Today, Magnetic Resonance Imaging (MRI) is a prominent technique used in medicine, produces a significant and varied range of tissue contrasts in each imaging modalities, and is frequently employed by medical professionals to identify brain malignancies. With brain tumor being a very deadly disease, early detection will help increase the likelihood that the patient will receive the appropriate medical care leading to either a full elimination of the tumor or the prolongation of the patient’s life. However, manually examining the enormous volume of magnetic resonance imaging (MRI) images and identifying a brain tumor or cancer is extremely time-consuming and requires the expertise of a trained medical expert or brain doctor to manually detect and diagnose brain cancer using multiple Magnetic Resonance images (MRI) with various modalities. Due to this underlying issue, there is a growing need for increased efforts to automate the detection and diagnosis process of brain tumor without human intervention. Another major concern most research articles do not consider is the low quality nature of MRI images which can be attributed to noise and artifacts. This article presents a Contrast Limited Adaptive Histogram Equalization (CLAHE) algorithm to precisely handle the problem of low quality MRI images by eliminating noisy elements and enhancing the visible trainable features of the image. The enhanced image is then fed to the proposed PCNN to learn the features and classify the tumor using sigmoid classifier. To properly train the model, a publicly available dataset is collected and utilized for this research. Additionally, different optimizers and different values of dropout and learning rates are used in the course of this study. The proposed PCNN with Contrast Limited Adaptive Histogram Equalization (CLAHE) algorithm achieved an accuracy of 98.7%, sensitivity of 99.7%, and specificity of 97.4%. In comparison with other state-of-the-art brain tumor methods and pre-trained deep transfer learning models, the proposed PCNN model obtained satisfactory performance. The human brain has billions of neurons, the primary functions of which are organ control and information processing. The complexity of the human brain exceeds what is currently understood. The cerebrum, brain stem, and cerebellum are the three components that make up the human brain . The skuSeveral deep learning models are so complicated especially very deep networks which has necessitated the creation of convolution layers arranged in parallel with multiple filters stacked into different blocks. Since models are chosen based on the nature of the data and problem requirement, the proposed method combines multiple filters to address this problem. This technique is proposed to assist very deep convolution neural network models overcome their flaws of vanishing gradient problem and solidify their capability by aggregating the features extracted from different filters in a fused manner. This proposed algorithm reduces generalization error, vanishing gradient problem, and minimizes prediction variance. Thus, the goal of this study is to analyze the performance of deep convolution neural network with multiple connected filters for brain tumor classification.We apply contrast limited adaptive histogram equalization algorithm for the elimination of noisy contents and enhancing the visual trainable features of these MRI brain images.We implemented a stacked connections of convolution layers with multiple filters in parallel to learn the enhanced MRI images and then classify the brain tumor using sigmoid classifier.The main contributions of this paper are as follows:The proposed network can automatically classify benign and malignant brain MRI images. In this study, We evaluate the performance of the proposed model and other state-of-the-art methods.The subsequent sections of this paper is organized in the following manner. Brain tumor classification is an extremely challenging process that requires the correct expertise, training, aptitude, and analysis procedures to detect . PositroNumerous automated approaches have recently been suggested and created by researchers in order to categorize brain cancers using MRI data . The autA CAD system including image segmentation, feature extraction, and multiclass classification of six kinds of brain tumors was created in 2013 by Sachdeva et al. . Prior tWith a CNN-based approach, the authors in  utilizedDifferent CNN algorithms have been utilized for brain tumor classification as seen in This paper focuses on the problem of low-quality brain tumor images. The novelties of our proposed model is in two-fold. First, a pre-processing technique is utilized to improve the inverse intensity and limit the histogram amplification of the image. Secondly, a parallelistic CNN model is proposed to learn distinctive features from the images using multiple filters of various sizes connected in parallel for the classification of brain tumor. A public dataset belonging to Kaggle is used to validate the performance of the proposed model.The method adopted in this study is explained in this section. Data collection, data pre-processing, and the proposed networks for feature learning and classification are the main stages of this paper. The subsequent subsections of this section presents the procedure of the proposed method.The Kaggle Brain Tumor dataset is used for this study which includes two categories of brain tumor and healthy class . This daAs a matter of fact, data quality can be affected by noise, artifacts and resolution, hence, fitting such data directly to the CNN model may result to poor outcomes. Data pre-processing is introduced to eliminate or subside the noise and improve the quality of the data, thereby enhancing the performance of the algorithm. This study adopted an algorithm of Contrast Limited Adaptive Histogram Equalization (CLAHE) to pre-process the data.This study utilized CLAHE as a pre-processing technique to enhance the contrast and features of the image by pronouncing abnormal patterns in the image. Contrast Limited Adaptive Histogram Equalization (CLAHE) algorithm produces a more realistic appearance among the histogram equalization family and it is capable of reducing noise amplification. We have examined the efficacy of CLAHE algorithm and adopted it to the MRI dataset, as shown in For this study we propose a parallelistic Convolutional Neural Network. Convolutional Neural Network is an organized approach used in the processing various kind of images including medical images. A convolutional neural network (CNN) is a type of neural network that specializes in learning constituent knowledge and is used for image recognition. CNN is an effective image processing and computing technique that uses deep learning to carry out both generative and descriptive tasks. It typically makes use of machine vision, which has the ability to recognize images.The proposed parallelistic convolution neural network (PCNN) involves learning filters of different sizes in a parallel manner to achieve a wider network instead of a deeper network. The proposed PCNN is made of 10 parallelistic modules divided into three blocks. Block A consists of three parallelistic modules of The proposed model has a total of 57 convolution layer and 13 max-pool. The input image are feed into the separate stacked convolution layers of multiple filters from which the outputs are concatenated as a single output which becomes the new input to the proceding parallelistic blocks that provides a more robust representation for detecting the tumor.The intended technique is depicted in h is the feature map heigth, w is the feature map width, f is filter size and s is the stride.In addition to producing neural networks more quickly and with greater stability, batch normalization was introduced to normalizes the inputs to the layers by re-centering and rescaling . The pooEquation .(1)LlossThis section presents thorough details of the experimental setup, performance metrics, performance of the proposed PCNN and comparison with other research methods.The proposed model is implemented on NVIDIA RTX 3060 GPU using Keras framework and tensorflow as backend. The entire dataset is split into 80:20 ratio for training and testing respectively. All the data are resized to Accuracy, sensitivity, specificity, precision, and F1-score are the evaluation metrics utilized to validate the performance of the proposed PCNN. The mathematical representation for each metric is denoted in Equations –7).(3).(3)7).Accuracy depicts the percentage of correctly predicted classes.Specificity measures the correctly predicted negatives cases.Equation . Recall The Reciever Operation Curve (ROC) shows the relationship between TP, FP, FN, and TN represent true positive, false positive, false negative, and true negative, respectively.On the brain dataset, we conducted two experiments to validate the efficacy of the proposed model. The first investigation is implementing the proposed PCNN on the raw brain dataset without pre-processing. Secondly, we implemented the proposed model on the CLAHE pre-processed brain dataset for brain tumor identification.The proposed framework of the parallelistic convolution neural network as shown in The proposed PCNN model shows satisfactory performance when implemented on CLAHE pre-processed MRI images compared to the raw MRI images. The proposed PCNN model was further evaluated in terms of precision–recall curve, as depicted in The performance of the proposed model in diagnosing brain tumor in MRI images from dataset obtained Kaggle repository has been demonstrated, and the classification result is presented in A comparison study is conducted between the proposed PCNN model and some recently published brain tumor classification methods. According to According to the results of the experiments as presented in Additionally, the satisfactory performance of the proposed PCNN can be attributed to our technique of stacking convolution layers with multiple filters of different sizes in parallel. The advantage of the multiple filters of different sizes is to achieve a wider receptive field to learn distinctive features without just memorizing the patterns which is limited in regular deep learning models which only utilizes one filter size at each convolution layer stacked vertically. We also introduce bottleneck technique to shrink the feature maps by using It is important to adopt the ROC curve to measure the overall accuracy (AUC) as well as the precision–recall curve to estimate the average precision of the proposed PCNN model when classifying delicate conditions like brain tumor. The ROC curves for the proposed PCNN model on the brain dataset is depicted in More so, many of the brain MRI images were blurry and lacking in features, which may have hindered the ability of the proposed PCNN to obtain and train relevant characteristics. The advantage of adopting CLAHE pre-processing algorithm is to enhance the low quality of the brain MRI images in order to identify high representation features of the MRI images with visible trainable characteristics. The proposed PCNN model performed admirably in identifying brain tumor.In terms of ROC and precision–recall curves, the proposed PCNN model outperforms the state-of-the-art methods for brain tumor classification, especially when dealing with low-quality brain MRI images. The curve of the proposed PCNN is nearest to the upper left corner of the graph and has the highest area under curve, depicting that it has higher sensitivity associated with high specificity according to the ROC graph in Nevertheless, other state-of-the-art methods have shown considerable performance in brain tumor classification, however, the researchers did not take into consideration the low quality of brain MRI images which is a concern in real-life application. It is a known fact that the quality of data can be affected by noise, resolution, and artifacts. The direct application of such data in an algorithm may affect the adaptability of the model in clinical application. Data pre-processing could help in mitigating the noise and improving the data quality, thereby enhancing the performance of the model.Ablation study is conducted to examine if hyper-parameter tuning may improve the performance of the proposed parallelistic convolution neural network. In this study, we considered both the raw MRI images and the pre-processed images. We term the unpre-processed MRI images as RAW and the pre-processed MRI images as CLAHE. The results of different optimizers at different learning rates and dropouts are shown in In this study, we proposed a parallelistic convolutional neural network (PCNN) with Contrast Limited Adaptive Histogram Equalization (CLAHE) algorithm with the aim of addressing the vanishing gradient problem of deeper convolutional neural network and low quality in MRI brain images respectively. We implemented the CLAHE pre-processing algorithm for the removal of noisy artifact and enhancing the visible trainable features of the brain MRI images. Then, the meaningful details from the brain MRI images are extracted using the PCNN model during training and classified using sigmoid classifier to achieve higher identification accuracy. The strategy of parallelistic convolution neural network is proposed to take complete advantage of convolutions of multiple filters stacked in parallel to achieve wider network and ensure re-usability of visual features between Parallelistic modules.Furthermore, average pooling was introduced to vectorize the feature embeddings instead of the conventional fully connected layer before the Sigmoid classifier to obtain predictions. By incorporating convolution layers of multiple layers stacked in a parallel manner, the proposed model outperforms several deep transfer learning models and state-of-the-art brain tumor methods. The evaluation results illustrate that the proposed PCNN obtains satisfactory performance with accuracy of 98.7%, sensitivity of 99.7%, specificity of 97.4%, precision of 98.2%, and f1-score of 98.6% than just utilizing the raw MRI brain images. In terms of comparison with the other established models, it is confirmed that the proposed PCNN model obtained state-of-the-art classification performance, which is a robust and efficient classification solution for brain tumor based on low quality MRI images. These experimental outcomes could effectively assist neurosurgeons and other clinicians to diagnose what stage of brain tumor is present in a patient’s MRI brain scan while preserving screening time.From the experimental analysis, the proposed PCNN achieved excellent results across all evaluation metrics. In this research, we focused more on improving the existing CNN models that has been proposed for classifying brain tumor using the same dataset from Kaggle repository. The proposed model only considered a balanced class of dataset with just two categories of tumor classification which is the limitation of this study. In the future, we will consider imbalance class of dataset and multiple categories of tumor class and also take into account different disease severity.More so, we intend to improve the robustness of the model by introducing a point-wise separable convolution in order to reduce the network weight which would make the model more computational efficient.


