Factors affecting the clinical course of COVID-19, an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans, are still poorly understood. G protein-coupled estrogen receptor (GPER) is a protein encoded by the GPER gene in humans. GPER is activated by binding to estradiol, a female sex hormone, leading to mediation of estradiol's rapid cellular effects. In this study, which was conducted for the first time, we aimed to investigate GPER levels and their diagnostic value in COVID-19 patients.

A total of 71 individuals [Female/Male (n = 36/35) range of ages 32 ∼ 62] were enrolled in this study and categorized into three groups: the patient group consisted of individuals diagnosed with COVID-19 and receiving supportive treatment in the intensive care unit (ICU), the mild group consisted of COVID-19 patients who received outpatient treatment, and the control group. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum GPER levels.

The general sex distribution of the patients was analyzed, revealing that 35(49.3 %) were male and 36(50.7 %) were female. GPER levels were significantly increased in severe COVID-19 females compared to control and mild course groups (p < 0.05). A GPER cut-off value of 2.95 ng/mL showed diagnostic accuracy in severe COVID-19 cases.

This study, conducted for the first time, demonstrates that GPER levels are significantly associated with COVID-19 severity in female patients, suggesting that GPER may serve as a diagnostic marker for the progression of COVID-19.

Cardiac aging involves progressive structural, functional, cellular, and molecular changes that impair heart function. This review explores key mechanisms, including oxidative stress, mitochondrial dysfunction, impaired autophagy, and chronic low-grade inflammation. Excess reactive oxygen species (ROS) damage heart muscle cells, contributing to fibrosis and cellular aging. Mitochondrial dysfunction reduces energy production and increases oxidative stress, accelerating cardiac decline. Impaired autophagy limits the removal of damaged proteins and organelles, while inflammation activates signaling molecules that drive tissue remodeling. Gender differences reveal estrogen's protective role in premenopausal women, with men showing greater susceptibility to heart muscle dysfunction and injury. After menopause, women lose this hormonal protection, increasing their risk of cardiovascular conditions. Ethnic disparities, particularly among underserved minority populations, emphasize how social factors such as access to care, environment, and chronic stress contribute to worsening cardiovascular outcomes. The coronavirus disease pandemic has introduced further challenges by increasing the incidence of heart damage through inflammation, blood clots, and long-term heart failure, especially in older adults with existing metabolic conditions like diabetes and high blood pressure. The virus's interaction with receptors on heart and blood vessel cells, along with a weakened immune response in older adults, intensifies cardiac aging. Emerging therapies include delivery of therapeutic extracellular vesicles, immune cell modulation, and treatments targeting mitochondria. In addition, lifestyle strategies such as regular physical activity, nutritional improvements, and stress reduction remain vital to maintaining cardiac health. Understanding how these biological and social factors intersect is critical to developing targeted strategies that promote healthy aging of the heart.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health concern. The entry of the virus into host cells is facilitated by the transmembrane protease serine 2 (TMPRSS2) receptor, and genetic variations in the TMPRSS2 gene may influence disease susceptibility. However, there is a lack of knowledge regarding TMPRSS2 genetic variants and haplotypes in the Jordanian population.

This study aimed to characterize the genotype and haplotype variations in the TMPRSS2 binding domain with SARS-CoV-2 among Jordanian volunteers.

The binding domain of TMPRSS2 with SARS-CoV-2 (Exons 9 and 10) was amplified using polymerase chain reaction (PCR) for a random sample of 120 healthy unrelated Jordanian volunteers, followed by Sanger DNA sequencing for the PCR products. The effect of the novel genetic variants on the TMPRSS2 protein structure was predicted using in silico methods.

The results showed significant (p < 0.05, chi-square) allele frequencies for known TMPRSS2 variants, with c.888C > T being the most prevalent among Jordanian volunteers. Novel genetic variants, including c.869A > G and c.923T > A, were also identified, with the latter being the most common novel variant. Haplotype analysis showed that the most prevalent TMPRSS2 haplotype is c.911G/1051A/1052T/1010 + 45C/1011 - 38T/1011 - 52C/1011 - 54A. In silico programs predicted that TMPRSS2 c.923T > A and c.1052T > A variants affect transmembrane proteins and catalytic sites.

This research provides information about the gene structure of the TMPRSS2 binding domain in Jordanians. Some of the identified variants, especially c.923T > A, may influence protein function, warranting further in vitro and in vivo investigations. In addition, further clinical research studies are needed to link the identified TMPRSS2 variants with COVID-19 susceptibility and severity among Jordanians.

Concern over COVID-19's long-term influence on women's reproductive health is growing, with emerging research suggesting potential links to ovarian dysfunction, menstrual irregularities, fertility challenges, and adverse pregnancy outcomes. Post-viral immune dysregulation is linked to both the development and exacerbation of autoimmune diseases, including multiple sclerosis (MS). Long COVID has been associated with immunological dysfunction, hormonal imbalances, and chronic inflammation, all of which may worsen autoimmune disorders and reproductive health issues. Long COVID is characterized by symptoms persisting for weeks or months beyond the acute infection phase. There are indications that prolonged COVID may contribute to autoimmune disease development through mechanisms such as immune hyperactivation, molecular mimicry, and dysregulated cytokine responses. Although this research field is still emerging, growing evidence suggests that SARS-CoV-2 infection may have lasting effects on women's health, highlighting the need for further studies into its underlying mechanisms and long-term clinical outcomes. This review compiles recent findings on the long-term impact of COVID-19 on women's reproductive health and its potential association with autoimmune disorders, particularly MS.

