Epidemiology and risk factors of 28-day mortality of hospital-acquired bloodstream infection in Turkish intensive care units: a prospective observational cohort study.

OBJECTIVES: To uncover clinical epidemiology, microbiological characteristics and outcome determinants of hospital-acquired bloodstream infections (HA-BSIs) in Turkish ICU patients. METHODS: The EUROBACT II was a prospective observational multicontinental cohort study. We performed a subanalysis of patients from 24 Turkish ICUs included in this study. Risk factors for mortality were identified using multivariable Cox frailty models. RESULTS: Of 547 patients, 58.7% were male with a median [IQR] age of 68 [55-78]. Most frequent sources of HA-BSIs were intravascular catheter [182, (33.3%)] and lower respiratory tract [175, (32.0%)]. Among isolated pathogens (n = 599), 67.1% were Gram-negative, 21.5% Gram-positive and 11.2% due to fungi. Carbapenem resistance was present in 90.4% of Acinetobacter spp., 53.1% of Klebsiella spp. and 48.8% of Pseudomonas spp. In monobacterial Gram-negative HA-BSIs (n = 329), SOFA score (aHR 1.20, 95% CI 1.14-1.27), carbapenem resistance (aHR 2.46, 95% CI 1.58-3.84), previous myocardial infarction (aHR 1.86, 95% CI 1.12-3.08), COVID-19 admission diagnosis (aHR 2.95, 95% CI 1.25-6.95) and not achieving source control (aHR 2.02, 95% CI 1.15-3.54) were associated with mortality. However, availability of clinical pharmacists (aHR 0.23, 95% CI 0.06-0.90) and source control (aHR 0.46, 95% CI 0.28-0.77) were associated with survival. In monobacterial Gram-positive HA-BSIs (n = 93), SOFA score (aHR 1.29, 95% CI 1.17-1.43) and age (aHR 1.05, 95% CI 1.03-1.08) were associated with mortality, whereas source control (aHR 0.41, 95% CI 0.20-0.87) was associated with survival. CONCLUSIONS: Considering high antimicrobial resistance rate, importance of source control and availability of clinical pharmacists, a multifaceted management programme should be adopted in Turkish ICUs.

VACCELERATE Site Network: Real-time definition of clinical study capacity in Europe.

BACKGROUND: The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines. METHODS: Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process. RESULTS: As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae/influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae/pneumococcus. CONCLUSIONS: The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe.

Human memory T cell dynamics after aluminum-adjuvanted inactivated whole-virion SARS-CoV-2 vaccination.

This study evaluates the functional capacity of CD4+ and CD8+ terminally-differentiated effector (TEMRA), central memory (TCM), and effector memory (TEM) cells obtained from the volunteers vaccinated with an aluminum-adjuvanted inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac). The volunteers were followed for T cell immune responses following the termination of a randomized phase III clinical trial. Seven days and four months after the second dose of the vaccine, the memory T cell subsets were collected and stimulated by autologous monocyte-derived dendritic cells (mDCs) loaded with SARS-CoV-2 spike glycoprotein S1. Compared to the placebo group, memory T cells from the vaccinated individuals significantly proliferated in response to S1-loaded mDCs. CD4+ and CD8+ memory T cell proliferation was detected in 86% and 78% of the vaccinated individuals, respectively. More than 73% (after a short-term) and 62% (after an intermediate-term) of the vaccinated individuals harbored TCM and/or TEM cells that responded to S1-loaded mDCs by secreting IFN-γ. The expression of CD25, CD38, 4-1BB, PD-1, and CD107a indicated a modulation in the memory T cell subsets. Especially on day 120, PD-1 was upregulated on CD4+ TEMRA and TCM, and on CD8+ TEM and TCM cells; accordingly, proliferation and IFN-γ secretion capacities tended to decline after 4 months. In conclusion, the combination of inactivated whole-virion particles with aluminum adjuvants possesses capacities to induce functional T cell responses.

Enhancing Public Health Communication Regarding Vaccine Trials: Design and Development of the Pan-European VACCELERATE Toolkit.

