Baseline Gastric Volume in Fasting Diabetic Patients Is Not Higher than That in Nondiabetic Patients: A Cross-sectional Noninferiority Study.

BACKGROUND: The physiology of diabetes mellitus can increase the risk of perioperative aspiration, but there is limited and contradictory evidence on the incidence of "full stomach" in fasting diabetic patients. The aim of this study is to assess the baseline gastric content (using gastric ultrasound) in diabetic and nondiabetic patients scheduled for elective surgery who have followed standard preoperative fasting instructions. METHODS: This was a prospective, noninferiority study of 180 patients (84 diabetic and 96 nondiabetic patients). Bedside ultrasound was used for qualitative and quantitative assessment of the gastric antrum in the supine and right lateral decubitus positions. Fasting gastric volume was estimated based on the cross-sectional area of the gastric antrum and a validated model. The hypothesis was that diabetic patients would not have a higher baseline fasting gastric volume compared to nondiabetic patients, with a noninferiority margin of 0.4 ml/kg. Secondary aims included the comparison of the incidence of full stomach (solid content or more than 1.5 mL/kg of clear fluid), estimation of the 95th percentile of the gastric volume distribution in both groups, and examination of the association between gastric volume, glycemic control, and diabetic comorbidities. RESULTS: The baseline gastric volume was not higher in diabetic patients (0.81 ± 0.61 ml/kg) compared to nondiabetic patients (0.87 ± 0.53 ml/kg) with a mean difference of -0.07 ml/kg (95% CI, -0.24 to 0.10 ml/kg). A total of 13 (15.5%) diabetic and 11 (11.5%) nondiabetic patients presented more than 1.5 ml/kg of gastric volume (95% CI for difference, -7.1 to 15.2%). There was little correlation between the gastric volume and either the time since diagnosis or HbA1C. CONCLUSIONS: The data suggest that the baseline gastric volume in diabetic patients who have followed standard fasting instructions is not higher than that in nondiabetic patients.

The interplay between lipid droplets and virus infection.

As an intracellular parasite, the virus usurps cellular machinery and modulates cellular metabolism pathways to replicate itself in cells. Lipid droplets (LDs) are universally conserved energy storage organelles that not only play vital roles in maintaining lipid homeostasis but are also involved in viral replication. Increasing evidence has demonstrated that viruses take advantage of cellular lipid metabolism by targeting the biogenesis, hydrolysis, and lipophagy of LD during viral infection. In this review, we summarize the current knowledge about the modulation of cellular LD by different viruses, with a special emphasis on the Hepatitis C virus, Dengue virus, and SARS-CoV-2.

Prevalence and Risk Factors for Chronic Postsurgical Pain after Cardiac Surgery: A Single-center Prospective Cohort Study.

BACKGROUND: Chronic postsurgical pain is a common complication of surgery. The role of psychologic risk factors like depression and anxiety is substantially understudied in cardiac surgery. This study sought to identify perioperative factors associated with chronic pain at 3, 6, and 12 months after cardiac surgery. The authors hypothesize that baseline psychologic vulnerabilities have a negative influence on chronic postsurgical pain. METHODS: The authors prospectively collected demographic, psychologic, and perioperative factors in a cohort of 1,059 patients undergoing cardiac surgery at the Toronto General Hospital between 2012 and 2020. Patients were followed and completed chronic pain questionnaires at 3, 6, and 12 months after surgery. RESULTS: The study included 767 patients who completed at least one follow-up questionnaire. The incidence of postsurgical pain (more than 0 out of 10) at 3, 6, and 12 months after surgery was 191 of 663 (29%), 118 of 625 (19%), and 89 of 605 (15%), respectively. Notably, among patients reporting any pain, the incidence of pain compatible with a neuropathic phenotype increased from 56 of 166 (34%) at 3 months to 38 of 97 (39%) at 6 months and 43 of 67 (64%) at 12 months. Factors associated with postsurgical pain scores at 3 months include female sex, pre-existing chronic pain, previous cardiac surgery, preoperative depression, baseline pain catastrophizing scores, and moderate-to-severe acute pain (4 or more out of 10) within 5 postoperative days. CONCLUSIONS: Nearly one in three patients undergoing cardiac surgery reported pain at 3 months of follow-up, with approximately 15% reporting persistent pain at 1 yr. Female sex, pre-existing chronic pain, and baseline depression were associated with postsurgical pain scores across all three time periods.

