Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic ...resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca
2+
release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans.
Abbreviations: 1,25D3: 1α, 25-dihydroxyvitamin D3; ATG5: autophagy related 5; Baf A1: bafilomycin A
1
; BECN1: beclin 1; CagA: cytotoxin-associated gene A; CFU: colony-forming unit; ChIP-PCR: chromatin immunoprecipitation-polymerase chain reaction; Con A: concanamycin A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTSD: cathepsin D; GPN: Gly-Phe-β-naphthylamide; H. pylori: Helicobacter pylori; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; MCOLN3: mucolipin 3; MCU: mitochondrial calcium uniporter; MOI: multiplicity of infection; NAGLU: N-acetyl-alpha-glucosaminidase; PDIA3: protein disulfide isomerase family A member 3; PMA: phorbol 12-myristate 13-acetate; PRKC: protein kinase C; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SS1: Sydney Strain 1; TRP: transient receptor potential; VacA: vacuolating cytotoxin; VD3: vitamin D3; VDR: vitamin D receptor
To date, there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant persons. ...This target trial emulation study aimed to address this gap by evaluating the use of nirmatrelvir/ritonavir in nonhospitalized pregnant women with symptomatic SARS-CoV-2 Omicron variant infection. Among patients diagnosed between 16 March 2022 and 5 February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or coronavirus disease 2019 (COVID-19) diagnosis. Primary outcomes were maternal morbidity and mortality index (MMMI), all-cause maternal death and COVID-19-related hospitalization, while secondary outcomes were individual components of MMMI, preterm birth, stillbirth, neonatal death and cesarean section. One-to-ten propensity-score matching was conducted between nirmatrelvir/ritonavir users and nonusers, followed by cloning, censoring and weighting. Overall, 211 pregnant women on nirmatrelvir/ritonavir and 1,998 nonusers were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28-day MMMI risk (absolute risk reduction (ARR) = 1.47%, 95% confidence interval (CI) = 0.21-2.34%) but not 28-days COVID-19-related hospitalization (ARR = -0.09%, 95% CI = -1.08% to 0.71%). Nirmatrelvir/ritonavir treatment was also associated with reduced risks of cesarean section (ARR = 1.58%, 95% CI = 0.85-2.39%) and preterm birth (ARR = 2.70%, 95% CI = 0.98-5.31%). No events of maternal or neonatal death or stillbirth were recorded. The findings suggest that nirmatrelvir/ritonavir is an effective treatment in symptomatic pregnant women with SARS-CoV-2 Omicron variant infection.
Abstract
Background
Evidence is lacking about any additional benefits of introducing remdesivir on top of dexamethasone, and the optimal timing of initiation.
Methods
In a territory-wide cohort of 10 ...445 coronavirus disease 2019 (COVID-19) patients from Hong Kong who were hospitalized between 21 January 2020 and 31 January 2021, 1544 had received dexamethasone during hospitalization. The exposure group consisted of patients who had initiated remdesivir prior to dexamethasone (n = 93) or co-initiated the 2 drugs simultaneously (n = 373), whereas the nonexposure group included patients who were given remdesivir after dexamethasone (n = 149) or those without remdesivir use (n = 929). Multiple imputation and inverse probability of treatment weighting for propensity score were applied and hazard ratios (HRs) of event outcomes were estimated using Cox regression models.
Results
Time to clinical improvement (HR = 1.23; 95% CI, 1.02–1.49; P = .032) and positive IgG antibody (HR = 1.22; 95% CI, 1.02–1.46; P = .029) were significantly shorter in the exposure group than that of nonexposure. The exposure group had a shorter hospital length of stay by 2.65 days among survivors, lower WHO clinical progression scale scores from 5 days of follow-up onwards, and lower risks of in-hospital death (HR = .59; 95% CI, .36–.98; P = .042) and composite outcomes; and without experiencing an increased risk of acute respiratory distress syndrome. Differences in the cumulative direct medical costs between groups were no longer significant from 17 days of follow-up onwards.
Conclusions
Initiation of remdesivir prior to or simultaneously with dexamethasone was associated with significantly shorter time to clinical improvement and positive IgG antibody, lower risk of in-hospital death, in addition to shorter length of hospital stay in patients with moderate COVID-19.
Initiation of remdesivir prior to or simultaneously with dexamethasone was associated with significantly shorter time to clinical improvement and positive IgG antibody, lower risk of death, in addition to a shorter length of hospital stay in patients with moderate COVID-19.
This retrospective cohort study aims to explore head-to-head clinical outcomes and complications associated with tocilizumab or baricitinib initiation among hospitalized COVID-19 patients receiving ...dexamethasone.
Among 10,445 COVID-19 patients hospitalized between January 21st 2020 and January 31st 2021 in Hong Kong, patients who had received tocilizumab (
= 165) or baricitinib (
= 76) while on dexamethasone were included. Primary study outcome was time to clinical improvement (at least one score reduction on WHO clinical progression scale). Secondary outcomes were disease progression, viral dynamics, in-hospital death, hyperinflammatory syndrome, and COVID-19/treatment-related complications. Hazard ratios (HR) of event outcomes were estimated using Cox regression models.