BACKGROUND: The pan-European VACCELERATE network aims to implement the first transnational harmonized and sustainable vaccine trial Volunteer Registry, being a single entry point for potential volunteers of large-scale vaccine trials across Europe. This work exhibits a set of harmonized vaccine trial-related educational and promotional tools for the general public, designed and disseminated by the pan-European VACCELERATE network. OBJECTIVE: This study primarily aimed to design and develop a standard toolkit to increase positive attitudes and access to trustworthy information for better access and increased recruitment to vaccine trials for the public. More specifically, the produced tools are focused on inclusiveness and equity, and are targeting different population groups, including underserved ones, as potential volunteers for the VACCELERATE Volunteer Registry (older individuals, migrants, children, and adolescents). The promotional and educational material is aligned with the main objectives of the Volunteer Registry to increase public literacy and awareness regarding vaccine-related clinical research or trials and trial participation, including informed consent and legal issues, side effects, and frequently asked questions regarding vaccine trial design. METHODS: Tools were developed per the aims and principles of the VACCELERATE project, focusing on trial inclusiveness and equity, and are adjusted to local country-wise requirements to improve public health communication. The produced tools are selected based on the cognitive theory, inclusiveness, and equity of differently aged and underrepresented groups, and standardized material from several official trustworthy sources (eg, COVID-19 Vaccines Global Access; the European Centre for Disease Prevention and Control; the European Patients' Academy on Therapeutic Innovation; Gavi, the Vaccine Alliance; and the World Health Organization). A team of multidisciplinary specialists (infectious diseases, vaccine research, medicine, and education) edited and reviewed the subtitles and scripts of the educational videos, extended brochures, interactive cards, and puzzles. Graphic designers selected the color palette, audio settings, and dubbing for the video story-tales and implemented QR codes. RESULTS: This study presents the first set of harmonized promotional and educational materials and tools (ie, educational cards, educational and promotional videos, extended brochures, flyers, posters, and puzzles) for vaccine clinical research (eg, COVID-19 vaccines). These tools inform the public about possible benefits and disadvantages of trial participation and build confidence among participants about the safety and efficacy of COVID-19 vaccines and the health care system. This material has been translated into several languages and is intended to be freely and easily accessible to facilitate dissemination among VACCELERATE network participant countries and the European and global scientific, industrial, and public community. CONCLUSIONS: The produced material could help fill knowledge gaps of health care personnel, providing the appropriate future patient education for vaccine trials, and tackling vaccine hesitancy and parents' concerns for potential participation of children in vaccine trials.

Knowledge and Attitudes of Turkish Physicians towards Human Monkeypox Disease and Related Vaccination: A Cross-Sectional Study.

Background: In May 2022, the monkeypox virus outbreak in multiple countries on various continents marked a potential resurgence of the disease as a global health issue. Considering the crucial role of physicians in mitigating the monkeypox outbreak, we sought to evaluate physicians' knowledge, attitude, concerns, and vaccine acceptance for monkeypox, in the shadow of the COVID-19 pandemic. Methods: A large-scale, cross-sectional survey was conducted among 283 physicians between 20 August−2 September 2022, in Turkey. The participants' sociodemographic characteristics, knowledge, attitudes, concerns, and vaccine acceptance toward monkeypox infection were collected via a questionnaire. Results: Our study revealed that 32.5% of physicians achieved a good level of knowledge; similarly, 31.4% of the physicians planned to have the monkeypox vaccine. Multivariate binary logistic regression analysis showed that female physicians (p = 0.031) and older people (≥30 vs. <30) were more likely to be knowledgeable about monkeypox (p = 0.007). We found that participants from divisions of internal medicine (p = 0.033) who knew about the monkeypox disease during medical school or residency (p = 0.005) and were previously exposed to COVID-19 disease (p = 0.005) were more likely to have a good knowledge score of monkeypox. We also found that physicians with a good knowledge score were more worried about monkeypox compared to COVID-19 (AOR: 2.22; 95% CI:1.13−4.33; p = 0.019). Additionally, those who had information on monkeypox during medical education (AOR = 2.16, 95% CI = 1.10−4.21; p = 0.024) were more likely to receive the smallpox vaccine to prevent monkeypox viral infection when available. Conclusions: The present study pointed out that physicians in Turkey have unsatisfactory levels of knowledge about the emerging monkeypox. This study results can impede attempts to detect and manage cases of monkeypox and should be addressed through appropriate and timely awareness and educational programs, alerts, and seminars. These might serve as the basis for policymakers' decisions about promoting national monkeypox vaccination strategies and addressing potential vaccine hesitancy and misinformation when needed.