From the beginning of the COVID-19 pandemic, there has been concern among clinicians whether the use of high-flow nasal cannula (HFNC) and continuous positive airway pressure (CPAP) contributes to aerosol generation and consequently spreading of pathogens. Most guidelines still classify these treatments as high-risk aerosol-generating procedures. The aim of this study was to evaluate differences in aerosol emissions and exposure with CPAP and HFNC compared to no breathing aid (NBA). Aerosol emissions of 16 healthy volunteers using CPAP, HFNC and NBA were measured with a portable aerosol spectrometer. During each measurement, the volunteers were instructed consecutively to breathe normally, breathe deeply, cough and read aloud a predefined text. The Wilcoxon signed-rank test was used in statistical analysis. Non-invasive ventilation (CPAP, HFNC) does not produce significantly more aerosol than the same respiratory activities without a breathing aid (median CPAP-NBA - 4.54 1/L, p = 0.816, and HFNC-NBA 2.27 1/L, p = 0.244), deep breathing (median CPAP-NBA - 2.27 1/L, p = 0.378 and HFNC-NBA 4.55 1/L, p = 0.623), speaking (median CPAP-NBA 0 1/L, p = 0.0523 and HFNC-NBA 9.09 1/L, p = 0.0140), or coughing (median CPAP-NBA - 17.31 1/L, p = 0.587 and HFNC-NBA 1.92 1/L, p = 0.365). The results indicate that both CPAP and HFNC have no clinically meaningful impact on aerosol emission. Therefore, the use of CPAP or HFNC does not expose healthcare personnel to greater concentrations of aerosols when compared to normal breathing in healthy participants.

Vitamin D plays a key role in regulating the immune system and vaccine response, and hypovitaminosis D is a known risk factor for mortality. However, its potential influence on mortality in SARS-CoV-2 vaccinated older adults remains underexplored. This study aims to examine survival differences between unvaccinated and vaccinated older adults with varying vitamin D levels, and to assess the impact of vitamin D on mortality.

We recruited patients aged 65 and over from the Geriatrics Unit of Azienda Ospedale - Università Padova. Clinical, pharmacological data, including vaccination status and vitamin D levels, were collected at admission, alongside mortality data 12 months post-hospitalization. Participants were divided into three groups: unvaccinated, vaccinated with vitamin D levels of 25-50 nmol/L, and vaccinated with levels > 50 nmol/L.

A total of 126 participants were included (56% women, mean age 83 years). No significant differences were found in COVID-19 severity among the three groups. After 12 months, 24 deaths were recorded: 17% in unvaccinated, 19% in vaccinated with low vitamin D, and 20% in vaccinated with high vitamin D (p = 0.94). Kaplan-Meier curves showed that mortality risk for vaccinated individuals with low vitamin D was similar to unvaccinated patients but significantly higher than vaccinated individuals with high vitamin D (p = 0.04). Vitamin D levels of 25-50 nmol/L were associated with a threefold increased risk of 12-month mortality (HR: 3.79, p < 0.001).

Vitamin D levels can impact mortality in older vaccinated individuals. Early correction of vitamin D deficiency could potentially enhance outcomes.

Accurate diagnosis and effective antiviral strategies are critical to combat acute infection and to avoid damage to the host. Due to their restricted radiation range and energy, Auger electron emitters have shown potential as a RNA-destructing radionuclide therapy in oncology and infection. Focusing on the process of angiotensin-converting enzyme 2 (ACE2)-mediated endocytosis, Technetium-99m-labeled DX600 (99mTc-DX600) was synthesized as an Auger electron vector to specifically bind to surface-expressed ACE2 proteins on 293T-hACE2 cells (293T cells stably expressing human ACE2), and Technetium-99m-loaded microvesicles (99mTc-MVs) served as an antiviral tracer and effector in pseudovirus infection. The whole-body ACE2 expression evaluation was non-invasive, meanwhile, the enhanced green fluorescent protein expression of pseudoviruses was substantially inhibited as a result of the 99mTc-DX600 loading of microvesicles, though the mitochondrial and DNA stabilities of the host cells were not affected. Furthermore, the in vivo distribution of 99mTc-DX600 in humanized ACE2 mice was demonstrated to be both ACE2-specific and long-lasting, and an antiviral effect was fully exhibited with two cycles of intravenous injection at a dosage of 37 MBq. Taking advantage of the ACE2-mediated interaction and natural trigger mechanism of virus-induced endocytosis, 99mTc-MV represents a theranostic biosensor of Auger electrons that can expose viral RNA to lethal amounts of radiation, with the host cells receiving no detrimental radiation.

SARS-CoV-2 poses significant challenges to people living with diabetes (PLWD). This systematic review aimed to explore the impact of COVID-19 on mortality, complications associated with diabetes and haematological parameters among PLWD.

Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials and LILACS were searched between 1 December 2019 and 14 January 2025.

Eligible studies included case-control and cohort studies involving PLWD categorised into two groups: those with confirmed SARS-CoV-2 infection and those without.

Meta-analyses estimated the odds ratios (ORs) and mean differences (MDs) of outcomes including mortality, intensive care unit (ICU) admission, diabetic ketoacidosis (DKA), acute kidney injury, hospitalisation length and haematological parameters. We pooled results using random-effects models and assessed study quality with the Newcastle-Ottawa Scale. A funnel plot was used to detect potential publication bias. The overall certainty of evidence was assessed using GRADE.

25 of 7266 unique studies were eligible, including 1 154674 PLWD (561 558 with COVID-19 and 593 116 without COVID-19). SARS-CoV-2 infection in PLWD was associated with significantly increased mortality (OR 2.52, 95% CI 1.45 to 4.36, I2=99%), acute kidney injury (3.69, 95% CI 2.75 to 4.94, I2=0%), random plasma glucose in subjects with type 1 diabetes (MD 20.38 mg/dL, 95% CI 7.39 to 33.36, I2=0%), haemoglobin A1C in subjects with type 2 diabetes (0.21%, 95% CI 0.05 to 0.38, I2=13%), creatinine (0.12 mg/dL, 95% CI 0.04 to 0.19, I2=0%), C reactive protein (38.30 mg/L, 95% CI 4.79 to 71.82, I2=82%) and D-dimer (1.52 µg/mL, 95% CI 0.73 to 2.31, I2=0%). No significant differences were observed in the incidence of ICU admission and DKA, hospitalisation length, haemoglobin, leucocyte, lymphocyte, neutrophil to lymphocyte ratio, platelet, blood urea nitrogen, estimated glomerular filtration rate, procalcitonin, albumin, ferritin and bilirubin among PLWD with and without SARS-CoV-2 infection.

