Coronavirus disease 2019 (COVID-19) pandemic has impacted many aspects of people’s lives all over the world. This Facebook survey study aimed to investigate the COVID-19-related factors that were associated with sleep disturbance and suicidal thoughts among members of the public during the COVID-19 pandemic in Taiwan. The online survey recruited 1970 participants through a Facebook advertisement. Their self-reported experience of sleep disturbance and suicidal thoughts in the previous week were collected along with a number of COVID-19-related factors, including level of worry, change in social interaction and daily lives, any academic/occupational interference, levels of social and specific support, and self-reported physical health. In total, 55.8% of the participants reported sleep disturbance, and 10.8% reported having suicidal thoughts in the previous week. Multiple COVID-19-related factors were associated with sleep disturbance and suicidal thoughts in the COVID-19 pandemic. Increased worry about COVID-19, more severe impact of COVID-19 on social interaction, lower perceived social support, more severe academic/occupational interference due to COVID-19, lower COVID-19-specified support, and poorer self-reported physical health were significantly associated with sleep disturbance. Less handwashing, lower perceived social support, lower COVID-19-specified support, poorer self-reported physical health, and younger age were significantly associated with suicidal thoughts. Further investigation is needed to understand the changes in mental health among the public since the mitigation of the COVID-19 pandemic. Coronavirus disease 2019 (COVID-19) is a novel infectious disease that emerged in Wuhan, China at the end of 2019 and rapidly spread worldwide .People in Taiwan also suffered from threats of COVID-19. The Taiwan Centers for Disease Control (Taiwan CDC) identified the risk of the COVID-19 pandemic and delivered necessary policy quickly at the end of January 2020. According to the situation report of Taiwan CDC , 443 casIn addition to the socio-economic burden that COVID-19 has caused, the pandemic may also have hazardous effects on the public’s mental health. Several studies had addressed the psychological impact of COVID-19. A web-based survey reported that the overall prevalence of anxiety symptoms, depressive symptoms, and poor sleep quality were 35.1%, 20.1%, and 18.2%, respectively, among the public affected by the COVID-19 outbreak in China . AnotherAlthough previous studies explored the high prevalence of psychological distress for the public during the COVID-19 pandemic, it was still insufficient for investigations regarding the risk factors associated with mental health problems, such as social support. An Egyptian population-based study demonstrated that only 24.2% of individuals had increased support from friends, while 40.6% of them reported increased support from family members during the COVID-19 pandemic . HoweverTherefore, the aim of the current study focused on the impact of COVID-19 on daily lives and how varying levels of support may affects people’s mental wellbeing, such as level of sleep disturbance and suicidal thoughts.Participants were recruited through a Facebook advertisement from April 10 to 23, 2020. Facebook users were eligible for this study if they were ≥20 years old and living in Taiwan. The Facebook advertisement included a headline, main text, pop-up banner, and link to the research website and questionnaire. The advertisement was designed to appear in the Facebook users’ “news feeds,” which is a continually updated list of posts from advertisers and the user’s connections (such as friends and the Facebook groups that they have joined). Our advertisement only targeted users’ news feeds, as opposed to other Facebook advertising locations , because news feed advertisements are most effective in recruiting research participants . The advThis study was approved by the Institutional Review Board (IRB) of Kaohsiung Medical University Hospital  20200011). As participation was voluntary and survey responses were anonymous, the IRB ruled that this study did not require informed consent. The study participants were given no incentive or reward for their participation. The links were provided regarding the COVID-19 information by the Taiwan CDC, Kaohsiung Medical University Hospital, and Medical College of National Cheng Kung University so participants could learn more about COVID-19.The sleep disturbance and suicidal thoughts of participants were assessed with the question on a 5-point Likert scale, with scores ranging from 0 (never) to 4 (extremely severe). Participants who rated the items of sleep disturbance and suicidal thoughts > 0 were classified as having sleep disturbance or suicidal thoughts, respectively . The detThe participants’ gender , age, and education level (high school or below vs. college or above) were collected. Moreover, whether the participants were healthcare workers was also identified.The five-item questionnaire developed by Liao and colleagues to assess individuals’ level of worry about H1N1  was applWith reference to a previous study, seven questions were developed to evaluate the changes to participants daily lives due to COVID-19 . The resFour questions were developed to assess the impact of COVID-19 on social interaction. The responses were transformed into 0  and 1 . Cronbach’s α was 0.78. Higher total scores for the four questions represented COVID-19 having a more severe impact on the individual’s social interactions .The academic/occupational interference was evaluated by the COVID-19 pandemic with one question. Participants responded to the question on a 5-point Likert scale ranging from 0 (entirely no interference) to 4 (extreme interference) .Three questions were used to measure the level of perceived social support. The responses to these three items were graded on a 5-point Likert scale, with scores ranging from 0 (entirely disappointed) to 4 (extremely satisfied). Cronbach’s α was 0.81. A higher total score represented a higher level of perceived social support.The participants’ level of COVID-19-specified support was estimated with five questions. The responses to the questions were graded on a 3-point Likert scale, ranging from 0 (entirely insufficient), 1 (mild insufficient), and 2 (sufficient). Cronbach’s α was 0.75. A higher total score represented higher satisfaction with the level of COVID-19-specified support .Two questions from the Self-Perceived Health Questionnaire developed by Ko and colleagues  were useDescriptive analysis was used to summarize the variables. Univariate logistic regression with crude odds ratios (cOR) was used to identify potential COVID-19-related factors associated with sleep disturbance and suicidal thoughts. Furthermore, all potential predictive variables identified from the first step were eligible for inclusion in the forward stepwise logistic regression models with adjusted odds ratios (aOR) to determine the independent predictors for sleep disturbance and suicidal thoughts. All tests were examined using a two-tailed test with the alpha level set at <0.05. All data were processed using SPSS version 23.0 for Windows .n = 31) and those aged below 20 years (n = 30), the data of 1970 participants  were entered for analysis. The mean age of the participants was 37.81 ± 11.00 years. A summary of the remaining characteristics for all participants are listed in Initially, there were 2031 respondents who filled in the online questionnaire. After excluding those respondents with missing values (p = 0.002), more severe worry about COVID-19 , more severe impact of COVID-19 on social interaction , lower perceived social support , lower self-reported physical health , higher academic/occupational interference , lower COVID-19-specified support , and more household disinfection .A total of 1099 (55.8%) participants reported sleep disturbance, and 212 (10.8%) reported having suicidal thoughts in the past week . Table 1p = 0.001), more severe impact of COVID-19 on social interaction , lower perceived social support , poorer self-reported physical health , more severe impact of COVID-19 on academic/occupational interference , and lower COVID-19-specified support  remained significant independent predictors associated with sleep disturbance.p < 0.001), being transgender , being non-healthcare workers , more severe worry about COVID-19 , lower perceived social support , poorer self-reported physical health , lower COVID-19-specified support , and less handwashing   .p < 0.001), less handwashing , lower perceived social support , poorer self-reported physical health , and lower COVID-19-specified support  remained significant independent predictors of suicidal thoughts (The results of the forward stepwise logistic regression demonstrated that younger age (aOR = 0.93; thoughts .The findings of the current study were discussed initially with the primary outcome, including sleep and suicidal thoughts. Then several independent predictors associated with sleep disturbance and suicidal thoughts were discussed. The current study was conducted using an online survey, which has been reported to be a promising method for evaluating how the general public understand and perceive a fast-moving infectious disease outbreak . In the The present study found that a high level of worry about COVID-19 was significantly associated with sleep disturbance. Previous study indicated that degree of worry was significantly associated with psychological distress measured by General Health Questionnaire-28 during 2009 A/H1N1 influenza . AnotherSocial distancing is one of the main protective behaviors against contracting COVID-19 . MoreoveTo prevent the spread of COVID-19, authorities all over the world announced stay-at-home and school-closure orders, which interfere with people’s academic/occupational performance. The present study found that the higher the academic/occupational interference by COVID-19 the higher the predicted sleep disturbance. Although academic and occupational activities may be restored as the risk of COVID-19 is mitigated, it takes time and consistent policies to restore economic prosperity. The unemployment rate increased because of the enormous impact of COVID-19 on the global economy. Research has found that the unemployment rate increased in parallel with the prevalence of depressive and anxiety disorders . AcademiThe daily lives of the public have changed due to the adoption of protective behaviors against contracting COVID-19 and searching for information on COVID-19. The present study found that less handwashing was significantly associated with suicidal thoughts in the multiple logistic regression. Handwashing is the most recommended behavior by the WHO to protect individuals from contracting COVID-19 . HoweverThe present study found that poorer self-reported physical health was significantly associated with sleep disturbance and suicidal thoughts. Several possible etiologies may account for this association. First, poorer physical health, such as chronic diseases or impaired physical function, may directly increase psychological distress . Second,Younger age was an independent predictor for suicidal thoughts as determined by multivariate logistic regression. It was also potentially associated with sleep disturbance. A recent study in China also demonstrated that younger subjects were at high risk of mental illnesses, such as general anxiety disorder during the COVID-19 pandemic . MoreoveThe present study has several limitations. First, although recruiting participants through the internet is a promising research method for targeting the general public, possible selection bias exists for those who are not netizens. Hence, a paper-and-pencil test and advertisements posted on public area may recruit participants who rarely surf the internet. Second, the cross-sectional design of this study during acute pandemic stage limited causal inference and the presence of sufficient information at follow-up. A prospective follow up study may further explore the causality between variables and change of measurements with time, especially during plateau or remission stage. Third, this study was conducted during the period of COVID-19 mitigation but not during period when COVID-19 first emerged in Taiwan. Therefore, the initial impact of COVID-19 cannot be identified. Finally, sleep pattern and suicidal thoughts were only measured by a single question, which may limit the implication of the current study. Formal questionnaires such as the Pittsburgh Sleep Quality Index may provide comprehensive assessment for sleep problems.The present study identified several COVID-19-related predictors for sleep disturbance and suicidal thoughts among people during the COVID-19 pandemic. This massively undesirable effect on mental health deserves more attention and support from authorities during the COVID-19 pandemic. For instance, a lower support system was associated with higher risk of sleep disturbance and suicidal thoughts, indicating the importance of timely support during pandemics. In addition, the significant association between less handwashing and suicidal thoughts demonstrated the possibility that individuals with suicidal thoughts may have poor coping strategies of infection control. Hence, intervention to those with mental health problems during the COVID-19 outbreak is necessary to enhance their coping with the threats of infection, which may decrease the risk of poor infection control. The study provides information that could aid timely intervention in the mental health of the public. Moreover, sleep disturbance and suicidal thoughts may occur not only during the COVID-19 pandemic but also during the restoration period. Further investigation is needed to fill the limitations of the current study. The prospective study with follow up at different stages of the pandemic can help us better understand the changes of association between mental health and multi-dimensional factors. Moreover, studies with multiple recruiting sources and detailed questionnaires of mental health problems can further extend the application of the findings of the current study.


