Background: COVID-19 is an asymptomatic condition in 40% of cases, and most symptomatic patients present with mild/moderate disease not requiring hospitalization or intensive care, especially during the Omicron wave, when the hospitalization rate was estimated to be 0.3%. The main port of entry for SARS-CoV-2 in the human body is the nasal cavity and the upper respiratory tract is affected since the early stages of the infection. Nasal irrigation or aerosol by isotonic or hypertonic saline solution is a traditional therapeutic approach for respiratory or nasal inflammation, also featured by prophylactic properties against upper respiratory infections. Methods: We conducted a prospective open-label controlled study to assess the superiority of an already existing medication (Tonimer Lab Panthexyl 800)—a sterile hypertonic solution containing seawater, xylitol, panthenol and lactic acid—to reduce the viral shedding time in patients affected by asymptomatic or mild COVID-19. COVID-19 patients (N = 108) were split into two groups: a treatment arm  and a control arm . The two groups, both testing initially positive for SARS-CoV-2 at real-time PCR (RT-PCR) on nasal swab, were followed up over time to assess the daily number of positive swab tests turning negative (study endpoint). Treatment effectiveness at various time lags since the first positive RT-PCR swab test was measured by rate of events in the experimental arm (EER) and in the control arm (CER), absolute risk increase (ARI) = (EER − CER), and number needed to treat (NNT) = (1/ARI). To investigate the endpoint, we used logistic and Cox regression models, expressing the result as odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (95%CI), respectively. The symptoms recorded with a modified COVID-Q questionnaire at both diagnosis and first negative antigenic swab test were compared in each group (treated versus controls) by exact symmetry test. Results: During the first five days of treatment, COVID-19 patients treated with Tonimer Lab Panthexyl 800 were more likely to become negative two days before controls. According to NNT, four subjects had to be treated for five days to achieve the study endpoint in one individual. The negativization rate in patients treated with Tonimer Lab Panthexyl 800 was significantly higher than patients’ treated with standard of care alone . There was no evidence of side effects. Conclusions: Nasal spray with Tonimer Lab Panthexyl 800 was effective against SARS-CoV-2, stopping viral shedding in the treatment arm two days before the control group. This treatment should be continued for at least five days after the first positive swab test for SARS-CoV-2. COVID-19 is an asymptomatic condition in 40% of cases, and most symptomatic patients present with mild/moderate disease not requiring hospitalization or intensive care, especially during the Omicron wave, when the hospitalization rate was estimated to be 0.3% [The main port of entry for SARS-CoV-2 in the human body is the nasal cavity, where the first cells infected by the virus are likely the multi-ciliated cells of the nasopharynx or trachea or the sustentacular cells of the nasal olfactory mucosa .During the Omicron transmission period, the effectiveness of COVID-19 vaccines progressively decreased, with primary as well as recurrent SARS-CoV-2 infections massively surging from December 2021 onward ,5.Since SARS-CoV-2 behaves as a “surface virus” in the nose, vaccine-resistant viral strains could arguably be washed off by nasal rinses, thereby reducing nasal viral shedding time (VST) ,7,8,9. NA recent meta-analysis evaluating both isotonic  and hypertonic (greater than 0.9% wt/vol) saline solutions against all sino-nasal diseases concluded that hypertonic saline rinses with NaCl concentration < 5% were more beneficial than isotonic saline for the management of sinonasal pathologies .−, Na+, SO42−, Mg2+, Ca2+ and K+ [The average salinity of undiluted seawater (a hypertonic solution) is about 3.5% wt/vol. Unlike saline, which consists of NaCl dissolved in distilled water, 99% of seawater salinity is due to six components: Cl+ and K+ . By draw+ and K+ .A recent narrative review considered 9 clinical studies and case reports, all supporting the use of hypertonic or isotonic solutions in the early stages of SARS-CoV-2 infection . In 8 stAlthough clinical data are still scanty, nasal and oral sprays display a more convenient application for elderly people or those who are unable to rinse/gargle . HoweverRegressed Nasal Infectivity and Shedding of SARS-CoV-2 by Achieving Negativization for COVID-19 Earlier (RE.NA.I.S.S.A.N.C.E.) clinical trial aimed to assess the efficacy of Tonimer Lab Panthexyl 800, an already existing formulation of sterile hypertonic solution spray, to shorten VST of SARS-CoV-2 from the nasal cavity of infected patientsIn view of the above, the Using an already existing medication (Tonimer Lab Panthexyl 800), a sterile hypertonic solution manufactured by Ganassini Corporate  containing seawater, xylitol, panthenol and lactic acid to be administered by nasal spray, we conducted a prospective open-label controlled clinical trial in one single center, the COVID-19 point of Treviso , in order to compare the anti-viral activity of the above drug with respect to standard of care against SARS-CoV-2 infection. The qualitative and quantitative formulation of Tonimer