Relevance of the Consensus Principles for Appropriate Antibiotic Prescribing in 2022.

BACKGROUND: In the late 1990s, as a response to rising antimicrobial resistance (AMR), an independent multinational, interdisciplinary group was formed specifically targeting primary care antibiotic prescribing for community-acquired respiratory tract infections (CA-RTIs). The group comprised senior clinicians from Canada, Israel, Spain, Sweden, UK and USA. The group's objectives were to provide recommendations for antibiotic stewardship in the community because, whilst it was widely accepted that inappropriate antibiotic use was contributing to AMR, it remained difficult to change prescribing behaviour. The group aimed to identify principles underlying appropriate antibiotic prescribing and guideline formulation to reduce morbidity from CA-RTIs, limit therapeutic failure and, importantly, curb AMR emergence. The group published a report in 2002, which has become known as the Consensus Principles. OBJECTIVES: (i) To consider the relevance of the Consensus Principles in 2022 by reviewing current global approaches to rising AMR. A wide range of factors, such as antibiotic overuse, most recently seen in COVID-19 patients, are still driving rising AMR even though there has been a high-level international response to the AMR threat; and (ii) as an introduction to this Supplement, which reports the findings of analyses of how AMR is being addressed in nine disparate countries (Brazil, India, Kuwait, Mexico, Pakistan, Russia, Saudi Arabia, Türkiye and Vietnam). Understanding how these initiatives are being pursued in different countries helps identify areas where more information is needed. CONCLUSIONS: Adherence to the Consensus Principles remains as important now as it was in 2002. Achieving appropriate antibiotic prescribing is a vital objective in order that the right patient receives the right antibiotics at the right time to ensure optimal clinical outcomes while at the same time helping to limit further increases in AMR.

Relative Vaccine Effectiveness of the Third Dose of CoronaVac or BNT162b2 Following a Two-Dose CoronaVac Regimen: A Prospective Observational Cohort Study from an Adult Vaccine Center in Turkey.

Coronavirus disease 2019 (COVID-19) continues to pose a threat to public health with the potential for the emergence of new variants. Vaccines are the milestones to control and slow down the damage of the pandemic. As of January 2021, a two-dose regimen with CoronaVac was authorized in Turkey. Due to the waning seroprevalence rate of SARS-CoV-2 over time, BNT162b2 or CoronaVac has been administered as the third dose following a two-dose CoronaVac regimen as a national vaccination policy. As of 14 January 2021, 5243 volunteers who received two doses of the CoronaVac vaccine at Hacettepe University Adult Vaccine Center were followed prospectively. In our study, relative vaccine effectiveness (VEff) for the third dose of the CoronaVac was 58.24% and 87.27% for BNT162b2 in preventing symptomatic COVID-19 cases. There were no hospitalizations, intensive care unit admissions, or deaths in third-dose booster groups with either BNT162b2 or CoronaVac, yielding 100% effectiveness. Both homologous or heterologous third-dose boosters provided further protection against severe COVID-19 and should be prioritized as an effective strategy to combat the COVID-19 pandemic.

