Diagnostic stewardship in infectious diseases: a scoping review.

Introduction. The term 'diagnostic stewardship' is relatively new, with a recent surge in its use within the literature. Despite its increasing popularity, a precise definition remains elusive. Various attempts have been made to define it, with some viewing it as an integral part of antimicrobial stewardship. The World Health Organization offers a broad definition, emphasizing the importance of timely, accurate diagnostics. However, inconsistencies in the use of this term still persist, necessitating further clarification.Gap Statement. There are currently inconsistencies in the definition of diagnostic stewardship used within the academic literature.Aim. This scoping review aims to categorize the use of diagnostic stewardship approaches and define this approach by identifying common characteristics and factors of its use within the literature.Methodology. This scoping review undertook a multi-database search from date of inception until October 2022. Any observational or experimental study where the authors define the intervention to be diagnostic stewardship from any clinical area was included. Screening of all papers was undertaken by a single reviewer with 10% verification by a second reviewer. Data extraction was undertaken by a single reviewer using a pre-piloted form. Given the wide variation in study design and intervention outcomes, a narrative synthesis approach was applied. Studies were clustered around common diagnostic stewardship interventions where appropriate.Results. After duplicate removal, a total of 1310 citations were identified, of which, after full-paper screening, 105 studies were included in this scoping review. The classification of an intervention as taking a diagnostic stewardship approach is a relatively recent development, with the first publication in this field dating back to 2017. The majority of research in this area has been conducted within the USA, with very few studies undertaken outside this region. Visual inspection of the citation map reveals that the current evidence base is interconnected, with frequent references to each other's work. The interventions commonly adopt a restrictive approach, utilizing hard and soft stops within the pre-analytical phase to restrict access to testing. Upon closer examination of the outcomes, it becomes evident that there is a predominant focus on reducing the number of tests rather than enhancing the current test protocol. This is further reflected in the limited number of studies that report on test performance (including protocol improvements, specificity and sensitivity).Conclusion. Diagnostic stewardship seems to have deviated from its intended course, morphing into a rather rudimentary instrument wielded not to enhance but to constrict the scope of testing. Despite the World Health Organization's advocacy for an ideology that promotes a more comprehensive approach to quality improvement, it may be more appropriate to consider alternative regional narratives when categorizing these types of quality improvement interventions.

Muscle energy technique for chronic obstructive pulmonary disease: A feasibility study / 中西医结合学报

OBJECTIVE@#This study aimed to investigate the feasibility of implementing a manual therapy technique (muscle energy technique, MET) protocol in a hospital pulmonary rehabilitation (PR) program for patients with moderate to severe chronic obstructive pulmonary disease (COPD). Please cite this article as: Baxter DA, Coyle ME, Hill CJ, Worsnop C, Shergis JL. Muscle energy technique for chronic obstructive pulmonary disease: A feasibility study. J Integr Med. 2023; 21(3): 245-253.@*METHODS@#Participants aged 40 years and over, with moderate to severe COPD, were recruited into this 12-week study. The primary outcome measures were feasibility (acceptability of the intervention and attendance/adherence to the trial) and safety (adverse events, AEs). All participants received the MET and PR therapies. Participants and assessors were unblinded. Semi-standardized MET was delivered on 6 occasions (a maximum of once per week) at the hospital directly before a PR session. Participants undertook PR sessions as per the hospital program at a frequency of two days per week for 8 weeks. Participants were contacted 4 weeks after their final MET treatment via a telephone call to assess acceptability of the intervention.@*RESULTS@#Thirty-three participants were enrolled, with a median age of 74 years (range 45-89 years). The median number of MET sessions that participants attended was 5 (range 0-6) out of a possible 6 sessions (83% attendance). At follow-up, participants overwhelmingly enjoyed the MET treatment with some subjectively reporting improved breathing. There were no major AEs related to the intervention, with the majority of AEs classified as expected events related to COPD exacerbations.@*CONCLUSION@#It is feasible to implement a manual therapy protocol using MET as an adjunct to PR in a hospital setting. Recruitment rates were satisfactory and there were no AEs related to the MET component of the intervention.