SARS-CoV-2 infection is associated with elevated risks of mortality and acute kidney injury and poor glycaemic control in PLWD, alongside increased levels of inflammatory and coagulation biomarkers. These findings underscore the urgent need for tailored clinical management strategies for PLWD with COVID-19.

CRD42023418039.

Since SARS-CoV-2 has caused unprecedented changes in the epidemiology of other infectious diseases, investigations on coinfection between SARS-CoV-2 and one of the famous vector-borne diseases, malaria, are crucial for disease control, especially in malaria-endemic areas. The clinical profiles, possible mechanisms for interactions, and representative control measures of COVID-19 and malaria coinfections have recently garnered public attention. The overlap in epidemiology, infection incubation, and clinical symptoms between COVID-19 and malaria coinfections has been thoroughly discussed to provide a detailed diagnostic procedure for coinfections, thereby guiding appropriate clinical interventions. Immunological and genetic evidence has shown that previous malaria exposure may protect the body from the poor prognosis of COVID-19. ACE2 downregulation and TLR-induced pathways play a role in this protective effect, as do CD8 + and CD4 + T-cell activation and coinhibitory receptor upregulation, which help maintain a balance of immune reactions. Finally, multiple control measures for coinfections were discussed, and malaria control efforts were enriched in the context of COVID-19. These efforts included (1) developing vaccinations; (2) evaluating the efficacy of anti-malarial drugs in the SARS-CoV-2 treatment; (3) exploring recent advances in natural products that are potentially useful for coinfection treatment; (4) researching and implementing bioinsecticides for malaria control, such as gene-driven mosquitoes, fungi, and bacterial symbionts; and (5) improving national electronic disease surveillance platforms in malaria-endemic regions. At last, the above findings summarized valuable lessons about malaria and COVID-19 control and expedite further investigations on coinfections with complex clinical presentations.

The SARS-CoV-2 spike protein interacts with ACE2, a key receptor within the renin-angiotensin-aldosterone system (RAAS), which plays a critical role in maintaining vascular homeostasis, regulating blood pressure, and modulating inflammation. An observational study analyzed the gene expression profiles of RAAS receptors and associated miRNAs in 88 hospitalized COVID-19 patients and 20 healthy controls, comparing the acute and post-acute phases to assess their impact on disease severity and recovery. Our findings revealed an association between reduced MAS1 expression in both advanced age (P = 0.03) and the need for oxygen supplementation (P = 0.04). Additionally, reduced ACE expression was associated with worse mortality outcomes (P = 0.01). Notably, ACE2 and TMPRSS2 expression was significantly decreased (P < 0.0001) in individuals requiring oxygen supplementation and in those with diabetes mellitus during both the acute and post-COVID-19 phases, further highlighting the impact of these conditions on RAAS. The miRNA analysis revealed significant downregulation of miR-200c (P = 0.005), miR-let-7 (P = 0.01), and miR-122 (P = 0.03) in acute-phase COVID-19 patients. This dysregulation contributes to the inflammatory response and highlights the interaction between viral entry and immune regulation. These results underscore the significance of the ACE2/Ang-(1-7)/MAS1 axis in inflammation regulation and suggest that targeting this pathway may have therapeutic potential. Our study provides valuable insights into the molecular mechanisms of COVID-19 pathogenesis and identifies the modulation of RAAS receptors and miRNAs as promising biomarkers for disease severity and potential therapeutic interventions. CLINICAL TRIAL: Not applicable.

Stilbenoids are a category of plant compounds exhibiting notable health-related benefits. After resveratrol, perhaps the most well-known stilbenoid is pinosylvin, a major phytochemical constituent of most plants characterised by the pine spines among others. Pinosylvin and its derivatives have been found to exert potent antibacterial and antifungal effects, while their antiparasitic and antiviral properties are still a subject of ongoing research. The antioxidant properties of pinosylvin are mostly based on its scavenging of free radicals, inhibition of iNOS and protein kinase C, and promotion of HO-1 expression. Its anti-inflammatory properties are based on a variety of mechanisms, such as COX-2 inhibition, NF-κB and TRPA1 activation inhibition, and reduction in IL-6 levels. Its anticancer properties are partly associated with its antioxidant and anti-inflammatory potential, although a number of other mechanisms are described, such as apoptosis induction and matrix metalloproteinase inhibition. A couple of experiments have also suggested a neuroprotective potential. A multitude of ethnomedical and ethnobotanical effects of pinosylvin-containing plants are reported, like antimicrobial, antioxidant, anti-inflammatory, hepatoprotective, and prokinetic actions; many of these are corroborated by recent research. The advent of novel methods of artificial pinosylvin synthesis may facilitate its mass production and adoption as a medical compound. Finally, pinosylvin may be a tool in promoting environmentally friendly pesticide and insecticide policies and be used in land remediation schemes.

Infection-related cardiovascular diseases (CVDs) pose a significant health challenge, driving the need for novel therapeutic strategies to target key receptors involved in inflammation and infection. Antimicrobial peptides (AMPs) show the potential to disrupt pathogenic processes and offer a promising approach to CVD treatment. This study investigates the binding potential of selected AMPs with critical receptors implicated in CVDs, aiming to explore their therapeutic potential. A comprehensive computational approach was employed to assess AMP interactions with CVD-related receptors, including ACE2, CRP, MMP9, NLRP3, and TLR4. Molecular docking studies identified AMPs with high binding affinities to these targets, notably Tachystatin, Pleurocidin, and Subtilisin A, which showed strong interactions with ACE2, CRP, and MMP9. Following docking, 100 ns molecular dynamics (MD) simulations confirmed the stability of AMP-receptor complexes, and MM/PBSA calculations provided quantitative insights into binding energies, underscoring the potential of these AMPs to modulate receptor activity in infection and inflammation contexts. The study highlights the therapeutic potential of Tachystatin, Pleurocidin, and Subtilisin A in targeting infection-related pathways in CVDs. These AMPs demonstrate promising receptor binding properties and stability in computational models. Future research should focus on in vitro and in vivo studies to confirm their efficacy and safety, paving the way for potential clinical applications in managing infection-related cardiovascular conditions.

