ABSTRACT
Background & Aim: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. If available, most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. Methods, Results & Conclusion(s): We have previously demonstrated the safety of adoptive cell therapy for COVID-19 patients with CD45RA negative cells containing SARS-CoV-2-specific T cells from a donor, chosen based on HLA compatibility and cellular response to SARS-CoV-2 peptide pools. After finishing a Phase 2 randomized multicenter clinical trial (RELEASE, NCT04578210), we concluded that the infusion is safe, effective, accelerates lymphocyte recovery and shows hallmarks of an immune response. To use adoptive cell therapy to treat COVID-19 it would be necessary to develop a biobank of living drugs. For that, we examined the immune evolution performing a longitudinal analysis from previously SARS-CoV-2 infected and infection- naive individuals covering 21 months from infection. Cellular responses were maintained over time while humoral responses increased after vaccination but were gradually lost. Therefore, the best donors would be recovered individuals and two months after vaccination. We also evaluated the effect of dexamethasone (current standard of care treatment for COVID-19 and other infections involving lymphopenia) and Interleukin-15 (cytokine involved in T-cell maintenance and survival) on CD45RA negative. Dexamethasone did not alter cell functionality, proliferation or phenotype at a clinical-practice concentration, while interleukin-15 increased the memory T-cell and T-regulatory cell activation state, and interferon gamma release. Furthermore, we applied the adoptive passive transfer of CD45RA negative cells containing pathogen-specific memory T-cells to other infectious diseases characterized by sustained lymphopenia. We infused six immunocompromised patients with Cytomegalovirus, BK virus, Aspergillus, and Epstein-Barr virus lymphoproliferative disease. Patients experienced pathogen clearance, resolution of symptoms and lymphocyte increase. Transient microchimerism was detected in three patients. The use of CD45RA negative cells containing specific memory T cells of a third-party donor for treating severe pathogenic diseases in immunocompromised patients is feasible, safe, and effective, and has an advantage over other cell therapies such as lower costs and a less complex regulatory environment.Copyright © 2023 International Society for Cell & Gene Therapy
ABSTRACT
BACKGROUND: In May 2020, the ACCESS (The vACCine covid-19 monitoring readinESS) project was launched to prepare real-world monitoring of COVID-19 vaccines. Within this project, this study aimed to generate background incidence rates of 41 adverse events of special interest (AESI) to contextualize potential safety signals detected following administration of COVID-19 vaccines. METHODS: A dynamic cohort study was conducted using a distributed data network of 10 healthcare databases from 7 European countries (Italy, Spain, Denmark, The Netherlands, Germany, France and United Kingdom) over the period 2017 to 2020. A common protocol (EUPAS37273), common data model, and common analytics programs were applied for syntactic, semantic and analytical harmonization. Incidence rates (IR) for each AESI and each database were calculated by age and sex by dividing the number of incident cases by the total person-time at risk. Age-standardized rates were pooled using random effect models according to the provenance of the events. FINDINGS: A total number of 63,456,074 individuals were included in the study, contributing to 211.7 million person-years. A clear age pattern was observed for most AESIs, rates also varied by provenance of disease diagnosis (primary care, specialist care). Thrombosis with thrombocytopenia rates were extremely low ranging from 0.06 to 4.53/100,000 person-years for cerebral venous sinus thrombosis (CVST) with thrombocytopenia (TP) and mixed venous and arterial thrombosis with TP, respectively. INTERPRETATION: Given the nature of the AESIs and the setting (general practitioners or hospital-based databases or both), background rates from databases that show the highest level of completeness (primary care and specialist care) should be preferred, others can be used for sensitivity. The study was designed to ensure representativeness to the European population and generalizability of the background incidence rates. FUNDING: The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE.