Patients who were given propofol and fentanyl as sedation during proning for more than 24 hours was significantly associated with the development of stroke . Patient risk factors were also studied  and showed that patients who were alcoholic beverage drinkers were significantly associated to the development of stroke during proning . The usual risk factors for stroke in the general population  were not associated with stroke development during proning, strengthening the fact that proning during COVID-19 infection is an independent risk factor for the development of stroke thus needing stroke surveillance during the duration of proning.There has been an increasing incidence of stroke cases among SARS-CoV-2 (COVID-19) patients who were deeply sedated and underwent proning positioning. We reviewed the association of proning and sedations used to the development of stroke, including demographic profiles of patients with COVID-19 infection in the critical care unit. There was a significant association seen among COVID-19 patients in the ICU who underwent proning to the development of stroke, with up to 15 times risk of having stroke ( There has been increasing incidence of stroke in the critically ill, deeply sedated proned SARS-CoV-2 (COVID-19)-infected patients. The hypercoagulability state of COVID-19-infected patients impacts the course of the disease. Although there has been no clear distinction between the number of comorbidities and the morbidity and mortality rates of these patients, there have been a significant number of patients who die of COVID-19 even without comorbidities. Part of the management of COVID-19 patients who developed acute respiratory distress syndrome (ARDS) is to do the proning position. Stroke is difficult to determine during the course of proning procedure since these patients are subjected to deep sedation, and there will be limited if not difficult neurologic assessment during the proning procedure. It is therefore unfortunate for postproned patients who were being weaned from sedation, examined to be unarousable, and diagnosed late to have stroke.All adult patients admitted to the critical care unit diagnosed with SARS-CoV-2 infection using RT-PCR from May 1, 2020, to May 31, 2021, were evaluated in this study. The sample size result was computed using OpenEpi, version 3, an open-source calculator. In order to get a 95% confidence level, a minimum population of 135 patients should be included in the study. The study evaluated a total of 206 patients which qualified the minimum amount required for the confidence level.The study included a total of 206 patients which qualified inclusion criteria. Of these 206 patients, the 135 patients will be selected using the random sampling method. All patients who were admitted to the critical care unit from the specified time frame were included in the study. The decision for proning to a patient was made upon the clinical criteria of the critical care physician which includes a P/F ratio of less than 150 which signifies acute respiratory distress syndrome (ARDS).All patients who were admitted due to COVID-19 infection in the critical care unit from May 1, 2020, until May 31, 2021, were reviewed using the MIDAS electronic system. Data acquired from the study subjects and laboratory values were tabulated and encoded. The study investigators were the only ones who were able to access the data gathered. To ensure data privacy, data obtained will be encoded in a password-protected Microsoft Excel file. Each study subject will be assigned number codes.α-level of significance.Baseline characteristics such as demographics and comorbidities as well as study subject outcomes were gathered and tabulated. The odds ratios (OR) and their respective 95% confidence intervals (95% CI) for the binary outcomes of each study were presented. The chi-square test was used to test the association of sex, risk factors, and comorbidities to the occurrence of stroke. The binary logistic regression model was used to estimate the odds ratio of proning and sedation to the development of stroke. All valid data will be included in the analysis. Missing variables will be neither replaced nor estimated. The null hypothesis will be rejected at a 0.05Neurologic complications of SARS-CoV-2 or popularly known as COVID-19 infection are known and posed a grave threat to critically ill patients undergoing the acute phase of the disease. It is of great concern that during the critical phase of the disease, where patients develop acute respiratory distress syndrome and are placed on prone with deep sedation, the development of stroke is detected late.Prone positioning (PP) of mechanically ventilated patients is an effective first-line intervention to treat patients with moderate to severe acute respiratory distress syndrome (ARDS) receiving invasive mechanical ventilation, as it improves gas exchanges and reduces mortality . AccordiPatients who were unable to awaken from deep sedation are common, and it is therefore late in the course to find that one of the causes of their unarousability is stroke. It is still unknown whether proning itself or the duration of the proning procedure and the effect of deep sedation can impact the incidence of stroke post proning. The duration of sedation can alter the course of the disease in these patients. A recent study by Brown et al. showed a significant relationship between prolonged sedation and the incidence of neurological complications in SARS-CoV-2-infected patients . The stuThere have been a number of complications caused by the infection of COVID-19. A study by Vinayagam and Sattu described the SARS-CoV-2 (COVID-19) infection as an entity potentially causing coagulability and thromboses and thus the risk for blood clots. It follows that the myriad of embolic events has the potential to send blood clots to any and all organs .Complications during proning position vary from airway compromise to peripheral nerve injury, the significance of which is the development of arterial or venous thrombosis which can herald the development of cerebral infarction. Blood pressure is a significant parameter in which episodes of hypotension may promote cerebral ischemia causing watershed infarctions, or uncontrolled blood pressure spikes may damage the already injured blood vessel walls causing rupture and cerebral hemorrhage. The different complications during proning position were described by Rahmani et al. in an attempt to determine the contraindications of patients for proning . They ciInterest in propofol as a sedative agent is increasing. Sedation by continuous infusion of midazolam in ICU patients may lead to accumulation and prolonged recovery . A studyAll of these factors, the duration of sedation and proning, complications during proning, and the hypercoagulable state of the SARS-CoV-2 infection itself render the critically ill patient a high risk for the development of stroke that can develop during the critical phase of the illness. Therefore, the diagnosis of stroke is hindered by the deep sedation and the lack of neurological assessment during the time of proning.A total of 206 patients were enrolled in the trial from May 1, 2020, to May 31, 2021, and all patients with a positive COVID-19 RT-PCR admitted to the critical care unit were included in the study. Baseline characteristics are shown in p value = 0.822). Those patients with hypertension , diabetes , and who were cigarette smokers  were also not associated with stroke in either prone or unproned patients. However, alcohol intake has a significant association with the development of stroke  in which all patients who developed stroke were cigarette smokers  and for those that did not develop stroke was 65.33 (SD = 15.104). Age itself is significantly associated with the development of stroke  patients who had severe COVID-19 infection and ARDS. There is a 40.6% stroke rate among those who were proned as compared to those who were not proned  in whichp value = 0.007, p value = 0.004, All patients who underwent proning developed stroke, showing a statistically significant effect of its association to the development of stroke .The duration of sedation was grouped into 2 variables: those whose sedation lasted only less than or equal to 24 hours, and those whose sedation lasted more than 24 hours. Duration of sedation and proning to more than 24 hours showed a significant effect on the development of stroke  in contrast to unproned patients  during the critical stage of COVID-19 illness compared to those with hemorrhagic type of stroke. The hypercoagulable state during the acute stage of COVID-19 critical illness may explain the higher rate of infarcts versus hemorrhage. Although, factors such as the duration and type of sedation used during proning position may have an effect on its development. A comparison between patients with severe COVID-19 infection with ARDS who are proned versus not proned showed an alarmingly high rate of stroke among patients who were proned, in contrast to those unproned which has no stroke occurrence. This might indicate that proning itself may be an independent risk factor for stroke among patients with severe COVID-19 infection with ARDS.Our study highlighted the high rate of cerebral infarction among proned . This indicates that proning more than 24 hours increases the risk of stroke by 12 times as compared to those who are not proned.Patients who underwent proning showed a huge significant relationship to the development of stroke wherein all who developed stroke were proned under the sedation of propofol and fentanyl, while those who were sedated with Precedex and midazolam did not show any statistical significance. Midazolam has been widely used among critical care units especially for sedation during mechanical ventilation due to its potency, rapid onset, and short duration of action . The durA study by Joswiak et al. indicated the benefit of prone position among patients diagnosed with ARDS by increasing the ratio of arterial oxygen partial pressure over inspired oxygen fraction and the right and left cardiac preload ; howeverCritically ill patients diagnosed with SARS-CoV-2 (COVID-19) infection who underwent proning are associated with an increased risk of developing stroke with infarction as the predominant etiology. The use of propofol and fentanyl as sedation during proning for more than 24 hours also is associated with an increased risk of developing stroke.