Respiratory viruses, such as influenza virus, rhinovirus, coronavirus, and respiratory syncytial virus (RSV), continue to impose a heavy global health burden. Despite existing vaccination programs, these infections remain leading causes of morbidity and mortality, especially among vulnerable populations like children, older adults, and immunocompromised individuals. However, the current therapeutic options for respiratory viral infections are often limited to supportive care, underscoring the need for novel treatment strategies. Autophagy, particularly macroautophagy, has emerged as a fundamental cellular process in the host response to respiratory viral infections. This process not only supports cellular homeostasis by degrading damaged organelles and pathogens but also enables xenophagy, which selectively targets viral particles for degradation and enhances cellular defense. However, viruses have evolved mechanisms to manipulate the autophagy pathways, using them to evade immune detection and promote viral replication. This review examines the dual role of autophagy in viral manipulation and host defense, focusing on the complex interplay between respiratory viruses and autophagy-related pathways. By elucidating these mechanisms, we aim to highlight the therapeutic potential of targeting autophagy to enhance antiviral responses, offering promising directions for the development of effective treatments against respiratory viral infections.

This umbrella review synthesizes and discusses systematic reviews (SRs) and meta-analyses (MAs) on auditory outcomes associated with COVID-19 infection and vaccination side effects. It is innovative in offering a comprehensive synthesis of evidence across adults and infants while summarizing vaccine-related auditory side effects.

This literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with no restrictions on population age or symptom severity. Four electronic databases were searched from their inception to October 2024. The Assessment of Multiple Systematic Reviews 2 checklist and Risk of Bias in Systematic Reviews tool were used to assess the quality of evidence and the risk of bias.

The systematic search identified 534 articles, narrowed down to 14 SRs following a full-text review: Nine focused on auditory outcomes of COVID-19; two, on outcomes in infants born to mothers infected during pregnancy; and three, on the auditory side effects of vaccination. A random-effects model revealed significantly high pooled estimates of hearing loss (5.0%, 95% CI [1.0, 9.0], p < .012, three MAs, N = 21,932) and tinnitus (13.5%, 95% CI [5.9, 21.1], p ≤ .001, four MAs, N = 36,236) in adults. However, current evidence in nonhospitalized patients indicates that auditory symptoms often improve after recovery. Studies also show a low rate of hearing loss in infants whose mothers contracted COVID-19 during pregnancy. Similarly, whereas COVID-19 vaccination has been linked to hearing loss and tinnitus, these effects are rare, and most patients experience improvement within weeks to months.

Evidence suggests a significantly high rate of hearing loss and tinnitus associated with COVID-19 in adults, although auditory symptoms remain rare in newborns and following vaccination. However, caution is warranted due to limitations and variability across the studies.

Emerging evidence suggests coronavirus disease 2019 (COVID-19) infection may increase the risk of developing dementia, although studies have reported conflicting findings. This meta-analysis aimed to synthesise the literature on the association between COVID-19 and the risk of new-onset dementia.

PubMed, Embase and Web of Science were searched for cohort studies or case-control studies that investigated new-onset dementia development among adult COVID-19 survivors compared to individuals without COVID-19 infection from inception to 9 November 2023. Studies that exclusively involved populations younger than 18 years, with known dementia or lacked adequate data about the risk of dementia were excluded. Two authors independently conducted the screening of eligible studies, data extraction and risk of bias assessment. The primary outcome was new-onset dementia following COVID-19 infection. Data were pooled using random-effects models, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated.

A total of 15 retrospective cohort studies encompassing 26 408 378 participants were included. Pooled analysis indicated COVID-19 was associated with an increased risk of new-onset dementia (HR = 1.49, 95% CI: 1.33-1.68). This risk remained elevated when compared with non-COVID cohorts (HR = 1.65, 95% CI: 1.39-1.95), and respiratory tract infection cohorts (HR = 1.29, 95% CI: 1.12-1.49), but not influenza or sepsis cohorts. Increased dementia risk was observed in both males and females, as well as in individuals older than 65 years (HR = 1.68, 95% CI: 1.48-1.90), with the risk remaining elevated for up to 24 months.

This meta-analysis demonstrates a significant association between COVID-19 infection and increased risk of developing new-onset dementia, which underscores the need for cognitive monitoring and early intervention for COVID-19 survivors to address potential long-term neurological impacts.

The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to resistance against multiple coronavirus disease 2019 (COVID-19) vaccines and therapeutic medications, making the development of effective therapeutics against SARS-CoV-2 a high priority. Studies have shown that bioactive polyphenols, particularly those with triphenol groups, can effectively inhibit the activity of SARS-CoV-2 3-chymotrypsin-like protease (3CLpro). However, the structural instability of polyphenols necessitates further research. To address this, we conducted a literature review to identify triphenol compounds that are either approved or currently undergoing clinical trials, assessing their potential to inhibit SARS-CoV-2 3CLpro. Exifone and benserazide hydrochloride were identified as the inhibitors of SARS-CoV-2 3CLpro among these compounds, using a fluorescence resonance energy transfer (FRET)-based assay. Benserazide hydrochloride was confirmed as a covalent binder to SARS-CoV-2 3CLpro through time-dependent inhibition and kinetic analysis, with its binding mode elucidated by molecular docking. Notably, exifone not only inhibited the protease activity but also blocked the interaction between the host cell receptor angiotensin-converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein receptor binding domain (S-RBD), as identified by surface plasmon resonance (SPR) and flow cytometry. Additionally, exifone demonstrated antiviral activity against various SARS-CoV-2-S pseudovirus variants. In conclusion, the discovery of exifone and benserazide hydrochloride underscores the potential of polyphenols in developing conserved 3CLpro inhibitors for coronaviruses, offering new strategies for the rapid development of effective drugs against both current and future coronavirus pandemics.

