Harnessing Multistep Chalcogen Bonding Activation in the α-Stereoselective Synthesis of Iminoglycosides.

The use of noncovalent interactions (NCIs) has received significant attention as a pivotal synthetic handle. Recently, the exploitation of unconventional NCIs has gained considerable traction in challenging reaction manifolds such as glycosylation due to their capacity to facilitate entry into difficult-to-access sugars and glycomimetics. While investigations involving oxacyclic pyrano- or furanoside scaffolds are relatively common, methods that allow the selective synthesis of biologically important iminosugars are comparatively rare. Here, we report the capacity of a phosphonochalcogenide (PCH) to catalyze the stereoselective α-iminoglycosylation of iminoglycals with a wide array of glycosyl acceptors with remarkable protecting group tolerance. Mechanistic studies have illuminated the counterintuitive role of the catalyst in serially activating both the glycosyl donor and acceptor in the up/downstream stages of the reaction through chalcogen bonding (ChB). The dynamic interaction of chalcogens with substrates opens up new mechanistic opportunities based on iterative ChB catalyst engagement and disengagement in multiple elementary steps.

Preimplementation of Critical Care Early Mobility Clinical Decision Support: A Content Validation Study.

Early mobility is a form of critical care rehabilitation ranging from in-bed exercise to ambulation and is known to limit post-intensive-care functional decline. Multiple barriers prevent widespread early mobility implementation. Clinical decision support systems can optimize the decision-making process and overcome barriers to care. However, critical care early mobility clinical decision support does not exist. Our objective was to develop and establish the content validation of the operational definitions for a novel critical care early mobility assessment instrument. Content validation was conducted in two steps: (1) development of operational definitions by the research team and (2) content validation with 10 nurse experts. Quality assessment and suitability of the operational definitions for 30 items, across four safety domains, were assessed using a 7 point-Likert scale. Item content validity index scores ranged from 0.6 to 0.1 after the first validation round. Domains containing items with item content validity index scores less than the lower limit of 0.78 were modified for clarity of language. Item content validity index scores ranged from 0.8 to 1.0, and the scale-level content validity index was 0.93 after the second content validation round. Excellent content validity of the operational definitions was achieved. This is the first methodological step in a larger project to develop clinical decision support for critical care early mobility.

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space.

Monoterpene indole alkaloids (MIAs) are endowed with high structural and spatial complexity and characterized by diverse biological activities. Given this complexity-activity combination in MIAs, rapid and efficient access to chemical matter related to and with complexity similar to these alkaloids would be highly desirable, since such compound classes might display novel bioactivity. We describe the design and synthesis of a pseudo-natural product (pseudo-NP) collection obtained by the unprecedented combination of MIA fragments through complexity-generating transformations, resulting in arrangements not currently accessible by biosynthetic pathways. Cheminformatic analyses revealed that both the pseudo-NPs and the MIAs reside in a unique and common area of chemical space with high spatial complexity-density that is only sparsely populated by other natural products and drugs. Investigation of bioactivity guided by morphological profiling identified pseudo-NPs that inhibit DNA synthesis and modulate tubulin. These results demonstrate that the pseudo-NP collection occupies similar biologically relevant chemical space that Nature has endowed MIAs with.

Communication and role clarity inform TeleICU use: a qualitative analysis of opportunities and barriers in an established program using AACN framework.

BACKGROUND: Understanding the use of tele-intensive care unit (ICU) services is an essential component in evaluating current practice and informing future use as the adoption and application of teleICU services expands. We sought to explore if novel ways to utilize teleICU services can emerge within an established, consulting-style teleICU model considering the program's flexible, provider-driven operation. METHODS: This was a qualitative study of one teleICU/hospital dyad using semi-structured interviews from a convenience sample of ICU (n = 19) and teleICU (n = 13) nurses. Interviews were analyzed using directed content analysis to identify themes that describe their experiences with teleICU using a deductive codebook developed from an expert consensus (American Association of Critical Care Nurses) AACN statement on teleICU nursing. RESULTS: Three themes were identified through the qualitative content analysis: [1] nurses described unique teleICU knowledge, including systems thinking and technological skills, [2] the teleICU partnership supported quality improvement initiatives, and [3] elements of the work environment influenced perceptions of teleICU and its use. When elements of the work environment, such as effective communication and role clarity, were not present, teleICU use was variable. CONCLUSIONS: Flexible, provider-driven approaches for integrating teleICU services into daily practice may help define the future use of the teleICU model's applicability. Future work should focus on the importance of effective communication and role clarity in integrating the emerging teleICU services into teleICU/ICU practice.

