There has been a proliferation of digital health interventions (DHIs) targeting dietary intake. Despite their potential, the effectiveness of DHIs are thought to be dependent, in part, on user ...engagement. However, the relationship between engagement and the effectiveness of dietary DHIs is not well understood. The aim of this review is to describe the association between DHI engagement and dietary intake. A systematic search of four electronic databases and grey literature for records published before December 2019 was conducted. Studies were eligible if they examined a quantitative association between objective measures of engagement with a DHI (subjective experience or usage) and measures of dietary intake in adults (aged ≥18 years). From 10,653 citations, seven studies were included. Five studies included usage measures of engagement and two examined subjective experiences. Narrative synthesis, using vote counting, found mixed evidence of an association with usage measures (5 of 12 associations indicated a positive relationship, 7 were inconclusive) and no evidence regarding an association with subjective experience (both studies were inconclusive). The findings provide early evidence supporting an association between measures of usage and dietary intake; however, this was inconsistent. Further research examining the association between DHI engagement and dietary intake is warranted.
Efficient manufacturing of recombinant Adeno-Associated Viral (rAAV) vectors to meet rising clinical demand remains a major hurdle. One of the most significant challenges is the generation of large ...amounts of empty capsids without the therapeutic genome. There is no standardized analytical method to accurately quantify the viral genes, and subsequently the empty-to-full ratio, making the manufacturing challenges even more complex. We propose the use of CRISPR diagnostics (CRISPR-Dx) as a robust and rapid approach to determine AAV genome titers. We designed and developed the CRISPR-AAV Evaluation (CRAAVE) assay to maximize sensitivity, minimize time-to-result, and provide a potentially universal design for quantifying multiple transgene constructs encapsidated within different AAV serotypes. We also demonstrate an on-chip CRAAVE assay with lyophilized reagents to minimize end user assay input. The CRAAVE assay was able to detect AAV titers as low as 7e7 vg/mL with high precision (<3% error) in quantifying unknown AAV titers when compared with conventional quantitative PCR (qPCR) method. The assay only requires 30 min of assay time, shortening the analytical workflow drastically. Our results suggest CRISPR-Dx could be a promising tool for efficient rAAV genome titer quantification and has the potential to revolutionize biomanufacturing process analytical technology (PAT).
Background
Donation after circulatory determination of death (DCD) is responsible for the largest increase in deceased donation over the past decade. When the Canadian DCD guideline was published in ...2006, it included recommendations to create standard policies and procedures for withdrawal of life-sustaining measures (WLSM) as well as quality assurance frameworks for this practice. In 2016, the Canadian Critical Care Society produced a guideline for WLSM that requires modifications to facilitate implementation when DCD is part of the end-of-life care plan.
Methods
A pan-Canadian multidisciplinary collaborative was convened to examine the existing guideline framework and to create tools to put the existing guideline into practice in centres that practice DCD.
Results
A set of guiding principles for implementation of the guideline in DCD practice were produced using an iterative, consensus-based approach followed by development of four implementation tools and three quality assurance and audit tools.
Conclusions
The tools developed will aid DCD centres in fulsomely adapting the Canadian Critical Care Society Withdrawal of Life-Sustaining Measures guideline.
Monkeypox is a rare, sometimes life-threatening zoonotic infection that occurs in west and central Africa. It is caused by Monkeypox virus, an orthopoxvirus similar to Variola virus (the causative ...agent of smallpox) and Vaccinia virus (the live virus component of orthopoxvirus vaccines) and can spread to humans. After 39 years without detection of human disease in Nigeria, an outbreak involving 118 confirmed cases was identified during 2017-2018 (1); sporadic cases continue to occur. During September 2018-May 2021, six unrelated persons traveling from Nigeria received diagnoses of monkeypox in non-African countries: four in the United Kingdom and one each in Israel and Singapore. In July 2021, a man who traveled from Lagos, Nigeria, to Dallas, Texas, became the seventh traveler to a non-African country with diagnosed monkeypox. Among 194 monitored contacts, 144 (74%) were flight contacts. The patient received tecovirimat, an antiviral for treatment of orthopoxvirus infections, and his home required large-scale decontamination. Whole genome sequencing showed that the virus was consistent with a strain of Monkeypox virus known to circulate in Nigeria, but the specific source of the patient's infection was not identified. No epidemiologically linked cases were reported in Nigeria; no contact received postexposure prophylaxis (PEP) with the orthopoxvirus vaccine ACAM2000.
The poor usability of electronic health records contributes to increased nurses' workload, workarounds, and potential threats to patient safety. Understanding nurses' perceptions of electronic health ...record usability and incorporating human factors engineering principles are essential for improving electronic health records and aligning them with nursing workflows. This review aimed to synthesize studies focused on nurses' perceived electronic health record usability and categorize the findings in alignment with three human factor goals: satisfaction, performance, and safety. This systematic review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Five hundred forty-nine studies were identified from January 2009 to June 2023. Twenty-one studies were included in this review. The majority of the studies utilized reliable and validated questionnaires (n = 15) to capture the viewpoints of hospital-based nurses (n = 20). When categorizing usability-related findings according to the goals of good human factor design, namely, improving satisfaction, performance, and safety, studies used performance-related measures most. Only four studies measured safety-related aspects of electronic health record usability. Electronic health record redesign is necessary to improve nurses' perceptions of electronic health record usability, but future efforts should systematically address all three goals of good human factor design.
Carbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread ...of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms.
To overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years.
Our CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment.
Collectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.
BACKGROUND
Anti–red blood cell (RBC) alloantibodies consisting of only the immunoglobulin G (IgG) 4 subtype are typically considered clinically insignificant. A US Food and Drug ...Administration–approved monoclonal anti‐human globulin (16H8) is nonreactive with IgG4, which has been considered a benefit to avoid testing interference from IgG4. However, 16H8 also does not recognize two natural IgG3 variants (IgG3‐03 and IgG3‐13). Thus, 16H8 may miss clinically significant alloantibodies in some settings.
STUDY DESIGN AND METHODS
Novel mouse anti‐human IgG hybridomas were generated and screened for reactivity with 32 human variants of anti‐KEL1 across different IgG subtypes, as well as mutants to allow epitope mapping. Anti‐IgG reactivity was determined using KEL1+ RBCs bound by each IgG variant as targets. Binding of anti‐IgG was determined by flow cytometry.
RESULTS
16H8 recognized an epitope involving amino acid 419, which is glutamate in IgG4, IgG3‐03, and IgG3‐13, explaining the lack of 16H8 reactivity with these subtypes/isoallotypes. A new monoclonal antibody (PUMA8) was isolated that, like 16H8, was nonreactive with IgG4 but without blind spots for known variants of IgG1, IgG2, or IgG3. PUMA8 recognized an epitope containing arginine at position 355, which is glutamine in IgG4. However, a recently described new IgG4 variant with an arginine at position 355 results in PUMA8 reactivity.
CONCLUSION
PUMA8 represents an alternative to 16H8 that avoids IgG4 but without blind spots for IgG3 variants. However, PUMA8 reacts with one recently described IgG4 variant. In addition to relevance to immunohematology, these studies highlight the importance of patient variation with regards to assay performance in an era of personalized medicine.
We investigated the anti-inflammatory and antibacterial activities of Hc-cath, a cathelicidin peptide derived from the venom of the sea snake, Hydrophis cyanocyntus, using in vivo models of ...inflammation and infection. Hc-cath function was evaluated in in vitro, in vivo in the wax moth, Galleria mellonella, and in mouse models of intraperitoneal and respiratory Pseudomonas aeruginosa infection. Hc-Cath downregulated LPS-induced pro-inflammatory responses in macrophages and significantly improved the survival of P. aeruginosa infected G. mellonella over a 5-day period. We also demonstrated, for the first time, that Hc-cath can modulate inflammation in a mouse model of LPS-induced lung inflammation by significantly reducing the release of the pro-inflammatory cytokine and neutrophil chemoattractant, KC, resulting in reduced cellular infiltration into the lungs. Moreover, Hc-cath treatment significantly reduced the bacterial load and inflammation in mouse models of P. aeruginosa intraperitoneal and respiratory infection. The effect of Hc-cath in our studies highlights the potential to develop this peptide as a candidate for therapeutic development.
More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly ...due to PD-1/PD-L1-associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.
BACKGROUND
Human immunoglobulin G (IgG) includes four different subtypes (IgG1, IgG2, IgG3, and IgG4), and it is also now appreciated that there are genetic variations within IgG subtypes (called ...isoallotypes). Twenty‐nine different isoallotypes have been described, with 7, 4, 15, and 3 isoallotypes described for IgG1, IgG2, IgG3, and IgG4, respectively. The reactivity of anti‐IgG with different isoallotypes has not been characterized.
STUDY DESIGN AND METHODS
A novel monoclonal anti‐K antibody (PugetSound Monoclonal Antibody 1 PUMA1) was isolated and sequenced, and a panel of PUMA1 variants was expressed, consisting of the 29 known IgG isoallotypes. The resulting panel of antibodies was preincubated with K‐positive red blood cells (RBCs) and then subjected to testing with currently approved anti‐IgG by flow cytometry, solid phase systems, gel cards, and tube testing.
RESULTS
A US Food and Drug Administration (FDA)‐approved monoclonal anti‐IgG (gamma‐clone) failed to recognize 2 of 15 IgG3 isoallotypes (IgG3‐03 and IgG3‐13) and 3 of 3 IgG4 isoallotypes (IgG4‐01, IgG4‐02, and IgG4‐03). In contrast, an FDA‐approved rabbit polyclonal anti‐IgG recognized each of the known human IgG isoallotypes.
CONCLUSION
These findings demonstrate “blind spots” in isoalloantibody detection by a monoclonal anti‐IgG. If a patient has anti‐RBC antibodies predominantly of an IgG3 subtype (the IgG3‐03 and/or IgG3‐13 variety), then it is possible that a clinically significant alloantibody would be missed. IgG‐03 and IgG‐13 have an estimated frequency of 1% to 3% in Caucasian populations and 20% to 30% in certain African populations. Nonreactivity with IgG4 is a known characteristic of this monoclonal anti‐IgG, but IgG4 isoallotypes have not been previously reported.
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