VACCELERATE Volunteer Registry: A European study participant database to facilitate clinical trial enrolment.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has evidenced the key role of vaccine design, obtention, production and administration to successfully fight against infectious diseases and to provide efficient remedies for the citizens. Although clinical trials were rapidly established during this pandemic, identifying suitable study subjects can be challenging. For this reason, the University Hospital Cologne established a volunteer registry for participation in clinical trials first in Germany, which has now been incorporated into the European VACCELERATE clinical trials network and grew to a European Volunteer Registry. As such, VACCELERATE's Volunteer Registry aims to become a common entry point for potential volunteers in future clinical trials in Europe. METHODS: Interested volunteers who would like to register for clinical trials in the VACCELERATE Volunteer Registry can access the registration questionnaire via http://www.vaccelerate.eu/volunteer-registry. Potential volunteers are requested to provide their current country and area of residence, contact information, including first and last name and e-mail address, age, gender, comorbidities, previous SARS-CoV-2 infection and vaccination status, and maximum distance willing to travel to a clinical trial site. The registry is open to both adults and children, complying with national legal consent requirements. RESULTS: As of May 2022, the questionnaire is available in 12 countries and 14 languages. Up to date, more than 36,000 volunteers have registered, mainly from Germany. Within the first year since its establishment, the VACCELERATE Volunteer Registry has matched more than 15,000 volunteers to clinical trials. The VACCELERATE Volunteer Registry will be launched in further European countries in the coming months. CONCLUSIONS: The VACCELERATE Volunteer Registry is an active single-entry point for European residents interested in COVID-19 clinical trials participation in 12 countries (i.e., Austria, Cyprus, Germany, Greece, Ireland, Lithuania, Norway, Portugal, Spain, Sweden and Turkey). To date, more than 15,000 registered individuals have been connected to clinical trials in Germany alone. The registry is currently in the implementation phase in 5 additional countries (i.e., Belgium, Czech Republic, Hungary, Israel and the Netherlands).

Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey.

BACKGROUND: CoronaVac, an inactivated whole-virion SARS-CoV-2 vaccine, has been shown to be well tolerated with a good safety profile in individuals aged 18 years and older in phase 1/2 trials, and provided a good humoral response against SARS-CoV-2. We present the interim efficacy and safety results of a phase 3 clinical trial of CoronaVac in Turkey. METHODS: This was a double-blind, randomised, placebo-controlled phase 3 trial. Volunteers aged 18-59 years with no history of COVID-19 and with negative PCR and antibody test results for SARS-CoV-2 were enrolled at 24 centres in Turkey. Exclusion criteria included (but were not limited to) immunosuppressive therapy (including steroids) within the past 6 months, bleeding disorders, asplenia, and receipt of any blood products or immunoglobulins within the past 3 months. The K1 cohort consisted of health-care workers (randomised in a 1:1 ratio), and individuals other than health-care workers were also recruited into the K2 cohort (randomised in a 2:1 ratio) using an interactive web response system. The study vaccine was 3 µg inactivated SARS-CoV-2 virion adsorbed to aluminium hydroxide in a 0·5 mL aqueous suspension. Participants received either vaccine or placebo (consisting of all vaccine components except inactivated virus) intramuscularly on days 0 and 14. The primary efficacy outcome was the prevention of PCR-confirmed symptomatic COVID-19 at least 14 days after the second dose in the per protocol population. Safety analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT04582344) and is active but no longer recruiting. FINDINGS: Among 11 303 volunteers screened between Sept 14, 2020, and Jan 5, 2021, 10 218 were randomly allocated. After exclusion of four participants from the vaccine group because of protocol deviations, the intention-to-treat group consisted of 10 214 participants (6646 [65·1%] in the vaccine group and 3568 [34·9%] in the placebo group) and the per protocol group consisted of 10 029 participants (6559 [65·4%] and 3470 [34·6%]) who received two doses of vaccine or placebo. During a median follow-up period of 43 days (IQR 36-48), nine cases of PCR-confirmed symptomatic COVID-19 were reported in the vaccine group (31·7 cases [14·6-59·3] per 1000 person-years) and 32 cases were reported in the placebo group (192·3 cases [135·7-261·1] per 1000 person-years) 14 days or more after the second dose, yielding a vaccine efficacy of 83·5% (95% CI 65·4-92·1; p<0·0001). The frequencies of any adverse events were 1259 (18·9%) in the vaccine group and 603 (16·9%) in the placebo group (p=0·0108) with no fatalities or grade 4 adverse events. The most common systemic adverse event was fatigue (546 [8·2%] participants in the vaccine group and 248 [7·0%] the placebo group, p=0·0228). Injection-site pain was the most frequent local adverse event (157 [2·4%] in the vaccine group and 40 [1·1%] in the placebo group, p<0·0001). INTERPRETATION: CoronaVac has high efficacy against PCR-confirmed symptomatic COVID-19 with a good safety and tolerability profile. FUNDING: Turkish Health Institutes Association.

