Impact of restricted visitation policies in hospitals on patients, family members and healthcare providers during the COVID-19 pandemic: a scoping review protocol.

INTRODUCTION: Flexible visitation policies in hospitals are an important component of care that contributes to reduced stress and increased satisfaction among patients and their family members. Early evidence suggests restricted visitation policies enacted in hospitals during the COVID-19 pandemic are having unintended consequences on patients, family members and healthcare providers. There is a need for a comprehensive summary of the impacts of restricted visitation policies on key stakeholders and approaches to mitigate that impact. METHODS AND ANALYSIS: We will conduct a scoping review as per the Arksey-O'Malley 5-stage scoping review method and the Scoping Review Methods Manual by the Joanna Briggs Institute. We will search relevant electronic databases (eg, CINAHL, MEDLINE, PsycINFO), grey literature and preprint repositories. We will include all study designs including qualitative and quantitative methodologies (excluding protocols) as well as reports, opinions and editorials, to identify the broad impact of restricted hospital visitation policies due to the COVID-19 pandemic on patients, family members or healthcare providers of hospitalised patients, and approaches taken or proposed to mitigate this impact. Two reviewers will calibrate the screening criteria and data abstraction form and will independently screen studies and abstract the data. Narrative synthesis with thematic analysis will be performed. ETHICS AND DISSEMINATION: Ethical approval is not applicable as this review will be conducted on published literature only. This scoping review will identify, describe and categorise impacts of restricted hospital visitation policies due to the COVID-19 pandemic on patients, family members and healthcare providers of hospitalised patients, and approaches that have been taken to mitigate impact. We will provide a comprehensive synthesis by developing a framework of restricted visitation policies and associated impacts. Our results will inform the development of consensus statements on restricted visitation policies to be implemented in future pandemics. PROSPERO REGISTRATION NUMBER: CRD42020221662.

Granule-Dependent NK Cell Killing of Cryptococcus Requires Kinesin to Reposition the Cytolytic Machinery for Directed Cytotoxicity.

Cryptococcus is the most important cause of fungal meningitis in immunocompromised individuals. Host defense against Cryptococcus involves direct killing by NK cells. That NK cells from HIV-infected patients fail to polarize perforin to the microbial synapse and kill C. neoformans led us to explore the mechanisms used to reposition and polarize the cytolytic granules to the synapse. Using live-cell imaging, we observed microtubule and granule movements in response to Cryptococcus that revealed a kinesin-dependent event. Eg5-kinesin bound to perforin-containing granules and was required for association with the microtubules. Inhibition of Eg5-kinesin abrogated dynein-dependent granule convergence to the MTOC and granule and MTOC polarization to the synapse and suppressed NK cell killing of Cryptococcus. In contrast, Eg5-kinesin was dispensable for tumor killing. This reveals an alternative mechanism of MTOC repositioning and granule polarization, not used in tumor cytotoxicity, in which Eg5-kinesin is required to initiate granule movement, leading to microbial killing.

Reproducibility of clinical research in critical care: a scoping review.

BACKGROUND: The ability to reproduce experiments is a defining principle of science. Reproducibility of clinical research has received relatively little scientific attention. However, it is important as it may inform clinical practice, research agendas, and the design of future studies. METHODS: We used scoping review methods to examine reproducibility within a cohort of randomized trials examining clinical critical care research and published in the top general medical and critical care journals. To identify relevant clinical practices, we searched the New England Journal of Medicine, The Lancet, and JAMA for randomized trials published up to April 2016. To identify a comprehensive set of studies for these practices, included articles informed secondary searches within other high-impact medical and specialty journals. We included late-phase randomized controlled trials examining therapeutic clinical practices in adults admitted to general medical-surgical or specialty intensive care units (ICUs). Included articles were classified using a reproducibility framework. An original study was the first to evaluate a clinical practice. A reproduction attempt re-evaluated that practice in a new set of participants. RESULTS: Overall, 158 practices were examined in 275 included articles. A reproduction attempt was identified for 66 practices (42%, 95% CI 33-50%). Original studies reported larger effects than reproduction attempts (primary endpoint, risk difference 16.0%, 95% CI 11.6-20.5% vs. 8.4%, 95% CI 6.0-10.8%, P = 0.003). More than half of clinical practices with a reproduction attempt demonstrated effects that were inconsistent with the original study (56%, 95% CI 42-68%), among which a large number were reported to be efficacious in the original study and to lack efficacy in the reproduction attempt (34%, 95% CI 19-52%). Two practices reported to be efficacious in the original study were found to be harmful in the reproduction attempt. CONCLUSIONS: A minority of critical care practices with research published in high-profile journals were evaluated for reproducibility; less than half had reproducible effects.

Re-examining Permissive Hypercapnia in ARDS: A Narrative Review.

Lung-protective ventilation (LPV) has become the cornerstone of management in patients with ARDS. A subset of patients is unable to tolerate LPV without significant CO2 elevation. In these patients, permissive hypercapnia is used. Although thought to be benign, it is becoming increasingly evident that elevated CO2 levels have significant physiological effects. In this narrative review, we highlight clinically relevant end-organ effects in both animal models and clinical studies. We also explore the association between elevated CO2, acute cor pulmonale, and ICU mortality. We conclude with a brief review of alternative therapies for CO2 management currently under investigation in patients with moderate to severe ARDS.

Endoribonucleases--enzymes gaining spotlight in mRNA metabolism.

The efficient turnover of messenger RNA represents an important mechanism that allows the cell to control gene expression. Until recently, the mechanism of mRNA decay was mainly attributed to exonucleases, comprising enzymes that degrade RNAs from the ends of the molecules. This article summarizes the endoribonucleases, comprising enzymes that cleave RNA molecules internally, which were identified in more recent years in eukaryotic mRNA metabolism. Endoribonucleases have received little attention in the past, based on the difficulty in their identification and a lack of understanding of their physiological significance. This review aims to compare the similarities and differences among this group of enzymes, as well as their known cellular functions. Despite the many differences in protein structure, and thus difficulties in identifying them based on amino acid sequence, most endoribonucleases possess essential cellular functions and have been shown to play an important role in mRNA turnover.

Identification of Apurinic/apyrimidinic endonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA.

Endonucleolytic cleavage of the coding region determinant (CRD) of c-myc mRNA appears to play a critical role in regulating c-myc mRNA turnover. Using (32)P-labeled c-myc CRD RNA as substrate, we have purified and identified two endoribonucleases from rat liver polysomes that are capable of cleaving the transcript in vitro. A 17-kDa enzyme was identified as RNase1. Apurinic/apyrimidinic (AP) DNA endonuclease 1 (APE1) was identified as the 35-kDa endoribonuclease that preferentially cleaves in between UA and CA dinucleotides of c-myc CRD RNA. APE1 was further confirmed to be the 35-kDa endoribonuclease because: (i) the endoribonuclease activity of the purified 35-kDa native enzyme was specifically immuno-depleted with APE1 monoclonal antibody, and (ii) recombinant human APE1 generated identical RNA cleavage patterns as the native liver enzyme. Studies using E96A and H309N mutants of APE1 suggest that the endoribonuclease activity for c-myc CRD RNA shares the same active center with the AP-DNA endonuclease activity. Transient knockdown of APE1 in HeLa cells led to increased steady-state level of c-myc mRNA and its half-life. We conclude that the ability to cleave RNA dinucleotides is a previously unidentified function of APE1 and it can regulate c-myc mRNA level possibly via its endoribonuclease activity.