SARS-CoV-2 targets angiotensin-converting enzyme-2 (ACE2), a key peptidase of the renin-angiotensin system (RAS), which regulates the balance of the vasoconstrictor/inflammatory peptide Ang II and the vasodilator/anti-inflammatory peptide Ang-(1-7). Few studies have quantified the circulating elements of the RAS longitudinally in SARS-CoV-2 infection and their association with COVID-19 outcomes. Thus, we evaluated the association of circulating RAS enzymes and peptides with mortality among patients with COVID-19. Blood samples were collected from 111 patients with COVID-19 and new-onset hypoxemia during the delta and omicron waves at 19 hospitals in the United States. Circulating RAS components were quantified via radioimmunoassay or ELISA at 0 (baseline), 1, 3, and 5 days after randomization. We used multivariable Cox regression to estimate the association of baseline and longitudinal RAS concentrations with 90-day mortality. Participants were aged 18-90 (means [SD]: 55 [14]) yr and 62% were male. There were 22 (20%) deaths over 90 days of follow-up. ACE2 levels above the sample median (≥4.9 pM; adjusted HR [95% CI]: 0.10 [0.02, 0.43]) and ACE2/ACE ratio (≥6.0 × 10-3; adjusted HR: 0.08 [0.02, 0.39]) were associated with significantly lower mortality. Similarly, when analyzed as continuous, log2-normalized, time-varying predictors from day 0 to day 5, twofold increments of ACE2 and ACE2/ACE ratio over this period were associated with lower mortality (adjusted HR: 0.79 [0.65, 0.97] and 0.78 [0.63, 0.97], respectively). Circulating Ang II, Ang-(1-7), and ACE levels were not associated with mortality. These results suggest higher circulating ACE2 protein in hospitalized patients with COVID-19 is associated with reduced mortality.NEW & NOTEWORTHY We measured circulating components of the renin-angiotensin system (RAS) longitudinally over 5 days among patients hospitalized with COVID-19 and new-onset hypoxemia. We found that higher serum angiotensin-converting enzyme (ACE)-2 protein and ACE2/ACE ratio, both at baseline and when analyzed as time-varying, repeated measures, were associated with lower 90-day mortality. Results suggest a role for circulating ACE2 as a biomarker of adverse outcomes and could inform treatment strategies targeting the RAS in severe COVID-19 illness.

Coronavirus disease 2019 (COVID-19) remains a health problem worldwide. The present study aimed to investigate the effect of blood pressure (BP) on the circadian pattern and prevalence of new-onset non-dipper hypertension in the post-COVID period in patients with known hypertension. This prospective single-center study included 722 patients hospitalized for COVID-19 infection. Ambulatory BP (ABP) data were collected during their initial hospitalization. The ABP data were reassessed 1 month after the patients were discharged. The results were compared with a healthy control group with known hypertension but without COVID-19 infection. After exclusion criteria were applied, the study included 187 patients with COVID-19 and 136 healthy hypertensive controls. Post-COVID ABP showed that patients with COVID-19 had significantly higher mean 24-h systolic and diastolic BP, mean nighttime systolic and diastolic BP, and mean daytime diastolic BP than the control group. In addition, new-onset non-dipper hypertension was significantly higher in patients with COVID-19. This study demonstrated for the first time that the circadian pattern is disturbed and a non-dipper pattern develops in individuals with known hypertension during the post-COVID period.

Several studies have reported a reduced risk of COVID-19-related mortality in patients taking antidiabetic medications. This is an umbrella review, meta-analysis, and Bayesian sensitivity assessment of SGLT2 inhibitors (SGLT2is) in COVID-19 patients with type 2 diabetes mellitus (T2DM).

A search was conducted on the MEDLINE (PubMed), EMBASE, Cochrane, and ClinicalTrials.gov databases on 5/12/2023. We performed an umbrella review of systematic reviews and meta-analyses on the effects of SGLT2is in T2DM patients with COVID-19 and critically appraised them using AMSTAR 2.0. Trials investigating SGLT2i use in COVID-19 patients post-hospitalisation and observational studies on prior SGLT2i use among COVID-19 patients were included in the meta-analysis, adhering to the PRISMA guidelines.

SGLT2is exhibited significantly lower odds of mortality (OR 0.67, 95% CI 0.53-0.84) and hospitalisation (OR 0.84, 0.75-0.94) in COVID-19 patients with T2DM. Bayesian sensitivity analyses corroborated most of the findings, with differences observed in hospitalisation and mortality outcomes. SGLT-2 inhibitors showed an OR of 1.20 (95% CI 0.64-2.27) for diabetic ketoacidosis. Publication bias was observed for hospitalisation, but not for mortality. The GRADE assessment indicated a low to very low quality of evidence because of the observational studies included.

The prophylactic use of SGLT2is reduces mortality and hospitalisation among COVID-19 patients, particularly in patients with diabetes. The utility of SGLT2is after hospitalisation is uncertain and warrants further investigation. A limited efficacy has been observed under critical conditions. Individualised assessment is crucial before integration into COVID-19 management.

During the 2019 coronavirus disease (COVID-19) pandemic, although patients were advised to continue using angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), it remains unclear whether the pandemic influenced the occurrence of adverse reactions to these drugs. This study aims to analyze and compare changes in ACEIs and ARBs adverse events before and during the COVID-19 pandemic, exploring its potential impact on the safety of these medications.

We used real-world data to explore the impact of the COVID-19 pandemic on adverse events related to ACEIs and ARBs.

During the pandemic, ACEI-related adverse events (70 cases) and ARB-related adverse events (7 cases) showed increased reporting rates and RORs, with a notable rise in ACEI-related ear and labyrinth disorders. Additionally, 170 new adverse event signals were detected for ACEIs (8 with significantly increased risk) and 191 signals for ARBs (2 with significantly increased risk).