First identified in November 2019 in Hubei Province, the coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 soon spread worldwide to become a global health pandemic. The COVID-19 preferentially damages the respiratory system that produces symptoms such as fever, cough, and shortness of breath. However, the infection often tends to disseminate to involve various organ systems. Recent evidence indicates that SARS-CoV-2 can cause significant neurological damage and resultant neurological symptoms and complications. Here, we provide a comprehensive and thorough review of original articles, case reports, and case series to delineate the possible mechanisms of nervous system invasion and damage by SARS-CoV-2 and subsequent consequences. We divided the neurological manifestations into three categories: (1) Central Nervous System involvement, (2) Peripheral Nervous System manifestations, and (3) Skeletal Muscle Injury. Headache and dizziness were found to be the most prevalent symptoms followed by impaired consciousness. Among the symptoms indicating peripheral nervous system invasion, anosmia and dysgeusia were commonly reported. Skeletal muscle injury predominantly presents as myalgia. In addition, encephalitis, myelitis, cerebrovascular disease, Guillain-Barre syndrome, and Miller Fischer syndrome were among the commonly noted complications. We also emphasized the association of pre-existing comorbidities with neurological manifestations. The aim of this review is to provide a deeper understanding of the potential neurological implications to help neurologists have a high index of clinical suspicion allowing them to manage the patient appropriately. The first coronaviruses were identified in animals affecting the respiratory, gastrointestinal, and central nervous system (CNS) . In the Nowadays, a highly contagious pandemic prevails, becoming the focus of concern for health care workers around the globe. This newly emergent coronavirus disease 2019 (COVID-19), first recognized in the city of Wuhan, Hubei Province of China in early December 2019, presents as an unusual case of pneumonia of unknown etiology . The symCOVID-19 has generated significant interest among scientists, researchers, and health care professionals across the globe. Since the emergence of the virus, extensive research is constantly underway to ensure up-to-date information on the manifestation of the virus is present. Relevant information on its mode of transmission, manifestations, pathogenesis, and potential mitigating strategies has started emerging. Although SARS-CoV-2 is primarily a respiratory infection, evidence suggests that patients with a severe infection also present with neurological symptoms such as headache, altered mental status (AMS), hypogeusia, anosmia, and neuralgia. The symptoms may deteriorate and lead to complications such as meningitis, encephalopathy, cerebrovascular events (CVEs), skeletal muscle injury, demyelinating disorders, Guillain-Barre syndrome, and Miller Fisher syndrome -7. HowevWe present a comprehensive literature review of all the data and evidence available regarding the neurological manifestations and complications of SARS-CoV-2 infection, to date. The goal of this comprehensive review is to provide a better understanding of the prevalence, severity, progression, and possible outcomes of COVID-19. Furthermore, this review will aim to acclimatize possible outcomes of COVID-19 with, rare but possible invasions of the nervous system in the presence of COVID-19. Being well equipped and updated about possible neurological presentations and complications will not only allow the ability to make a timely diagnosis but also help adopt appropriate management modalities to prevent further complications. Due to the abundance of new researches emerging daily, recently published work, as well as pre-print case reports, small case series, and original papers have been discussed in this review to elucidate the continuum of neurological conditions in SARS-CoV-2 positive cases.The pathogenesis of COVID-19 infection on the nervous system can be explained by nervous system invasion and nervous system damage.Mechanism of nervous system invasion by COVID-19Through various mechanisms that have been suggested in regard to the neurological symptoms prevalent in COVID-19, currently, the most accepted mechanisms of the neurological spread of SARS-CoV-2 are that of hematogenous spread and retrograde axonal spread. Figure A. Hematogenous SpreadGenetic sequences of the RNA of SARS-COV-2 contain a spike protein sequence that recognizes the ACE2 receptors on the surface of the cellular membrane. ACE2, a metalloproteinase, is present on the surface epithelium of alveoli, intestine, arteries, and veins and acts as functional receptors for SARS-COV-2 . These rB. Retrograde Axonal SpreadAnother widely suggested route of invasion is through dissemination via the olfactory nerve. In this route, the virus first invades peripheral neurons and advances towards the CNS system via a mechanism that is referred to as retrograde axonal transport, through synaptic spaces. Although yet to be proven, dissemination into the CNS via olfactory nerve through the cribriform plate has been supported by the presence of the virus in the nasal epithelium, olfactory bulb, and by the development of hyposmia . Thus, tDue to the multiple methods of entry of SARS-CoV-2 into the CNS, eradicating the CNS symptoms can prove to be difficult and may pose a serious challenge as clinicians work, undoubtedly, around the clock.Mechanism of nervous system damage by COVID-19Neurological damage by SARS-CoV-2 is likely to occur in the three following ways, as shown in Figure A. Hypoxic InjurySevere pneumonia secondary to SARS-CoV-2 infection causes respiratory insufficiency and subsequent hypoxia. Chronic systemic hypoxia ultimately causes damage to the brain. The hypoxic state coupled with hypercapnia, peripheral vasodilatation, anaerobic metabolism, and accumulation of toxic metabolites progressively induces cerebral injury due to the development of neural swelling and cerebral edema .B. Immune-mediated InjuryThe immune-mediated mechanism of cerebral insult is mainly attributed to the phenomenon, known as the cytokine storm. Cytokine storm involves the overproduction and release of excess amounts of leukocytes and cytokines, especially IL-6 into the blood to help fight infection. Abundant cytokines and leukocytes, in turn, cause increased activation of macrophages, lymphocytes, and endothelial cells leading to over-activation of the complement system and coagulation cascade. Hyperactive immune response, therefore, results in potentially fatal hypercytokinemia and subsequent disseminated intravascular coagulation, ultimately leading to multi-organ failure -16.C. Cerebrovascular InjuryA rise in the luminal pressure of cerebral vessels due to the binding of the virus to ACE2 receptors on blood vessels may also lead to the consequence of intracerebral hemorrhage . DysfuncNeurological manifestations of COVID-19Patients with SARS-CoV-2 may have symptoms of varying degrees, ranging from a mild cough/fever to multiple organ dysfunction that can progress to multiple organ system failures. Clinical data has currently demonstrated that some COVID-19 patients may also have symptoms similar to that of intracranial infections such as headache, dizziness, altered mental status (AMS), and epilepsy. Also, an increasing number of COVID-19 patients experience a sudden loss of odor or taste sensation indicating a peripheral nervous system (PNS) invasion. Therefore, olfactory and taste disorders (OTD) can also be observed in COVID-19 .In a retrospective, observational case series, from Wuhan, China, Mao et al. evaluated 214 COVID-19 positive patients (mean age = 52.7 years) hospitalized in Union Hospital of Huazhong University of Science and Technology in Wuhan, China . ResultsAccording to the results by Mao et al., the most commonly reported CNS symptoms were dizziness (n = 36 [16.8%]) and headache (n = 28 [13.1%]); whereas the most frequently reported PNS symptoms were taste (n = 12 [5.6%]) and smell (n = 11 [5.1%]) impairment . These fIn a single-center prospective case series, Helms et al. investigated neurological features of 58 COVID-19 positive patients admitted in Strasbourg University Hospital, France. Neurological manifestations were recorded in 49 out of 58 (84%) patients with COVID-19-related acute respiratory distress syndrome (ARD) including encephalopathy, notable confusion and agitation, and corticospinal tract signs such as ankle clonus, hyperreflexia, and Babinski reflex. As assessed by the confusion assessment method for the intensive care unit (CAM-ICU) scale, agitation was the most common symptom occurring in 69% of hospitalized patients (n = 40) followed by confusion in 26/40 patients (65%). Corticospinal tract signs n = 39, 67%) were the second most common neurological manifestation in these patients. The study also reported a dysexecutive syndrome in 14 out of 39 patients at discharge which encompasses behavioral and cognitive features like poor attention span, disorientation, and poorly defined command-response gestures [% were thYin et al., retrospectively, evaluated clinical features of 106 COVID-19 positive patients with neurological manifestations in Huoshenshan Hospital in Wuhan, China. The patients were divided into two groups of severe and non-severe disease. Fever  was found to be the most common symptom. Among neurological symptoms, myalgia  was the leading symptom. Myalgia was followed by paralysis of extremities , depressed consciousness , and positive focal neurological signs  in occurrence. The study also revealed that patients in the severe group were likely to have AMS . A high Post-viral loss of sense of smell is one of the leading causes of anosmia in adults, accounting for up to 40% anosmia cases. Mechanism of post-viral anosmia is poorly understood; however, it is plausible that infection of olfactory bulb via direct invasion through olfactory neurons plays a key role . In addiIn a cross-sectional survey, Giacomelli et al. interviewed 59 patients of COVID-19 admitted to L. Sacco Hospital in Milan, Italy. Of these, 20 (33.9%) patients reported either taste (dysgeusia or ageusia) or olfactory disorders (hyposmia or anosmia) [Bagheri et al. reported the results of an Iranian cohort of COVID-19 patients as participants. The results stated that anosmia and hyposmia was a symptom in 48.3% of the responses, while 83.38% of responses reported a reduced taste sensation . 