Big Data generated across diverse fields of clinical medicine are increasingly becoming accessible across some of the most rapidly developing world regions. This is particularly the fact with the Asia-Pacific region of Asia or “APAC”. It is now positioned as the second largest global market for pharmaceuticals and medical devices, behind North America while overrunning the pace of development in Western European EU5 pharmaceutical markets. The competitiveness of multinational pharmaceutical manufacturers based in this region is documented by the recent 2021 ranking of four Chinese companies  among the Top 25, per their annual net revenues. Long-term forecasts predict that pharmaceutical expenditure will continue to rise faster than real GDP growth across the APAC region , although with higher costs. Sacubitril-valsartan is cost-effective for hypertension in contemporary Chinese circumstances under the willingness-to-pay threshold of three times per capita GDP .Zhao et al. have studied the effect of the coronavirus pandemic while using a hybrid model architecture for analyzing and optimizing COVID-19 data throughout all of the provinces of mainland China. A variety of advanced analytical methods such as Logistic regression (LR), Autoregressive Integrated Moving Average Model (ARIMA), support vector regression (SVR), multilayer perceptron (MLP), Recurrent Neural Networks (RNN), Gate Recurrent Unit (GRU), and long short-term memory (LSTM) were exploited for this purpose. The authors report that the number of quarantines, mortality rate, and the deployment of public self-protection measures to reduce the epidemic were carefully measured. They believe such projections may be used by governmental authorities to guide future illness prevention and control health policy choices .Meng et al.).Another Chinese research group worked on an intriguing health econometric comparison, estimating the impact of donafenib's and sorafenib's cost-effectiveness when both are indicated as the first-line treatment of unresectable or metastatic hepatocellular carcinoma. In a methodologically stringent framework applied to Chinese patients  they have proven that donafenib is unlikely to be cost-effective compared with sorafenib in this indication field. A plausible price reduction strategy applied to the market penetration of donafenib might increase its cost-effectiveness in the future evolving market landscape in China .A mixed Pakistani- Saudi research group has brought our attention to interesting methodological challenges in statistics applied to clinical oncology. Namely, the authors attempt to improve the variance estimator of the Kaplan–Meier survival function, in a mathematical setting with zero, moderate, and heavy censoring. The authors propose an innovative modified cumulative hazard function, the plot of which provides far more detailed insight in the case of heavy censoring (Summing up, the array of aforementioned contributions alongside this conclusive Editorial article point to the rapidly increasing role of Big Data and their advanced analytics in the eastern and western Asia regions. South-East Asia presents a hotbed of innovation strategies in artificial intelligence and the fourth industrial revolution, led by Chinese think tanks. Thus, it means that the administration of such data sets and their AI-assisted analytical opportunity in the healthcare arena might present distinctive room for the opportunity of further development . This isMJ prepared the manuscript draft. KL revised it for important intellectual content. All authors contributed to the article and approved the submitted version.This study has been co-financed through the Grant OI 175 014 of the Ministry of Education Science and Technological Development of the Republic of Serbia.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In an emergency context, the intra-action review helps countries to assess their progress and document what has worked and not worked.we reviewed and identified the key lessons and challenges documented in the reports from intra-action review of COVID vaccine roll out in 22 African countries.all countries documented high level political commitment, but a serious shortage of COVID-19 vaccines and funding. Seven countries identified gaps in microplanning because of lack of funding or due to the unpredictability in the type and volume of vaccine supplies. The shortage of operational funding also affected training of health workers and hampered the expansion of service delivery. The countries implemented multi-channel communications and social mobilisation activities, alongside social media engagement and social listening. However, country capacity was limited in terms of timely responding to infodemics. Hesitancy among health workers and the general population was a challenge in most of the countries.countries have gained valuable experiences exploring various COVID-19 vaccination delivery models, including implementing the integration of COVID-19 vaccination within routine health care programs. There is a need to regularly monitor or do studies measuring public perceptions towards COVID-19 vaccination in order to drive the demand generation efforts, as well as use evidence in addressing hesitancy. On 11Various public health measures are being implemented since the start of the pandemic, and the development of vaccines has been progressing very fast. As of 31 December 2021, a total of 197 types of vaccines are under clinical development and 134 are in pre-clinical stages .Several initiatives aimed at providing equitable access to COVID-19 vaccines have been launched in the past 18 months. In the initial months of vaccine introduction, eligible countries were mostly sourcing their vaccines from the COVAX facility, while many countries (including non-GAVI eligible countries) organised a direct purchase or received vaccines from other countries through bilateral negotiations and donations . UnequalAs the number and types of vaccines granted WHO Emergency Use Listing (EUL) grows, and as the supply of vaccines to countries in the African Region improves, addressing service delivery issues continues to require intensive efforts at different levels; including regulation and registration of vaccines, operational readiness, supply chain and logistics, surveillance data and monitoring, vaccine safety and surveillance for adverse event following immunisation (AEFI), and risk communication .In the months from April to December 2021, 26 countries in the WHO African Region conducted desk reviews of the progress with the introduction of COVID-19 vaccines. These multi-stakeholder desk reviews, called Intra-Action Reviews (IARs) were conducted using a standard protocol, reviewing processes and outcomes across various thematic areas including: planning and coordination; regulation and vaccine safety; training and deployment of human resources; service delivery; risk communications and community engagement; monitoring and data analytics . The proThis study discusses the challenges of the COVID-19 vaccine roll-out and the lessons learned at different levels in African countries throughout 2021, according to the findings documented in the various intra-action review reports, with a view to help optimize the vaccination response in 2022.We reviewed the reports of 22 out of the 26 countries that have completed the intra-action review exercises to better understand what the major challenges and lessons were with regards to COVID-19 vaccine roll out. The intra-action review reports from São Tomé and Principe, the Republic of Congo, Madagascar and Zimbabwe were not available to review at the time of this write-up. Twenty-one out of the 22 IARs were conducted as desk review activities, while Kenya conducted a full-scale post-introduction evaluation, including field visits to selected counties and health facilities.Two of the investigators went through the reports and codified the lessons and best practices according to thematic areas. The data were analysed thematically according to seven implementation domains: 1) planning and coordination; 2) training and human resources; 3) vaccine and cold chain logistics; 4) communication, demand generation and community engagement; 5) service delivery; 6) safety monitoring and surveillance for adverse events; 7) monitoring and data analytics.Frequency statistics were used to describe programmatic findings and operational challenges among the countries in this series. We also reviewed the data related to doses of vaccine received, and administrative vaccination coverage for the 22 countries by the end of December 2021 to provide some context to the IAR findings. Coverage with at least one dose of COVID-19 vaccine was defined as the proportion of persons who received a first dose of any COVID-19 vaccine out of the total population. Full vaccination was defined as receipt of 2 doses of AstraZeneca, Sinopharm, SinoVac, Pfizer-BioNTech, Moderna, Sputnik V vaccine or 1 dose of Janssen COVID-19 vaccine.All 22 intra-action review exercises were conducted between April and October 2021. As of the end of December 2021, these 22 countries have attained full COVID-19 vaccination coverage rates, ranging from 0.13% for DR Congo to 44% in Botswana. Only four countries in this group have attained full vaccination coverage rates above 10%. Less than 5% of the total population is fully vaccinated in 12 of the 22 countries. The principal findings, challenges and lessons learnt in these countries are described below.Fifteen (68%) countries indicated that there was adequate high-level political commitment and engagement in the respective countries to promote COVID-19 vaccination. In Ghana, the Inter-Ministerial Coordinating Committee is chaired by the President of the Republic. The national coordination of COVID vaccination was supported by the Inter-agency coordination committee (ICC) in 9 countries, with an expanded role to cover COVID vaccination beyond the usual terms of reference covered by the ICC. Weaknesses in the national level coordination of COVID vaccination was noted in 13 (59%) countries. These gaps were documented in the coordination of activities between the different arms of COVID response or among the health partners or between the health sector and other sectors. Eight countries reported that the regulatory approval of COVID-19 vaccines was processed in an expedited manner. Botswana, Guinea and Togo had some dedicated local funding for the purchase of COVID-19 vaccines or to support operational roll out.All 22 countries developed their national COVID-19 vaccination plans in late 2020 - early 2021, well before the types and volumes of vaccines available to them as well as the timing of delivery were known. These plans were based on the global guidance, and using the prioritisation criteria proposed by the global Strategic Advisory Group of Experts (SAGE). The national plans were all developed with a view to phasing the service delivery starting with high priority grouping and proceeding to include other groups in a phased manner. Four countries identified that these national plans required updating by the time of the IAR exercise, considering the receipt of different types of vaccines, the vaccine consumption rates and expiry dates.In the months until September 2021, the volume of vaccines