Evaluation of a Multidisciplinary Pain, Agitation, and Delirium Guideline in Mechanically Ventilated Critically Ill Adults.

Background: A multidisciplinary team updated an institution-specific pain, agitation, and delirium (PAD) guideline based on the recommendations from the Society of Critical Care Medicine (SCCM) PAD guidelines. This institution-specific guideline emphasized protocolized sedation with increased as needed boluses, and nonbenzodiazepine infusions, daily sedation interruption, and pairing of spontaneous awakening (SAT) and breathing trials (SBT). Objective: The purpose of this study was to evaluate the impact of implementation of a PAD guideline on clinical outcomes and medication utilization in an academic medical center intensive care unit (ICU). It was hypothesized that implementation of an updated guideline would improve clinical outcomes and decrease usage of benzodiazepine infusions. Methods: Pre-post retrospective chart review of 2417 (1147 pre, 1270 post) critically ill, mechanically ventilated adults in a medical/surgical ICU over a 2-year period (1 year pre and post guideline implementation). Results: After guideline implementation, average ventilation days was reduced (3.98 vs 3.43 days, P = .0021), as well as ICU and hospital length of stay (LOS) (4.79 vs 4.34 days, P = .048 and 13.96 vs 12.97 days, P = .045, respectively). Hospital mortality (19 vs 19%, P = .96) and acute physiology and chronic health evaluation (APACHE) IV scores (77.28 vs 78.75, P = .27) were similar. After guideline implementation, the percentage of patients receiving midazolam infusions decreased (422/1147 [37%] vs 363/1270 patients [29%], P = .0001). The percentage of patients receiving continuous infusion propofol (679/1147 [59%] vs 896/1270 [70%], P = .0001) and dexmedetomidine (78/1147 [7%] vs 147/1270 [12%], P = .0001) increased. Conclusions: Implementing a multidisciplinary PAD guideline utilizing protocolized sedation and daily sedation interruption decreased ventilation days and ICU and hospital LOS while decreasing midazolam drip usage.

Insights into the Kinetics of the Resistance Formation of Bacteria against Ciprofloxacin Poly(2-methyl-2-oxazoline) Conjugates.

The influence on the resistance formation of polymers attached to antibiotics has rarely been investigated. In this study, ciprofloxacin (CIP) was conjugated to poly(2-methyl-2-oxazoline)s with an ethylene diamine end group (Me-PMOx28-EDA) via two different spacers (CIP modified with α,α'-dichloro- p-xylene-xCIP, CIP modified with chloroacetyl chloride-eCIP). The antibacterial activity of the conjugates against a number of bacterial strains shows a great dependence on the nature of the spacer. The Me-PMOx39-EDA-eCIP, containing a potentially cleavable linker, does not exhibit a molecular weight dependence on antibacterial activity in contrast to Me-PMOx27-EDA-xCIP. The resistance formation of both conjugates against Staphylococcus aureus and Escherichia coli was investigated. Both conjugates showed the potential to significantly delay the formation of resistant bacteria compared to the unmodified CIP. Closer inspection of a possible resistance mechanism by genome sequencing of the topoisomerase IV region of resistant S. aureus revealed that this bacterium mutates at the same position when building up resistance to CIP and to Me-PMOx27-EDA-xCIP. However, the S. aureus cells that became resistant against the polymer conjugate are fully susceptible to CIP. Thus, conjugation of CIP with PMOx seems to alter the resistance mechanism.

Using Kotter's Change Framework to Implement and Sustain Multiple Complementary ICU Initiatives.

This article describes the planning, implementation, and outcomes of 2 complementary quality initiatives, bedside handoff and nurse-initiated interdisciplinary bedside rounds, in a 24-bed medical/surgical intensive care unit. Systematic approaches such as Kotter's change model and unit-based champions were used to redesign care processes and standardize daily communication and workflows. Active partnership with the patient and the family during these changes promoted a strong intensive care unit culture of patient- and family-centered care.