Lab Panthexyl 800 can be viewed in Marca Trevigiana (991/CE) and was registered on Clincaltrial.gov on 14 July 2022 (NCT05458336) [The RENAISSANCE clinical trial was approved by the ethical committee of the Local Health Unit N. 2 5458336) .VST was defined as the time between the first positive and first negative  nasal swab test . The onsAgreeing to take part within 48 h since testing positive for SARS-CoV-2 at RT-PCR;Age >18 years;Mild/moderate COVID-19 symptoms or asymptomatic SARS-CoV-2 infection;Provision of written informed consent;Completion of COVID-19-Q questionnaire  at studyThe following criteria of inclusion/exclusion were applied to select COVID-19 patients for this study: Patients testing positive for SARS-CoV-2 at RT-PCR, asymptomatic/pre-symptomatic or affected by mild/moderate COVID-19 symptoms not requiring hospitalization were recruited at the COVID-19 hub of Treviso .a treatment arm ; anda control arm .COVID-19 patients were broken down into two groups: The recruitment started with patients assigned to the treatment arm, enrolled from 23 February 2022 until 18 March 2022. Patients assigned to the control group were instead enrolled from 16 March 2022 until 30 March 2022.After acquiring verbal consent to enroll, the otolaryngology healthcare staff of Ca’ Foncello Hospital of Treviso explained patients in detail the use of the COVID-19 Antigen Rapid Test Device , evaluating their ability to perform it autonomously. All patients were provided with a set of swabs for self-testing against SARS-CoV-2, to be performed on a daily basis at home during the isolation for COVID-19 until the first negative antigenic test result. Patients were allowed to return the signed informed document by e-mail at a later stage, to have more time to reflect on their decision to take part in this clinical trial. The information/consent form also acceptance to allow the research team to directly access sensitive/clinical data of study participants.All study participants were asked to complete a modified COVID-Q questionnaire  providedAs soon as a negative antigenic test result was obtained, the patient was required to contact the research team for a second interview on COVID-19 symptoms, identical to that administered at study entry.Participants assigned to the treatment arm were allowed to take the standard of care, i.e., any medications recommended against COVID-19 plus Tonimer Lab Panthexyl 800 mOsm/Kg (CE 0546), a hypertonic solution based upon seawater enriched with xilitol and panthenol. These subjects were provided with a cylinder used to spray the nasal cavities three times/day for as much as 15 days maximum. In order to avoid potential false negative test results, patients treated with Tonimer Lab Panthexyl 800 had to self-test against SARS-CoV-2 with an antigenic test before nasal sprays.Treatment effectiveness (study endpoint) was the reduction of VST in treatment as compared to the control arm during the same time-frame of follow-up.One nasal spray based on sodium hypochlorite reportedly reduced viral titers of SARS-CoV-2 in vitro by more than two orders of magnitude . We hypo2) test.The main characteristics of the two study groups, all expressed as categorical variables, were compared with the chi-squared  = number of events/number of patients in the experimental arm);Rate of events in the control arm (CER) = number of events/number of patients in the control arm.In this prospective clinical trial two groups of subjects (treated and controls), both testing initially positive for SARS-CoV-2 at RT-PCR on nasal swabs, were followed over time to ascertain the daily number of positive swabs turning negative in each group. The effectiveness of the treatment was derived from the following two proportions:Absolute risk increase (ARI) = (EER − CER). It expresses, generally in decimal values, the absolute increase in the risk of events in the treated group compared to controls. The sign of ARI is positive when EER > CER and negative otherwise.Number needed to treat (NNT) = (1/ARI). NNT represents the expected number of patients required in order to achieve one beneficial outcome event. This estimate is easy to calculate and expresses the benefits of an intervention in the same unit of measurement (number of patients).Using the above data, and given that treatment was beneficial , the clinical significance measures were calculated as follows :AbsoluteLogistic regression, expressing the results as odds ratio (OR) with a 95% confidence interval (95%CI). OR is the ratio of the probability of the event in the treatment arm against the probability of the event in the control group. It is expressed in decimal values. OR > 1.00 or < 1.00 expresses, respectively, a beneficial or a detrimental effect of the treatment.Cox regression , expressing the results as hazard ratio (HR) with a 95% confidence interval (95%CI). HR investigates the effect of the treatment on the time until first negative antigenic swab test result. Since this was a beneficial intervention , a positive HR indicates a protective effect of the associated variable. Cox regression allows the investigation of the effect of multiple variables at the same time. Since all terms displayed in In this clinical trial measuring a dichotomous endpoint, the statistical significance of treatment effectiveness was assessed by using the following analyses:Intention to