76.24% Another cross-sectional study supporting the smell and taste dysfunction has been done by Yan et al. . This stTable Central nervous system complications of COVID-19Figure A. Meningitis and EncephalitisAs per currently available research, at least three case reports of SARS-CoV-2 encephalitis have been reported -28. The Moriguchi et al. shared their experience in dealing with a 24-year-old man who presented with sudden onset convulsions with obvious neck stiffness followed by loss of consciousness and a one-day history of fever . He had Ye et al. also reported a case of SARS-CoV-2 infection-related encephalitis. A Wuhan male patient presented with an altered level of consciousness which progressed to confusion . He had B. EncephalopathyMao et al. reported headache and encephalopathy in 40% of patients in their cohort but the details and the diagnostic criteria used were not described . In a reAnother very recent report from Michigan, United States, describes the first reported case of acute hemorrhagic necrotizing encephalopathy (AHNE) in COVID-19 patients . A femalC. Cerebrovascular DiseaseAnother striking observation is the prevalence of COVID-19-associated cerebrovascular events (CVE). A significant body of evidence indicates that respiratory infection, in particular, is an independent risk factor for acute cerebrovascular disease . A retroSharifi et al. reported a case of intracerebral hemorrhage in a 79-year-old COVID-19 positive Iranian male . The patD. Acute MyelitisIn a case reported by Zhao et al., a 66-year-old male presented with bilateral flaccid paralysis coupled with urinary and bowel incontinence . FollowiE. Demyelinating DisorderApart from encephalitis and toxic encephalopathy, demyelinating disorders of CNS following a viral infection are also common. Recently, Zanin et al. reported a case of a 54-year-old woman having demyelinating lesions in the brain and spine induced by SARS-CoV-2 . She wasShe also had anosmia and ageusia for the past few days and a history of anterior communicating artery aneurysm which was treated 20 years back. Her head CT was normal; chest X-ray revealed interstitial pneumonia and PCR for SARS-COV-2 came positive. EEG showed two seizures and MRI of the brain revealed alterations of the periventricular white matter, hyperintense lesions in T2-weighted imaging (T2WI), without the restriction of diffusion nor contrast enhancement. Similar lesions were found in the cervical and dorsal spinal cord at the bulbo-medullary junction. Surprisingly, CSF PCR for SARS-COV-2 was negative. Other conditions such as multiple sclerosis, viral and bacterial infection were ruled out. This case suggests that the pathogenesis of viral infection was due to systemic inflammatory response syndrome (SIRS). The pro-inflammatory condition caused by virus-induced cytokine storm seems to be responsible for glial cell activation and subsequent demyelination . ProductTable Peripheral nervous system complications of COVID-19Figure A. Anosmia and AgeusiaAnosmia and ageusia are common neurological findings in patients with COVID-19 as described above. Mao et al. reported taste impairment in 5.6% and smell impairment in 5.1% patients from a Chinese cohort . In thisIn another case report, an African American female presented with distorted taste sensation and a diminished sense of smell which eventually progressed to complete anosmia . She latAnother report describes a physician who developed mild flu-like symptoms with a sudden onset of persistent anosmia and ageusia. Sniffin’ Sticks test was used to verify anosmia while the ageusia was tested with taste screening among other tests .B. Guillain-Barre SyndromeGuillain-Barre syndrome (GBS) is an acute immune-mediated disease of the peripheral nerves and nerve roots. It is associated with various infectious agents and presents with ascending flaccid paralysis with areflexia/hyporeflexia spread over a course of days to weeks. It can often involve cranial nerves, with the involvement of the facial nerve being the most common . An assoToscano et al. also reported the incidence of neurologic symptoms specifically pointing towards GBS in five COVID-19 patients . These sC. Miller Fisher SyndromeMiller Fisher syndrome (MFS) presents with acute onset external ophthalmoplegia, ataxia coupled with the loss of tendon reflexes. Usually, MFS occurs following a viral illness similar to GBS. The most common infectious agents are Haemophilus influenzae, Campylobacter jejuni, and CMV . GutiérrThe first patient is a 50-year-old male who presented with complaints of impaired sense of smell and taste, areflexia, ataxia, right fascicular oculomotor nerve palsy, right internuclear ophthalmoparesis, albuminocytologic dissociation and positive testing for GD1b-IgG antibodies. With an oropharyngeal swab positive for SARS-CoV-2, his treatment was soon started with intravenous immunoglobulin. Soon after treatment, all of his neurological symptoms resolved besides anosmia and ageusia. The second patient, a 39-year-old male, presented with ageusia, areflexia, bilateral abducens palsy, and albuminocytologic dissociation. This was preceded a few days before with diarrhea and low-grade fever. With a positive oropharyngeal swab for COVID-19, this patient was treated with acetaminophen and showed complete neurological recovery. His diagnosis was polyneuritis cranialis, often called isolated multiple cranial neuropathies.Though the occurrence of MFS and polyneuritis cranialis might be less likely, it is pivotal to consider these complications in a COVID-19 patient with a similar presentation.Table Skeletal muscle injuryMuscle injury is defined as a patient having myalgia and increased serum creatine kinase levels above 200 U/L . As depiThe exact mechanism underlying muscle injury in SARS-COV-2 patients is yet to be known, however, it is hypothesized that expression of ACE2 receptors on skeletal muscles and viral invasion through these functional receptors play a key role in the pathogenesis of injury . AnotherAssociation of neurological manifestations of COVID-19 with pre-existing comorbiditiesAnother area of concern is the increased susceptibility of patients with pre-existing comorbidities to develop COVID-19-associated neurological manifestations. Data from various studies suggest that patients with underlying disorders are more likely to have a severe infection and thus, are more prone to developing neurological symptoms and complications.Mao et al. found that neurological symptoms were more frequent in severe disease patients (45.5% vs 30.2%) . The resTo further elucidate the effect of comorbidities on the severity of SARS-CoV-2 infection, Yang et al. carried out a meta-analysis to investigate the prevalence of comorbidities in the COVID-19 patients and its correlation with severity of the disease. The results showed that hypertension and diabetes were the most prevalent comorbidities, followed by cardiovascular and respiratory diseases . The pooFurthermore, patients with pre-existing neurological comorbidities also tend to develop neurological manifestations as supported by a retrospective case series of 106 COVID-19 positive patients with comorbid neurological conditions; 74.4% had a previous cerebral infarction, 18.9% had dementia, 9.4% had acute cerebral infarction, five had followed by sequelae of a cerebral hemorrhage in 4.7%, intracranial mass lesions in 3.8%, epilepsy in 2.8%, Parkinson’s disease in 1.9%, myelopathy in 0.9% . The eviNeurologists' viewpointFrom a neurologist's perspective considering the rapid patient influx, usual non-emergency procedures have been rescheduled like elective epilepsy monitoring to make sure that beds are vacant for COVID-19 patients.Another newly emerging dimension of medicine is the telehealth systems. With the outdoors having an increased risk of viral transmission, many patients have been directed towards online consultations. Teleneurology has made sure that the patients are facilitated in every way possible. Efforts to limit doctor-patient interaction are made to reduce viral transmission. Doctors have been trying to reduce the number of elective diagnostic and surgical procedures unless necessary. To limit exposure, medical students are being taught through online classes and are being provided with online study material.For a neurologist in such times, it is necessary to be open-minded when treating a COVID-19 patient. Neurologists are expected to thoroughly evaluate the patient’s presenting features and compliment them with radiographic findings and cerebrospinal fluid analysis. Differentiating the direct effect of coronavirus against the systemic effects  of the virus on the nervous system is also encouraged. Neurologists need to be careful and take all the necessary precautions for the safety of their patients as well as themselves. Both the neurologists and patients must don protective disposable masks, latex gloves, caps, and carry sanitizers containing ethanol or hydrogen peroxide. All patients as well as doctors must regularly have their temperature checked before they enter the consultation room. It is imperative that proper counseling regarding sanitary techniques to limit viral transmission is done for every patient -7.Adopting a more futuristic approach may prevent long-term damage -7. BeariGiven the global dimension of the COVID-19 and rising number of fatalities every day, it is essential that this issue is tackled through a multidisciplinary clinical and research perspective. As the impact of SARS-CoV-2 on the nervous system increases, neurologists face a very real challenge in terms of attempting to note the early onset of neurological symptoms. This review summarizes the available information in a concise and more absorbable manner so readers may benefit from it. The review states that the coronavirus may alter the neuronal mechanism either directly, or may exaggerate a preexisting condition. Knowing that this viral infection can result in long-term damage, we propose that patients should be followed up by careful imaging and laboratory as well as neurological assessment to determine the magnitude of brain damage.