Genetic variety of ORF3a shapes SARS-CoV-2 fitness through modulation of lipid droplet.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leads to the accumulation of lipid droplets (LD), the central hubs of the lipid metabolism, in vitro or in type II pneumocytes and monocytes from coronavirus disease 19 (COVID-19) patients and blockage of LD formation by specific inhibitors impedes SARS-CoV-2 replication. Here, we showed that ORF3a is necessary and sufficient to trigger LD accumulation during SARS-CoV-2 infection, leading to efficient virus replication. Although highly mutated during evolution, ORF3a-mediated LD modulation is conserved in most SARS-CoV-2 variants except the Beta strain and is a major difference between SARS-CoV and SARS-CoV-2 that depends on the genetic variations on the amino acid position 171, 193, and 219 of ORF3a. Importantly, T223I substitution in recent Omicron strains (BA.2-BF.8) impairs ORF3a-Vps39 association and LD accumulation, leading to less efficient replication and potentially contributing to lower pathogenesis of the Omicron strains. Our work characterized how SARS-CoV-2 modulates cellular lipid homeostasis to benefit its replication during virus evolution, making ORF3a-LD axis a promising drug target for the treatment of COVID-19.

Modulation of cellular machineries by Zika virus-encoded proteins.

The strain of Zika virus (ZIKV) that circulated during the 2015 epidemic in Brazil has been associated with more than 2000 cases of microcephaly from September 2015 through November 2016. The viral genome determines the biology and pathogenesis of a virus and the virus employs its own gene products to evade host immune surveillance, manipulate cellular machineries, and establish efficient replication. Therefore, understanding the functions of virus-encoded protein not only aids the knowledge of ZIKV biology but also guides the development of anti-ZIKV drugs. In this review, we focus on 10 proteins encoded by ZIKV and summarize their functions in ZIKV replication and pathogenesis according to studies published in the past 6 years.

KSHV-encoded ORF45 activates human NLRP1 inflammasome.

At steady state, the NOD-like receptor (NLR)-containing pyrin domain (PYD) (NLRP)1 inflammasome is maintained in an auto-inhibitory complex by dipeptidyl peptidases 8 and 9 (DPP8 and DPP9) and is activated by pathogen-encoded proteases after infection. Here, we showed that the open reading frame (ORF)45 protein of the Kaposi's sarcoma-associated herpesvirus activated the human NLRP1 (hNLRP1) inflammasome in a non-protease-dependent manner, and we additionally showed that the Linker1 region of hNLRP1, situated between the PYD and NACHT domains, was required for the auto-inhibition and non-protease-dependent activation of hNLRP1. At steady state, the interaction between Linker1 and the UPA subdomain silenced the activation of hNLRP1 in auto-inhibitory complexes either containing DPP9 or not in a manner independent of DPP9. ORF45 binding to Linker1 displaced UPA from the Linker1-UPA complex and induced the release of the C-terminal domain of hNLRP1 for inflammasome assembly. The ORF45-dependent activation of the NLRP1 inflammasome was conserved in primates but was not observed for murine NLRP1b inflammasomes.

Glial-modulating agents for the treatment of pain: protocol for a systematic review.

INTRODUCTION: Evidence suggests a role for Central nervous system glia in pain transmission and in augmenting maladaptive opioid effects. Identification of drugs that modulate glia has guided the evaluation of glial suppression as a pain management strategy. This planned systematic review will describe evidence of the efficacy and adverse effects of glial-modulating drugs in pain management. METHODS AND ANALYSIS: A detailed search will be conducted on the Cochrane Central Register of Controlled Trials, Medline, and Embase from their inception until the date the final searches are run to identify relevant randomised controlled trials. The reference lists of retrieved studies, as well as online trial registries, will also be searched. English language, randomised, double-blind trials comparing various glial-modulating drugs with placebo and/or other comparators, with participant-reported pain assessment, will be included. Two reviewers will independently evaluate studies for eligibility, extract data and assess trial quality and potential bias. Risk of bias will be assessed using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. Primary outcomes for this review will include any validated measure of pain intensity and/or pain relief. Dichotomous data will be used to calculate risk ratio and number needed to treat or harm. The quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: This systematic review does not require formal ethics approval. The findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42021262074.

The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication.