Can Lay Community Advisors Improve the Clarity of Research Participant Recruitment Materials and Increase the Likelihood of Participation?

Despite decades of effort, lower income people and ethnic minorities continue to be underrepresented as participants in health research. A group of racially and ethnically diverse, lower income community members (Community Advisors on Research Design and Strategies: CARDS®) was trained to review study designs and procedures and provide recommendations to researchers for increasing participation and making research materials more understandable to members of underrepresented communities. In this mixed methods study, one participant group (n = 55) was shown research materials (recruitment documents and a consent form) developed by a research team and approved by the local IRB. A second group (n = 45) was shown the same materials after they had also been reviewed and revised by CARDS. Interviews, which included both fixed-response and open-ended questions, were used to assess reactions of participants in both groups to the materials, including their hypothetical willingness to volunteer for the research described. Group differences were examined using the Chi-square distribution test. Proportional difference effect sizes were estimated using arcsine transformation. The qualitative data were subjected to conventional content analysis. Participants in the group shown the recruitment materials revised by CARDS were more likely to say they understood the documents, more likely to ask for more information about the study, and more likely to say they would participate in the research. Results of content analysis suggested a four-phase sequential process for deciding whether to participate in the research. © 2016 Wiley Periodicals, Inc.

Arterial catheters as a source of bloodstream infection: a systematic review and meta-analysis.

OBJECTIVE: Catheter-related bloodstream infections are associated with significant costs and adverse consequences. Arterial catheters are commonly used in the critical care setting and are among the most heavily manipulated vascular access devices. We sought to evaluate the prevalence of arterial catheter-related bloodstream infection. DATA SOURCES: PubMed, CinAHL, EMBASE, and Web of Science. STUDY SELECTION: Included studies reported prevalence rate of catheter-related bloodstream infection for arterial catheters used for critical illness or postoperative monitoring. For the purposes of this study, catheter-related bloodstream infection was defined as positive blood culture collected from an arterial catheter and from the periphery with the same organism in a patient demonstrating systemic signs of sepsis. DATA EXTRACTION: The study population, site of insertion, antiseptic preparation, catheter days, and prevalence of catheter-related bloodstream infection were abstracted. When data were not available, authors were contacted for further information. DATA SYNTHESIS: Forty-nine studies met criteria including 222 cases of arterial catheter-related bloodstream infection in 30,841 catheters. Pooled incidence was 3.40/1,000 catheters or 0.96/1,000 catheter days. Prevalence was considerably higher in the subgroup of studies that cultured all catheters (1.26/1,000 catheter days) compared with those studies that cultured only when the arterial catheter was suspected as the source for the catheter-related bloodstream infection (0.70/1,000 catheter days). Pooled data also found a significantly increased risk of infection for femoral site of insertion compared with radial artery for arterial catheter placement (relative risk, 1.93; 95% CI, 1.32-2.84; p = 0.001) CONCLUSIONS: Arterial catheters are an underrecognized cause of catheter-related bloodstream infection. Pooled incidence when catheters were systematically cultured and correlated to blood culture results indicated a substantial burden of arterial catheter-related bloodstream infection. Selection of a radial site over a femoral site will help reduce the risk of arterial catheter-related bloodstream infection. Future studies should evaluate technologies applied to preventing central venous catheter-related bloodstream infection to arterial catheters as well.

Using electronic health records to classify risk for adverse safety events with ICU patient Mobility: A Cross-Sectional study.