available for countries was quite small; the delivery schedules and amounts were erratic. Sixteen (73%) of the 22 countries in this series outlined this shortage and erratic supply of vaccines as a major challenge for planning and implementation. Liberia reported that, due to the low volume of vaccine supplies, it was difficult to meet the demand for vaccines after the country launched intensive communication and demand generation activities. Uganda reported that it was particularly difficult to plan for a vaccination activity of unknown duration and with inadequate inputs. Introducing multiple types of new vaccines into national immunisation programs in a short period of time, and especially having vaccines with short shelf-lives was a significant operational challenge in 15 (68%) countries.Seven countries identified gaps in microplanning because of lack of funding or due to the unpredictability in the type and volume of vaccine supplies. Another major challenge was the shortage or delayed disbursement of funds for the roll-out of vaccination activities, reported by 18 (82%) of the 22 countries.Countries used existing immunisation program expertise and working systems to roll out COVID-19 vaccines. All countries reported that they leveraged the skills within the program and within the health sector in rolling out COVID-19 vaccines. However, there was a need for health worker training because of the peculiar characteristics of the new COVID-19 vaccine products, the target groups which differ from other vaccination services, and the phased approach. Fourteen (64%) countries reported that the training of health workers and provision of technical guidance was suboptimal. The trainings were mostly conducted online or done very briefly in order to avoid large and extended physical gatherings. Moreover, the recommended demonstration or drill sessions were not held. Simulation exercises were not systematically conducted at national and subnational level in any of the countries. These challenges were mostly related to insufficient or delayed disbursement of funding, and the hasty roll-out of vaccines once shipments started to arrive. In 4 countries, additional staff were recruited in order to meet the needs for service delivery. Ten countries identified inadequate supervision as a problem.Ten (45%) countries noted that they started service delivery in limited sites because of the shortage of vaccines and funding. Vaccination service was provided in static and outreach sites in all 22 countries, but mobile teams were implemented in 11 countries. In Sierra Leone, there were reports that mobile teams are not well trusted by the community, and are not often used. Service delivery was also affected by other factors. For example, many countries in Western Africa experienced declines in vaccine uptake during the month of Ramadan.Three countries indicated that they implemented vaccination services in hard-to -reach populations (including refugees and displaced persons). Liberia provided vaccination to refugees along counties bordering Guinea, Ivory Coast and Sierra Leone, while Ethiopia extended services to internally displaced persons hosted in some provinces. The Democratic Republic of the Congo (DRC) set up vaccination sites in certain prisons and mining sites. All the countries stated that, revisions were made on the initial NDVP phasing to expand vaccination services to broader population groups after a few months of implementation. This was due to low COVID-19 vaccine uptake among the priority groups, and the risk of vaccine expiry since received vaccine shipments had a short shelf-life. A reduced rate of vaccination and/ or concerns about hesitancy among women were noted in Liberia, South Sudan, Sierra Leone, Cameroon and Chad.All the countries recommended better integration with routine services, in terms of actual service delivery, social mobilisation and communication. Three countries reported that COVID-19 vaccination was negatively affecting routine immunisation services through the disruption of scheduled outreaches and static services. In the Gambia, vaccination teams were overwhelmed with work negatively affecting routine vaccination services, and the demand and uptake of human papillomavirus (HPV) vaccination was negatively affected by the COVID-19 vaccine introduction. In Kenya, nearly two thirds of the counties reported having routine immunization services and coverage affected by the introduction of the Covid-19 vaccines. Liberia reported challenges with balancing COVID-19 vaccination activities and routine immunization especially outreach services.Zambia had very good integration of COVID vaccination services with TB, HIV antiretroviral treatment (ART) clinics and with family planning services. Sierra Leone recommended integrating COVID vaccination along with other interventions during periodic health days like child health days, those commemorating malaria control, tuberculosis control, and the annual African Vaccination week etc. Cameroon recommended that the strategy to increase access to COVID-19 vaccines should consider integrating vaccination within pre-existing health services, including chronic illness follow-up clinics.Twelve (55%) countries indicated that they implemented multichannel/multimedia communication and social mobilisation activities, while 9 countries introduced some sort of social listening and rumor tracking systems. All the countries included social media engagement as part of their communications strategies. However, many of the countries indicated weaknesses in their capacity to respond to the rumors in a timely manner. Botswana introduced a successful branded mobilisation campaign called “#ArmReady” just before the start of COVID-19 vaccination. Eleven countries set up toll-free telephone call centers for the provision of relevant information to the public. Nineteen (86%) countries indicated that weak implementation of communication and community engagement activities impacted on their coverage. Misinformation through the social media was mentioned as a major challenge in 13 countries. Hesitancy to take COVID vaccine was noted among health workers in 10 (45%) countries, and in other population groups in 7 countries.Five countries indicated that there was inadequate knowledge of the behavioural drivers influencing vaccine hesitancy. In seven countries, some sort of survey was done to gather evidence on the public perception of COVID-19 vaccination and tailor their messaging accordingly. South Sudan implemented focus group discussions among members of various public groups, and a survey among health workers to understand perceptions and attitudes towards COVID vaccines. Ghana and Togo conducted studies on the knowledge, attitude and practices (KAP) regarding COVID-19 vaccines in order to adapt messages, while Cameroon explored vaccine acceptability among the population and recommended carrying out qualitative studies to understand the reasons for vaccine hesitancy in certain groups.Uganda reported that the scarcity of vaccines was one factor that fuelled mistrust. In the Gambia, inadequate AEFI investigation and feedback, as well as conflicting messages on the target group were mentioned as important factors for hesitancy. In Eswatini, it was reported that an increased number of adverse events during the third wave may have contributed to vaccine hesitancy and reduced vaccine uptake.In Kenya and Uganda, teachers and health care workers were identified as vaccine hesitant, while weak vaccine acceptance was also identified among health workers in Burkina Faso, Cameroon and Niger. The uptake of second doses was low in Liberia and Gambia due to stockout issues. In addition, Liberia mentioned AEFIs with the first dose vaccine as a reason for defaulting on the second dose. In Zambia, second dose vaccine was offered at specific sites only, different from the initially planned outreach/mobile sites. This was done as a result of low vaccine stocks and led to some hesitancy and high defaulter rate.All the countries built their AEFI reporting on existing systems. However, digital tools were introduced for AEFI reporting following COVID-19 vaccination in 6 countries. AEFI reporting was considered very weak in 18 (82%) countries, with 8 (36%) countries identifying weak coordination between various parallel AEFI reporting systems or channels. Ethiopia and Uganda reported discrepancies in the numbers reported through the pharmacovigilance system and the AEFI surveillance reporting run though the immunisation program. In Kenya, one of the factors for weak health worker reporting of AEFIs was the fear of consequences from senior managers.In 7 countries, multiple different channels were set up for AEFI reporting by health workers and the public, including passive reporting by clients using telephone hot lines and active reporting by health workers. The national AEFI committees, tasked with the responsibility of reviewing serious AEFI cases and doing the causality assessment and classification, were not functioning optimally, with subsequent delays in the causality assessment and feedback in 11 (50%) of the 22 countries. The shortage of AEFI kits was documented as a challenge in 8 (36%) countries. A few countries mentioned the challenge of media reporting of alleged AEFI cases ahead of any official investigation and communication. Such reporting was considered even more problematic in the case of severe AEFIs, when the media reports implicate the vaccines or the vaccination process, without being informed by the results of causality assessment by the national AEFI committees.Cold chain space was adequate in 14 (64%) of the 22 countries, mainly since the volume of vaccines available was limited throughout most of 2021. Eight countries had gaps in ultra-cold chain equipment for the storage of mRNA vaccines at national level. Sixteen (73%) countries reported the challenge of shortage of vehicles and/ or lack of funding for fuel to move vaccines and vaccinators outside of urban and district centers. In 4 countries, beyond the Ministry of Health, other stakeholders and partners  assisted with moving vaccines and vaccination teams to subnational depots or to the district level. Ghana utilised drones to deliver more than 450,000 vaccines to 42 districts across the country by the time of the IAR.Nine (41%) countries indicated that vaccine distribution was done efficiently across districts. Five countries implemented reverse logistics systems to collect and redistribute vaccines from districts with low utilisation rates to areas where there were bigger needs and utilisation rates. Senegal and Zambia rolled out the Logistimo software for stock management in a limited number of districts.There was an attempt to introduce digital monitoring tools in most countries to track stocks and to monitor coverage. Eight countries implemented real-time digital monitoring systems to keep track of coverage and vaccine stocks. The DHIS2 Tracker platform was used for data capture and management in 7 countries. Three countries introduced verifiable vaccination records including QR codes. In addition, Ghana introduced holograms on the vaccination cards. Only Kenya and Eswatini reported having a defaulter tracing system or an automated second dose reminder system to ensure that persons who took