This study, based on real-world data, revealed significant signals indicating that ACEI use during the COVID-19 pandemic may have increased the risk of renal adverse events and ear labyrinth diseases. The study emphasized the need for increased caution when using ACEIs and ARBs during the pandemic.

The aim of this study was to assess the oral condition of individuals diagnosed with COVID-19 and its impact on their quality of life. The cross-sectional study participants were patients with or without a diagnosis of COVID-19, on room air, and conscious, admitted to the ICUs and wards of Public Hospital Units in São Luís, Maranhão, Brazil. The data collected included: demographic information, length of stay, comorbidities, and type of diet, obtained from medical records; Oral Health-Related Quality of Life (OHRQoL) [Oral Health Impact Profile (OHIP-14)]questions patients were asked; oral health (measured by the Bedside Oral Exam Scale); oral hygiene status (assessed by the Oral Hygiene Index - Simplified and lingual: degree of lingual coating); and salivary flow. The prevalence of COVID-19 was associated with gender (p = 0.038), with a higher incidence observed in male patients (61.9%). Moreover, there was a correlation between the hospitalization sector (p = 0.037) and the frequency of ICU admissions (53.7%). The prevalence of comorbidities was comparable between the two groups. Relative to oral health, 53% of individuals with confirmed COVID-19 had moderate oral health, while 9% exhibited poor oral health. The prevalence of hyposalivation was higher in the group with a confirmed diagnosis of COVID-19. The quality of life of individuals with confirmed COVID-19 was most significantly impacted by moderate to severe oral health concerns. The most significant alteration in oral health was a reduction in salivary flow, negatively impacting the quality of life of individuals hospitalized for COVID-19 complications.

COVID-19 was a nightmare in humankind's history that challenged our advanced medical technology. All credit goes to the researchers who played a crucial role in curbing COVID-19 and proved our medical technology supremacy. However, COVID-19 has left some mysterious scars on human well-being. It is believed that COVID-19 has a significant negative impact on various cardiovascular (CVS) and central nervous system (CNS) diseases, especially in the case of CNS diseases like Alzheimer's. Surprisingly, COVID-19 affects the respiratory system, whereas Alzheimer's disease (AD) alters brain function. To explain this phenomenon, several hypotheses were proposed, but the mechanism needs to be clearly understood. Another critical thing to be concerned about is that COVID-19 will worsen pre-existing conditions and lead to the onset of AD. In the race to curb COVID-19, the invention of vaccines was speeded up, and it is necessary to fight against COVID-19. However, postvaccination follow-up is mandatory when an individual is a victim of AD. In this review article, we compiled the various dreadful effects of the COVID-19 virus on AD, the Post effects of the virus on AD, and the effect of the COVID-19 vaccination on AD. This article provides a new direction for research concerning COVID-19 and AD.

Various repurposing drugs have been tested for their efficacy on coronavirus disease 2019 (COVID-19), including antimalarial drugs. During the pandemic, Chloroquine (CQ) and Hydroxychloroquine (HCQ) demonstrated good potential against COVID-19, but further studies showed both drugs had side effects that were more dangerous than the efficacy. This made World Health Organization (WHO) ban the usage for COVID-19 patients. In this context, there is a need to explore other antimalarial drugs as potential therapies for COVID-19. This study provides a descriptive synthesis of clinical trials evaluating antimalarial drugs for COVID-19 treatment conducted after the withdrawal of CQ and HCQ. The method was a literature study using the keywords "antimalarial", "COVID-19", "SARS-CoV-2", "clinical trial", and "randomized controlled trial" on the MEDLINE, Scopus, and Cochrane databases. Inclusion criteria were published clinical trials with randomized controlled trials (RCTs) on the efficacy and safety of single antimalarial drugs for COVID-19, published in English and excluding combination therapies. The results showed 3 antimalarial drugs, namely Quinine Sulfate (QS), Atovaquone (AQ), and Artemisinin-Piperaquine (AP), had gone through clinical trial to assess efficacy and safety against COVID-19 patients. Out of the 3 drugs, only AP showed significant results in the primary outcome, which was the time required to reach undetectable levels of SARS-CoV-2. Furthermore, the intervention group took 10.6 days, and the control group took 19.3 days (p=0.001). Based on this review, AP showed significant potential as a therapy in the fight against COVID-19.

SARS-CoV-2, which originated in China in late 2019, quickly fueled the global COVID-19 pandemic, profoundly impacting health and the economy worldwide. A series of vaccines, mostly based on the full SARS-CoV-2 Spike protein, were rapidly developed, showing excellent humoral and cellular responses and high efficacy against both symptomatic infection and severe disease. However, viral evolution and the waning humoral neutralizing responses strongly challenged vaccine long term effectiveness, mainly against symptomatic infection, making necessary a strategy of repeated and updated booster shots. In this repeated vaccination context, antibody repertoire diversification was evidenced, although immune imprinting after booster doses or reinfection was also demonstrated and identified as a major determinant of immunological responses to repeated antigen exposures. Considering that a small domain of the SARS-CoV-2 Spike protein, the receptor binding domain (RBD), is the major target of neutralizing antibodies and concentrates most viral mutations, the following text aims to provide insights into the ongoing debate over the best strategies for vaccine boosters. We address the relevance of developing new booster vaccines that target the evolving RBD, thus focusing on the relevant antigenic sites of the SARS-CoV-2 new variants. A combination of this strategy with immunofusing and computerized approaches could minimize immune imprinting, therefore optimizing neutralizing immune responses and booster vaccine efficacy.

The healthcare system has been greatly affected by the COVID-19 pandemic, resulting in an increase in secondary and co-infections among patients. Factors like pulmonary damage and weakened immune systems make patients more susceptible to fungal infections. Mucormycosis, an opportunistic fungal infection, prospers in environments with limited oxygen, and elevated glucose levels due to conditions such as diabetes and steroid use, as well as in acidic environments from metabolic acidosis and diabetic ketoacidosis, where it demonstrates heightened germination ability. Recognizing these complications is critical to minimize harm to patients. The insights gained from this review can improve our understanding of how fungal infections develop in connection to COVID-19, leading to better predictive algorithms, tailored care plans, enhanced antifungal treatments, quicker diagnostics, and improved management strategies.