BACKGROUND: Integrating early mobility (EM) expert consensus recommendations into an algorithm that uses electronic health record (EHR) data provides an opportunity for ICU nurse decision support. OBJECTIVE: This study aimed to compare clinical differences in ICU EM algorithm domains among patients with and without documented EM and examine discordance between algorithm classification and documented EM. METHODS: Secondary analysis of EHR data from adults admitted to the ICU from one health system's electronic data warehouse. We extracted demographic, clinical, and EM data for up to the first three days after ICU admission and applied the algorithm to classify patients as low/high-risk by clinical domain (respiratory, cardiovascular, neurological, activity order, overall) each day. We used the Wilcoxon rank sum test or Fisher's exact test to compare clinical criteria and algorithm classification between patients with and without documented EM. RESULTS: From a total of 4,088 patients, documented EM increased each ICU day. Patients with EM were more likely to be classified by the algorithm as low-risk than those who stayed in bed each day. While a large proportion of low-risk patients remained in bed each day (813 day 1; 920 day 2; 881 day 3), some patients classified as high-risk had documented EM. CONCLUSIONS: A significant portion of patients identified as overall low-risk by the algorithm remained in bed, while some high-risk patients achieved EM. Variability between risk definitions and documented patient activity exists and understanding additional factors that nurses use to support EM decision-making is needed. IMPLICATIONS FOR CLINICAL PRACTICE: EHR data can be used with a mobility algorithm to classify patients at low and high-risk for ICU EM. In the future, with additional refinements, an algorithm may augment clinician decision-making.

The Halogen Bond to Ethers - Prototypic Molecules and Experimental Electron Density.

Halogen bonds to dialkyl ether molecules have remained largely unexplored. We here address the synthesis and the structural chemistry of the first halogen-bonded noncyclic alkyl ethers, combining 1,4-diiodotetrafluorobenzene and the prototypic or commonly used ethers dimethyl ether, tetrahydrofuran, and methyl-tert-butyl ether as halogen acceptors. Two different structural motifs based on moderately strong halogen bonds were obtained: Discrete trimolecular aggregates are formed, and unexpected halogen-bonded supramolecular chain adducts feature oxygen-bifurcated halogen bonds with 1:1 donor:acceptor ratio. Both structure types may be selectively obtained even for the same ether by adjusting the stoichiometry in the crystallization experiments. The geometric features of the etheric oxygen center were found to be flexible, in contrast to the almost linear geometry about the halogen donor atom. A high-resolution X-ray diffraction experiment on the extended adduct of dimethyl ether allowed us to study the electronic details of the acceptor-bifurcated I···O···I halogen bonds. The electron density in the bond critical points and derived properties such as the Laplacian indicate essentially electrostatic interactions and explain the geometrical flexibility of ethers in halogen bonds. Our studies demonstrate the great versatility of ethers as halogen bond acceptors, that can occur in many geometrical arrangements and whose contribution to nature's structural designs should not be underestimated.

Patient, Practice, and Organizational Factors Associated With Early Mobility Performance in Critically Ill Adults.

BACKGROUND: Adoption of early mobility interventions into intensive care unit (ICU) practice has been slow and varied. OBJECTIVES: To examine factors associated with early mobility performance in critically ill adults and evaluate factors' effects on predicting next-day early mobility performance. METHODS: A secondary analysis of 66 ICUs' data from patients admitted for at least 24 hours. Mixed-effects logistic regression modeling was done, with area under the receiver operating characteristic curve (AUC) calculated. RESULTS: In 12 489 patients, factors independently associated with higher odds of next-day mobility included significant pain (adjusted odds ratio [AOR], 1.16; 95% CI, 1.09-1.23), documented sedation target (AOR, 1.09; 95% CI, 1.01-1.18), performance of spontaneous awakening trials (AOR, 1.77; 95% CI, 1.59-1.96), spontaneous breathing trials (AOR, 2.35; 95% CI, 2.14-2.58), mobility safety screening (AOR, 2.26; 95% CI, 2.04-2.49), and prior-day physical/occupational therapy (AOR, 1.44; 95% CI, 1.30-1.59). Factors independently associated with lower odds of next-day mobility included deep sedation (AOR, 0.44; 95% CI, 0.39-0.49), delirium (AOR, 0.63; 95% CI, 0.59-0.69), benzodiazepine administration (AOR, 0.85; 95% CI, 0.79-0.92), physical restraints (AOR, 0.74; 95% CI, 0.68-0.80), and mechanical ventilation (AOR, 0.73; 95% CI, 0.68-0.78). Black and Hispanic patients had lower odds of next-day mobility than other patients. Models incorporating patient, practice, and between-unit variations displayed high discriminant accuracy (AUC, 0.853) in predicting next-day early mobility performance. CONCLUSIONS: Collectively, several modifiable and nonmodifiable factors provide excellent prediction of next-day early mobility performance.