COVID-19 emerged in late 2019 and has rapidly spread through many countries globally. The causative SARS-CoV-2 virus was not known until recently, and there is little or no natural immunity in human populations. There is an urgent need for vaccines and drugs to combat this new pandemic. In just a few months, huge efforts and resources by government, academia, and industry have been thrown into the race to develop a vaccine. This brief review summarizes and discusses the array of technologies being applied to vaccine development, highlighting the strengths and weaknesses of the various approaches. In March 2020, SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO)3, and as of 18 July 2020, there are over 14 million confirmed cases with over 594,000 deaths worldwide. These figures are expected to rise (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports)2. With the emergence of SARS-CoV-2, there are currently over 2,400 listed studies on the National Institute of Health database  aimed at identifying a solution to this pandemic. The development of a much-needed vaccine against SARS-CoV-2 is of utmost importance. To date, there are more than 100 vaccine candidates being developed by industry and academic institutions using a wide range of technologies including live attenuated, viral vectored, DNA/RNA-based, protein-based, and inactivated vaccines6. At the time of writing, 19 vaccines are recorded as being in clinical trials . SARS-CoV-2 was first identified in Wuhan, China, and has since spread globally at an alarming rate, with over 200 countries and territories being infected trials 4–7. Th7. There are many other advantages associated with DNA-based vaccines. Notably, they are renowned for their safety profile since the vectors employed are non-replicating and encode and express only the target antigen. The vectors therefore are unable to revert to a disease-causing form, which is a risk with viral vectors. Another key advantage with DNA-based vaccination is the absence of vector-specific immunity, which allows these products to be utilized in prime and boost regimens with multiple products intended for the same patient8. RNA-based vaccines are also a promising alternative owing to their potential for low-cost manufacture and good safety profile in animal studies11. However, both DNA- and RNA-based vaccines have their own set of challenges. Both vaccines could suffer from the drawback of having low immunogenicity, as DNA vaccines could potentially integrate into the human genome, while there are concerns about the stability of RNA vaccines12. As there are currently no approved DNA or RNA vaccines for medical use in humans13, the question about low immunogenicity has not yet been resolved  has announced that the Coalition for Epidemic Preparedness Innovations (CEPI) has awarded $6.9 million of funding to INOVIO to work with IVI and the Korea National Institute of Health (KNIH) for a phase I/II clinical trial of INO-4800 in South Korea. The trial will be conducted in parallel with INOVIO’s phase I study, which is currently ongoing with 40 healthy adults receiving the vaccine candidate and will eventually be expanded to older adults15. An RNA vaccine candidate, mRNA-1273, is being developed by Moderna in collaboration with NIAID. The Biomedical Advanced Research and Development Authority (BARDA), a division of the Office of the Assistant Secretary for Preparedness and Response (ASPR) within the US Department of Health and Human Services (HHS), has agreed to cooperate to hasten the development of mRNA-1273 by pledging up to $483 million in funding16. Healthy adults aged 18 to 55 were recruited for phase I trials. Two injections of mRNA-1273 were given 28 days apart at a dose of 25 μg, 100 μg, or 250 μg. Dire adverse events were absent, and no trial halting rules were met, although one participant in the 25 μg group withdrew because of an unsolicited adverse event, transient urticaria, which was postulated to be linked to the first vaccination. Live virus neutralization capable of reducing SARS-CoV-2 infectivity by 80% or more was detected at day 43 post-vaccination in all participants. Of the three doses evaluated, the 100 μg dose was optimal based on its capacity to trigger high neutralization responses and Th1-skewed CD4 T cell responses. The reactogenicity profile at 100 μg was better than for the other two doses. The safety, reactogenicity, and immunogenicity of mRNA-1273 are currently being evaluated in phase II trials using two vaccinations given 28 days apart. A total of 600 participants, 300 aged 18–54 and 300 aged 55 and above, have been assigned to three groups: placebo, 50 μg of vaccine, or 100 μg of vaccine at both vaccinations17. A phase III trial of mRNA-1273 is expected to begin in July with an estimated 30,000 participants. With the expected final dose of 100 μg, Moderna is confident to scale up manufacturing to approximately 500 million to 1 billion doses per year18.DNA- and RNA-based platforms present the greatest potential for speed of production since culturing and fermentation are not required for their synthesis. The potential of this approach is showcased by Moderna, whose vaccine candidate advanced to clinical testing just 2 months after sequence identificationesolved . The lac19. Additionally, certain viral vectors such as adeno-associated virus may not be cost effective owing to their low titer production20. Ultimately, viral vectors still present themselves as a valid choice for vaccine development against SARS-CoV-2, as illustrated by their successful use in the eradication of smallpox20. Examples of such vaccines currently under development are ChAdOx1-S, Ad5-nCoV, aAPC, and LV-SMENP-DC. The latter two vaccines, developed by Shenzhen Geno-Immune Medical Institute, are currently in phase I (aAPC) and phase II (LV-SMENP-DC) clinical studies. The Ad5-nCoV vaccine pioneered by CanSino Biologics is the first SARS-CoV-2 vaccine to reach phase II clinical trials5. Phase I clinical studies for Ad5-nCoV were conducted between March 16 and March 27. No serious adverse events within 28 days of vaccination were reported in vaccine recipients. Specific antibodies, including neutralizing antibodies, increased significantly at day 14 and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination29. A phase II study is currently underway with 500 participants registered in three different groups: 250 participants will receive the vaccine, 125 participants will receive a lower vaccine dose, and 125 participants will receive placebo. The immune response will be tested at 0, 14, and 28 days and 6 months after vaccination30. ChAdOx1-S, developed by the University of Oxford in partnership with AstraZeneca, is the first vaccine candidate to reach phase III clinical trials5. A study has reported that a single dose of the vaccine is able to elicit a strong immune response in rhesus macaques31. Additionally, a trial study conducted in pigs demonstrated that ChAdOx is able to elicit a greater antibody response when given a booster shot, suggesting that a two-dose approach may give better protection in humans against SARS-CoV-232. However, it should be noted that nose swabs and oropharynx and mediastinal lymph node testing revealed viral gRNA in both vaccinated and control animal groups at 3 and 5 days post-inoculation. Interestingly, viral genome was detected in cervical lymph node in the vaccinated group but not in the control group. Detection of virus in these tissues indicates the vaccine does not provide complete protection against SARS-CoV-2 infection. Viral RNA (gRNA and sgRNA) load in lung tissue was also shown to vary dramatically between individual animals but was determined to be significantly lower in the vaccinated group than in the control group. Another troubling result to note from this study is that despite observing neutralizing antibodies in vaccinated animals, the titers reported were extremely low31. Generally, neutralizing antibodies elicited by effective vaccines can be diluted more than a thousand-fold and still maintain their effectiveness33. However, the results reported by Oxford show that the serum could be diluted only 4- to 40-fold before losing its neutralizing activity33. ChAdOx1-S was well tolerated in humans, with a trial of over 320 vaccinated individuals showing no strong adverse effects34. The phase III clinical trials of this vaccine will involve 8,000 individuals in the United Kingdom, 5,000 individuals in Brazil, and 2,000 individuals in South Africa35. AstraZeneca has reached an agreement with Europe’s Inclusive Vaccines Alliance (IVA) to supply up to 400 million doses of ChAdOx1-S starting by the end of 2020 at no profit. The total manufacturing capacity of this vaccine currently stands at 2 billion doses34.Virus-based vectors are powerful tools for vaccination. Their effectiveness stems from their ability to infect cells, which allows them to be highly efficient, specific, and able to trigger robust immune responses. Despite their advantages, viral vectors have several disadvantages . For exa36. Inactivated vaccines are produced using bacteria or viruses by deactivating them with heat, chemicals, or radiation. These processes terminate the pathogen’s ability to replicate, leading to them being more stable and having higher safety profiles. These attributes allow for their use in immunocompromised individuals37. However, the characteristics that contribute to their strengths are also weaknesses. As the pathogens are inactivated, these vaccines generally stimulate a much weaker immune response than live vaccines and require several doses for effective immunity to be established. The immune response to an inactivated vaccine is also typically humoral. Antibody titers against the targeted antigen will diminish with time, leading to the need for booster shots36  of PiCoVacc at day 0, 7, and 14 before virus challenge at week 3. It was demonstrated that monkeys vaccinated with PiCoVacc produced anti-SARS-CoV-2 neutralizing antibody titers similar to those of recovered patients. This study also indicated that PiCoVacc is safe, as there was no infection enhancement or immunopathological exacerbation observed in vaccinated monkeys. PiCoVacc is currently in phase I human clinical trials as stated above. The company plans to initiate phase II and III clinical trials with PiCoVacc by the end of this year39. There are two other inactivated vaccine candidates being developed by the Beijing Institute of Biological Products and the Wuhan Institute of Biological Products, respectively, both of which are currently in phase I/II clinical trials. Both institutes are collaborating with Sinopharm for the development of these vaccines.Inactivated vaccines have been successfully employed over the past 70 years and are widely used todayhots36 . Regardlin vitro andin vivo experiments against different respiratory viruses in mice, human cells, and non-human primates, providing lasting immunity with just a single dose25. LAV have a simple production process using well-established Vero cells, which are currently the most widely accepted cell line by regulatory authorities for vaccine development, since they have been in use for vaccine manufacturing for nearly 40 years. LAVs are also proven to grow and infect microcarrier beads in large-scale fermenters up to 6,000 L and in serum free media with zero loss in production output40. Existing manufacturing infrastructure can be easily utilized because of its cost effectiveness for large-scale manufacturing41. LAV has certain drawbacks, notably the existing possibility of reversion to virulence, which has strong safety implications, especially in immunocompromised patients26 , developed by codon deoptimization. This technology has proven itself to be cost effective for large-scale manufacturing and has a smooth regulatory approval pathway, as it has demonstrated high efficacy and potency in bothents26 . Nonethe45. However, as with other vaccine platforms, protein subunit vaccines come with their own set of challenges, with the most prominent one being their lack of efficacy. A subunit vaccine presents an antigen to the immune system without the involvement of viral particles using a specific, isolated protein of the pathogen. In the likely scenario where the isolated proteins are denatured, they will become associated with other antibodies different from what was initially targeted, leading to the lack of efficacy46 . Although antibodies are generally protective, rare cases have been documented in which pathogen-specific antibodies enhance disease—a phenomenon known as ADE. ADE is most prominently associated with dengue virusSafety aspects of the COVID-19 vaccines under development are of the utmost importance. Thorough clinical trials need to be carried out prior to marketing of the vaccine. Recent reports in India on the possibility of launching a vaccine in record time without allowing sufficient time for clinical trials are disturbing. Although COVID-19 vaccine development is of the utmost global importance, it is crucial that we do not cut corners and that vaccines are approved only after having passed through rigorous clinical trials.There are an extraordinary number of COVID-19 vaccines currently under development around the world. Highly optimistic timeframes of 12–18 months to get to the distribution of approved vaccines are being touted. Vaccines typically take many years or even decades to develop, e.g. the smallpox vaccine took 25 years to develop for human use, the HPV vaccine 15 years, the rotavirus vaccine 15 years, and the influenza vaccine 28 years. The COVID-19 vaccine initiatives aspire to have vaccines ready for distribution by 2021. This is a truly remarkable and unprecedented timeframe for vaccine development. The majority of vaccines won’t progress beyond pre-clinical or early clinical testing, but, of course, we need only one effective COVID-19 vaccine to halt this pandemic. Fewer than 10% of drugs or vaccines that enter clinical trials ever progress to become available for human use. For example, 30% fail at phase I trials. Of those that progress to phase II, 69% fail and then a further 42% fail at phase III. Of those products that successfully pass through phase III trials, a further 15% do not gain regulatory approval. Because of the drastically shorter time being allotted for the pre-clinical development of COVID-19 vaccine candidates, it is conceivable that a higher proportion of these candidates may fail during clinical testing. In addition to vaccine development, a number of resource-intensive activities will need to be undertaken in parallel, particularly the construction of manufacturing facilities capable of producing at a global scale. We are hopeful the unmatched resources being directed into the international vaccine R&D effort will lead to a successful vaccine capable of stopping this new pandemic.