Multi-omic spatial profiling reveals the unique virus-driven immune landscape of COVID-19 placentitis

COVID-19 placentitis, a rare complication of maternal SARS-CoV-2 infection, only shows detectable virus in the placenta of a subset of cases. We provide a deep multi-omic spatial characterisation of placentitis from obstetrically complicated maternal COVID-19 infection. We found that SARS-CoV-2 infected placentas have a distinct transcriptional and immunopathological signature. This signature overlaps with virus-negative cases supporting a common viral aetiology. An inverse correlation between viral load and disease duration suggests viral clearance over time. Quantitative spatial analyses revealed a unique microenvironment surrounding virus-infected trophoblasts characterised by PDL1-expressing macrophages, T-cell exclusion, and interferon blunting. In contrast to uninfected mothers, ACE2 was localised to the maternal side of the placental trophoblast layer of almost all mothers with placental SARS-CoV-2 infection, which may explain variable susceptibility to placental infection. Our results demonstrate a pivotal role for direct placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

Comparison of a prototype SARS-CoV-2 lateral flow immunoassay with the BinaxNOW™ COVID-19 Antigen CARD

BackgroundRobust diagnostics, capable of detecting multiple variant of SARS-CoV-2 are necessary to mitigate the COVID-19 pandemic. In this study we directly compare the diagnostic capabilities of an LFI engineered with monoclonal antibodies (mAbs) originating from SARS-CoV-2 NP immunizations to the Abbott BinaxNOW COVID-19 Antigen CARD. MethodsHere we established a library of 18 mAbs specific to SARS-CoV-2 NP and used two of these mAbs (1CV7 and 1CV14) to generate a prototype antigen-detection lateral flow immunoassay (LFI). Samples consisting of remnant RT-PCR positive patient nasopharyngeal swabs preserved in viral transport media (VTM) were tested on the 1CV7/1CV14 LFI and the commercially available BinaxNOW test. Assays were allowed to resolve and results were recorded by two observers. FindingsA total of 98 remnant SARS-CoV-2 positive patient specimens were tested on both the 1CV7/1CV14 LFI and the BinaxNOW test. The 1CV7/1CV14 LFI detected 71 of the total 98 specimens, while the BinaxNOW test detected 52 of the 98 specimens. Additionally, the 1CV7/1CV14 LFI consistently detected samples with higher RT-PCR cycle threshold values than the BinaxNOW test. InterpretationThe 1CV7/1CV14 LFI outperformed the BinaxNOW test in the detection of BA.2, BA.2.12.1, and BA.5 Omicron sub-variants when testing remnant RT-PCR positive patient nasopharyngeal swabs diluted in viral transport media. BA.1 and BA.4 detection was comparable. The data suggest that mAbs derived from SARS-CoV-2 NP can aid in a more sensitive diagnostic immunoassay for COVID-19. FundingThe study was funded by the University of Nevada, Renos Research and Innovation Office, DxDiscovery, Inc. internal funds, and through AuCoin Laboratory internal funds. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSSince the onset of the pandemic, rapid antigen tests have proven themselves to be an accessible, accurate diagnostic platform. The widespread distribution of these tests has aided in curbing the COVID-19 pandemic. Data has shown that the tests manufactured at the beginning of the pandemic, utilizing monoclonal antibodies (mAbs) isolated from severe acute respiratory syndrome coronavirus (SARS-CoV), are less sensitive at detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron and Omicron subvariants. The reduced sensitivity can lead to diagnostic escape, and possible surges in COVID-19 caseloads Added value of this studyIn this study, a total of 98 remnant RT-PCR confirmed SARS-CoV-2 positive clinical specimens were tested on both a prototype rapid antigen test in the form of a lateral flow immunoassay (LFI) (referred to as the 1CV7/1CV14 LFI) and the available Abbott BinaxNOW COVID-19 Antigen CARD. The 1CV7/1CV14 LFI detected markedly more specimens (71 of 98) specimens than the BinaxNOW test (52 of the 98). Implications of all the available evidenceThis research suggests that that the use of mAbs isolated from immunizations with protein from SARS-CoV-2 may result in a diagnostic assay that is more sensitive in detection of SARS-CoV-2 Omicron subvariants, in comparison to the existing BinaxNOW COVID-19 Antigen CARD.