Current status of therapeutic alternatives for COVID-19: A narrative review.

Since December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has exploded and led to a global crisis. Currently, the global case numbers topped 200 million, and toll of dead exceeded 4 million around the world. The pathogenesis of coronavirus disease 2019 (COVID-19) is driven by two processes. During the first stage of the infection that lasts around 5-7 days, replication of SARS-CoV-2 occurs. In the second stage, the disease may progress due to an exaggerated inflammatory response leading to tissue damage. Therefore, it is anticipated that antiviral agents would be effective during the early phase of the disease, while immunomodulator agents are likely to be more beneficial in the second stage of COVID-19. This basic concept of disease development led to explore several antiviral and immunomodulator agents for the treatment of COVID-19. Currently, remdesivir is the only available Food and Drug Administration-approved antiviral agent for the treatment of COVID-19. However, some other agents have been approved by various mechanisms, including Emergency Use Authorizations, Emergency Investigational New Drug applications, compassionate use or expanded access programs. In addition, a variety of repurposed agents that were approved for other indications are being investigated for the treatment of COVID19 in clinical trials. A myriad of publications including randomized controlled trials (RCTs) are emerging continuously and are accessible as peer-reviewed, pre-print and press release formats. Considering the critical importance of RCTs in generating evidence and providing further guidance on COVID-19 treatment, we herein reviewed only RCTs and meta-analyses. The discussion includes antiviral agents (hydroxychloroquine, lopinavir/ritonavir, remdesivir, favipiravir and ivermectin) and, various immunomodulatory drugs (corticosteroids, tocilizumab, baricitinib, and IL-1 inhibitors). Other investigational therapies including darunavir/cobicistat, umifenovir, sofosbuvir/daclatasvir, sofobuvir/ledipasvir, ribavirin, nitazoxanide and interferon-based regimens were not evaluated due to insufficient data on the efficacy and safety of these agents.

Outcome of noncritical COVID-19 patients with early hospitalization and early antiviral treatment outside the ICU

Background/aim: Despite the fact that the COVID-19 pandemic has been going on for over 5 months, there is yet to be a standard management policy for all patients including those with mild-to-moderate cases. We evaluated the role of early hospitalization in combination with early antiviral therapy with COVID-19 patients in a tertiary care university hospital. Materials and methods: This was a prospective, observational, single-center study on probable/confirmed COVID-19 patients hospitalized in a tertiary care hospital on COVID-19 wards between March 20 and April 30, 2020. The demographic, laboratory, and clinical data were collected. Results: We included 174 consecutive probable/confirmed COVID-19 adult patients hospitalized in the Internal Medicine wards of the University Adult Hospital between March 20 and April 30, 2020. The median age was 45.5 (19­92) years and 91 patients (52.3%) were male. One hundred and twenty (69%) were confirmed microbiologically, 41 (23.5%) were radiologically diagnosed, and 13 (7.5%) were clinically suspected (negative microbiological and radiological findings compatible with COVID-19); 35 (20.1%) had mild, 107 (61.5%) moderate disease, and 32 (18.4%) had severe pneumonia. Out of 171 cases, 130 (74.3%) showed pneumonia; 80 were typical, and 50 showed indeterminate infiltration for COVID-19. Patients were admitted within a median of 3 days (0-14 days) after symptoms appear. The median duration of hospitalization was 4 days (0-28 days). In this case series, 13.2% patients were treated with hydroxychloroquine alone, 64.9% with hydroxychloroquine plus azithromycin, and 18.4% with regimens including favipiravir. A total of 15 patients (8.5%) were transferred to the ICU. Four patients died (2.2%). Conclusion: In our series, 174 patients were admitted to the hospital wards for COVID-19, 69% were confirmed with PCR and/or antibody test. At the time of admission, nearly one fifth of the patients had severe diseases. Of the patients, 95.4% received hydroxychloroquine alone or in combination. The overall case fatality rate was 2.2%.