As of December 14, 2020, children and adolescents aged <18 years have accounted for 10.2% of coronavirus disease 2019 (COVID-19) cases reported in the United States.This investigation included children and adolescents aged <18 years who received testing for presence of SARS-CoV-2 in nasopharyngeal swab specimens by RT-PCR at outpatient testing health care centers (including drive-up testing locations) or emergency departments associated with the University of Mississippi Medical Center (UMMC) during September 1–November 5, 2020  with a person with known COVID-19, school or child care attendance, and family or community exposures ≤14 days before the SARS-CoV-2 test. For participants who attended in-person school or child care, parents or guardians were asked about the frequency of mask use among students and staff members inside the facility. Parents were also asked about frequency of mask use and social distancing by child and among other persons present for each community exposure. Descriptive and statistical analyses were performed to compare case-patients with control participants, assessing differences in demographic characteristics, school, community exposures, and close contact. Logistic regression models accounting for child sex, age group, and race/ethnicity were used to estimate aORs and 95% CIs, comparing odds of exposures among case-patients and control participants. In each model, SARS-CoV-2 test result  was the outcome variable, and each exposure response was the predictor variable. Statistical analyses were conducted using SAS software .Among the 397 participants, 82 (21%) were aged <4 years, 214 (54%) were female, 217 (55%) were non-Hispanic Black, and 145 (37%) were non-Hispanic White . ParticiCompared with control participants, case-patients were more likely to have attended gatherings with persons outside their household, including social functions , activities with children , or to have had visitors at home  during the 14 days before the SARS-CoV-2 test ; 27% of In this investigation, children and adolescents who received positive test results for SARS-CoV-2 were more likely than were similarly aged participants who had negative test results to have had reported close contact with a person with confirmed COVID-19 and less likely to have had reported consistent mask use by students and staff members inside the school facility. Among participants with close contact with a person with COVID-19, close contacts of case-patients were more likely to be family members and less likely to be school or child care classmates than were those of control participants. Attending in-person school or child care during the 2 weeks before the SARS-CoV-2 test was not associated with increased likelihood of a positive SARS-CoV-2 test result. The majority of respondents reported universal mask use inside school and child care facilities as recommended by Mississippi State Department of Health,Among children and adolescents with COVID-19, 69% reported close contact with a person with COVID-19, similar to previous findings among children and adults (The findings in this report are subject to at least four limitations. First, the sample included 397 children and adolescents tested during September–November 2020 at health care facilities associated with one large academic medical center in Mississippi and might not be representative of children and adolescents in other geographic areas of the United States. Further, parents of eligible children who could not be contacted or refused to participate could be systematically different from those who were interviewed for this investigation. Second, unmeasured confounding is possible, such that reported behaviors might represent factors, including concurrently participating in activities in which possible exposures could have taken place, that were not included in the analysis or measured in the study. Most respondents were aware of their child’s SARS-CoV-2 test results and interviews were conducted several weeks after testing, factors which could have influenced parent responses. Third, parent report of frequency of mask or cloth face covering use at schools and child care programs was not verified. Finally, case or control status might be subject to misclassification because of imperfect sensitivity or specificity of PCR-based testing.This investigation highlights differences in community and close contact exposures and in-school mask use between children and adolescents who received a positive SARS-CoV-2 test result and those who received a negative SARS-CoV-2 test result during the beginning of the 2020–21 academic year in Mississippi. Continued efforts to prevent transmission at schools and child care programs are important, as are assessments of various types of activities and exposures to identify risk factors for COVID-19 as children engage in classroom and social interactions (Community and close contact exposures contribute to the spread of COVID-19.Among children and adolescents aged <18 years in Mississippi, close contact with persons with COVID-19 and gatherings with persons outside the household and lack of consistent mask use in school were associated with SARS-CoV-2 infection, whereas attending school or child care was not associated with receiving positive SARS-CoV-2 test results.Close contacts with persons with COVID-19 and gatherings contribute to SARS-CoV-2 infections in children and adolescents. Consistent use of face masks and social distancing continue to be important to prevent COVID-19 spread.


Chikungunya virus (CHIKV) infection has been commonly detected in tropical countries. The clinical manifestations of CHIKV infection are similar to those of rheumatoid arthritis. Outbreaks of CHIKV infection in Thailand have been reported, and the inductions of various cytokines and chemokines in CHIKV patients during those outbreaks have been shown. Although immune responses in CHIKV infection have been increasingly reported, the mechanisms associated with pathology induction are still not clearly understood. This review focuses on cytokine and chemokine production in CHIKV infection, in association with the severity of joint inflammation. Several cytokines and chemokines involved in the induction or regulation of inflammatory responses were shown to associate with the severe and persistent symptoms in CHIKV infection. Further studies on the difference in immune responses observed in an autoimmune disease, rheumatoid arthritis, infectious disease, and CHIKV infection, would provide additional insights useful for proper CHIKV therapy, especially in patients with severe joint pains. Togaviridae family. It can be transmitted to humans by Aedes aegypti and Aedes albopictus mosquitoes. CHIKV infection was first identified in 1952, and has re-emerged over the last two decades. Currently, there are three genotypes with distinct antigenic characters: West African, East/Central/South African (ECSA) and Asian genotypes [Chikungunya virus (CHIKV) is an arthropod-borne alphavirus of the enotypes ,4, and ienotypes . Since tenotypes ,8,9 and enotypes . CHIKV infection is not life-threatening, and the symptoms may include fever, headache, muscle pain, joint swelling, and rash. Most patients experience swelling and joint pain, and symptoms can last for months or years. There is still no licensed vaccine or antiviral drug against CHIKV available. The molecular mechanisms underlying pathologies observed in CHIKV infection are not clearly understood, and it has not yet been established whether CHIKV can induce arthralgia directly. However, the clinical features of patients with CHIKV infection are similar to those of patients with rheumatoid arthritis (RA). It has been suggested that immune responses to CHIKV infection may promote the symptoms observed in patients with severe joint pain ,12,13. FOur group reported an outbreak of CHIKV infection in the southern part of Thailand in 2008 . Most paTo investigate the roles of immune responses in the severity of CHIKV infection, several studies were conducted on patients with different levels of disease severity. Additionally, another study, performed in the southern part of Thailand, investigated the role of cytokines in CHIKV infection. This study divided subjects into non-CHIKV, mild, and severe groups. Blood samples were collected on the day of presentation and 30 days later. This study showed that IL-6 levels were higher in patients with severe symptoms than in the mild symptom group. However, the severe group had significantly lower IL-8 levels than the CHIKV patients with mild symptoms .Venugopalan et al.  reportedCytokine profiles were compared during acute CHIKV infection in patients with chronic joint pain (a median of 20 months after infection) and age-and gender-matched patients without joint pain. Strong cytokine responses during acute infection correlated with a decreased incidence of chronic joint pain. Low TNF-α, IL-2, IL-4, and IL-13 levels during acute infection were suggested to be predictive markers for chronic joint pain. This study determined the level of cytokines present in large sample groups (n = 121 in each group). In addition, patients with and without joint pain were compared. This report suggested that cytokine production during the acute phase facilitates viral clearance. In addition, cytokines such as IL-4 and IL-13 produced early could prevent immune-mediated arthritis [Another study determined cytokine and chemokine profiles during the acute phase (mean 2.97 ± 1.27 d after illness onset). The results were compared with those for healthy controls. Levels of IFN-α, IL-6, IL-8, IL-10, IFN-γ, monokine induced by gamma interferon (MIG), MCP-1 and IP-10 were significantly increased compared with controls . IL-17A,Neurological symptoms were not commonly observed in CHIKV-infected patients. Cytokines in CHIKV-infected patients with neurological symptoms have been reported . In thisIn a study by Colavita et al. , the cytThe cytokine levels in patients with high and low viral loads were compared. Patients with high viral load had higher levels of IFN-α and IL-6 in the acute phase. Studies in animal models showed the correlation of viremia with these two cytokine levels ,27. IL-1In addition to cytokines, components of immune regulation may play roles in the control of cytokine production. IL-18 binding protein (IL-18BP) is the secreted protein which can bind to IL-18 with high affinity. Binding of IL-18BP inhibits the IL-18 activity resulting in the reduction of IFN-γ production induced by IL18 . We prevRegulatory T cells (Tregs) are cells involved in immune regulation. A lower number of Tregs is associated with autoimmune diseases. In another study, Kulkarni et al.  assessedAlthough a number of studies have examined cytokine and chemokine in CHIKV infection, studies that investigate patients with varying levels of disease severity are necessary to confirm the role of immune responses in pathologies observed in CHIKV infection. In addition, certain cytokines are produced at certain times after CHIKV infection. The studies concerning disease severity and the kinetics of cytokine production are crucial for a detailed understanding of immunopathogenesis in CHIKV infection. Cytokines involved in inflammation and immune regulation were investigated in terms of severity of CHIKV infection. Cynomolgus macaques infected with CHIKV demonstrate similar features to human patients. It has been shown in this animal model that CHIKV antigen could be detected in various tissues up to 3 months post-infection. This suggests that the persistence of CHIKV could be another factor responsible for prolonged cytokine induction . Rheumatoid arthritis is an autoimmune disease, in which joint and systematic inflammation is commonly observed. Several inflammatory cytokines have been shown to be influence RA severity . IL-6 isIL-8 is a chemokine that shows elevated levels in RA. Both IL-6 and IL-8 are major cytokines involved in joint inflammation in RA ,37. GeneIn summary, reports on immune responses to CHIKV infection have suggested that certain cytokines are involved in the determining the severity of CHIKV infection. However, a larger sample size that includes samples from various time points would elucidate the role of each cytokine and the differences in data obtained from different studies. Moreover, the amount or type of CHIKV infection present in different individuals could play a role in the emergence of different clinical manifestations. Lastly, host immunogenetics could be another factor influencing the differences observed in CHIKV infection ,46.