ABSTRACT
Introduction: Status epilepticus (SE) is a neurologic emergency with high-mortality rates that requires early diagnosis and prompt treatment to improve the patient's chances. A SE is called refractory (RSE) when seizures are uncontrollable despite intravenous (IV) benzodiazepine in addition to anti-epileptic drugs (AED). If seizures continue despite IV-AED and/or IV-anesthetics, that is designated as super-RSE (SRSE). Recently, new-onset RSE (NORSE) has been described. The current armamentarium of AEDs, immunomodulation-drugs and non-pharmacological therapies available, including neuromodulation techniques, has been used to treat RSE. Lately, the use, efficacy, and safety of repetitive-transcranial-magnetic-stimulation (rTMS) are well known. Method(s): In October 2020, a 23-year-old male with a low level of consciousness and clinical SE was admitted to an intensive care unit. A febrile peak, the previous week, was the only pertinent data. SARS-CoV2 test was negative, although it became positive a week later. While in the hospital, SE therapeutic protocol was followed (antivirals, antibiotics, and AEDs, anesthetics, including cortical electrical silence pentothal-induced, immunomodulation drugs (tocilizumab, anakinra), and ketogenic diet) without achieving seizure control. Despite the lack of continuous electroencephalography (EEG) monitorization, daily EEGs were recorded and a diffuse slow-wave cortical activity led the way to bihemispheric fronto-temporal (FT) seizures;left-FT SE was also registered. On the 49th day, the decision was made to administer rTMS. Previously, the epileptiform zone had been located in the right-FT region. He received ten sessions of low-frequency (1-Hz) rTMS in a middle point between C4/T4. No side effects were reported. Result(s): After the first sessions, the patient's level of consciousness improved, and the EEG showed progressive improvement of the cortical slowing and the epileptiform activity over the following days. By the time of discharge, EEG activity was almost normal with some epileptiform discharge still present on the EEG record. Conclusion(s): To our knowledge, a few case series have been published on the use of low-frequency rTMS as a therapeutic approach in SE. Low-frequency rTMS applied over the active epileptogenic focus may swap the cortical excitability toward an inhibitory direction by inducing synaptic plasticity through a long-term depression mechanism, which translates into SE suppression. We cannot confirm that rTMS was the only reason for the positive outcome in this particular patient. However, the outstanding improvement of the EEG activity since the administration of rTMS, accompanied by the progressive recovery of the level of consciousness, means that this technique should be taken into account as a potential therapeutic option in the early onset of SE given its efficacy, and its harmless characteristics. Copyright © 2022
ABSTRACT
Introduction: Some COVID-19 vaccines (Moderna and Pfizer) have been associated with an elevated risk of myocarditis in younger adults. However, observational studies were unable to stratify by dose and had limited ability to evaluate the effect of adenovirus-based COVID-19 vaccines due to the limited distribution of these in their study populations [1-4]. Objective(s): Estimate the incidence rates (IR), rate differences (RD) and incidence rate ratios (IRR) of myocarditis and pericarditis before and after each dose of mRNA (Pfizer and Moderna) and adenovirusplatform (AstraZeneca and Janssen) COVID-19 vaccines. Method(s): We conducted a population-based cohort design with nested self-controlled risk interval (SCRI) study. Participants were followed from 1st January 2020 to 31st December 2021. Data were derived from healthcare data from five population-based data sources in four European countries: Italy, the Netherlands, the United Kingdom (UK), and Spain. The main outcome was first occurrence of myocarditis or pericarditis. RD and IR before COVID-19 disease and after each COVID-19 vaccine dose in those without COVID-19 were calculated. The SCRI calculated IRR with 60-day control period prior to vaccination and 28-day risk windows, with adjustment for seasonality. All analyses were stratified by age (<30 and >= 30 years) and in the cohorts refined age-bands for<30 were utilised. Result(s): The study cohort comprised 35,365,669 persons with median age between 39-49 years, 57.4% received at least one COVID-19 vaccine dose and 77.6% of these received two. Myocarditis background rates were highest in persons 18-29 years (IR 2.8, 95% CI [1.5-4.1] to 6.4 [3.8-9.0] across UK, the Netherlands and Spain, and for 12-17 years in Italy (IR = 9.9 [5.3-14.4]). Pericarditis rates were higher in persons>30 years (standardised IR from 11.6 [10.9-12.4] to 29.7 [19.8-22.1] across databases). RD of myocarditis were significantly elevated after Moderna dose 2 in persons between 18-29 years in Italy. Significantly reduced RD of pericarditis in the age group above 30 years was seen for Pfizer, Moderna and AstraZeneca. The SCRI showed significantly higher myocarditis IRR after dose 1 of Pfizer (IRR = 3.3 [1.2-9.4]), and also after dose 2 of Pfizer and Moderna in persons 12-29 years (IRR of 7.8 [2.6-23.5] and 6.1 [1.1-33.5], respectively). No association was observed between COVID-19 vaccination and pericarditis in the SCRI. In a sensitivity analysis, occasional significant association was seen for AstraZeneca dose 2 and myocarditis. Conclusion(s): Myocarditis is rare, but rates were increased significantly after both doses of Pfizer and the second dose of Moderna vaccines in persons below 30 years of age. This was not seen for pericarditis.