The initiation of tocilizumab or baricitinib had no significant differences in time to clinical improvement (HR = 0.86, 95%CI 0.57-1.29,
= 0.459), hospital discharge (HR = 0.85, 95%CI 0.57-1.27,
= 0.418), recovery without the need for oxygen therapy (HR = 1.04, 95%CI 0.64-1.67,
= 0.883), low viral load (HR = 1.49, 95%CI 0.85-2.60,
= 0.162), and positive IgG antibody (HR = 0.97, 95%CI 0.61-1.54,
= 0.909). Time to viral clearance (HR = 1.94, 95%CI 1.01-3.73,
= 0.048) was shorter in the tocilizumab group with marginal significance, compared to that of baricitinib. Meanwhile, the two treatment modalities were not significantly different in their associated risks of in-hospital death (HR = 0.63, 95%CI 0.29-1.35,
= 0.233), severe liver injury (HR = 1.15, 95%CI 0.43-3.08,
= 0.778), acute renal failure (HR = 2.33, 95%CI 0.61-8.82,
= 0.213), hyperinflammatory syndrome (HR = 2.32, 95%CI 0.87-6.25,
= 0.091), thrombotic and bleeding events (HR = 1.39, 95%CI 0.32-6.00,
= 0.658), and secondary infection (HR = 2.97, 95%CI 0.62-14.31,
= 0.173).
Among hospitalized patients with moderate-to-severe COVID-19 on background dexamethasone, the initiation of tocilizumab or baricitinib had generally comparable effects on time to clinical improvement, hospital discharge, recovery, low viral load, and positive IgG antibody; risks of in-hospital death, hepatic and renal complications, hyperinflammatory syndrome, thrombotic and bleeding events, and secondary infection. On the other hand, tocilizumab users might achieve viral clearance slightly faster than baricitinib users. Further studies and clinical trials are needed to confirm our findings regarding the evaluation of tocilizumab and baricitinib in COVID-19 patients with different disease severities, at varying stages or timing of drug initiation, and considering the concomitant use of other therapeutics.
Summary
Background and Aim
To investigate and quantify the risks of AKI and ALI associated with remdesivir use, given the underlying diseases of SARS‐CoV‐2 infection.
Methods
This self‐controlled ...case series (SCCS) study was conducted using electronic hospital records between 23 January 2020 and 31 January 2021 as retrieved from the Hong Kong Hospital Authority which manages all laboratory‐confirmed COVID‐19 cases in Hong Kong. Outcomes of AKI and ALI were defined using the KDIGO Guideline and Asia Pacific Association of Study of Liver consensus guidelines. Incidence rate ratios (IRR) for AKI and ALI following the administration of remdesivir (exposure) in comparison to a non‐exposure period were estimated using the conditional Poisson regression models.
Results
Of 860 COVID‐19 patients administered remdesivir during hospitalisation, 334 (38.8%) and 137 (15.9%) had incident ALI and AKI, respectively. Compared with the baseline period, both ALI and AKI risks were increased significantly during the pre‐exposure period (ALI: IRR = 6.169, 95% CI = 4.549–8.365; AKI: IRR = 7.074, 95% CI = 3.763–13.298) and remained elevated during remdesivir treatment. Compared to the pre‐exposure period, risks of ALI and AKI were not significantly higher in the first 2 days of remdesivir initiation (ALI: IRR = 1.261, 95% CI = 0.915–1.737; AKI: IRR = 1.261, 95% CI = 0.889–1.789) and between days 2 and 5 of remdesivir treatment (ALI: IRR = 1.087, 95% CI = 0.793–1.489; AKI: IRR = 1.152, 95% CI = 0.821–1.616).
Conclusion
The increased risks of AKI and ALI associated with intravenous remdesivir treatment for COVID‐19 may be due to the underlying SARS‐CoV‐2 infection. The risks of AKI and ALI were elevated in the pre‐exposure period, yet no such increased risks were observed following remdesivir initiation when compared to the pre‐exposure period.
Accelerating imaging speed in optical microscopy is often realized at the expense of image contrast, image resolution, and detection sensitivity--a common predicament for advancing high-speed and ...high-throughput cellular imaging. We here demonstrate a new imaging approach, called asymmetric-detection time-stretch optical microscopy (ATOM), which can deliver ultrafast label-free high-contrast flow imaging with well delineated cellular morphological resolution and in-line optical image amplification to overcome the compromised imaging sensitivity at high speed. We show that ATOM can separately reveal the enhanced phase-gradient and absorption contrast in microfluidic live-cell imaging at a flow speed as high as ~10 m/s, corresponding to an imaging throughput of ~100,000 cells/sec. ATOM could thus be the enabling platform to meet the pressing need for intercalating optical microscopy in cellular assay, e.g. imaging flow cytometry--permitting high-throughput access to the morphological information of the individual cells simultaneously with a multitude of parameters obtained in the standard assay.