RSK1, an essential cellular kinase for Kaposi's sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attaching SUMO to RSK1 has not yet been identified. By genome-wide screening, we found that KSHV ORF45 is necessary and sufficient to enhance RSK1 SUMOylation. Mechanistically, KSHV ORF45 binds to SUMOs via two classic SUMO-interacting motifs (SIMs) and functions as a SIM-dependent SUMO E3 ligase for RSK1. Mutations on these ORF45 SIMs resulted in much lower lytic gene expressions, viral DNA replication, and mature progeny virus production. Interestingly, KSHV ORF45 controls RSK1 SUMOylation and phosphorylation via two separated functional regions: SIMs and amino acid 17-90, respectively, which do not affect each other. Similar to KSHV ORF45, ORF45 of Rhesus Macaque Rhadinovirus has only one SIM and also increases RSK1 SUMOylation in a SIM-dependent manner, while other ORF45 homologues do not have this function. Our work characterized ORF45 as a novel virus encoded SUMO E3 ligase, which is required for ORF45-RSK1 axis-mediated KSHV lytic gene expression.

Association of Medicaid Expansion With Neuraxial Labor Analgesia Use in the United States: A Retrospective Cross-Sectional Analysis.

BACKGROUND: The Affordable Care Act has been associated with increased Medicaid coverage for childbirth among low-income US women. We hypothesized that Medicaid expansion was associated with increased use of labor neuraxial analgesia. METHODS: We performed a cross-sectional analysis of US women with singleton live births who underwent vaginal delivery or intrapartum cesarean delivery between 2009 and 2017. Data were sourced from births in 26 US states that used the 2003 Revised US Birth Certificate. Difference-in-difference linear probability models were used to compare changes in the prevalence of neuraxial labor analgesia in 15 expansion and 11 nonexpansion states before and after Medicaid expansion. Models were adjusted for potential maternal and obstetric confounders with standard errors clustered at the state level. RESULTS: The study sample included 5,703,371 births from 15 expansion states and 5,582,689 births from 11 nonexpansion states. In the preexpansion period, the overall rate of neuraxial analgesia in expansion and nonexpansion states was 73.2% vs 76.3%. Compared with the preexpansion period, the rate of neuraxial analgesia increased in the postexpansion period by 1.7% in expansion states (95% CI, 1.6-1.8) and 0.9% (95% CI, 0.9-1.0) in nonexpansion states. The adjusted difference-in-difference estimate comparing expansion and nonexpansion states was 0.47% points (95% CI, -0.63 to 1.57; P = .39). CONCLUSIONS: Medicaid expansion was not associated with an increase in the rate of neuraxial labor analgesia in expansion states compared to the change in nonexpansion states over the same time period. Increasing Medicaid eligibility alone may be insufficient to increase the rate of neuraxial labor analgesia.

Trends in eclampsia in the United States, 2009-2017: a population-based study.

BACKGROUND: Reducing the prevalence of eclampsia, a major cause of maternal and perinatal morbidity, is a maternal health priority. However, sparse data exist examining trends in the USA prevalence of eclampsia. OBJECTIVE: The aim of this study was to assess temporal trends in the prevalence of eclampsia among live births in the United States from 2009 to 2017. STUDY DESIGN: This population-based cross-sectional study included live births in 41 USA states and the District of Columbia between 2009 and 2017. The prevalence of eclampsia among all women, women with chronic hypertension and hypertensive disorders of pregnancy were reported by 1000 live births. Risk ratios adjusted for maternal characteristics were used to assess temporal trends. RESULTS: Of 27 866 714 live births between 2009 and 2017, 83 000 (0.30%) were associated with eclampsia. The adjusted risk of eclampsia decreased 10% during the 7 most recent years of the cohort, with an adjusted risk ratio of 0.90 [95% confidence interval (95% CI): 0.87-0.93] in 2017 relative to 2009. Relative to 2009, the adjusted risk of eclampsia in 2017 was substantially lower among women with chronic hypertension (adjusted risk ratio: 0.51; 95% CI: 0.46-0.57) and women with hypertensive pregnancy disorders (adjusted risk ratio: 0.43; 95% CI: 0.40-0.47). Among nonhypertensive women, there was a slight increase in the adjusted risk of eclampsia in 2017 relative to 2009 (adjusted risk ratio: 1.14; 95% CI: 1.10-1.17). CONCLUSION: Despite reductions in the eclampsia prevalence among women with chronic hypertension and hypertensive disorders of pregnancy, public health initiatives are needed to reduce the overall eclampsia prevalence, especially in nonhypertensive women.

RSK1 SUMOylation is required for KSHV lytic replication.