ABSTRACT
Introduction: Some COVID-19 vaccines (Moderna and Pfizer) have been associated with an elevated risk of myocarditis in younger adults. However, observational studies were unable to stratify by dose and had limited ability to evaluate the effect of adenovirus-based COVID-19 vaccines due to the limited distribution of these in their study populations [1-4]. Objective: Estimate the incidence rates (IR), rate differences (RD) and incidence rate ratios (IRR) of myocarditis and pericarditis before and after each dose of mRNA (Pfizer and Moderna) and adenovirusplatform (AstraZeneca and Janssen) COVID-19 vaccines. Methods: We conducted a population-based cohort design with nested self-controlled risk interval (SCRI) study. Participants were followed from 1st January 2020 to 31st December 2021. Data were derived from healthcare data from five population-based data sources in four European countries: Italy, the Netherlands, the United Kingdom (UK), and Spain. The main outcome was first occurrence of myocarditis or pericarditis. RD and IR before COVID-19 disease and after each COVID-19 vaccine dose in those without COVID-19 were calculated. The SCRI calculated IRR with 60-day control period prior to vaccination and 28-day risk windows, with adjustment for seasonality. All analyses were stratified by age (< 30 and > 30 years) and in the cohorts refined age-bands for < 30 were utilised. Results: The study cohort comprised 35,365,669 persons with median age between 39-49 years, 57.4% received at least one COVID-19 vaccine dose and 77.6% of these received two. Myocarditis background rates were highest in persons 18-29 years (IR 2.8, 95% CI [1.5-4.1] to 6.4 [3.8-9.0] across UK, the Netherlands and Spain, and for 12-17 years in Italy (IR = 9.9 [5.3-14.4]). Pericarditis rates were higher in persons > 30 years (standardised IR from 11.6 [10.9-12.4] to 29.7 [19.8-22.1] across databases). RD of myocarditis were significantly elevated after Moderna dose 2 in persons between 18-29 years in Italy. Significantly reduced RD of pericarditis in the age group above 30 years was seen for Pfizer, Moderna and AstraZeneca. The SCRI showed significantly higher myocarditis IRR after dose 1 of Pfizer (IRR = 3.3 [1.2-9.4]), and also after dose 2 of Pfizer and Moderna in persons 12-29 years (IRR of 7.8 [2.6-23.5] and 6.1 [1.1-33.5], respectively). No association was observed between COVID-19 vaccination and pericarditis in the SCRI. In a sensitivity analysis, occasional significant association was seen for AstraZeneca dose 2 and myocarditis. Conclusion: Myocarditis is rare, but rates were increased significantly after both doses of Pfizer and the second dose of Moderna vaccines in persons below 30 years of age. This was not seen for pericarditis.
ABSTRACT
The transmission of COVID-19 through a population depends on many factors which model, incorporate, and integrate many heterogeneous data sources. The work we describe in this paper focuses on the data management aspect of EpiGraph, a scalable agent-based virus-propagation simulator. We describe the data acquisition and pre-processing tasks that are necessary to map the data to the different models implemented in EpiGraph in a way that is efficient and comprehensible. We also report on post-processing, analysis, and visualization of the outputs, tasks that are fundamental to make the simulation results useful for the final users. Our simulator captures complex interactions between social processes, virus characteristics, travel patterns, climate, vaccination, and non-pharmaceutical interventions. We end by demonstrating the entire pipeline with one evaluation for Spain for the third COVID wave starting on December 27th of 2020. © 2022, Springer Nature Switzerland AG.