Predictive value of cytokine/chemokine responses for the disease severity and management in children and adult cases with COVID-19.

The disease course of children with coronavirus disease 2019 (COVID-19) seems milder as compared with adults, however, actual reason of the pathogenesis still remains unclear. There is a growing interest on possible relationship between pathogenicity or disease severity and biomarkers including cytokines or chemokines. We wondered whether these biomarkers could be used for the prediction of the prognosis of COVID-19 and improving our understanding on the variations between pediatric and adult cases with COVID-19. The acute phase serum levels of 25 cytokines and chemokines in the serum samples from 60 COVID-19 pediatric (n = 30) and adult cases (n = 30) including 20 severe or critically ill, 25 moderate and 15 mild patients and 30 healthy pediatric (n = 15) and adult (n = 15) volunteers were measured using commercially available fluorescent bead immunoassay and analyzed in combination with clinical data. Interferon gamma-induced protein 10 (IP-10) and macrophage inflammatory protein (MIP)-3ß levels were significantly higher in patient cohort including pediatric and adult cases with COVID-19 when compared with all healthy volunteers (p ≤ .001 in each) and whereas IP-10 levels were significantly higher in both pediatric and adult cases with severe disease course, MIP-3ß were significantly lower in healthy controls. Additionally, IP-10 is an independent predictor for disease severity, particularly in children and interleukin-6 seems a relatively good predictor for disease severity in adults. IP-10 and MIP-3ß seem good research candidates to understand severity of COVID-19 in both pediatric and adult population and to investigate possible pathophysiological mechanism of COVID-19.

A randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the efficacy and safety of SARS-CoV-2 vaccine (inactivated, Vero cell): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective is to evaluate the efficacy of an inactivated and aluminium hydroxide adsorbed SARS-CoV-2 vaccine (Sinovac, China) in voluntary participants after 14 days of the second dose against RT-PCR confirmed symptomatic COVID-19 cases. The secondary objectives include evaluating the efficacy after at least one dose of the vaccine against RT-PCR confirmed symptomatic COVID-19 cases; the efficacy of two doses of the vaccine on the rates of hospitalization and death; the safety of the vaccine including adverse reactions up to one year after the 2nd dose of vaccination; and the immunogenicity of the vaccine and its duration up to 120 days. TRIAL DESIGN: This is a phase III, randomized, double-blind, placebo-controlled case driven clinical trial to assess the efficacy and safety of the vaccine. The study is planned to be carried out within two separate cohorts in voluntary participants aged between 18-59 years old. The first cohort includes healthcare professionals actively working in healthcare units, who are assumed to have higher risk of acquiring COVID-19, and the second cohort includes other immunocompetent subjects in the same age group, who are at a regular risk for COVID-19 disease. In Cohort 1, healthcare professionals will be randomized to receive two intramuscular doses of investigational product or the placebo in a 1:1 ratio and they will be monitored for 12 months by active surveillance of COVID-19. In Cohort 2, immunocompetent subjects will be randomized to receive vaccine or the placebo in a 2:1 ratio. PARTICIPANTS: Healthcare professionals of both genders, including medical doctors, nurses, cleaners, hospital technicians, and administrative personnel who work in any department of a healthcare unit and immunocompetent individuals of both genders are included. Pregnant (confirmed by positive beta-hCG test) and breastfeeding women as well as those intending to become pregnant within three months after vaccination are excluded. Other exclusion criteria include history of COVID-19 test positivity (PCR or immunoglobulin test results), any form of immunosuppressive therapy including corticosteroids within 6 months, history of bleeding disorders, asplenia, and administration of any form of immunoglobulins or blood products within 3 months. Exclusion criteria for the second dose include any serious adverse events related with the vaccine, anaphylaxis or hypersensitivity after vaccination, or any confirmed or suspected autoimmune or immunosuppressive disease (including HIV infection). Participants are only included after signing the voluntary informed consent form, ensuring cooperation in visits, undergoing screening for evaluation, and conforming to all the inclusion and exclusion criteria. All clinical sites are located in Turkey. INTERVENTION AND COMPARATOR: The vaccine was manufactured by Sinovac Research & Development Co., Ltd. It is a preparation made from a novel coronavirus (strain CZ02) grown in the kidney cell cultures (Vero Cell) of the African green monkey and contains inactivated SARS-CoV-2 virus, aluminium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride. A dose of 0.5 mL contains 600 SU of SARS-CoV-2 virus antigen. The placebo contains aluminium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride (0.5mL/dose). Scheduled visits and additional unscheduled weekly visits will be performed for the first 13 weeks and neutralizing antibody test, IgG test, T-Cell activation test, pregnancy test, and RT-PCR tests along with total antibody test will be performed. Adverse events and serious adverse events during the follow-up will be recorded on diary cards. Diary cards will collect information on the timing and severity of COVID-19 symptoms and solicited adverse events recorded by the subjects during one-year follow-up period. All serious adverse events will be managed and necessary treatment will be ensured according to the local regulations. All serious adverse events following vaccination will be reported to the ethics committee, the Ministry of Health, and the study sponsor within 24 hours of detection. MAIN OUTCOMES: The primary efficacy endpoint is the incidence of symptomatic cases of COVID-19 disease confirmed by RT-PCR two weeks after the second dose of vaccination. Secondary efficacy endpoints are the incidence of hospitalization/mortality rates among one or two dose regimens, duration of immunogenicity rates up to 120 days, the seroconversion rate, the seropositivity rate, neutralizing antibody titer, and IgG levels 14 days after each dose of vaccination. The primary safety endpoint is the severity and frequency of local and systemic adverse reactions during the period of one week after vaccination. The study would be terminated if more than 15% of the subjects have grade ≥3 adverse events related to vaccination including local reactions. RANDOMISATION: Eligible subjects will be randomized at their Study Day 0 to two study groups using an Interactive Web Response System (IWRS; developed by Omega CRO, Ankara, Turkey) in both risk groups. The IWRS system customizes the randomization algorithm. After enrolment in the study, each participant will be randomly assigned to either of the two treatment arms at a ratio of 1:1 in the high-risk group and at a ratio of 2:1 in the normal risk group. Each enrolled participant will be assigned to a code and will receive the treatment labelled with the code. BLINDING (MASKING): The trial is a double-blind study to avoid introducing bias. The blinding may be broken by the investigator in the event of a medical emergency in which knowledge of the identity of the study vaccine is critical for management of the subject's immediate treatment. The Data and Safety Monitoring Board is to be contacted in case of breaking the blinding for a study object. The blood samples will be taken from both placebo and vaccinated groups, in order not to break the blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The study is planned to be carried out with two separate cohorts. The Cohort 1 includes healthcare professionals working in healthcare units and the Cohort 2 consists of immunocompetent subjects having normal risk for COVID-19 disease. The Cohort 2 will be initiated after the evaluation of the interim safety report of the Cohort 1 by the Data and Safety Monitoring Board. Both cohorts will be followed-up via RT-PCR to confirm symptomatic COVID-19 cases. If the clinical efficacy of the vaccine is shown in the Cohort 1 or 2, the subjects randomized into the placebo arm will also be vaccinated. In the Cohort 1, 588 subjects should be included in both arms with the assumption that the risk of infection with COVID-19 will be 5% for the placebo arm and 2% for the vaccine arm in the high-risk group. Considering 10% of drop-out rate and 5% of seropositivity or PCR positivity at baseline, 680 subjects should be screened at both arms of the Cohort 1. Group sample sizes of 7545 SARS-CoV-2 vaccine and 3773 placebo suits at a two-sided 95% confidence interval for the difference in population proportions with a width equal to 1.0%, when the estimated incidence rate for vaccinated group is 1.0% and the estimated incidence rate for placebo group is 2.0%. Drop-out rate is assumed to be 10% and seropositivity or PCR positivity at baseline is assumed to be 5%; accordingly, 13000 participants are needed to be enrolled totally in both cohorts. The remaining 11640 subjects will be screened in the Cohort 2 and eligible subjects will be randomized at a ratio of 2:1. TRIAL STATUS: Protocol version 6.0 - 15 October 2020. Recruitment started on 15.09.2020 and is expected to end on February 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04582344 . Registered 8 October 2020 FULL PROTOCOL: The full protocol of the trial is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Lung and kidney perfusion deficits diagnosed by dual-energy computed tomography in patients with COVID-19-related systemic microangiopathy.