RSK1, a downstream kinase of the MAPK pathway, has been shown to regulate multiple cellular processes and is essential for lytic replication of a variety of viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV). Besides phosphorylation, it is not known whether other post-translational modifications play an important role in regulating RSK1 function. We demonstrate that RSK1 undergoes robust SUMOylation during KSHV lytic replication at lysine residues K110, K335, and K421. SUMO modification does not alter RSK1 activation and kinase activity upon KSHV ORF45 co-expression, but affects RSK1 downstream substrate phosphorylation. Compared to wild-type RSK1, the overall phosphorylation level of RxRxxS*/T* motif is significantly declined in RSK1K110/335/421R expressing cells. Specifically, SUMOylation deficient RSK1 cannot efficiently phosphorylate eIF4B. Sequence analysis showed that eIF4B has one SUMO-interacting motif (SIM) between the amino acid position 166 and 170 (166IRVDV170), which mediates the association between eIF4B and RSK1 through SUMO-SIM interaction. These results indicate that SUMOylation regulates the phosphorylation of RSK1 downstream substrates, which is required for efficient KSHV lytic replication.

ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent for the coronavirus disease 2019 (COVID-19) pandemic and there is an urgent need to understand the cellular response to SARS-CoV-2 infection. Beclin 1 is an essential scaffold autophagy protein that forms two distinct subcomplexes with modulators Atg14 and UVRAG, responsible for autophagosome formation and maturation, respectively. In the present study, we found that SARS-CoV-2 infection triggers an incomplete autophagy response, elevated autophagosome formation but impaired autophagosome maturation, and declined autophagy by genetic knockout of essential autophagic genes reduces SARS-CoV-2 replication efficiency. By screening 26 viral proteins of SARS-CoV-2, we demonstrated that expression of ORF3a alone is sufficient to induce incomplete autophagy. Mechanistically, SARS-CoV-2 ORF3a interacts with autophagy regulator UVRAG to facilitate PI3KC3-C1 (Beclin-1-Vps34-Atg14) but selectively inhibit PI3KC3-C2 (Beclin-1-Vps34-UVRAG). Interestingly, although SARS-CoV ORF3a shares 72.7% amino acid identity with the SARS-CoV-2 ORF3a, the former had no effect on cellular autophagy response. Thus, our findings provide the mechanistic evidence of possible takeover of host autophagy machinery by ORF3a to facilitate SARS-CoV-2 replication and raise the possibility of targeting the autophagic pathway for the treatment of COVID-19.

Patterns of Gene Expression in Cutaneous T-Cell Lymphoma: Systematic Review of Transcriptomic Studies in Mycosis Fungoides.

Mycosis fungoides (MF) is the most prevalent type of skin lymphoma. In its early stages, it has a favorable prognosis. However, in its late stages, it is associated with an increased risk of mortality. This systematic review aimed to identify the transcriptomic changes involved in MF pathogenesis and progression. A literature search was conducted using the database PubMed, followed by the extraction of 2245 genes which were further filtered to 150 recurrent genes that appeared in two or more publications. Categorization of these genes identified activated pathways involved in pathways such as cell cycle and proliferation, chromosomal instability, and DNA repair. We identified 15 genes implicated in MF progression, which were involved in cell proliferation, immune checkpoints, resistance to apoptosis, and immune response. In highlighting the discrepancies in the way MF transcriptomic data is obtained, further research can focus on not only unifying their approach but also focus on the 150 pertinent genes identified in this review.

Gastric content and perioperative pulmonary aspiration in patients with diabetes mellitus: a scoping review.

BACKGROUND: Gastric emptying may be delayed in patients with diabetes mellitus (DM). However, the incidence of full stomach in fasting patients with DM and their risk of pulmonary aspiration under anaesthesia is not well understood. METHODS: A scoping review was undertaken to map the literature on aspiration risk in DM. A search was conducted in seven bibliographic databases, including MEDLINE and Embase, for original articles that studied aspiration risk, gastric emptying, or gastric content and volume. Selection and characterisation were performed by two independent reviewers using a predefined protocol registered externally. RESULTS: The search identified 5063 unique records, and 16 studies (totalling 775 patients with DM) were selected: nine studied gastric emptying and seven studied gastric content or volume. There were no studies reporting the incidence of aspiration in subjects with DM. All nine studies reported delayed emptying in patients with DM compared with healthy controls. Amongst the seven studies that compared gastric residual content/volume (GRV) in the perioperative period, five reported clinically negligible GRV in both patients with DM and controls, whereas two observed a higher incidence of 'full' stomach in patients with DM. CONCLUSIONS: The evidence concerning the aspiration risk for surgical patients with DM is based on a limited number of studies, mostly unblinded, reporting physiological data on gastric emptying and gastric volume as surrogate markers of aspiration risk. Data on fasting gastric content and volume in patients with DM are limited and contradictory; hence, the true risk of aspiration in fasting patients with DM is unknown.