ABSTRACT
Background: Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients. This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19. Identification of Specific memory T cells and NK cells: i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life. ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life. Pilot Phase I- Safety, feasibility, and dose escalation: Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells. Phase II- Efficacy: Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the e perimental arm was monitored weekly during the first month. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. [Formula presented] Disclosures: Soria: Celgene: Other: Fees;Gilead: Other: Fees;AbbVie: Other: Fees.
ABSTRACT
The implications for individual countries acting on their self-interest are radically different depending on the country’s size and power. Dependence on an unarticulated international procurement supply system of essential goods has led to devastating results for Latin America, mainly at the beginning of the COVID-19 pandemic. We cannot expect superpowers to willingly cede control and base their actions on the interests of the global community, especially under the resource-starved conditions created by the pandemic. To counterweigh the power of some developed countries, regional integration efforts in the Global South must be strengthened, and they must be at the core of new global health coordination models. © 2021 Longwoods Publishing Corp.. All rights reserved.
ABSTRACT
The European Union (EU) has a potential major influence on patients' global access to medicines. Historically, this influence most notably came through the EU's trade and aid agendas that intentionally targeted foreign markets. Now, the EU's own internal pharmaceutical policy appears to indirectly shape global access to medicines (ex. EU's large-scale Covid-19 vaccine procurement and export bans). To understand the ways the EU's internal and external policies impact on global access to medicines, this Scoping Review synthesises evidence of the EU's global regulatory influence and its impacts on access to medicines in non-EU low- and middle-income countries (LMICs). By searching 8 databases and grey literature, documents published in English, Spanish, Portuguese, or Russian between 1995-2021 that addressed an EU law, regulation, or policy in relation to access to medicines in LMICs were included. This review identifies three mechanisms through which EU action impacts on medicines in LMICs. One, the EU's external, treaty-based agreements with LMICs can affect their pharmaceutical trade, sales, and use. Two, EU's internal market regulation, standards, and methods are used as models or sources of inspiration for pharmaceutical governance in LMICs. Three, ‘soft' forms of EU influence manifest through the EU's technical assistance, its research and development (aid) funding, and its ‘capacity building' activities towards LMIC actors in the field of pharmaceuticals. Examples of impacts of EU action ranged from the development of new medicines primarily for LMICs, to changes in the availability of generics and on medicines spending in LMICs, and the potential for a more efficient yet less autonomous local market approval process. Most evidence of impact was not peer reviewed. This study raises the question of how to support resilient and efficient global pathways for drug development and regulation while still being responsive and accountable to the local public interest. Key messages There are 3 mechanisms through which EU action impacts on medicines in LMICs: treaty-based agreements, EU internal market regulation, and ‘soft' EU influence. EU decision makers need a reliable understanding of how the EU’s internal and external policies impact on pharmaceuticals globally.
ABSTRACT
Background: Patients with kidney transplants seem to be at particularly high risk for severe COVID19 disease due to their impaired immune responses and comorbidities Methods: We performed an observational study of kidney transplant recipients with SARS-CoV2 infection admitted at Fundación Valle del Lili from June to December 2020. To be eligible for this study, patients have symptoms compatible, a positive RT-PCR and inpatient management. Asymptomatic patients were excluded Results: We enrolled a total of 50 patients. 64% were male, and the median age was 53.5 years (range 46-60). The comorbidities were: 36(70%) hypertension, 16(32%) diabetes mellitus, 5(10%) obesity. The most common immunosuppressive regimen was tacrolimus 76% and prednisone 88%.The median time from symptoms onset to the positive RT-PCR was 7 days. The most common initial symptom was fever (64%), and fatigue (58%), cough (44%) and dyspnea (36%). Baseline levels of CRP was 6.43 mg/dL (3.25-11.22). The median lymphocyte count was 785 mm3/uL (550-1230). Baseline D-Dimer was 0.767 ug/ml (0.484-1153.5), ferritin median level was 1011ng/ml (670-2145). Clinical outcomes are shown in Table. Six of the patients died (12%), 4/6 were by sepsis-related multi-organ failure and 2/6 were by ARDS Conclusions: Major complications such as acute kidney injury, acute respiratory distress syndrome and mortality related to COVID-19 infection observed in our study are lower than those reported in other countries.