their first dose return for their second shots at the right time.The lack of clearly enumerated target population was documented as a problem for adequate coverage monitoring at the operational level in 4 countries. Nine countries did not have the adequate number of digital devices for use at all service delivery centers. In addition, the shortage of data entry clerks at the operational level was a challenge for timely data availability at the national level in 9 countries. Shortage of monitoring tools (various paper forms or electronic data capture tools) was noted in 9 countries. This was mainly linked to the inability to access operational funds.The COVID-19 vaccination coverage rates in the countries in this study indicate that the majority have not yet attained 10% coverage with more than half at levels below 5% as of the end of December 2021. The coverage rates contrast sharply with coverage attained in developed countries in 2021 .The first year of COVID-19 vaccination was characterised by the shortage of vaccines for most countries in the African Region. The global supply of vaccines started to show some improvement in August 2021. Equally important was the lack of predictability of vaccine supplies. Multiple small size shipments arriving with erratic schedules did not help countries to plan appropriately for large scale interventions. This also multiplies the administrative and logistical procedures to receive, clear and distribute vaccines. The successful deployment of COVID-19 vaccination in Israel and Bhutan is partly due to their small size and timely acquisition of large number of doses to cover a significant proportion of their population ,13.Some new COVID vaccines have product characteristics  different from existing program vaccines and therefore require alternative refrigeration, handling and delivery approaches. The short shelf-life of COVID-19 vaccines was a major challenge for many countries, putting pressure on program managers to distribute and implement vaccination activities without taking time to do the necessary elaborate and cascading preparations that go into such kind of decentralised mass vaccination efforts.et al. argue that the introduction of new vaccines require substantial additional planning and organizational complexity to ensure optimal vaccine delivery, posing a wide range of challenges to often overstretched and underfunded health care systems, across all components of the vaccine supply chain [Shortage of operational funding was a major finding reported from 18 countries in our study. The introduction of new vaccines and the conduct of mass vaccination campaigns normally require intensive preparations, which take time and require resources. To attain high quality coverage, there are many critical preparatory steps that cannot be missed -17. GuigThe fact that most of the national immunisation programs could not readily access funding to cover the costs for COVID-19 vaccine introduction has undermined key activities like training, microplanning, supervision and transportation and limited the number of vaccination teams and service delivery sites. For optimal outcomes, health worker training should be practical as much as possible, with drills and simulation exercises, which have not been adequately explored among these countries. In addition to gaps in funding, the online mode of training due to the COVID restrictions may have posed limitations, unlike in other previous campaigns .A World Bank report based on the COVID vaccination readiness from March 2021 concluded that a country´s ability to roll out adult vaccination programs does not necessarily depend on the strength of childhood immunisation programs . The reaThe reviews have also highlighted the need for better integration of COVID-19 vaccination with other interventions, especially with routine services. This is even more important from the perspective of optimising resources, and minimising missed opportunities for vaccinating eligible persons. The integration of COVID vaccination with other health service activities like family planning and ART treatment clinics, has been well received and is running well in Zambia. These experiences need to be reviewed and documented well to help other countries learn the lessons. In the context of limited resources, careful planning and adequate preparation are critical for integration to work optimally. Careful selection of the service delivery platform, consideration of the nature of interventions, the target groups, as well as operational issues like coordination, training and supervision are all critical when considering the integration of interventions .Vaccination service delivery in developing countries is challenged by poor access to preventive health care because of lack of infrastructure, limited resources and an overstretched health workforce, among others . In ordeThe expansion to the target population done by a number of countries beyond the initial prioritisation in their national deployment plans was due to low uptake among the priority populations, and the short shelf-lives of the vaccine doses. At least 9 countries in the European Union implemented suspensions, delays and adjustments to the timelines by June 2021, due to various reasons including reported adverse events .The perception of COVID-19 risks among the public directly affects the demand for vaccines. The low number of COVID-19 case reports in between the well-publicised waves of transmission may have convinced people to take a wait-and-watch approach. The authors´ observations and analysis of trends of vaccination in countries in the African Region shows that the uptake of vaccines has more or less mirrored the waves of COVID transmission across countries, especially with the emergence of new variants. In addition, the relatively low mortality from COVID in the majority of African countries, as compared to other parts of the world, is likely to be an important factor for people´s decisions whether to get vaccinated or not.Vaccine hesitancy refers to a delay in acceptance or refusal of vaccination despite availability of vaccination services . The rapet al. argue that trust in vaccine approval, the perceived effectiveness of the vaccine for protecting others, and conspiracy beliefs are the most significant drivers of intentions to vaccinate [In our study, a number of countries have documented some type of vaccine hesitancy related to various factors. Misinformation was identified as a major challenge. There was some product-specific hesitancy targeting AstraZeneca vaccine in many countries in the African region following the widely publicised reports of thrombotic adverse events after AstraZeneca vaccination . Eswatinaccinate . The Netaccinate .Studies on public attitudes to COVID-19 vaccination in various African countries show important gaps along with differences in acceptance rates between urban and rural areas . An exceDuring the IARs, at least 5 countries have documented hesitancy among health care workers. Similar findings have been documented in studies published from other countries -40. HesiCountries in the African Region have adequate experience with mass vaccination campaigns over the last two decades . With amThe IAR reports identified a number of new practices including the use of digital platforms for the pre-registration of clients, the use of mobile tools for the capture of data on reported AEFIs; the use of cold chain temperature monitoring tools while moving vaccines to subnational depots, the use of different software platforms for real-time capture of service monitoring data. The ultimate lesson to be learnt is the need for countries to make better investments in terms of establishing emergency preparedness and allocate adequate emergency resources to mobilise when a crisis arises ,41.This study has some limitations. The findings from these 22 countries do not represent the situation across the whole African Region, and are specific to the time and the context in the weeks and months prior to the IAR exercises. Moreover, the challenges and practices reported here are highly contextual and may be subnational in nature and not necessarily reflect the situation nationwide. The depth of documentation in the IAR reports was not uniform, and the reports may not capture all the key elements that came out of the review exercise. All except the Kenya study were done as desk exercises. The timing of the IAR exercise vis-à-vis the vaccine supply situation also determines the findings. Most of the COVID-19 vaccination IAR exercises were conducted in the months of low vaccine supply, and the experience with COVID vaccination was only for a few months by the time of the IAR. Most of the exercises were done as stand-alone reviews focusing on the vaccination pillar of the response, and tend to have adequate details on the vaccine. A few of the IAR exercises were done as part of an intra-action review focusing on the whole COVID-19 response effort, thus may be lacking the necessary granularity on the vaccination response.Intra-action reviews are useful tools in identifying strengths and weaknesses of ongoing COVID-19 vaccination activities. WHO recommends that countries conduct IARs regularly, as this enables evaluation of critical challenges and good practices. In addition, the recognition of innovative ideas and practices is important from the perspective of motivating the workforce. The roll-out of COVID vaccination presents various challenges that can be addressed through the mobilisation of political will and resources, as well as careful preparation. The IARs present perfect opportunities to identify and address program gaps. In addition, COVID-19 vaccination also presents opportunities for innovations in various areas of program performance that require careful documentation and dissemination for possible scaling-up.Various COVID-19 vaccines have been developed and have been put to use within a year of the start of the pandemic - Hesitancy towards COVID-19 vaccines has been documented in many countries;Mass vaccination exercises require clearly committed and quantified resources, careful planning and adequate preparation;Intra-action reviews are widely used in emergency contexts to document early lessons and implement the necessary adjustments to the implementation of interventions, similar to post-introduction evaluations in the case of new vaccine introductions.Despite strong high level political commitment at national level, COVID-19 vaccination in most countries was heavily challenged by the erratic supply of vaccines and a shortage of operational funds. Funding gaps prevented countries from putting in place the required intensive preparations, and the short shelf-life of the vaccines led to rushed implementation;Countries identified gaps in health workers training and supervision, as well as in AEFI reporting and safety monitoring - countries have gained valuable experiences exploring various COVID-19 vaccination service delivery models, including implementing the integration of COVID vaccination within routine health care programs;There is a need to regularly monitor or do studies measuring public perceptions towards COVID-19 vaccination in order to drive the communication and demand generation efforts, as well as use evidence in addressing hesitancy.


