Morbidity and mortality outcomes of patients requiring isolated tricuspid valve surgery: a retrospective cohort study of 537 patients in New South Wales between 2002 and 2018.

OBJECTIVES: The aim of the study was to evaluate mortality and morbidity outcomes following open-heart isolated tricuspid valve surgery (TVSx) with medium to long-term follow-up. DESIGN: Retrospective cohort study. SETTING: New South Wales public and private hospital admissions between 1 January 2002 and 30 June 2018. PARTICIPANTS: A total of 537 patients underwent open isolated TVSx during the study period. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was all-cause mortality tracked from the death registry to 31 December 2018. Secondary morbidity outcomes, including admission for congestive cardiac failure (CCF), new atrial fibrillation (AF), infective endocarditis (IE), pulmonary embolism (PE) and insertion of a permanent pacemaker (PPM) or implantable cardioverter-defibrillator (ICD), were tracked from the Admitted Patient Data Collection database. Independent mortality associations were determined using the Cox regression method. RESULTS: A total of 537 patients underwent open isolated TVSx (46% male): median age (IQR) was 63.5 years (43.9-73.8 years) with median length of stay of 16 days (10-31 days). Main cardiovascular comorbidities were AF (54%) and CCF (42%); 67% had rheumatic tricuspid valve. In-hospital and total mortality were 7.4% and 39.3%, respectively (mean follow-up: 4.8 years). Cause-specific deaths were evenly split between cardiovascular and non-cardiovascular causes. Predictors of mortality included a history of CCF (HR=1.78, 95% CI 1.33 to 2.38, p<0.001) and chronic pulmonary disease (HR=2.66, 95% CI 1.63 to 4.33, p<0.001). In-hospital PPM rate was 10.0%. At 180 days, 53 (9.9%) patients were admitted for CCF, 25 (10.1%) had new AF, 7 (1.5%) had new IE and <1% had PE, post-discharge PPM or ICD insertion. CONCLUSION: Open isolated TVSx carries significant mortality risk, with decompensated CCF and new AF the most common morbidities encountered after surgery. This report forms a benchmark to compare outcomes with newer percutaneous tricuspid interventions.

Automated CT Analysis of Body Composition as a Frailty Biomarker in Abdominal Surgery.

Importance: Prior studies demonstrated consistent associations of low skeletal muscle mass assessed on surgical planning scans with postoperative morbidity and mortality. The increasing availability of imaging artificial intelligence enables development of more comprehensive imaging biomarkers to objectively phenotype frailty in surgical patients. Objective: To evaluate the associations of body composition scores derived from multiple skeletal muscle and adipose tissue measurements from automated segmentation of computed tomography (CT) with the Hospital Frailty Risk Score (HFRS) and adverse outcomes after abdominal surgery. Design, Setting, and Participants: This retrospective cohort study used CT imaging and electronic health record data from a random sample of adults who underwent abdominal surgery at 20 medical centers within Kaiser Permanente Northern California from January 1, 2010, to December 31, 2020. Data were analyzed from April 1, 2022, to December 1, 2023. Exposure: Body composition derived from automated analysis of multislice abdominal CT scans. Main Outcomes and Measures: The primary outcome of the study was all-cause 30-day postdischarge readmission or postoperative mortality. The secondary outcome was 30-day postoperative morbidity among patients undergoing abdominal surgery who were sampled for reporting to the National Surgical Quality Improvement Program. Results: The study included 48 444 adults; mean [SD] age at surgery was 61 (17) years, and 51% were female. Using principal component analysis, 3 body composition scores were derived: body size, muscle quantity and quality, and distribution of adiposity. Higher muscle quantity and quality scores were inversely correlated (r = -0.42; 95% CI, -0.43 to -0.41) with the HFRS and associated with a reduced risk of 30-day readmission or mortality (quartile 4 vs quartile 1: relative risk, 0.61; 95% CI, 0.56-0.67) and 30-day postoperative morbidity (quartile 4 vs quartile 1: relative risk, 0.59; 95% CI, 0.52-0.67), independent of sex, age, comorbidities, body mass index, procedure characteristics, and the HFRS. In contrast to the muscle score, scores for body size and greater subcutaneous and intermuscular vs visceral adiposity had inconsistent associations with postsurgical outcomes and were attenuated and only associated with 30-day postoperative morbidity after adjustment for the HFRS. Conclusions and Relevance: In this study, higher muscle quantity and quality scores were correlated with frailty and associated with 30-day readmission and postoperative mortality and morbidity, whereas body size and adipose tissue distribution scores were not correlated with patient frailty and had inconsistent associations with surgical outcomes. The findings suggest that assessment of muscle quantity and quality on CT can provide an objective measure of patient frailty that would not otherwise be clinically apparent and that may complement existing risk stratification tools to identify patients at high risk of mortality, morbidity, and readmission.