The aim of this study is to compare postoperative outcomes and follow-up of two different modifications facilitating surgical technique of frozen elephant trunk (FET) procedure for complex thoracic aortic diseases - zone 0  and zone 3 (fixation with islet-shape arch repair).From May 2012 to December 2018, data were collected from 139 patients who had been treated with FET procedure for complex thoracic aortic diseases. According to Ishimaru arch map, patients with proximal anastomotic site of hybrid graft at zone 0 and zone 3 were grouped as Group A  and Group B , respectively. Mean age of study population was 54.7±11.4 years, and 111 patients were male (79.9%).P=0.32). Three patients from both groups had transient spinal cord ischemia (P=0.334). Although mean total perfusion time was longer in Group A, duration of visceral ischemia, when compared with Group B, was shorter (P<0.001). Five-year survival rate was 82.8% in Group A and 81.5% in Group B (P=0.876).In-hospital mortality was observed in 20 (14.4%) patients . There was no significant difference between both groups in terms of in-hospital mortality. Four patients from Group A and three patients from Group B had permanent neurological deficit (FET procedure is a feasible repair technique in the treatment of complex aortic diseases, providing satisfactory early results. Because of its advantageous aspects, zone 0 fixation with debranching is the preferred technique in our clinic. Afterwards, Kato et al. took the first steps of one-stage treatment by implantation of the stent graft through anterograde route and this method had been evolved into the ‘frozen elephant trunk’ (FET) procedure after various modifications in time-6. According to the aortic arch mapping system described by Ishimaru and Mitchell, direction of FET modifications was drawn. In the classical application of FET procedure, surgeons from Western countries generally seem to prefer total arch replacement in an islet-shape, while Asian colleagues usually prefer supra-aortic de-branching. Initially, the surgeons used to anastomose the proximal portion of the stent graft to the distal of the left subclavian artery at zone 3, in order to ensure longer segment stabilization of descending aorta. As with the hybrid arch repairs, surgeons have tried variations of the zone and aortic arch repair to provide technical convenience and increase the benefit to the patients-11. In our study, we compared the postoperative outcomes and follow-up of the complex thoracic aortic diseases treated with FET procedure, using either fixation zone 0 with total arch de-branching, or fixation zone 3 with islet-shape arch repair.The evolution of the treatment of complex aortic diseases began after the ‘elephant trunk procedure’, described by Brost, and hybrid repair methods with lower mortality rates replaced conventional surgeryFrom May 2012 to December 2018, the data of 139 patients who had been treated with FET procedure due to complex thoracic aortic diseases were collected. According to Ishimaru arch map, the patients with proximal anastomotic site of the hybrid graft at zone 0 and zone 3 were grouped as Group A and Group B, respectively. All the patients with any pathological involvement, such as dissection, aneurysm, or occlusion at their supra-aortic branches, were strictly included in Group A. The remaining patients received one of the two surgical modifications, depending on the surgeon’s experience and perioperative preference upon observing the aortic intimal quality. The Research Ethics Committee of our institute approved this retrospective study (No. 2017.6/8-53). The mean age of the study population was 54.7±11.4 years, and 111 patients were male (79.9%). Data were collected for patients’ demographics, indications for intervention, risk factors, procedures, and outcomes. The follow-up protocol included postoperative computerized tomography angiography (CT-A) before discharge, a clinical examination, and a CT-A three months postoperatively and annually thereafter. Emergency operation was performed in 64 patients, who applied with acute type A aortic dissection (n=61), acute complicated type B aortic dissection (n=10), and ruptured thoracic aortic aneurysm (n=1). The preoperative clinical details and patient characteristics are given in The patients who underwent surgery within the first 14 days from the beginning of back pain and other symptoms of dissection were considered as acute dissection. Early outcomes were accepted as complications in 30-day and in-hospital mortalities. Thoracoabdominal CT-A was utilized in diagnosis and follow-up of aortic pathologies. Spinal cord ischemia (SCI) was defined as new-onset transient or permanent paraparesis or paraplegia after surgery. Renal failure was defined as the need for hemodialysis, and respiratory failure was defined as the need for re-intubation or tracheostomy postoperatively.® GmbH, Germany) prostheses were used in all cases. As previously described, central venous catheter, arterial monitorization at left arm, and near-infrared spectroscopy (or NIRS) were used routinely in all patients. Aortic arch repair was performed at moderate hypothermia using bilateral selective antegrade cerebral perfusion (flow rate = 10-15 mL/kg/min). Median sternotomy was performed in all patients. While right subclavian artery was used for direct arterial cannulation, venous drainage was provided through right atrium. A venting cannula was placed through upper-right pulmonary vein. Myocardial protection was ensured with blood cardioplegia. Proximal aorta repair was done during cooling phase. After aortic clamp was removed, selective antegrade cerebral perfusion was initiated. E-vita Open Plus prosthesis was introduced and released in an antegrade fashion into the true lumen of the descending aorta over the wire with the guidance of transesophageal echocardiography and it was fixed to the aorta with single U-sutures at the selected zone. Stent graft size was determined by measuring the actual lumen diameter of aorta in preoperatively performed CT-A imaging. Two different anastomotic techniques were used when aortic arch replacement was performed:In our study, the E-vita Open Plus .Details of aortic and concomitant cardiac procedures are shown in Post hoc analyzes of meaningfulness between the zone groups were performed by one-way ANOVA Bonferroni post hoc test. After Kruskal-Wallis test, Mann-Whitney U test was used with Bonferroni correction. Survival was calculated by the Kaplan-Meier analysis and log rank (Mantel Cox) analysis was applied to the survival comparison in the zone groups. For statistical significance, a P-value < 0.05 at a 95% confidence interval was considered significant. Chi-square post hoc analyzes with Bonferroni correction was considered significant at values < 0.0167, and adjusted P-values were used in other post hoc assessments. For statistical analysis, IBM Corp. Released 2012, IBM SPSS Statistics for Windows, Version 21.0, Armonk, NY: IBM Corp. was used.In descriptive statistics, continuous mean ± standard deviation, median, minimum, and maximum values, and categorical data are given together with number and percentage values. In the statistical comparison of the data, Chi-square test, Fisher’s exact test, and likelihood ratio were appropriately used for categorical data. Fisher’s exact test and likelihood ratio test were used when the expected value in any of the cells in the probability tables evaluated was < 5. Testing distributions for normality for continuous data was assessed by Kolmogorov-Smirnov analysis, and one-way analysis of variance (ANOVA) and Kruskal-Wallis tests were used in the intergroup comparisons. P=0,534).Early mortality was observed in 20 (14.4%) patients, 12 of these (60%) had acute type A aortic dissection. These mortalities were due to bleeding (n=8), multiple organ failure (n=4), malperfusion (n=2), neurological complication (n=2), and low cardiac output (n=4). There was no statistical difference between groups in terms of early mortality rates (P=0.41). Two patients died due to malperfusion syndrome with bowel and limb ischemia. The postoperative outcome data are given in Seven patients (5%) had permanent neurologic deficit (stroke and hemiplegia) and five patients (3.6%) had transient SCI (paraplegia and paraparesis). Two patients with paraplegia and three patients with paraparesis recovered completely with the aid of physiotherapy within a few months after surgery. Although the mean visceral ischemia time (81.2±14.2 min) was higher in patients with SCI, no significant difference was found between the patients with SCI and those without SCI (68.1±2.3 min) (There were four late deaths at a mean follow-up time of 65.9±2.5 months. Two patients died from each of the groups. One patient of Group A treated for chronic type A aortic dissection was lost due to acute