OBJECTIVES: There is increasing evidence that thrombotic events occur in patients with coronavirus disease (COVID-19). We evaluated lung and kidney perfusion abnormalities in patients with COVID-19 by dual-energy computed tomography (DECT) and investigated the role of perfusion abnormalities on disease severity as a sign of microvascular obstruction. METHODS: Thirty-one patients with COVID-19 who underwent pulmonary DECT angiography and were suspected of having pulmonary thromboembolism were included. Pulmonary and kidney images were reviewed. Patient characteristics and laboratory findings were compared between those with and without lung perfusion deficits (PDs). RESULTS: DECT images showed PDs in eight patients (25.8%), which were not overlapping with areas of ground-glass opacity or consolidation. Among these patients, two had pulmonary thromboembolism confirmed by CT angiography. Patients with PDs had a longer hospital stay (p = 0.14), higher intensive care unit admission rates (p = 0.02), and more severe disease (p = 0.01). In the PD group, serum ferritin, aspartate aminotransferase, fibrinogen, D-dimer, C-reactive protein, and troponin levels were significantly higher, whereas albumin level was lower (p < 0.05). D-dimer levels ≥ 0.485 µg/L predicted PD with 100% specificity and 87% sensitivity. Renal iodine maps showed heterogeneous enhancement consistent with perfusion abnormalities in 13 patients (50%) with lower sodium levels (p = 0.03). CONCLUSIONS: We found that a large proportion of patients with mild-to-moderate COVID-19 had PDs in their lungs and kidneys, which may be suggestive of the presence of systemic microangiopathy with micro-thrombosis. These findings help in understanding the physiology of hypoxemia and may have implications in the management of patients with COVID-19, such as early indications of thromboprophylaxis or anticoagulants and optimizing oxygenation strategies. KEY POINTS: • Pulmonary perfusion abnormalities in COVID-19 patients, associated with disease severity, can be detected by pulmonary DECT. • A cutoff value of 0.485 µg/L for D-dimer plasma levels predicted lung perfusion deficits with 100% specificity and 87% sensitivity (AUROC, 0.957). • Perfusion abnormalities in the kidney are suggestive of a subclinical systemic microvascular obstruction in these patients.

The effects of blood group types on the risk of COVID-19 infection and its clinical outcome

Background/aim: COVID-19 (Coronavirus disease of 2019) is an infectious disease outbreak later on declared as a pandemic, caused by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2). It spreads very rapidly and can result in severe acute respiratory failure. The clinical studies have shown that advanced age and chronic diseases increase the risk of infection. However, influence of the blood groups on COVID-19 infection and its outcome remains to be confirmed. The aim of this study is to investigate whether there exists a relationship between the blood groups of the patients and risk of SARS-CoV-2 infection and the clinical outcomes in COVID-19 patients Material and method: 186 patients with PCR confirmed diagnosis of COVID-19 were included in this study. Age, sex, blood groups, comorbidities, need for intubation and intensive care unit follow up and mortalities of the patients were analyzed retrospectively. 1881 healthy individuals, who presented to the Hacettepe University Blood Bank served as the controls. Results: The most frequently detected blood group was blood group A (57%) amongst the COVID-19 patients. This was followed by blood group O (24.8%). The blood group types did not affect the clinical outcomes. The blood group A was statistically significantly more frequent among those infected with COVID-19 compared to controls (57% vs. 38%, P < 0.001; OR: 2.1). On the other hand, the frequency of blood group O was significantly lower in the COVID-19 patients, compared to the control group (24.8% vs. 37.2%, P: 0.001; OR: 1.8). Conclusions: The results of the present study suggest that while the blood group A might have a role in increased susceptibility to the COVID-19 infection, the blood group O might be somewhat protective. However, once infected, blood group type does not seem to influence clinical outcome.