Mitigating the psychological impacts of COVID-19 restrictions: The Behavioural Activation in Social Isolation (BASIL) pilot randomised controlled trial to prevent depression and loneliness among older people with long term conditions

BackgroundOlder adults with long-term conditions have become more socially isolated (often due to advice to shield to protect them from COVID-19) and are thus at particular risk of depression and loneliness. There is a need for brief scalable psychosocial interventions to mitigate the psychological impacts of social isolation. Behavioural Activation is a plausible intervention, but a trial is needed. MethodsWe undertook an external randomised pilot trial (ISRCTN94091479) designed to test recruitment, retention and engagement with, and the acceptability and preliminary effects of the intervention. Participants aged [≥] 65 years with two or more long-term conditions were recruited between June and October 2020. Behavioural Activation was offered to intervention participants (n=47), and control participants received usual care (n=49). FindingsRemote recruitment was possible and 45/47 (95.7%) randomised to the intervention completed one or more sessions (median 6 sessions). 90 (93.8%) completed the one month follow-up, and 86 (89.6%) completed the three month follow-up. The between-group comparison for the primary clinical outcome at one month was an adjusted between group mean difference of -0.50 PHQ-9 points (95% CI -2.01 to 1.01), but only a small number of participants had completed the intervention at this point. At three months, the PHQ-9 adjusted mean difference was 0.19 (95% CI -1.36 to 1.75). When we examined loneliness, the between-group difference in the De Jong Gierveld Loneliness scale at one month was 0.28 (95% CI -0.51 to 1.06), and there was statistically significant between group difference at three months (-0.87; 95% CI -1.56 to -0.18). Participants who withdrew had minimal depressive symptoms at entry. InterpretationBehavioural Activation is a plausible intervention to mitigate the psychological impacts of COVID-19 isolation for older adults. The intervention can be delivered remotely and at scale, but should be reserved for older adults with evidence of depressive symptoms. The significant reduction in loneliness is unlikely to be a chance finding, and this will now be confirmed in a fully powered RCT. FundingThis study was funded by National Institute for Health Research (NIHR) Programme Grants for Applied Research (PGfAR) RP-PG-0217-20006

Supramolecular cylinders target bulge structures in the 5-prime UTR of the RNA genome of SARS-CoV-2 and inhibit viral replication

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with Molecular Dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5 UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in the stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel antiviral agents.

The hyperlipidaemic drug fenofibrate significantly reduces infection by SARS-CoV-2 in cell culture models

The SARS-CoV-2 pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure dimerization of ACE2, the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in ELISA and whole cell binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, these studies identify fenofibrate as a potential therapeutic agent requiring urgent clinical evaluation to treat SARS-CoV-2 infection. TeaserThe approved drug fenofibrate inhibits infection by SARS-COV-2

Ferrets not infected by SARS-CoV-2 in a high-exposure domestic setting

Ferrets (Mustela putorius furo) are mustelids of special relevance to laboratory studies of respiratory viruses and have been shown to be susceptible to SARS-CoV-2 infection and onward transmission. Here, we report the results of a natural experiment where 29 ferrets in one home had prolonged, direct contact and constant environmental exposure to two humans with symptomatic COVID-19. We observed no evidence of SARS-CoV-2 transmission from humans to ferrets based on RT-PCR and ELISA. To better understand this discrepancy in experimental and natural infection in ferrets, we compared SARS-CoV-2 sequences from natural and experimental mustelid infections and identified two surface glycoprotein (Spike) mutations associated with mustelids. While we found evidence that ACE2 provides a weak host barrier, one mutation only seen in ferrets is located in the novel S1/S2 cleavage site and is computationally predicted to decrease furin activity. These data support that host factors interacting with the novel S1/S2 cleavage site may be a barrier in ferret SARS-CoV-2 susceptibility and that domestic ferrets are at low risk of natural infection from currently circulating SARS-CoV-2. This may be overcome in laboratory settings using concentrated viral inoculum, but the effects of ferret host-adaptations require additional investigation.