respiratory distress syndrome two years after surgery and the other Group A patient with chronic type B aortic dissection died two months after surgery due to post-dissection aneurysm rupture before scheduled thoracic endovascular repair (TEVAR). In Group B, one of the patients treated for acute type A aortic dissection died after reoperation for type 1A endoleak from the proximal suture line of FET stent graft due to stroke eight months after the first operation. The other Group B patient who had low cardiac ejection fraction due to congestive heart failure died 18 months after surgery.During the follow-up period, TEVAR was performed in 12 patients as second stage therapy, due to extensive thoracic aortic aneurysm or post-dissection aneurysm (n=6) and stentinduced new entry (n=6). Two patients from Group B underwent supra-aortic de-branching with TEVAR due to type 1A endoleak from anastomotic suture line of FET stent graft. There was no difference between re-intervention and total mortality rates between the groups  and 2.. The description of new intervention models has been needed especially in the high-risk patient group for conventional surgery to reduce complications, prevent perioperative mortality, and cope with the challenges posed in major surgery in treatment of complex aortic diseases. Conventional elephant trunk technique defined by Borst pioneered the hybrid aortic surgery and with the improvement of the skeletonized grafts with stents, this technique has advanced into 'stented elephant trunk', 'open stent grafting', and FET procedures.Complex thoracic aortic diseases include pathologies bearing lethal complications, such as dissection or aneurysms, and have extensive aortic involvement, including ascending aorta, aortic arch, and descending aorta. Conventional surgery is challenging with high mortality and morbidity rates,11, fixation of the stent graft to the distal of the left subclavian artery is preferred as zone 3 (fixation zone 3), in order to provide longer segment stabilization of descending aorta.Over time, FET has undergone various modifications to facilitate the surgical technique based on the experience of the surgeon. However, decision-making is based on the extent of the disease and the concomitant pathology of the aortic arch. Western surgeons tend to perform hemiarch-like arch repair by preparing the arch vessels as an islet-shape and extending the graft to the small curvature in order to shorten the operation time. On the Asian side, total arch repair is completed with an additional fourth branch assist, which provides earlier distal body perfusion and warming during supra-aortic de-branching. Except for few authors. The pathology with the highest mortality rates was found to be acute type aortic dissections. When results were evaluated according to arch replacement, in-hospital mortality rates ranged from 0 to 12.8% in islet-shaped repair,17-19, while in supra-aortic de-branching case series it was between 3,2% and 8.8%,20,21. There are limited number of cases found in the English literature about the total arch de-branching with fixation zone 0. Hospital mortality rate of 3.2% was reported in the study of Shimimaru with 126 patients, and Havericht et al. found no mortality in their case series of 26 patients. It was observed that the zone selection and arch replacement technique did not make any difference in mortality between the groups in our study.Hospital mortality rates ranged from 0 to 17.2% in studies performed with fixation zone 3 without discrimination of arch replacement technique due to aortic involvement and comorbid factors in complex thoracic aortic diseases. In our study, there were no differences in SCI and stroke rates between two groups, and the rates were consistent with the literature. These favorable results in our center are accomplished by relying on all protective measures during all FET procedures.Unrelated to the surgical technique, FET procedure itself is a risk factor for neurological deficit development due to the presence of cervical vessels in the surgical field and its influence on spinal artery circulation. Using bilateral ASCP in moderate hypothermia to protect from cerebrovascular events, placement of the stent graft above the T8 level, keeping the ASCP time < 90 minutes in moderate hypothermia, and obtaining short durations of body circulatory arrest with early distal perfusion are well-accepted protection methods against SCI. Despite all protection methods, SCI and stroke rates for FET procedure range from 0.8% to 21.7% and 2.6% to 13%, respectively. The use of all techniques in a wide variety of patient groups has both perioperative and postoperative benefits, such as (i) shortened lower body circulatory arrest and hypothermia time, (ii) less spinal artery coverage, (iii) anastomotic simplicity and better bleeding control, and (iv) stabilization of dissection in cervical branches. Yet, it has its own disadvantages too, (i) the presence of un-resected aortic tissue may cause dilation in the future due to endoleaks, (ii) the occurrence of stroke risk due to supra-aortic de-branching, and (iii) risk of recurrent laryngeal nerve and phrenic nerve damage. However, in our study, there were no differences between the techniques in terms of postoperative outcomes as well as renal insufficiency, bleeding, and intensive care unit and hospital stays.The aim of modified FET techniques is to improve the postoperative results by reducing the prevalence of postoperative renal failure and re-explorations for bleeding as well as providing technical facilitation and perform re-interventions safely without increasing the risk of surgery. TEVAR was performed successfully in 12 patients without any complications in our study.FET, described as a one-stage therapy especially for aortic dissections, reduces the rate of re-interventions providing shrinkage of aortic diameter by reducing the pressure on the aortic wall in aneurysms and including rapid false lumen thrombosis in dissections compared with conventional supracoronary graft replacement. However, post-dissection aneurysm and its complications required re-intervention due to reentries in the distal aorta. In our study, distal aortic re-interventions were performed because of stent-induced new entry (n=6) or scheduled secondary intervention thoracic aortic aneurysm or post-dissection aneurysm (n=6). Furthermore, in thoracic aortic aneurysms with mega aortic syndromes, it is possible to create a suitable landing zone for the second stage without any complications owing to the conventional elephant trunk graft. FET procedure by fixation zone 3 with islet-shape arch repair is suitable in cases when a concomitant valvular or coronary intervention is required, to decrease perfusion time and related complications.In our opinion, the fixation zone 0 and de-branching technique should be preferred in case of a second stage procedure requirement, such as presence of excessive number of distal reentries, in young and Marfan syndrome patients and in aneurysmatic aorta  with a post-dissection aneurysm risk and extensive thoracic aortic aneurysms. However, it should not be forgotten that although shorter segment coverage of descending aorta is protective against spinal cord injury, this leads to poor spinal artery collateralization and may increase the risk during second stage intervention. However, when islet-shaped arch repair is performed, there is a possibility of a second arch repair with a new supra-aortic de-branching due to enlargement of the remaining diseased aortic tissue. After all, FET offers a variety of surgical technique combinations specific to the patient and the pathology.In order to shorten the CPB duration, patients with left subclavian artery lateralization or sufficient posterior cerebral circulation may be treated with fixation zone 2 by coverage of the left subclavian artery as in TEVARThis is a retrospective cohort study in which complex thoracic aortic diseases were caused by various diseases and thus it was limited in terms of the inability to separate outcomes for each disease. There might have been a bias between groups due to complexity of aortic involvement which probably might affect surgical results. More accurate results will be obtained by enlargement of patient series and randomization of groups. Because of its advantageous aspects, such as surgical anastomotic facilities, early visceral perfusion, and stabilization of the cervical vessels, zone 0 fixation with supra-aortic de-branching is the preferred technique in our clinic.In conclusion, FET procedure, which makes the repair techniques of surgery more feasible in the treatment of complex aortic diseases, provides satisfactory early results. Personalized treatment should be applied according to the characteristics of each pathology and the patient's comorbid factors.