Mortality outcomes in 35,433 patients admitted for acute haemorrhagic stroke in Australia: A population-linkage study.

Background: Haemorrhagic stroke (HS) is an important cardiovascular cause of mortality worldwide. Trends in admission rates and outcomes, and predictors of outcomes, post-HS in Australia remain unclear. Methods: All New South Wales residents, Australia, hospitalized with HS from 2002 to 2017 were identified from the Admitted-Patient-Data-Collection database. Admission rates were adjusted to population size by sex, age-groups and calendar-year. Mortality was tracked from the death registry to 31-Dec-2018 and adjusted for admission calendar-year, age, gender, referral source, surgical evacuation following HS and comorbidities. Results: The cohort comprised 35,433 patients (51.1% males). Overall age-adjusted mean(±SD) admission rates were higher for males (63.6 ± 6.2 vs 49.9 ± 4.4 admissions-per-100,000-persons-per-annum). Annual admission rates declined for both sexes from 2002 to 2017 especially in those ≥60yo. In-hospital and 1-year mortality rates were higher for females than males (25.0% vs 20.0% and 40.6% vs 35.9% respectively, all p < 0.001). Adjusted in-hospital and 1-year mortality declined for men and women, overall decreasing by 45% (odds ratio 0.55, 95% confidence interval [CI] = 0.47-0.64), and 31% (hazard ratio 0.69,95%CI = 0.63-0.76) respectively between 2002 and 2017. Independent predictors of increased in-hospital and 1-year mortality included increasing age and Charlson comorbidity index, while male sex, a history of hyperlipidaemia and current smoking, and surgical evacuation following HS were associated with reduced mortality (all p < 0.001). Conclusion: HS incidence increases markedly with age. Although age-adjusted HS admission rates and post HS mortality have fallen, HS remains associated with high early and 1-year mortality, with females consistently associated with worse outcomes. Strategies to improve outcomes of these patients remain a clinical priority.

Healthcare exposures and associated risk of endocarditis after open-heart cardiac valve surgery.

BACKGROUND: Infective endocarditis (IE) following cardiac valve surgery is associated with high morbidity and mortality. Data on the impact of iatrogenic healthcare exposures on this risk are sparse. This study aimed to investigate risk factors including healthcare exposures for post open-heart cardiac valve surgery endocarditis (PVE). METHODS: In this population-linkage cohort study, 23,720 patients who had their first cardiac valve surgery between 2001 and 2017 were identified from an Australian state-wide hospital-admission database and followed-up to 31 December 2018. Risk factors for PVE were identified from multivariable Cox regression analysis and verified using a case-crossover design sensitivity analysis. RESULTS: In 23,720 study participants (median age 73, 63% male), the cumulative incidence of PVE 15 years after cardiac valve surgery was 7.8% (95% CI 7.3-8.3%). Thirty-seven percent of PVE was healthcare-associated, which included red cell transfusions (16% of healthcare exposures) and coronary angiograms (7%). The risk of PVE was elevated for 90 days after red cell transfusion (HR = 3.4, 95% CI 2.1-5.4), coronary angiogram (HR = 4.0, 95% CI 2.3-7.0), and healthcare exposures in general (HR = 4.0, 95% CI 3.3-4.8) (all p < 0.001). Sensitivity analysis confirmed red cell transfusion (odds ratio [OR] = 3.9, 95% CI 1.8-8.1) and coronary angiogram (OR = 2.6, 95% CI 1.5-4.6) (both p < 0.001) were associated with PVE. Six-month mortality after PVE was 24% and was higher for healthcare-associated PVE than for non-healthcare-associated PVE (HR = 1.3, 95% CI 1.1-1.5, p = 0.002). CONCLUSIONS: The risk of PVE is significantly higher for 90 days after healthcare exposures and associated with high mortality.