The Effect of Stay-at-Home Orders on COVID-19 Infections in the United States

Governments issue "stay at home" orders to reduce the spread of contagious diseases, but the magnitude of such orders effectiveness is uncertain. In the United States these orders were not coordinated at the national level during the coronavirus disease 2019 (COVID-19) pandemic, which creates an opportunity to use spatial and temporal variation to measure the policies effect with greater accuracy. Here, we combine data on the timing of stay-at-home orders with daily confirmed COVID-19 cases and fatalities at the county level in the United States. We estimate the effect of stay-at-home orders using a difference-in- differences design that accounts for unmeasured local variation in factors like health systems and demographics and for unmeasured temporal variation in factors like national mitigation actions and access to tests. Compared to counties that did not implement stay-at-home orders, the results show that the orders are associated with a 30.2 percent (11.0 to 45.2) reduction in weekly cases after one week, a 40.0 percent (23.4 to 53.0) reduction after two weeks, and a 48.6 percent (31.1 to 61.7) reduction after three weeks. Stay-at-home orders are also associated with a 59.8 percent (18.3 to 80.2) reduction in weekly fatalities after three weeks. These results suggest that stay-at-home orders reduced confirmed cases by 390,000 (170,000 to 680,000) and fatalities by 41,000 (27,000 to 59,000) within the first three weeks in localities where they were implemented.

Nanomaterials for bone tissue regeneration: updates and future perspectives.

Joint replacement and bone reconstructive surgeries are on the rise globally. Current strategies for implants and bone regeneration are associated with poor integration and healing resulting in repeated surgeries. A multidisciplinary approach involving basic biological sciences, tissue engineering, regenerative medicine and clinical research is required to overcome this problem. Considering the nanostructured nature of bone, expertise and resources available through recent advancements in nanobiotechnology enable researchers to design and fabricate devices and drug delivery systems at the nanoscale to be more compatible with the bone tissue environment. The focus of this review is to present the recent progress made in the rationale and design of nanomaterials for tissue engineering and drug delivery relevant to bone regeneration.

Accidental oxygen disconnection in the emergency department.

Accidental oxygen disconnection during rapid sequence intubation (RSI) in the emergency department is a potentially catastrophic yet avoidable event. We report three cases of inadvertent oxygen disconnection during RSI, which resulted in significant oxygen desaturation. This error can potentially be prevented by thorough preparation, focusing on teamwork training, ensuring an ergonomic environment, and by making simple modifications to existing equipment.

Pneumococcal polysaccharide revaccination: immunoglobulin g seroconversion, persistence, and safety in frail, chronically ill older subjects.

OBJECTIVES: To determine the 1-month postpneumococcal polysaccharide-revaccination immunoglobulin G (IgG) antibody response, its persistence at 1 year, and tolerability of revaccination in frail, chronically ill older nursing facility residents. DESIGN: Prospective study conducted between December 1998 and July 2000. SETTING: Six skilled nursing facilities in the Minneapolis-St. Paul, Minnesota, metropolitan area. PARTICIPANTS: Sixty-seven subjects aged 65 and older having received primary vaccination with pneumococcal polysaccharide vaccine (PPV) at least 5 years before enrollment. INTERVENTION: Revaccination with one dose of 23-valent PPV. MEASUREMENTS: Adverse events and concentrations of seven individual pneumococcal polysaccharide type-specific IgG antibodies (against serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) and their aggregate before and 1 and 12 months after revaccination. RESULTS: A significant increase in all individual and aggregate median antibody concentrations over baseline was observed 1 month after revaccination. However, after 1 year, the increase remained significant only for serotypes 6B and 18C and the aggregate parameter. One month after revaccination, the mean increase in antibody concentration over baseline was significantly greater than 1.4-fold for six of the seven serotypes and the aggregate. However, the increase was not significantly greater than 1.4 at 1 year for any of the serotypes or the aggregate. Minor, self-limited localized adverse reactions and systemic reactions occurred in 11.3% of the subjects. CONCLUSIONS: In frail, chronically ill older nursing facility residents, revaccination with 23-valent PPV at least 5 years after primary vaccination (whether primary vaccination occurred before or after age 65) is associated with a significant, albeit brief, immunological response for most of the serotypes tested. Revaccination was well tolerated.