 keV, 15 keV, 18 keV and 25 keV, on a powder X-ray diffraction synchrotron beamline at room temperature. Structural changes are discussed with respect to absorbed X-ray dose at each experimental setting associated with the respective photon energy. In addition, the X-ray radiation hardness of the catalyst is discussed, by utilising the diffraction data collected at the different energies to determine a dose limit, which is often considered in protein crystallography and typically overlooked in small molecule crystallography. This work not only gives fundamental insight into how damage manifests in this organometallic catalyst, but will encourage careful consideration of experimental X-ray parameters before conducting diffraction on similar radiation-sensitive organometallic materials.

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Beyond Patient-Provider Relationships: Expanding the Roles and Boundaries of Families during Patient End-of-Life.

Role conflict and strain occur when healthcare providers are required to cross boundaries, either voluntarily or involuntarily, to meet the needs of their dying patients. This research is an unobtrusive digital ethnography of a publicly accessible online forum for healthcare providers (N = 242 posts); it explores the boundaries set by families and healthcare providers, and identifies how healthcare providers navigate and which circumstances require them to sometimes cross these professional boundaries. Results indicate that patient-and-family-centered care may not be fully achieved due to the ambiguity in the expected roles played by both families and healthcare providers during patient death and dying. Grounded in data, an expanded model of the therapeutic alliance, which includes the family, is suggested.