We examined the relationship between RAAS inhibitor use and Omicron infection in mildly symptomatic patients. This retrospective case-control observational study included 50,121 patients with mild Omicron infection from the largest "Fangcang" shelter hospital in Shanghai between April 9, 2022, and May 21, 2022. Using 1:1 propensity score matching (PSM), we classified 4394 COVID-19 patients into hypertension and non-hypertension groups, and 406 hypertensive patients into RAAS inhibitor and non-RAAS inhibitor groups. The risk of initial symptoms of infection, cumulative negative conversion rates, time to nucleic-acid negative conversion, and viral loads were compared. In the hypertension group, the median number of days for nucleic-acid negative conversion was 7.0 (IQR, 5.0-9.0), which was greater than non-hypertensive group (median (IQR) 6.0 (4.0-8.0), P < 0.001, Cohen's d = 0.29); the mean and minimum cycle threshold values (CT-values) were significantly lower (P < 0.001, Cohen's d = 0.23). In the RAAS inhibitors group, the median number of days for nucleic-acid negative conversion was 7.0 days (IQR, 5.0-9.0), which was shorter than the non-RAAS inhibitors group ([median (IQR)] 8.0 (6.0-10.0), P < 0.001, Cohen's d = 0.34), the cumulative negative conversion rates at 3-8 days being all higher than non-RAAS inhibitors groups (P < 0.05). The most significant difference in negative conversion rate between the RAAS inhibitor and non-RAAS inhibitor group was on the 4th day. No significant difference was observed in mean and minimum CT-values from RAAS inhibitor and non-RAAS inhibitor groups (P > 0.05). RAAS inhibitor use in patients with hypertension is associated with nucleic-acid negative conversion duration and negative conversion rate. RAAS inhibitors clearly do not aggravate or prolong COVID-19.

COVID-19, caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), is primarily a respiratory illness but significantly affects the cardiovascular system as well. After entering the body through the respiratory tract, the virus directly and indirectly disrupts the vascular system. Vascular endothelial cells (ECs), which express ACE2 and TMPRSS2, are targets for viral invasion. However, the predominant cause of widespread vascular damage is the "cytokine storm" induced by the immune response. This leads to EC activation, inflammation, neutrophil activation, and neutrophil-platelet aggregation, causing endothelial injury. Additionally, increased expression of plasminogen activator inhibitor-1 disrupts the balance between prothrombotic and fibrinolytic processes, while activation of the renin-angiotensin-aldosterone system adds oxidative stress to the vascular endothelium. In the heart, SARS-CoV-2 invades ECs, leading to apoptosis and pyroptosis, exacerbated by inflammation and elevated catecholamines. These factors contribute to arrhythmias, strokes, and myocardial infarction in severe cases of COVID-19. This narrative review aims to explore the mechanisms by which SARS-CoV-2 affects the cardiovascular system and to highlight the resulting complications. It also identifies research gaps and discusses potential therapeutic strategies to mitigate the cardiovascular impacts of COVID-19.

Recently, angiotensin-converting enzyme 2 (ACE2) gene has emerged as a potential candidate gene for susceptibility to SARS-CoV-2 infection. We investigated whether ACE2 G8790A (rs2285666) polymorphism could be a genetic marker for susceptibility to COVID-19 and disease severity in Egyptian children and adolescents.

This was a prospective case-control study included 580 cases diagnosed with COVID-19, and 580 matched control children and adolescents. The ACE2 G8790A (rs2285666) polymorphism was genotyped using polymerase chain reaction (PCR) and ACE2 serum level was measured by ELISA.

The ACE2 A/A genotype and A-allele were significantly more represented in cases with COVID-19 as compared to control group (44% vs. 30%; OR = 2.83; [95% CI: 1.27-2.63]; p = 0.006; for the A/A genotype) and (65% vs. 51%; OR = 1.9; [95% CI: 1.06-1.72]; p = 0.01; for the A-allele). The presence of ACE2 G/G genotype was an independent risk factor for severe disease (adjusted OR: 2.08; [95% CI: 1.57-6.78]; p = 0.003).

The ACE2 G8790A (rs2285666) polymorphism may confer susceptibility to COVID-19 in Egyptian children and adolescents. The ACE2 G/G genotype and G-allele was associated with lower ACE2 serum levels and may constitute independent risk factors for disease severity.

The long-term respiratory sequelae of COVID-19 infection in children remain poorly understood and may differ across countries. This study aims to investigate the respiratory sequelae, including residual respiratory symptoms and pulmonary function in Thai children. The secondary aim is to identify factors associated with the respiratory sequelae.

This is an observational study involving 56 healthy children, aged between 7 and 18 years, who were diagnosed with COVID-19 infection from July 2021 to February 2023. Clinical data relating to COVID-19 infection and persistent symptoms after the infection were assessed after the infection up to 6 months. Spirometry was performed to assess pulmonary function.

Post-COVID-19 symptoms were identified in 14 patients (25%), with fatigue, cough, and dyspnea being common symptoms (28%-35%). A significant correlation was found between post COVID-19 symptoms and pneumonia (OR = 6.00, 95%CI [1.54,23.33], p = .01). Abnormal pulmonary function was identified in 10 patients (17.8%) with obstructive impairment being the most common. However, there was no significant association between clinical factors and pulmonary function impairment.

Prolonged respiratory symptoms and abnormal pulmonary function following COVID-19 infection are not uncommon in children. The post-COVID-19 symptoms are possibly associated with COVID-19 pneumonia.