The advancement of folliculogenesis is coincident with the sequential acquisition of oocyte developmental competence. In practical bovine/porcine ART, cumulus-oocyte complexes (COCs) aspirated from small antral follicles have low developmental competence relative to COCs from medium/large antral follicles, as evidenced by a poor capacity to support embryogenesis up to the blastocyst stage. This is in part because of incomplete differentiation of cumulus cells in small antral follicles, in particular under-developed functionality of EGF signalling. Gonadotrophins and oocyte-secreted paracrine factors cooperate to establish EGF receptor functionality in cumulus cells, which appears to be involved in the acquisition of oocyte developmental competence. Here we review the modification of follicular cumulus cells during antral folliculogenesis involved in oocyte developmental competence. The developmental competence of an oocyte, referring to its capacity to support fertilization, preimplantation embryo and subsequent full-term development, is inherently linked to environmental cues it receives from the follicular somatic cell compartment . The folOocytes acquire increasing developmental competence sequentially with advancing folliculogenesis and as such oocyte and follicle development are inter-dependent processes . Hence, Key propagators of the ovulatory cascade within the follicle are the EGF-like peptides; amphiregulin (AREG), epiregulin, and betacellulin, which are produced by mural granulosa cells in response to LH, and signal via the EGF receptor (EGFR) that is expressed on mural granulosa and CCs .in vitro maturation (IVM) are critically dependent on this knowledge.This review will focus on the recent advances in our knowledge of the contribution of endocrine and paracrine cues in the differentiation of follicular granulosa and CCs during antral folliculogenesis, and their contribution to oocyte developmental competence. This knowledge is important for the application of advanced reproductive technologies in domestic animal breeding and in humans. The successful clinical application of the key reproductive technologies of superovulation  and oocyte It is now well established that the EGF network is an essential propagator of the ovulatory signal in the Graafian follicle to the cumulus-oocyte complex COC; . The conet al. (2003) hypothesized that porcine COCs from small antral follicles (3-4 mm) have an under-developed EGFR. Indeed, there is a growing body of evidence showing that the development of a functional EGF network in follicular granulosa cells is suppressed until the peri-ovular stage as a mechanism of limiting ovulation to the dominant follicle(s), and thus to the developmentally competent oocyte(s); Areg expression in mouse cumulus cells leads to reduced fecundity  demonstrated that in vitro treatment of porcine small antral COCs with FSH promotes EGF responsiveness and subsequent EGFR signaling. EGFR signaling is essential for cumulus expansion, and requires activity of the FSH downstream effector protein kinase A  signaling and paracrine signals from the oocyte is essential in this process. FSH plays a major and essential role in follicle development. Follicles of Fshbet al.  recently showed that small antral porcine COCs can be induced to respond to AREG following exposure to the FSH effector cAMP. However, this required the exogenous addition of GDF9 or BMP15, since cAMP alone had little effect on AREG-induced meiotic maturation, cumulus expansion, ERK1/2 phosphorylation, or blastocyst development in small antral oocytes in the absence of GDF9 and BMP15  activation, including interferon-stimulated genes .An important function of follicular somatic cells in follicles approaching ovulation is to prepare the oocyte for final maturation, in part by promotion of cumulus EGFR signaling, as well as prevention of inflammation and promotion of cell-to-cell communication. The latter facilitates the efficient transfer of molecules from the somatic compartment of the follicle to the oocyte. These processes are likely to constitute important components of oocyte developmental competence in humans and ruminants.


Two-dimensional transthoracic echocardiography images for a 49-year-old female with a history of ventricular septal defect status post repair, type 2 diabetes mellitus, and hyperlipidemia whose evaluation of her lower extremity edema showed parachute mitral valve. The outcomes are dependent on the spectrum of associated lesions.2 The pathognomonic pear-shaped view is seen in the apical long views on transthoracic echo, with the atrium forming the base of the pear and mitral valve leaflets forming the apex. The chordae tendinea are often short and thick. This, coupled with the convergent papillary insertion, leads to decreased mobility of the valve leaflets, thus causing stenosis. In adults, parachute mitral valves are rare and can be asymptomatic or associated with mild stenosis.3Parachute mitral valve is a rare congenital anomaly characterized by unifocal attachment of the chordae tendinea of anterior and posterior mitral valve leaflets to a single papillary muscle. They are thought to develop due to disturbed lamination of the anterior and posterior part of the trabecular ridge, which normally forms the anterolateral and posterolateral papillary muscles respectively between the 5th and 19th week of gestation.


Neurofilaments (NFs) constitute the main structural proteins of the cytoskeleton of neurons both in the central (CNS) and peripheral (PNS) nervous system and are abundantly assembled in large myelinated axons. NFs are composed of four subunits, the light (NFL), medium (NFM), and heavy (NFH) chains plus α-internexin in CNS or peripherin in PNS. Small amounts of NFs, particularly NFLs, may be released from axons into blood and cerebrospinal fluid (CSF) in healthy individuals and this release increases with age. More significant amounts are loosed upon traumatic brain injury, stroke and in several neuroinflammatory, and neurodegenerative conditions , Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). This is a very important topic, considering that disease-modifying drugs are available for the treatment of diseases like MS and their efficacy often relies on early diagnosis, also bearing in mind that the study of the presymptomatic phases of neurological diseases is fundamental in understanding their early pathological mechanisms.While CSF and blood NFLs are mostly used to monitor the severity degree of neurological diseases and the efficacy of therapies, recent evidence has highlighted the importance of their measurement in the identification of neurodegenerative diseases in their presymptomatic phases. Polymeris et al. investigated the association of estimated glomerular filtration rate (eGFR) and body mass index (BMI) with serum NFL in a large cohort of elderly patients with atrial fibrillation. In a multivariable model adjusted for all clinical variables, eGFR and BMI showed strong inverse association with NFL levels and in these associations both eGFR and BMI interacted with age. Age, eGFR and, to a lesser extent, BMI alone or all combined explained a significant proportion of NFL level variance. This study, providing crucial information on NFL homeostasis, places emphasis on how renal function and BMI contribute to NFL levels in the elderly, suggesting considering these and further physiological factors in NFL measurement interpretation.NFL release increases with age as well as in some pathologies, characteristic of old age, but little is known about how other comorbidities or physiological factors may affect this release. In their original article, Thebault et al. summarized important issues relative to analytical and clinical validity of serum NFL measurement, fundamental issues for their routine clinical use together with the currently applied tools to diagnose and monitor MS. The authors focused on preanalytical and assay standardization and data analysis methodologies and highlighted the main physiological determinants of serum NFL levels, possible confounding effects of comorbidities, the presence of anti-NFL antibodies, the lesion location, and physiologic kinetics of NFL distribution and clearance.Four manuscripts focused on NFL measurement in MS, perhaps the most popular application of this biomarker. Serum NFL levels correlate with disease activity and treatment efficacy, are predictive of poorer clinical outcomes, are elevated years before the clinical onset and in clinically isolated syndromes are predictive of conversion to clinically definite MS. In their review, Ferreira-Atuesta et al. further emphasized the correlation between axonal damage and loss with progression and disability in MS, highlighting the pros and cons of NFLs as biomarker in MS. They thoroughly illustrated the correlation between NFL levels and clinical and radiological findings in MS, also considering the potential use of the biomarker in MS mimics. The authors also extensively discussed the currently used technologies, the correlation between NFL measurements in CSF and blood and the need of optimal and sensitive cut-off values. Finally, they interestingly focused on the influence of coexisting peripheral nerve and CNS diseases and antibodies raised against NFL on reliable measurements and clinical interpretation of NFL levels, also looking at other biomarkers to be examined independently or in relation to NFLs.Pukoli et al. reported on the relationship between neuroactive metabolites, produced in the kynurenine pathway (KP) and activated by several pro-inflammatory cytokines, and the pathomechanisms of MS. The authors described how some neuroactive KP metabolites, produced by microglia and macrophages, may have a role in MS development, producing free radicals in the presence of redox active metals like Fe2+; activating N-methyl-D-aspartate receptors, resulting in excitotoxicity; inhibiting the re-uptake of glutamate by astrocytes resulting in neurotoxicity; and decreasing glutamine synthetase activity so limiting the recycling of glutamate to glutamine in astrocytes. Several studies confirmed the activation of KP in MS: during the early phase of MS the production of neuroprotective kynurenine metabolites counteracts the effects of neurotoxic metabolites, while during disease progression the excess of neurotoxic metabolites contributes to the progression of MS. Interestingly, kynurenine neurotoxic metabolites play a central role in axonal damage also through the destabilization of cytoskeleton by causing hyperphosphorylation of proteins like NFL and a positive association between KP metabolites and plasma NFL levels has been demonstrated.Masvekar et al. tried to develop and validate a CSF-biomarker-based molecular surrogate representing MS lesional activity, mediated by immune cells migrating from the periphery to the CNS and commonly reflected by contrast-enhancing lesions (CELs) on magnetic resonance imaging (MRI). They analyzed CSF and serum samples for 20 inflammatory and axonal damage biomarkers. The authors interestingly found a significant association of some biomarkers and NFL levels in CSF with lesional activity. IL12p40 and CHI3L1 seemed reproducibly the best CSF biomarkers of MS lesional activity. Though serum NFL levels were correlated with CSF NFLs, serum NFL measurement did not differentiate between non-active and active MS lesional inflammatory activity subgroups and were weakly correlated with number of CELs and pro-inflammatory biomarkers associated with lesional inflammatory activity.In their original article, Saak et al. explored the hypothesis that elevated serum NFL may suggest nervous system involvement in patients with primary myopathies. They determined serum NFL levels in patients with myotonic dystrophy type I (DMI) and II (DMII), mitochondrial diseases or facioscapulohumeral muscular dystrophy (FSHD), also including a control group of patients with genetic defects exclusively expressed in muscle. Finding significatively elevated levels of serum NFL in DMI, DMII and mitochondrial disease patients, the authors demonstrated that serum NFL levels may be used as biomarker of neuronal damage in muscle diseases with established nervous system involvement. They interestingly further showed that serum NFL were also raised in FSHD patients, for whom the involvement of the nervous system is not usually clinically apparent, suggesting serum NFL as a biomarker for neuronal damage in primary neuropathies.Diekämper et al. using DaTscan SPECT. In these patients there was a strong correlation between NFL and plasma NFH levels and the changes of presynaptic dopamine transporter density in the pathological conditions involving putamen concomitant to nigrostriatal degeneration. Therefore, NFL concentration could help to understand the degree of impairment of motor functions also in Parkinson's disease.A cohort of patients affected by movement disorders with nigrostriatal neurodegeneration were studied by Zanardini et al. explored the possibility that exosomes could be correlated to NFL and the main proteins involved in FTD. NFL and exosome dosages could be important in genetic FTD and might be useful mainly before the clinical onset allowing to anticipate the therapeutic treatments.The review of Verde et al. CSF NFL levels correlated positively with disease progression and negatively with survival in ALS. In FTD, NFL were more elevated than in healthy people and slightly more elevated than in other dementias. The NFL level in CSF correlates with the disease progression, but the