In 2016, India reported 709 acute diarrheal disease (ADD) outbreaks . Tribal populations are at higher risk with 27% not having accessibility to safe drinking water and 75% households not having toilets. On June 26, 2017 Pedda-Gujjul-Thanda, a tribal village reported an acute diarrheal disease (ADD) outbreak. We investigated to describe the epidemiology, identify risk factors, and provide evidence-based recommendations.We defined a case as ≥3 loose stools within 24 h in Pedda-Gujjul-Thanda residents from June 24–30, 2017. We identified cases by reviewing hospital records and house-to-house survey. We conducted a retrospective cohort study and collected stool samples for culture. We assessed drinking water supply and sanitation practices and tested water samples for faecal-contamination.p < 0.001) than others (20%[55/269]). Symptoms included diarrhea (100%), fever (17%), vomiting (16%) and abdominal pain (13%). Drinking water from five shallow bore-wells located in downhill colonies was significantly associated with illness . In multi-variate analysis, drinking water from the shallow bore-wells located in downhill colonies , illiteracy , good hand-washing practice  and household water treatment  were significantly associated with illness. Two stool cultures were negative for Vibrio cholerae. Heavy rainfall was reported from June 22–24. Five of six water samples collected from shallow bore-wells located in downhill colonies were positive for faecal contamination.We identified 191 cases  with median age 36 years (range 4–80 years) and no deaths. The attack-rate (AR) was 37% (191/512). Downhill colonies (located on slope of hilly terrains of the village) reported higher ARs (56%[136/243], An ADD outbreak with high attack rate in a remote tribal village was associated with drinking water from shallow downhill bore-wells, likely contaminated via runoff from open defecation areas after heavy rains. Based on our recommendations, immediate public health actions including repair of leakages at contaminated water sources and alternative supply of purified canned drinking water to families, and as long-term public health measures construction of house-hold latrines and piped-water supply initiated. Globally there are an estimated 1.7 billion cases and 2.2 million deaths from acute diarrheal disease (ADD) every year .Lack of access to safe drinking water and basic sanitation are the leading causes of ADD burden globally and in India. It is estimated that globally 58% of ADD deaths are attributed to inadequate drinking water, sanitation and hygiene . The WHOThe “indigenous” populations are socially, culturally and economically isolated and usually lack access to basic drinking-water and sanitation services. Therefore, they are vulnerable to ADD outbreaks and other emerging and re-emerging diseases . The UniOn June 26, 2017, Kama-reddy district of Telangana state reported 55 ADD cases from the Pedda-Gujjul-Thanda village. We conducted the outbreak investigation to describe the epidemiology, identify risk factors, and provide evidence-based recommendations.Pedda-Gujjul-Thanda village is a small tribal village with a total population of 563. The village is remotely located as an isolated community with a hilly terrain and is resource-limited with poor accessibility to sanitation and hygiene facilities. The nearest health care facility available for the residents is located at a distance of 10 km from the village.We defined a case as three or more loose stools within 24 h in a resident of the Pedda-Gujjul-Thanda village from June 22, 2017 to July 2, 2018.To find cases, we reviewed medical records of local health care facilities accessed by village residents in the nearby town. We conducted a medical camp in the village during the outbreak period for five days. We conducted a house-to-house survey in the village to find more cases, which are niether reported to health facility nor medical camp.We conducted a retrospective cohort study to identify risk factors associated with illness. We defined the cohort as residents of Pedda-Gujjul-Thanda village from June 22, 2017 to July 2, 2018. Village resident was the unit of analysis. For data collection, we trained five teams of local paramedical staff. Using a pre-structured questionnaire, we collected data on demographic characteristics and risk factors related to drinking water, sanitation and hygiene. Good hand-washing practice was defined as reported washing of hands with soap and water every time after defecation and before eating. A bore-well less than 30-m-deep, as assessed from the records of village administration, was considered a shallow bore-well.Vibrio cholerae, Salmonella and Shigella on nutrient agar, MacConkey agar and deoxycholate citrate agar. Enteric pathogens were identified by biochemical reaction and by agglutination with anti-sera. We collected details of recent rainfall and conducted an environmental survey with household as sampling unit to assess drinking water, sanitation and hygiene practices. We assessed availability of residual chlorine in all village bore-wells and tested four of five bore-wells in the most affected colonies for faecal contamination by H2S method in field. Water was filled up to the ‘fill line’ of the sample bottle and incubated at room temperature (250–370 C) for 36–48 h and observed for colour change in the medium. A water sample was suspected to be contaminated with faecal matter, if it turned black [Two stool samples were collected by the treating physician from admitted patients on the first day of hospital admission and transported to the state reference laboratory within two hours in Cary-Blair transport medium. The samples were cultured for ed black , 11. BecWe analysed the data to describe the occurrence of cases over time, place, and person. We calculated relative risks (RR) with 95% confidence intervals (CI), population attributable risk percentages and conducted multiple logistic regression analysis with the dependent variables including consumption of shallow-downhill bore-well water, report of visible contaminants like mud in drinking water, illiteracy, household water treatment and good hand-washing practice. We used Epi Info version 7.2 for statistical analysis.We identified 191 ADD cases , with a village attack rate (AR) of 37% (191/512). The attack rate increased with age, with highest among > 60-year age group (55%) and lowest among children under-10 years (11%) , vomiting (16%) and abdominal pain (13%). 72% (138/191) cases reported to health care facilities and the medical camp conducted in the village. Among the 191 cases, 159 (83%) had mild illness treated with oral rehydration solution; 30 (16%) had moderate dehydration treated with intravenous fluids on out-patient basis, and 2 (1%) with severe dehydration were admitted in the district hospital for treatment with antibiotics (metronidazole and ciprofloxacin) and intravenous fluids.Cases started reported on June 26, 2017, with onset of symptoms from 24 June 2017. Maximum cases were reported on June 27, 2017, and no new cases were reported after June 30, 2017 . Katroth sub-tribe resided in colonies A, B and G; Badhawath in colonies C and D; Nenawath in colony E and Baromath in colony F  participated in the study. Among the 512 participants, median age was 28 years (range 1–80 years) with 52% females; 50% reported as illiterate with agriculture as the main source of livelihood for 76%.We analysed possible risk factors associated with ADD Table . DrinkinVibrio cholerae, Salmonella and Shigella on culture. Among 110 households, 100 (91%) were available for environmental survey. Among the 100 houses surveyed, 79 (79%) were kutcha  type, made of mud, thatch and other low-quality material. Only 5 (5%) households had a designated toilet at home while the remaining 95 (95%) practiced open defecation at a site located on the slope of the hill behind the downhill colonies B and C  from 22 to 24 June 2017.Stool samples collected from two hospitalized cases showed no growth for  C Figs.  and 3. BThe village residents were discouraged from using shallow bore-well water and were provided with safe canned drinking water until all leakages were secured. Leakages in water supply from the bore-wells were identified and secured. Chlorine tablets were distributed for household level water disinfection. We informed the residents to avoid open defecation near drinking water sources and residential premises. Public health staff conducted health education daily to improve awareness among the villagers about water, sanitation, and hygiene. After active implementation of these control measures, cases declined rapidly in the village Fig. .A rapid systematic epidemiological investigation of this outbreak identified water contamination points and likely mode of contamination. Based on these findings and our recommendations, the local health department instituted immediate public health actions including repair of leakages at contaminated water sources and alternative supply of purified canned drinking water to families. Effective implementation of public health measures limited the exposure of the community to contaminated water source resulting in rapid containment of the outbreak.Waterborne disease outbreaks tend to have cases spread over a time-period due to ongoing exposure to the contaminated water. In contrast, the pattern of epidemic curve in the present waterborne disease outbreak resembled that of food-borne with a point source exposure. Heavy rains contributed to the run-off of water from the open defecation site into the ground water of shallow wells located on slopes of hilly terrain resulting in heavy contamination and sudden rise of cases. Rapid control measures in the small village, implemented effectively within a short period of time, may have led to rapid decline of cases. The available epidemiological evidence also did not support generation of hypothesis of food-borne origin of the outbreak. In an outbreak reported among school children in Northern Greece in 2012, investigation revealed a waterborne viral gastroenteritis outbreak with a point source pattern, due to consumption of heavily contaminated water from a tap, which was not in use for two weeks during Christmas vacation [Attack rate was high in this outbreak (37%), possibly due to exposure to high pathogen load subsequent to gross faecal contamination of water sources. In the absence of other alternative water sources, this tribal community was exclusively dependent on the contaminated water source for drinking, therefore exposing a large section of the community to risk. Geetha et al. analysed 32 diarrheal outbreaks in south India in non- tribal communities and reported lower attack rates varying from 0.6 to 21.5% . HoweverDue to inadequate availability of communally managed safe public water points by the local authority, this community in Pedda-Gujjul-Thanda village was dependent on privately constructed shallow bore-wells for water supply. These are economical but likely to be unsafe. In this outbreak, open defecation site was present on the downhill slope in proximity to the residential premises and water resources, increasing the risk of drinking water contamination. Among the entire village population, 61% of ADD cases were attributable to drinking water from the ‘shallow downhill bore-wells’ (Population Attributable Fraction 61%), which was also evident from rapid outbreak containment following the elimination of exposure to this single risk factor. Since this exposure factor is amenable to long-term public health intervention, permanent elimination of shallow downhill bore-wells as water source was recommended, replacing them with properly secured deep bore-wells.E. coli and enteric viruses to be high in shallow sources of ground water especially when they are in close proximity to polluting sources [E. coli O157 outbreak in United States occurred in 1999 at a county fair (781 ill persons and 2 deaths) was due to groundwater source from a temporary unregulated well at the fairground [Shallow bore-wells are known for their susceptibility to contamination from surface land-use activities , 18. Stu sources –21. Cons sources , 23. A m sources . In deveirground .Swachh Bharat Mission (SBM)’ to ensure availability and management of water and sanitation for all. SDG 6 aims at achieving universal access to basic sanitation service by 2030; and it has been reported that between 2000 and 2017, the proportion lacking even a basic sanitation service decreased from 44 to 27% [Our findings have implication for India’s progress towards United Nation’s Sustainable Development Goal (SDG) 6 and India’s nation-wide campaign ‘4 to 27% . SBM aim4 to 27% , 27. TheThe tribal community initially obstructed the effective delivery of health care services; however, after involvement of the local stakeholders and tribal leaders, the acceptance towards medical treatment and community health services improved. Notwithstanding, most of the patients were still reluctant and did not consent for giving stool specimens for laboratory diagnosis. Establishing a rapport with the reticent tribal community was a major challenge faced by the outbreak investigation team. Lack of microbiological aetiology confirmation of the outbreak remained a limitation of the investigation due to limited stool samples and laboratory-capacity constraints of the remote area.Recognizing the pivotal importance of SDGs, national health policy of India (2017) has set the health-related cross-sectorial goal “access to safe water and sanitation to all by 2020” . GreaterThis was a community-wide acute diarrheal disease outbreak with high village attack rate in a remote tribal village of Telangana with poor availability of safe water, sanitation and hygiene (WASH) facilities. A rapid and systematic epidemiological investigation identified drinking of faecal-contaminated water from the shallow bore-wells as the leading cause for this outbreak. These bore-wells were likely contaminated from runoff after rain from open defecation areas located on a downhill slope. Prompt and targeted public health action contained the number of cases.