This review explores the bidirectional relationship between the human microbiome and SARS-CoV-2 infection, elucidating its implications for COVID-19 susceptibility, severity, and therapeutic strategies. Metagenomic analyses reveal notable alterations in microbiome composition associated with SARS-CoV-2 infection, impacting disease severity and clinical outcomes. Dysbiosis within the respiratory, gastrointestinal, oral, and skin microbiomes exacerbates COVID-19 pathology through immune dysregulation and inflammatory pathways. Understanding these microbial shifts is pivotal for devising targeted therapeutic interventions. Notably, co-infection of oral pathogens with SARS-CoV-2 worsens lung pathology, while gut microbiome dysbiosis influences viral susceptibility and severity. Potential therapeutic approaches targeting the microbiome include probiotics, antimicrobial agents, and immunomodulatory strategies. This review underscores the importance of elucidating host-microbiota interactions to advance precision medicine and public health initiatives in combating COVID-19 and other infectious diseases.

Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells, thereby initiating downstream signal transduction pathways. Dysfunctions in neutrophils and disruptions in neutrophil homeostasis have been implicated in the pathogenesis of numerous diseases, including cancer and inflammatory disorders, often due to aberrant intracellular signaling. This review provides a comprehensive synthesis of neutrophil biological functions, integrating recent advancements in this field. Moreover, it examines the biological roles of receptors on neutrophils and downstream signaling pathways involved in the regulation of neutrophil activity. The pathophysiology of neutrophils in numerous human diseases and emerging therapeutic approaches targeting them are also elaborated. This review also addresses the current limitations within the field of neutrophil research, highlighting critical gaps in knowledge that warrant further investigation. In summary, this review seeks to establish a comprehensive and multidimensional model of neutrophil regulation, providing new perspectives for potential clinical applications and further research.

The skin barrier plays a crucial role in protecting our body against external agents. Disruption of this barrier's function leads to increased susceptibility to infections and dermatological diseases. Damaged skin can be due to the use of detergents, sunburn or excessive scratching. In the context of the COVID-19 pandemic the recommended hygiene measures to prevent the spread of SARS-CoV-2, such as wearing masks, frequent handwashing, and the use of sanitizers, can also potentially alter the skin barrier.

The purpose of the study was to characterize the barrier function of ex vivo models of damaged human skin.

Skin barrier damage was induced through different chemical and mechanical treatments, representative of the potential factors damaging human skin. The skin barrier function was evaluated in terms of permeability, dermal absorption capacity, stratum corneum thickness and gene expression of barrier markers. As inflammation is linked to skin barrier integrity, inflammatory markers were also analyzed.

The different treatments applied to ex vivo skin models allow the simulation of diverse degrees of skin damage, making these models valuable for assessing the efficacy of topical products targeted at skin repair and for studying the effects of compromised skin barrier on viral penetration.

Field evidence indicates differences in the rate and severity of COVID-19 infection among Afghans and Iranians, potentially influenced by individual genomic variances. Therefore, investigating the potential causes of these disparities holds significant clinical importance. This study aims to explore and compare variations in the genes encoding angiotensin-converting enzyme 1 (ACE1) and angiotensin-converting enzyme 2 (ACE2), along with total ACE activity levels in the blood of Afghans and Iranians with COVID-19, to assess any potential correlation with disease severity. In this case-control study, 124 Afghans and 124 Iranians with COVID-19 residing in Rafsanjan city, Iran, were examined. Blood samples were collected from all subjects, and serum was isolated for measuring total ACE activity using the kinetic method. DNA extraction was performed using the salting-out method, and gene polymorphisms of ACE1 and ACE2 were determined through polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism techniques. The DD genotype and D allele, as well as the GG genotype and G allele, were more prevalent among individuals with severe COVID-19 cases compared with those with mild symptoms, indicating an increased risk of severe infection. Although the Iranian group exhibited higher levels of these genetic components, along with longer hospital stays, intensive care unit admissions, and mortality rates than the Afghan group, the differences were not statistically significant. Furthermore, individuals with the DD genotype displayed double the total ACE activity levels compared with those with the II genotype, with the ID genotype falling in between. The presence of the DD genotype and D allele, as well as the GG genotype and G allele, likely serves as a significant risk factor for COVID-19 susceptibility, potentially heightening the risk of severe infection among Iranians compared with Afghans.

This retrospective study aimed to evaluate the 30 and 60-day survival of critically ill patients with COVID-19 and AKI.

Inflammatory and biochemical biomarkers, length of intensive care unit (ICU) stay and mortality at Day 30 and Day 60 after ICU admission were analyzed. A total of 44 patients treated with continuous renal replacement therapy (CRRT) with cytokine adsorber (CA group) were compared to 58 patients treated with CRRT alone (non-CA group).

Patients in CA group were younger, had better preserved kidney function prior to the beginning of CRRT and had higher levels of interleukin-6. There were no statistically significant differences in their comorbidities and in other measured biomarkers between the two groups. The number of patients who died 60 days after ICU admission was statistically significantly higher in non-CA group (p = 0.029).

Treatment with CRRT and cytokine adsorber may have positively influenced 60-day survival in our COVID-19 ICU patients with AKI.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19). Severe and fatal COVID-19 cases often display cytokine storm i.e. significant elevation of pro-inflammatory cytokines and acute respiratory distress syndrome (ARDS) with systemic hypoxia. Understanding the mechanisms of these pathogenic manifestations would be essential for the prevention and especially treatment of COVID-19 patients. Here, using a dual luciferase reporter assay for hypoxia-response element (HRE), we initially identified SARS-CoV-2 nonstructural protein 5 (NSP5), NSP16, and open reading frame 3a (ORF3a) to upregulate hypoxia-inducible factor-1α (HIF-1α) signaling. Further experiments showed NSP16 to have the most prominent effect on HIF-1α, thus contributing to the induction of COVID-19 associated pro-inflammatory response. We demonstrate that NSP16 interrupts von Hippel-Lindau (VHL) protein interaction with HIF-1α, thereby inhibiting ubiquitin-dependent degradation of HIF-1α and allowing it to bind HRE region in the IL-6 promoter region. Taken together, the findings imply that SARS-CoV-2 NSP16 induces HIF-1α expression, which in turn exacerbates the production of IL-6.