differences seem not so important to justify a diagnostic utility. The authors underlined the importance to dose NFL in blood and described the recent advances which showed longitudinal kinetics in presymptomatic patients carrying causative mutations for ALS and FTD. Moreover, NFL could be important in ALS patients as pharmacodynamic biomarker in therapeutic clinical trials.The importance of NFL in ALS and FTD was reviewed by Dreger et al. to better define the NFL potential as biomarker in ALS. The authors applied the D50 progression model to overcome the heterogeneity of clinical presentation in patients. Enrolled patients were divided in three groups characterized by high, intermediate and low disease progression on the basis of D50 values. A significant difference and positive correlation between CSF NFL levels and disease activity were found comparing the groups. This model can therefore be recommended in future studies as a useful tool.An interesting research was proposed by Abu-Rumeileh and Parchi, focusing on prion and Creutzfeldt–Jakob diseases. NFL levels showed interesting prognostic and diagnostic performances and may be used as biomarker to predict clinical onset in PRNP (prion protein) mutation carriers. In addition, authors gained attention on the follow-up of cerebrovascular diseases. Then, the quantification of NFL in CSF and in blood could be a very useful tool in precision medicine also applied to rapidly progressive dementias.The clinical and biological implications of NFL dosage in rapidly progressive dementias were reviewed by Frempong et al. Although serum NFL result higher in FRDA patients than in controls, they do not correlate with genetic and clinical severity, like GAA repeat length or disease progression and were paradoxically higher in young patients, decreasing with age as the pathology progresses. These evidences make difficult the use of NFL as a biomarker in FRDA. The authors proposed some hypotheses to explain the anomalous NFL kinetics in FRDA patients, like a relatively large early loss of peripheral axons not contributing to clinical progression or the reflection of other components of the pathophysiology of FRDA like abnormal lipid metabolism and lipid peroxidation.The use of NFL measurement in Friedreich ataxia (FRDA) was deepened in the review of Evers et al. NFL levels were studied comparing the results of both cohorts with those obtained in a further control cohort of children with febrile infections without convulsion. The results of the study evidenced that NFL levels did not reveal significant differences among the three cohorts of analyzed patients. Applying multivariate analysis, age was the best predictor of NFL levels followed by sex and C reactive protein. The study demonstrated an age-dependent decrease of NFL levels from early childhood until school age.The possible role of serum NFL levels in children with epileptic or febrile seizures was explored in the research article of Eisenstein et al. tested the possibility to use NFL as biomarker especially in patients with MRI contraindications. The NFL levels were compared in children, young patients and controls in relation to the clinical severity and chosen brain region volumes. Increased NFL levels were related to worse smell identification, color vision and visual acuity. Higher NFL values were also correlated to smaller thalamic and brainstem volume and faster annual rate of decrease in thalamic volume during time. Therefore, NFL dosage could be a useful biomarker to follow the neurodegenerative process in this type of patients.The extent of neurodegeneration is monitored by challenging clinical measures and MRI in Wolfram syndrome. The Research Topic of In conclusion, many questions are still open to better understanding the role of NFL levels in traumatic brain injury, stroke, neuroinflammatory and neurodegenerative conditions. This Research Topic of articles raises the most important issues to be considered in translating research findings in clinical practice.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The current case report presents a case of a road traffic accident comprising dental avulsion of maxillary incisors. A 30-year-old male reported missing teeth following trauma in his upper front tooth region. The avulsion of maxillary right central and lateral incisors along with laceration in upper and lower lips was evident. The avulsed teeth were stored in milk after a brief extra-oral dry time of one hour and were carried to the department with a one-hour delay. After clinical and radiographic investigations, no mobility or fractures were apparently noticed. The avulsed 11 and 12 had closed apices with intact crown and root surfaces. Following an extra-oral endodontic therapy, immediate replantation was scheduled. Subsequently, the alveolar sockets were irrigated with saline to dislodge the clot and any gross debris that was present. Teeth were reimplanted into the socket after placement of PRF membrane around the root surface. A semi-rigid wire and composite splinting were done for a span of two weeks and antibiotics were prescribed. An exploratory CBCT taken revealed a cortical bone loss in the buccal region of 12 and 11. An interdisciplinary approach to regenerate the osseous defect was then carried out. A follow-up of two weeks, four weeks, three months, six months, and a year was done. Evaluation performed after a year revealed the absence of clinical symptoms and satisfactory healing with no signs of resorption radiographically. Traumatic injuries of the dentition are frequently seen in children and young adults in which luxative injuries are seen in primary dentition and crown fractures are commonly seen in permanent dentition. Among the traumatic dental injuries (TDI), avulsion comprises 0.5 to 16% of permanent teeth .According to Andreasen et al., avulsion is defined as the complete displacement of a tooth from its socket in alveolar bone owing to trauma. In permanent teeth, avulsion occurs commonly in the maxilla due to fights and sports injuries. Maxillary central incisors are widely affected and commonly seen in the age group between seven and nine years .Incomplete root maturation and reduced resistance to extrusive forces by the alveolar bone/periodontal ligament (PDL) at the time of eruption are the two major etiological factors of avulsion ,5. The tReplantation is considered to be the treatment of choice for an avulsed tooth since it maintains the aesthetic and function of the patient . AlthougAn ideal storage media for an avulsed tooth must maintain the function and viability of the PDL cells, so that the fibroblasts of the PDL cells repair the damaged root surface. Storage media for an avulsed teeth are broadly classified as artificial and natural media. Natural storage media like coconut water, milk and saliva are more readily available than artificial medias like Viaspan, Hank’s Balance Salt Solution. The pH (6.5-6.8) and osmolality (250mOsm) of the storage media should be compatible with the PDL cells and it must also contain nutrients required for cell growth .Extra-oral dry time plays a vital role in determining the outcome of avulsed teeth. An extra-oral dry time of more than 60 minutes has deleterious effects on the PDL cells like decrease in the regenerative ability and resorption of the root . Thus, tA 29-year-old male patient reported to the Department of Conservative Dentistry and Endodontics with trauma due to a road traffic accident in his maxillary anterior region. The patient was however found to have no systemic ailments associated while obtaining the medical history. He was further evaluated for any other physical injuries and neurological disturbance following the trauma. The patient was conscious and well-oriented to place, time, and person during the time of examination. He had sustained an injury to his upper anterior teeth along with an associated soft tissue laceration present in both upper and lower lips. During the extra-oral examination, it was evident that the upper and lower lips were swollen as well as lacerated. During Intra-oral examination, the patient presented with the missing maxillary right central (11) and lateral incisors (12) Figures , 1B. AlsAccess opening and pulp extirpation was done. The canal was well cleaned with ethylenediamine tetra-acetic acid (EDTA), saline and povidone iodine. Rotary Protaper gold file system  was used for the mechanical shaping of canal. An intracanal medicament of calcium hydroxide was placed inside the root canal and access opening was sealed with Glass Ionomer cement. Root canal obturation alone was deferred, to reduce the extra-oral duration of the avulsed incisors. 1.23% Acidulated phosphate fluoride (APF) was used for 15 minutes to treat the root surface. Meanwhile, 10 ml of patient’s venous blood was collected, and centrifugation procedure was carried out to obtain platelet-rich fibrin (PRF) Figure . The memOral antibiotics were prescribed for the patient for five days and the importance of anti-tetanus booster was emphasized. After two weeks, the obturation of 11 and 12 was done with gutta percha and the access cavity was sealed with light cure composite. On exploratory CBCT taken after two weeks, a loss of labial cortex was evident in 11 and 12 region Figures , 3B and Upon periodontal examination, clinical attachment loss of 10 mm was evident and regenerative periodontal surgery was advised. A vertical incision was given, and a full thickness muco-periosteal flap was elevated in relation to 11-13. Bone graft  Figure  and guidConsecutive to the periodontal regenerative procedures, splinting duration was extended further, for about five weeks Figure . FollowiImmediate replantation is considered an excellent treatment of choice for an avulsed permanent tooth owing to its ability to maintain the alveolar form, function, and PDL cell viability. In the current case, the immediate replantation of 11 and 12 was done following an extra-oral time of 2 hours. The literature states that replantation of avulsed teeth usually occurs one and four hours after trauma. Outcome and the rate of survival for avulsed teeth depend upon factors like extraoral dry time, storage media, and root defects if any are present . An ideaTreatment of the root surface of an avulsed tooth with fluoride is recommended to decrease the rate of root resorption. Treatment with 2% APF provides resistance to inflammatory and replacement root resorption because fluoride acts directly on dentin, cementum, and enamel converting the hydroxyapatite into fluoroapatite . It alsoA delay in the replantation of avulsed teeth will lead to resorption of the root due to the presence of necrotic PDL, thus it is required to remove the dead PDL. Mechanical debridement is considered a simple and effective way of removing the PDL as it does not aggressively remove the tissue . AccordiIrrespective of the root treatment, the replanted teeth should be root canal treated. This is to remove the necrosed pulp tissues present inside the canal. In the present study, root canal treatment was initiated extra-orally, followed by placement of intracanal medicament, calcium hydroxide. Calcium hydroxide helps in reducing inflammatory resorption, counteracting the endotoxins , and altFollowing the placement of intracanal medicament, a temporary access filling was done. The root surfaces of the teeth were covered by a PRF membrane. PRF is obtained by centrifuging the patient’s own blood, and it does not require any anti-coagulants. The main advantage of platelet concentrates is their ability to improve wound healing by the presence of various growth factors. This growth factor improves the viability of PDL cells and also improves their differentiation and growth.Stabilization of the avulsed teeth is of utmost importance as it prevents further damage to the pulp and periodontal tissues and aids in its healing . Trope eThe usage of CBCT in treating TDI was first employed in the year 2007. The recent IADT guidelines suggests the use of CBCT in diagnosing the severity and type of traumatic injuries. In the current case report, following the emergency management, an exploratory CBCT was taken, to determine the severity of the injury, which revealed labial cortical bone fracture. To manage the bone interdisciplinary, approach was carried out by performing periodontal regenerative procedures.GTR refers to the use of a barrier membrane at the interface with gingival/epithelial connective tissue, PDLs, and alveolar bone to facilitate periodontal tissue regeneration, while GBR pertains to the regeneration of alveolar bone. In the current case, the periodontal regeneration was achieved by placing bone graft followed by GTR membrane. This novel approach aids in angiogenesis, osteogenic migration and wound stabilization which promotes the formation of granulation tissue that is rich in vascularity and offers better healing .Reimplanted avulsed teeth must be under continuous follow-ups at time intervals of two weeks, four weeks, six months, one year, and then every year later for at least five years . Both clThe patient’s knowledge about avulsion and its management is of utmost importance in the outcome of the avulsed teeth. Instructions on the transportation and storage of the avulsed teeth must be an important patient education as it plays a pivotal role in the treatment. Regardless of the time, replantation itself serves as the best treatment of choice as it maintains the form and function of the bone for later prosthetic needs if there might be any failure in the future.