Outcomes Following Implantable Cardioverter-Defibrillator Insertion in Patients 80 Years of Age or Older: A Statewide Population Cohort Study.

BACKGROUND: Patients ≥ 80 years of age are underrepresented in major implantable cardioverter-defibrillator (ICD) trials, and real-world data are lacking. In this study, we sought to assess ICD utilisation, outcomes, and their predictors, in an unselected statewide population including patients ≥ 80 years old. METHODS: We extracted details of ICDs implanted from 2009 to 2018 in New South Wales (NSW), Australia from the Centre for Health Record Linkage administrative data sets. Analysis was stratified into age groups of < 60 years, 60-79 years, and ≥ 80 years. RESULTS: A total of 9304 patients (mean age 66.1 ± 13.1 years; 12.1% ≥ 80 years) had de novo ICD placement at an average rate of 1163 ± 122 patients per annum, with more implants in men in all age groups. After adjusting for NSW population size by sex, age group, and calendar year, mean implantation rates were 5.5 ± 0.6, 63.2 ± 8.6, and 52.7 ± 10.8 per 100,000 persons per annum in patients aged < 60 years, 60-79 years, and ≥ 80 years, respectively. In-hospital mortality was 0.4% and did not differ among age groups. However, 1-year mortality was 2.1%, 5.9%, and 10.7%, in those < 60 years, 60-79 years, and ≥ 80 years of age, respectively (P < 0.001), with hazard ratios for those aged ≥ 80 years of 4.3 (95% confidence interval [CI] 3.1-6.0) and those aged 60-79 years of 2.6 (95% CI 1.9-3.5) relative to those aged < 60 years (both P < 0.001) after adjusting for ICD indications, sex, implantation year, referral source, and comorbidities. In those aged ≥ 80 years, age > 83 years, congestive cardiac failure, chronic renal failure, neurodegenerative disease, and a higher Charlson comorbidity index score were each independent predictors of 1-year mortality. CONCLUSIONS: ICD use in patients aged ≥ 80 years and 60-79 years was 10-fold that in patients aged < 60 years, and perioperative outcomes were good in all ages, but there was substantially increased 1-year mortality in those aged ≥ 80 years. Careful selection based on age and comorbidity may further reduce 1-year mortality in patients ≥ 80 years old receiving ICDs.

Trends in Isolated Mitral Valve Repair or Replacement Surgery in Australia: A Statewide Cohort Linkage Study.

BACKGROUND: Global trends in mitral valve surgery (MVSx) suggest increasing repair compared with replacement, especially in the United States and European countries. The relative use, and outcomes of, MV repair and replacement in Australia are unknown. METHODS: New South Wales residents who underwent isolated MVSx between 2001 and 2017 were identified from the Admitted-Patient-Data-Collection database. Mortality outcomes were tracked to 31 Dec 2018 and adjusted based on age, sex, urgency of operation, and comorbidity status. RESULTS: The study cohort comprised 5,693 patients: 2020 (35%) underwent repair (MVr), 1,656 (29%) underwent mechanical replacement (mech.MVR), and 2017 (35%) underwent bioprosthetic replacement (bio.MVR). Respective median ages [interquartile range] were 67 yo [59-75 yo], 64 yo [55-71 yo], and 75 yo [68-80 yo] (p<0.001 across groups). Between 2001 and 2017, total MVSx increased steadily with population growth. Whereas the relative use of MVr remained static (34% to 38%), that for bio.MVR (22% to 50%) and mech.MVR (45% to 13%) changed significantly. MVr had the best outcome with 1.2% in-hospital, 2.5% 1-year, and 21.6% total cumulative mortality during a median follow-up of 6.5 years. Compared to MVr, the adjusted hazard ratio (aHR) for mech.MVR and bio.MVR for long-term mortality were 1.41 (95% confidence interval [CI]=1.24-1.61) and 1.73 (95% CI=1.53-1.95), respectively. Heart failure and sepsis were the main cardiovascular and noncardiovascular causes of death in all groups. CONCLUSION: In this statewide Australian cohort examined over 17 years, MVr is potentially underutilised despite having superior outcomes to MVR. Access to quality dataset which provides the indication for MVSx and quantitative clinical factors is critical to further improve MVr coverage and outcome MVSx.