Crystal structures and Hirshfeld surface analyses of tetra-kis-(4,5-di-hydro-furan-2-yl)silane and tetra-kis-(4,5-di-hydro-furan-2-yl)germane.

The title compounds Si(C4H5O)4 (1) and Ge(C4H5O)4 (2) are di-hydro-furyl compounds of silicon and germanium and are useful building blocks for the functionalization of these elements. Both structures crystallize in space group P21/n in the monoclinic crystal system with two mol-ecules in the asymmetric unit: the Si and Ge atoms adopt slightly distorted tetra-hedral geometries, while the C4H5O moieties exhibit shallow envelope conformations. Through a Hirshfeld surface analysis of the structures, inter-actions within the crystal packing could be elucidated: compound 1 features a polymeric chain in the (101) plane via C-H⋯O hydrogen bonds whereas in 2 C-H⋯O hydrogen bonds create a polymeric chain in the (010) plane.

Silver-based coordination polymers assembled by dithioether ligands: potential antibacterial materials despite received ideas.

We report on the first examples on the antibacterial activity towards Gram-negative and Gram-positive bacteria of 2D silver-based coordination polymers obtained by self-assembly with acetylenic dithioether ligands. Their structure imparts a good stability that allows a sustainable release of Ag+ in the media.

Identifying Comorbid Subtypes of Patients With Acute Respiratory Failure.

BACKGROUND: Patients with acute respiratory failure have multiple risk factors for disability following their intensive care unit stay. Interventions to facilitate independence at hospital discharge may be more effective if personalized for patient subtypes. OBJECTIVES: To identify subtypes of patients with acute respiratory failure requiring mechanical ventilation and compare post-intensive care functional disability and intensive care unit mobility level among subtypes. METHODS: Latent class analysis was conducted in a cohort of adult medical intensive care unit patients with acute respiratory failure receiving mechanical ventilation who survived to hospital discharge. Demographic and clinical medical record data were collected early in the stay. Clinical characteristics and outcomes were compared among subtypes by using Kruskal-Wallis tests and χ2 tests of independence. RESULTS: In a cohort of 934 patients, the 6-class model provided the optimal fit. Patients in class 4 (obesity and kidney impairment) had worse functional impairment at hospital discharge than patients in classes 1 through 3. Patients in class 3 (alert patients) had the lowest magnitude of functional impairment (P < .001) and achieved the earliest out-of-bed mobility and highest mobility level of all subtypes (P < .001). CONCLUSIONS: Acute respiratory failure survivor subtypes identified from clinical data available early in the intensive care unit stay differ in post-intensive care functional disability. Future research should target high-risk patients in early rehabilitation trials in the intensive care unit. Additional investigation of contextual factors and mechanisms of disability is critical to improving quality of life in acute respiratory failure survivors.

Clinicians' perceptions on implementation strategies used to facilitate ABCDEF bundle adoption: A multicenter survey.

BACKGROUND: Intensive care unit (ICU) clinicians struggle to routinely implement the ICU Liberation bundle (ABCDEF bundle). As a result, critically ill patients experience increased risk of morbidity and mortality. Despite extensive research related to the barriers and facilitators of bundle use, little is known regarding which implementation strategies are used to facilitate its adoption and sustainability. OBJECTIVES: To identify implementation strategies used to increase adoption of the ABCDEF bundle and how those strategies are perceived by end-users (i.e., ICU clinicians) related to their helpfulness, acceptability, feasibility, and cost. METHODS: We conducted a national, cross-sectional survey of ICU clinicians from the 68 ICU sites that previously participated in the Society of Critical Care Medicine's ICU Liberation Collaborative. The survey was structured using the 73 Expert Recommendations for Implementing Change (ERIC) implementation strategies. Surveys were delivered electronically to site contacts. RESULTS: Nineteen ICUs (28%) returned completed surveys. Sites used 63 of the 73 ERIC implementation strategies, with frequent use of strategies that may be readily available to clinicians (e.g., providing educational meetings or ongoing training), but less use of strategies that require changes to well-established organizational systems (e.g., alter incentive allowance structure). Overall, sites described the ERIC strategies used in their implementation process to be moderately helpful (mean score >3<4 on a 5-point Likert scale), somewhat acceptable and feasible (mean score >2<3), and either not-at-all or somewhat costly (mean scores >1<3). CONCLUSIONS: Our results show a potential over-reliance on accessible strategies and the possible benefit of unused ERIC strategies related to changing infrastructure and utilizing financial strategies.