In response to the ongoing COVID-19 pandemic, public health care measures have been implemented to limit spread of the contagion and ensure adequate healthcare resource allocation. Correlating with these measures are observed changes in the incidence and outcomes of cardiovascular conditions in the absence of COVID-19 infection. The pandemic has resulted in a reduction in acute coronary syndrome, heart failure and arrhythmia admissions but with worsened outcomes in those diagnosed with these conditions. This is concerning of an underdiagnosis of cardiovascular diseases during the pandemic. Furthermore, cardiovascular services and investigations have decreased to provide healthcare allocation to COVID-19 related services. This threatens an increasing future prevalence of cardiovascular morbidity in healthcare systems that are still adapting to the challenges of a continuing pandemic. Adaption of virtual training and patient care delivery platforms have been shown to be useful, but adequate resources allocation is needed to ensure effectiveness in vulnerable populations. ThisIschemic heart disease (IHD) is the number one cause of death globally and was accountable for approximately 16% of deaths worldwide in 2019 . In deveEarly reperfusion in ST segment elevation myocardial infarctions (STEMI) has been shown to reduce mortality –11 with Although there was a decrease in the number of ACS presentations in the first 6 months of 2020, the number of deaths from IHD increased in this same period . This coThe number of admissions for ACS began to return to levels similar to those seen in pre-pandemic periods several months into the pandemic but were still reduced when compared to previous year control intervals . In EuroRationalization of this discrepancy in ACS presentations likely involves a change in social, ecological and physical behavior during the early COVID-19 period. During the early stages of the pandemic, fear of nosocomial infection with COVID-19 in hospitals was reported to cause trepidation amongst the general population in presenting to these centers , 25. WhiThe absolute number of percutaneous coronary interventions (PCI) performed decreased when compared to historical control periods  but therThis corresponded with decreases in the number of coronary artery bypass grafting (CABG) procedures performed during the same period with multi-center studies in England showing an 80% reduction compared to the weekly average for the year prior . It shouHeart failure hospitalizations were also seen to decrease following the implementation of social distancing and public health measures. This has been reported in observational data in North America , 38, 39 2DS2-VASc score when compared to preceding control periods , decreased during the early period of the COVID-19 pandemic  43). Ob. Ob43).  periods . Despite periods . Decreas periods , 55. Thi periods , 56. Of  periods , 58. The periods  included periods . In conjVentricular arrythmias present a substantial risk of sudden death. Major world events and natural disasters have been associated with temporal increases in ventricular arrhythmias and sudden cardiac death , 61. TheA pictorial summary of the impact of the COVID-19 pandemic on cardiovascular admissions is shown in Hypertension is estimated to affect 1.4 billion patients globally and 46% of adults in the USA , 69. SusIn the context of profound changes in hospital operations to address the increased demand for medical personal and resources, there have been observed changes in cardiac procedures. Globally, there was a decrease by over 40% in cardiac diagnostic procedures in March 2020 when compared to the same period in 2019 with even greater declines seen in April 2020 . The gloIn a study of a UK district hospital there was a 43% decrease in the number of invasive coronary angiography, 63% reduction in computed tomography coronary angiography, and cancelations of all transesophageal echocardiograms, transcatheter aortic valve implantation and electrophysiological studies . This stElectrophysiological studies  as well The redistribution of resources, community uncertainty and changes in models of care poses great challenges in cardiology training, research and outpatient management. The aforementioned decreases in cardiac procedures and investigations threatens the quality of training in cardiology. Decreases in invasive and non-invasive procedures impacts trainee exposure and therefore proficiency in these skills. Furthermore, redistribution of staff to meet emergent needs in patient care has been observed in many centers  during oCardiac rehabilitation programs were also temporarily suspended in many areas to assist in limiting spread of disease. This has led to the implementation of home cardiac rehabilitation programs which faces similar challenges to telehealth but also has the potential of expanding availability of these programs, particularly to geographically isolated individuals . ResearcIn addition to the impacts on cardiovascular research, training in cardiology has changed greatly in response to COVID-19. Negative impacts of the pandemic on cardiovascular research and training, in conjunction with the potential of increasing cardiac morbidity from delayed presentations, poses a great threat to future outcomes in patients with cardiovascular conditions. This may result in a “perfect storm” of an increasing population of more clinically complex patients whose treatment is impeded by stunted advances in cardiovascular medicine and lack of adequately trained staff. Compounding the concerns of growing cardiovascular morbidity during the pandemic and post pandemic period is the growing healthcare burden of “long COVID.” Upto a third of patients with COVID-19 report symptoms following resolution of infection . CardiovWith the continued spread of COVID-19 and emergence of variants, the impacts of the pandemic are projected to continue , 107. ThTo limit pathogen exposure to staff and outpatients, many outpatient clinics have shifted to a telehealth model of care . Whilst Diagnosis of cardiac arrythmia in the outpatient setting during the pandemic has proven challenging, with a decrease in health care contact and the reliance on telehealth impacting the accessibility of electrocardiograms. Practice updates have been published to address this issue with the utilization of direct-to-consumer electrocardiogram devices and prescribed ambulatory rhythm monitors, but this has limitations to widespread use including cost, need for expansion of infrastructure in health systems and patient education . Given pGiven the concerns of increasing cardiovascular morbidity secondary to patients deferring presentation during the pandemic, optimal training of staff and resource allocation to cardiology is essential. The described impacts of the pandemic on cardiology trainee exposure and therefore proficiency are likely to continue whilst physical distancing measures remain in place. Simulation training in cardiology has been an area of growing interest in recent years and provides promise as a method of developing procedural skills whilst limiting risk of infection to staff . FurtherTelemedicine has not only been shown to provide a roadmap to management paradigms in acute cardiovascular disease, establish cardiac rehabilitation and chronic disease programs but also explore primary prevention options . SimilarThere has been a significant reduction in all-cause cardiovascular hospitalizations during the COVID-19 pandemic, consistent with the rapid establishment of social containment measures worldwide. Subsequently, there were observed reductions in cardiovascular procedures and significant interruptions to training. These trends were most apparent in the early pandemic period and correlated with increased cardiovascular mortality. Given the potential impacts of increasing cardiovascular morbidity on healthcare systems focused upon management of COVID-19, action is required to minimize these indirect impacts of the pandemic on cardiovascular services.AB and MK contributed to conception and design of the study and conducted the data collection. MK wrote the first draft of the manuscript. AB contributed to sections of the manuscript. MK created the figures with review by AB. Both authors contributed to manuscript revision, read, and approved the submitted version.