Differential effects of microRNAs miR-21, miR-99 and miR-145 on lung regeneration and inflammation during recovery from influenza pneumonia.

In a mouse model of influenza pneumonia, we previously documented that proliferating alveolar type II (AT2) cells are the major stem cells involved in early lung recovery. Profiling of microRNAs revealed significant dysregulation of specific ones, including miR-21 and miR-99a. Moreover, miR-145 is known to exhibit antagonism to miR-21. This follow-up study investigated the roles of microRNAs miR-21, miR-99a, and miR-145 in the murine pulmonary regenerative process and inflammation during influenza pneumonia. Inhibition of miR-21 resulted in severe morbidity, and in significantly decreased proliferating AT2 cells due to impaired transition from innate to adaptive immune responses. Knockdown of miR-99a culminated in moderate morbidity, with a significant increase in proliferating AT2 cells that may be linked to PTEN downregulation. In contrast, miR-145 antagonism did not impact morbidity nor the proliferating AT2 cell population, and was associated with downregulation of TNF-alpha, IL1-beta, YM1, and LY6G. Hence, a complex interplay exists between expression of specific miRNAs, lung regeneration, and inflammation during recovery from influenza pneumonia. Inhibition of miR-21 and miR-99a (but not miR-145) can lead to deleterious cellular and molecular effects on pulmonary repair and inflammatory processes during influenza pneumonia.

The Association of Helicobacter pylori Biofilm with Enterovirus 71 Prolongs Viral Viability and Survival.

The transition time during which a virus leaves its host and infects the next susceptible host is critical for virus survival. Enterovirus 71 (EV71) is stable in aqueous environments, but its molecular interactions with bacteria and their biofilms are not well-established. Helicobacter pylori is a highly successful gut bacterial pathogen, with its capacity to form biofilms being linked to its transmission. Given that both are gut-associated microbes, we hypothesized that biofilms formed by H. pylori may play a significant role in the survival of EV71 in the external environment. In this study, we examine the interactions of EV71 with the preformed biofilm of H. pylori to mimic its natural state in the environment. Immunofluorescence confocal microscopy and scanning electron microscopy revealed that EV71 particles persisted for up to 10 days when incubated with the H. pylori biofilm. Furthermore, the presence of the H. pylori biofilm significantly augmented viral viability, as verified through virus plaque assays. Interestingly, the viability of EV71 was dependent on the quantity of H. pylori biofilm formation. Thus, two H. pylori strains able to generate large amounts of biofilm could facilitate EV71 viability for up to 17 days, whereas two other H. pylori strains that produced moderate or low quantities of biofilm could not prolong virus viability. It is interesting that biofilm contains N-acetyl-glucosamine and glycosaminoglycan, and that EV71 has binding affinity to cell-surface heparan sulfate glycosaminoglycan, which acts as an EV71 attachment receptor. The synergistic ability of H. pylori biofilm to promote EV71 viability for extended periods implies that H. pylori biofilm may serve as an additional pathway of EV71 transmission.

Influenza A and B Viruses in Fine Aerosols of Exhaled Breath Samples from Patients in Tropical Singapore.