ABSTRACT
BACKGROUND: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. METHODS: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210. FINDINGS: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. INTERPRETATION: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe. FUNDING: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.
ABSTRACT
Background: To investigate the prevalence and clinical and laboratory characteristics of the cases with pulmonary embolism (PE) in the pace of coronavirus disease-2019 (COVID-19). Materials and methods: COVID-19 patients' records were retrospectively scanned from the hospital's automation system and recorded on patients' files. Results: Of 1452 COVID-19 patients, 17 (1.2%) were diagnosed with PE. Compared cases with PE with controls, it was seen that mean age was higher (p=0.036), male gender was prominent (p=0.016), patients presented with dyspnea symptoms further (p<0.001), while O2 saturation measured at room air on admission was lower (p=0.002). In PE patients, glucose (p=0.007), D-dimer (p<0.001), C-reactive protein (p<0.001) and ferritin levels (p=0.002) were higher than controls. In Receiver-Operator Characteristics analysis, the cut-off value of D-dimer in predicting PE was found to be 4211 ng/mL (p<0.001). COVID-19 patients were diagnosed with PE median five (min:max=0:36) days after hospitalization. Additionally, PE patients were found to have longer hospitalization time (p<0.001), the requirement for caring in the intensive care unit (p<0.001), and intubation (p=0.001), and non-invasive mechanical ventilation (p<0.001) in more patients, compared to controls. Mortality rates were similar in both groups, with three and 106 deaths in PE and control groups, respectively. Lower-extremity Doppler ultrasonography was performed in 196 patients, and thrombi were detected in the femoral vein in four patients, also presenting with PE. Conclusions: Even if there is no embolism without any obvious clinic of PE in all cases with COVID-19, such cases should be screened for PE in the presence of significant D-dimer elevation. © 2021 A. CARBONE Editore. All rights reserved.
ABSTRACT
This research work has the purpose of analyzing and proposing strategies that allow to face the complexities brought by the pandemic within a supply chain. Under the context of the Covid 19 pandemic, a scenario analysis is carried out to propose strategies adaptable to similar problems. It was identified that those companies that had prior planning to deal with eventualities managed to overcome the effects of the crisis with greater success. This work highlights the need for companies to know and incorporate strategies that allow sustainability in the long term. © 2021 IEEE.
ABSTRACT
The Covid-19 pandemic growth has led to a large desire for safety restrictions among citizens near or in Covid-19 affected areas. This includes requiring the use of masks when outdoors and an occupancy limit being placed when indoors. Some of these restrictions have been enforced by the government and can lead to infraction charges on those who choose to ignore them, but some restrictions are up to the decision of the respective individuals. This has led to varying levels of safety being applied when outside. This is especially concerning when some businesses may not be taking proper precautions to avoid the spread of Covid-19. To counterbalance this issue while also spreading awareness of the businesses that are careful enough to follow such precautions, the app My-Covid-Safe-Town (MCST) is created. MCST allows for individuals (i.e., patrons) to find businesses that fit the standard of safety and to specifically point out the steps being taken by each business to avoid the spread of the pandemic.
ABSTRACT
Déclaration de liens d’intérêts: Les auteurs déclarent ne pas avoir de liens d’intérêts.
ABSTRACT
Çok sayıda bulaşıcı olmayan hastalık ve viral enfeksiyonlar dahil akut solunum yolu hastalıkları için vitamin D yetersizliǧi potansiyel risk faktörü olarak kabul edilmektedir. D3 vita- mini grubundaki hastalara 10 ml fıstık yaǧında çözülmüş 200 000 IU D3 vitamini içeren solüsyon verilmiştir. Yazışma Adresi / Correspondence Address Manolya Kara VM Medical Park Pendik Hastanesi, Çocuk Saǧlıǧı ve Hastalıkları Kliniǧi, Ístanbul-Türkiye E-mail: manolya_kara@yahoo.com Gelis Tarihi: 19.02.2021 Kabul Tarihi: 24.02.2021 Çevrimiçi Yayin Tarihi: 02.04.2021