Type 2 diabetes mellitus (T2DM) patients with Coronavirus Disease 2019 (COVID-19) have poorer prognosis. Inconclusive evidence suggested dipeptidyl peptidase-4 inhibitors (DPP4i) might reduce ...inflammation and prevent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry, hence further evaluation on DPP4i is needed.
1214 Patients with T2DM were admitted with COVID-19 between 21st January 2020 and 31st January 2021 in Hong Kong. Exposure was DPP4i use within the 90 days prior to admission for COVID-19. Assessed outcomes included clinical deterioration, clinical improvement, low viral load, positive Immunoglobulin G (IgG) antibody, hyperinflammatory syndrome, proportion of IgG antibody, clinical status and length of hospitalization. Multivariable logistic and linear regression models were performed to estimate odds ratios (OR) and their 95% confidence intervals (CI) of event outcomes and continuous outcomes, respectively.
DPP4i users (N = 107) was associated with lower odds of clinical deterioration (OR=0.71, 95%CI 0.54 to 0.93, P = 0.013), hyperinflammatory syndrome (OR=0.56, 95%CI 0.45 to 0.69, P < 0.001), invasive mechanical ventilation (OR=0.30, 95%CI 0.21 to 0.42, P < 0.001), reduced length of hospitalization (-4.82 days, 95%CI –6.80 to –2.84, P < 0.001), proportion of positive IgG antibody on day-3 (13% vs 8%, p = 0.007) and day-7 (41% vs 26%, P < 0.001), despite lack of association between DPP4i use and in-hospital mortality.
DPP4i use was associated with reduced odds of clinical deterioration and hyperinflammatory syndrome. Prospective studies are warranted to elucidate the role of DPP4i in T2DM and COVID-19.
There was initially insufficient understanding regarding suitable pharmacological treatment for pediatric Coronavirus Disease 2019 (COVID-19) patients. Lopinavir-ritonavir (LPV/r) was originally used ...for the treatment of Human Immunodeficiency Virus-1 (HIV-1) infection. It was also used in patients with severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) with positive results. Nonetheless, results from recent randomized controlled trials and observational studies on COVID-19 patients were unfavorable. We sought to evaluate the clinical outcomes associated with early treatment with LPV/r for pediatric COVID-19 patients.
A total of 933 COVID-19 patients aged ≤ 18 years were admitted between 21 January 2020 and 31 January 2021 in Hong Kong. Exposure was receiving LPV/r within the first two days of admission. Time to clinical improvement, hospital discharge, seroconversion and hyperinflammatory syndrome, cumulative costs, and hospital length of stay were assessed. Multivariable Cox proportional hazard and linear models were performed to estimate hazard ratios (HR) and their 95% confidence intervals (CI) of time-to-event and continuous outcomes, respectively.
LPV/r users were associated with longer time to clinical improvement (HR 0.51, 95% CI 0.38-0.70; p < 0.001), hospital discharge (HR 0.51, 95% CI 0.38-0.70; p < 0.001) and seroconversion (HR 0.59, 95% CI 0.43-0.80; p < 0.001) when compared with controls. LPV/r users were also associated with prolonged hospital length of stay (6.99 days, 95% CI 6.23-7.76; p < 0.001) and higher costs at 30 days (US$11,709 vs US$8270; p < 0.001) as opposed to controls.
Early treatment with LPV/r for pediatric COVID-19 patients was associated with longer time to clinical improvement. Our study advocates the recommendation against LPV/r use for pediatric patients across age groups.
LINKED CONTENT
This article is linked to Wong et al papers. To view these articles, visit https://doi.org/10.1111/apt.16894 and https://doi.org/10.1111/apt.16921
This study was conducted in order to evaluate the association between metformin use and clinical outcomes in type 2 diabetes mellitus (T2DM) patients hospitalized with coronavirus disease 2019 ...(COVID-19).
Patients with T2DM with confirmed diagnosis of COVID-19 and admitted between January 21, 2020, and January 31, 2021 in Hong Kong were identified in our cohort. Exposure was defined as metformin use within 90 days prior to admission until hospital discharge for COVID-19. Primary outcome was defined as clinical improvement of ≥1 point on the WHO Clinical Progression Scale (CPS). Other outcomes were hospital discharge, recovery, in-hospital death, acidosis, hyperinflammatory syndrome, length of hospitalization, and changes in WHO CPS score.
Metformin use was associated with greater odds of clinical improvement (OR = 2.74,
= 0.009), hospital discharge (OR = 2.26,
= 0.009), and recovery (OR = 2.54,
= 0.005), in addition to lower odds of hyperinflammatory syndrome (OR = 0.71,
= 0.021) and death (OR = 0.41,
= 0.010) than control. Patients on metformin treatment had a shorter hospital stay (-2.76 days,
= 0.017) than their control counterparts. The average WHO CPS scores were significantly lower in metformin users than non-users since day 15 (
< 0.001). However, metformin use was associated with higher odds of acidosis.
Metformin use was associated with lower mortality and lower odds for hyperinflammatory syndrome. This provides additional insights into the potential mechanisms of the benefits of metformin use in T2DM patients with COVID-19.
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