Influenza is a highly contagious respiratory illness that commonly causes outbreaks among human communities. Details about the exact nature of the droplets produced by human respiratory activities such as breathing, and their potential to carry and transmit influenza A and B viruses is still not fully understood. The objective of our study was to characterize and quantify influenza viral shedding in exhaled aerosols from natural patient breath, and to determine their viral infectivity among participants in a university cohort in tropical Singapore. Using the Gesundheit-II exhaled breath sampling apparatus, samples of exhaled breath of two aerosol size fractions ("coarse" > 5 µm and "fine" ≤ 5 µm) were collected and analyzed from 31 study participants, i.e., 24 with influenza A (including H1N1 and H3N2 subtypes) and 7 with influenza B (including Victoria and Yamagata lineages). Influenza viral copy number was quantified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Infectivity of influenza virus in the fine particle fraction was determined by culturing in Madin-Darby canine kidney cells. Exhaled influenza virus RNA generation rates ranged from 9 to 1.67 × 105 and 10 to 1.24 × 104 influenza virus RNA copies per minute for the fine and coarse aerosol fractions, respectively. Compared to the coarse aerosol fractions, influenza A and B viruses were detected more frequently in the fine aerosol fractions that harbored 12-fold higher viral loads. Culturable virus was recovered from the fine aerosol fractions from 9 of the 31 subjects (29%). These findings constitute additional evidence to reiterate the important role of fine aerosols in influenza transmission and provide a baseline range of influenza virus RNA generation rates.

A systematic review of automated segmentation of 3D computed-tomography scans for volumetric body composition analysis.

Automated computed tomography (CT) scan segmentation (labelling of pixels according to tissue type) is now possible. This technique is being adapted to achieve three-dimensional (3D) segmentation of CT scans, opposed to single L3-slice alone. This systematic review evaluates feasibility and accuracy of automated segmentation of 3D CT scans for volumetric body composition (BC) analysis, as well as current limitations and pitfalls clinicians and researchers should be aware of. OVID Medline, Embase and grey literature databases up to October 2021 were searched. Original studies investigating automated skeletal muscle, visceral and subcutaneous AT segmentation from CT were included. Seven of the 92 studies met inclusion criteria. Variation existed in expertise and numbers of humans performing ground-truth segmentations used to train algorithms. There was heterogeneity in patient characteristics, pathology and CT phases that segmentation algorithms were developed upon. Reporting of anatomical CT coverage varied, with confusing terminology. Six studies covered volumetric regional slabs rather than the whole body. One study stated the use of whole-body CT, but it was not clear whether this truly meant head-to-fingertip-to-toe. Two studies used conventional computer algorithms. The latter five used deep learning (DL), an artificial intelligence technique where algorithms are similarly organized to brain neuronal pathways. Six of seven reported excellent segmentation performance (Dice similarity coefficients > 0.9 per tissue). Internal testing on unseen scans was performed for only four of seven algorithms, whilst only three were tested externally. Trained DL algorithms achieved full CT segmentation in 12 to 75 s versus 25 min for non-DL techniques. DL enables opportunistic, rapid and automated volumetric BC analysis of CT performed for clinical indications. However, most CT scans do not cover head-to-fingertip-to-toe; further research must validate using common CT regions to estimate true whole-body BC, with direct comparison to single lumbar slice. Due to successes of DL, we expect progressive numbers of algorithms to materialize in addition to the seven discussed in this paper. Researchers and clinicians in the field of BC must therefore be aware of pitfalls. High Dice similarity coefficients do not inform the degree to which BC tissues may be under- or overestimated and nor does it inform on algorithm precision. Consensus is needed to define accuracy and precision standards for ground-truth labelling. Creation of a large international, multicentre common CT dataset with BC ground-truth labels from multiple experts could be a robust solution.

Pharmacokinetic Similarity of ABP 654, an Ustekinumab Biosimilar Candidate: Results from a Randomized, Double-blind Study in Healthy Subjects.