Rural age-friendly ecosystems for older adults: An international scoping review with recommendations to support age-friendly communities.

Background and Aims: The population of older adults in rural areas is rising, and they experience higher rates of poverty and chronic illness, have poorer health behaviors, and experience different challenges than those in urban areas. This scoping review seeks to (1) map the state of the science of age-friendly systems in rural areas regarding structural characteristics, processes for delivering age-friendly practices, and outcomes of age-friendly systems, (2) analyze strengths, weakness, opportunities, and threats of age-friendly system implementation, and (3) make person, practice, and policy-level recommendations to support active aging and development of age-friendly communities. Methods: An international scoping review was conducted of articles that used age-friendly framing, had a sample age of 45 years of age or older, self-identified as rural, and reported empiric data. Searches were conducted in PubMed, CINAHL, AgeLine, PsychINFO, EMBASE, Scopus, and Academic Search Elite on October 26, 2021, and rerun March 10, 2023. Data were charted across three analytic layers: socioecological model, Donabedian's framework, and SWOT analysis. Results: Results reveal limited data on outcomes relevant to organizations, such as return on investment or healthcare utilization. While the SWOT analysis revealed many strengths of age-friendly systems, including their impact on persons' outcomes, it also revealed several weaknesses, threats, and gaps. Namely, age-friendly systems have weaknesses due to reliance on trained volunteers and staff, communication, and teamwork. System-level threats include community and health system barriers, and challenges in poor/developing areas. Conclusions: While age-friendly systems in this review were heterogeneous, there is an opportunity to focus on unifying elements including the World Health Organization age-friendly cities framework or 4Ms framework for age-friendly care. Despite the many benefits of age-friendly systems, we must acknowledge limitations of the evidence base, pursue opportunities to examine organizational metrics to support implementation and sustainability of age-friendly systems, and leverage improvements in age-friendliness at a community level.

A highly enantioselective intramolecular 1,3-dipolar cycloaddition yields novel pseudo-natural product inhibitors of the Hedgehog signalling pathway.

De novo combination of natural product (NP) fragments by means of efficient, complexity- and stereogenic character-generating transformations to yield pseudo-natural products (PNPs) may explore novel biologically relevant chemical space. Pyrrolidine- and tetrahydroquinoline fragments rarely occur in combination in nature, such that PNPs that embody both fragments might represent novel NP-inspired chemical matter endowed with bioactivity. We describe the synthesis of pyrrolo[3,2-c]quinolines by means of a highly enantioselective intramolecular exo-1,3-dipolar cycloaddition catalysed by the AgOAc/(S)-DMBiphep complex. The cycloadditions proceeded in excellent yields (up to 98%) and with very high enantioselectivity (up to 99% ee). Investigation of the resulting PNP collection in cell-based assays monitoring different biological programmes led to the discovery of a structurally novel and potent inhibitor of the Hedgehog signalling pathway that targets the Smoothened protein.

Post-intensive care syndrome: A review for the primary care NP.

ABSTRACT: Post-intensive care syndrome is a costly and complicated collection of physical, cognitive, and mental health problems experienced by survivors of critical illness. The primary care NP is uniquely positioned to assess, monitor, manage, and treat patients with this syndrome following hospital discharge.

Crystal structures and Hirshfeld surface analyses of bis-(4,5-di-hydro-furan-2-yl)di-methyl-silane and (4,5-di-hydro-furan-2-yl)(meth-yl)di-phenyl-silane.

The title compounds, C10H16O2Si (1) and C17H18OSi (2), are classified as di-hydro-furylsilanes, which show great potential as building blocks for various functionalized silanes. They both crystallize in the space group P in the triclinic crystal system. Analyses of the Hirshfeld surfaces show packing-determining inter-actions for both compounds, resulting in a polymeric chain along the [011] for silane 1 and a layered-inter-connected structure along the b-axis direction for silane 2.