ABP 654 is a proposed biosimilar to ustekinumab reference product (RP) which works through antagonism of interleukin-12 and interleukin-23. Ustekinumab RP is used for the treatment of chronic inflammatory conditions, including some forms of plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. A randomized, double-blinded, single-dose, 3-arm, parallel-group study was conducted to assess the pharmacokinetic (PK) similarity of ABP 654 with ustekinumab RP sourced from the United States (US) and the European Union (EU); the PK similarity of ustekinumab US versus ustekinumab EU; and the comparative safety, tolerability, and immunogenicity of all 3 products. A total of 238 healthy subjects were randomized 1:1:1 and stratified by gender and ethnicity (Japanese versus non-Japanese) to receive a single 90 mg subcutaneous injection of ABP 654 or ustekinumab US or ustekinumab EU. PK similarity was established based on 90% confidence intervals (CIs) for the primary endpoints of area under the concentration-time curve from time 0 extrapolated to infinity (AUCinf ) and maximum observed serum concentration (Cmax ) being contained within the prespecified margin of 0.8-1.25. No clinically meaningful differences in immunogenicity were found among the 3 products. Adverse events were similar between treatment groups and consistent with the safety profile of ustekinumab RP. Results indicate that ABP 654, ustekinumab US and ustekinumab EU share similar PK and safety profiles.

Clinical characteristics and outcomes of peritoneal dialysis (PD)-related peritonitis after colonoscopy.

Colonoscopy is known to be associated with peritonitis in peritoneal dialysis (PD) patients. Antibiotic prophylaxis is recommended before colonoscopy. This study aims to investigate the clinical characteristics and outcomes of patients with PD-related peritonitis after colonoscopy. PD patients who were followed up in Pamela Youde Nethersole Eastern Hospital, with colonoscopy done from 1 January 2009 to 31 December 2019, were included for record review retrospectively. During this period, 74 patients underwent 115 colonoscopies. Fourteen patients (12.2%) developed PD-related peritonitis within 1 week after colonoscopy. There was no statistically significant difference in mean age, PD vintage, PD modality and history of PD-related peritonitis between patients with or without colonoscopy-related peritonitis. Polypectomy was more common in patients who developed peritonitis (78.6%) compared to those without peritonitis (35.6%) (p = 0.006). Ten of the 14 PD patients who had colonoscopy-related peritonitis responded to medical treatment while 4 patients required PD catheter removal. Two patients converted to maintenance haemodialysis and two died. Only 33% of Gram-negative bacteria isolated were sensitive to intravenous cefuroxime which was given as prophylactic antibiotic before colonoscopy. In conclusion, the overall risk of PD patients developing peritonitis post colonoscopy was 12.2%. Polypectomy was associated with higher risk of colonoscopy-related peritonitis. Large-scale study is needed to delineate effective antibiotic prophylaxis for colonoscopy-related peritonitis.

Prolonged Primary Rhinovirus Infection of Human Nasal Epithelial Cells Diminishes the Viral Load of Secondary Influenza H3N2 Infection via the Antiviral State Mediated by RIG-I and Interferon-Stimulated Genes.

Our previous study revealed that prolonged human rhinovirus (HRV) infection rapidly induces antiviral interferons (IFNs) and chemokines during the acute stage of infection. It also showed that expression levels of RIG-I and interferon-stimulated genes (ISGs) were sustained in tandem with the persistent expression of HRV RNA and HRV proteins at the late stage of the 14-day infection period. Some studies have explored the protective effects of initial acute HRV infection on secondary influenza A virus (IAV) infection. However, the susceptibility of human nasal epithelial cells (hNECs) to re-infection by the same HRV serotype, and to secondary IAV infection following prolonged primary HRV infection, has not been studied in detail. Therefore, the aim of this study was to investigate the effects and underlying mechanisms of HRV persistence on the susceptibility of hNECs against HRV re-infection and secondary IAV infection. We analyzed the viral replication and innate immune responses of hNECs infected with the same HRV serotype A16 and IAV H3N2 at 14 days after initial HRV-A16 infection. Prolonged primary HRV infection significantly diminished the IAV load of secondary H3N2 infection, but not the HRV load of HRV-A16 re-infection. The reduced IAV load of secondary H3N2 infection may be explained by increased baseline expression levels of RIG-I and ISGs, specifically MX1 and IFITM1, which are induced by prolonged primary HRV infection. As is congruent with this finding, in those cells that received early and multi-dose pre-treatment with Rupintrivir (HRV 3C protease inhibitor) prior to secondary IAV infection, the reduction in IAV load was abolished compared to the group without pre-treatment with Rupintrivir. In conclusion, the antiviral state induced from prolonged primary HRV infection mediated by RIG-I and ISGs (including MX1 and IFITM1) can confer a protective innate immune defense mechanism against secondary influenza infection.

The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses.

Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus (Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broad-spectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) phosphorylation and Golgi vesiculation by peruvoside treatment. The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation. Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337 (T1337). We also showed 100% of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum. These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside, host-directed antivirals for positive-sense RNA virus-mediated disease, in the interim where no vaccine is available.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. METHODS: We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed. RESULTS: Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements. CONCLUSIONS: Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

Evolution of SARS-CoV-2 Variants: Implications on Immune Escape, Vaccination, Therapeutic and Diagnostic Strategies.

The COVID-19 pandemic caused by SARS-CoV-2 is associated with a lower fatality rate than its SARS and MERS counterparts. However, the rapid evolution of SARS-CoV-2 has given rise to multiple variants with varying pathogenicity and transmissibility, such as the Delta and Omicron variants. Individuals with advanced age or underlying comorbidities, including hypertension, diabetes and cardiovascular diseases, are at a higher risk of increased disease severity. Hence, this has resulted in an urgent need for the development of better therapeutic and preventive approaches. This review describes the origin and evolution of human coronaviruses, particularly SARS-CoV-2 and its variants as well as sub-variants. Risk factors that contribute to disease severity and the implications of co-infections are also considered. In addition, various antiviral strategies against COVID-19, including novel and repurposed antiviral drugs targeting viral and host proteins, as well as immunotherapeutic strategies, are discussed. We critically evaluate strategies of current and emerging vaccines against SARS-CoV-2 and their efficacy, including immune evasion by new variants and sub-variants. The impact of SARS-CoV-2 evolution on COVID-19 diagnostic testing is also examined. Collectively, global research and public health authorities, along with all sectors of society, need to better prepare against upcoming variants and future coronavirus outbreaks.

SARS-CoV-2 Omicron variant shedding during respiratory activities.

OBJECTIVES: As the world transitions to COVID-19 endemicity, studies focusing on aerosol shedding of highly transmissible SARS-CoV-2 variants of concern (VOCs) are vital for the calibration of infection control measures against VOCs that are likely to circulate seasonally. This follow-up Gesundheit-II aerosol sampling study aims to compare the aerosol shedding patterns of Omicron VOC samples with pre-Omicron variants analyzed in our previous study. DESIGN: Coarse and fine aerosol samples from 47 patients infected with SARS-CoV-2 were collected during various respiratory activities (passive breathing, talking, and singing) and analyzed using reverse transcription-quantitative polymerase chain reaction and virus culture. RESULTS: Compared with patients infected with pre-Omicron variants, comparable SARS-CoV-2 RNA copy numbers were detectable in aerosol samples of patients infected with Omicron despite being fully vaccinated. Patients infected with Omicron also showed a slight increase in viral aerosol shedding during breathing activities and were more likely to have persistent aerosol shedding beyond 7 days after disease onset. CONCLUSION: This follow-up study reaffirms the aerosol shedding properties of Omicron and should guide continued layering of public health interventions even in highly vaccinated populations.

Influence of glycan structure on the colonization of Streptococcus pneumoniae on human respiratory epithelial cells.

Virtually all living cells are encased in glycans. They perform key cellular functions such as immunomodulation and cell-cell recognition. Yet, how their composition and configuration affect their functions remains enigmatic. Here, we constructed isogenic capsule-switch mutants harboring 84 types of capsular polysaccharides (CPSs) in Streptococcus pneumoniae. This collection enables us to systematically measure the affinity of structurally related CPSs to primary human nasal and bronchial epithelial cells. Contrary to the paradigm, the surface charge does not appreciably affect epithelial cell binding. Factors that affect adhesion to respiratory cells include the number of rhamnose residues and the presence of human-like glycomotifs in CPS. Besides, pneumococcal colonization stimulated the production of interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractantprotein-1 (MCP-1) in nasal epithelial cells, which also appears to be dependent on the serotype. Together, our results reveal glycomotifs of surface polysaccharides that are likely to be important for colonization and survival in the human airway.