treat (ITT) analysis was adopted. ITT analysis includes all randomized patients in the groups to which they were allocated, regardless of their adherence to the entry criteria, the treatment received and any subsequent deviation from the study protocol .The symptoms recorded with a modified COVID-Q questionnaire at both COVID-19 diagnosis and first negative antigenic test were compared to each other using the exact symmetry test (which for 2 × 2 tables are reduced to an exact McNemar test). The presence of one group that received the intervention (treatment group) and one group that did not (control group) allows the separation of the effect of the intervention from that of other circumstances.Stata 14.2  was employed for the analysis.One hundred twenty subjects testing positive for SARS-CoV-2  were consecutively recruited from the COVID-19 center of Treviso between 23 February 2022 through 30 March 2022. Twelve subjects had to be dropped from the analysis: three in the treatment arm for inconsistency of dates of the swab test; 7 in the experimental arm and two in the control arm because of failing to return the signed informed consent form after initial verbal agreement. The final number of study participants included 50 patients treated with Tonimer Lab Panthexyl 800 against 58 controls, for a total number of 108 study participants.Number of negative antigenic swab test results (study endpoint) in treatment versus control arm;Proportion of endpoint in the experimental ) versus control (control event rate (CER)) group;Absolute risk increase (ARI), computed as the difference between EER and CER.The lack of negative antigenic swab test results on days 2 to 4 in the control group is noteworthy. Using day 6 as the cutoff point because EER ≅ CER, it can be seen that ARI presents only positive results from day 2 to day 5, suggesting that the endpoint (negative antigenic swab test result) in the treatment arm was more common during the first days of Tonimer Lab Panthexyl 800 application.CER and EER points and trend lines were coded using different signs. Therefore, the two plots of The encircled image (first part of the scatter plot) has been magnified to better visualize some details. As can be seen, the curved trend appears linear and the sets of points (EER and CER) cluster together closely. Interestingly, the horizontal distance between the red and blue line is of about two days. Therefore, with respect to controls, subjects treated with Tonimer Lab Panthexyl 800 nasal spray achieved negativization of nasal swab test for SARS-CoV-2 approximately two days earlier than controls.p = 0.004 in the Cox proportional hazard regression model, confirming that the new treatment during the first 5 days since first positive PCR test for SARS-CoV-2 was significantly more effective than the standard of care alone in reducing nasal VST.The hazard ratio (HR) was 6.12 with a 95% confidence interval ranging from 1.76 to 21.32 and Dry cough”, in the treatment group the number of subjects without the symptom was 18 at study entry and 36 at exit, a highly significant difference (p < 0.001). Likewise, in the control group, 23 subjects without dry cough before the study became 42 after the end of the study, resulting in a highly significant difference (p < 0.001). The parallel common trend in both groups suggests a natural change towards a normal state of health. The latter pattern was observed most often. Considering “Productive cough”, the differences between study entry and exit were not significant but figures still suggested an improvement. There was no evidence of adverse effects, e.g., before–after deterioration in the treatment but in the control arm.Furthermore, apart from a few symptoms improving more in controls , most conditions  waned more frequently in the treatment arm, which was also characterized by reduced use of anti-pyretic as well as nasal spray medications .COVID-19 patients treated with Tonimer Lab Panthexyl 800 were more likely to become negative two days before controls during the first five days of treatment. NNT analysis indicated that four subjects had to be treated for five days to achieve a reduction in VST in one patient . BeneficSince symptoms did not increase with treatment, no adverse effects could be attributable to Tonimer Lab Panthexyl 800. Moreover, improvement of most symptoms was stronger in the treatment than in control arm.Twelve individuals were excluded from the analysis after being assigned to their study arm: 9 patients failing to return the signed informed consent and three incurring a protocol violation, since positive and negative swab test results occurred on the same day of recruitment. In such cases, patients can be excluded from ITT analysis .We had an unequal number of observations. Nonetheless, the estimated power was 0.9081 using a two-sided test to detect an experimental-group proportion of 0.28 (observations = 50) against the control-group proportion of 0.05 (observations = 58) assuming a 5% significance level.Finally, information on time since the onset of the first symptom  was not available. However, COVID-19 presents with a rather variable clinical spectrum—especially among patients affected by mild/moderate disease—with a high proportion of asymptomatic patients, hence information on symptom onset is inevitably prone to recall bias.Although the procedure for using the medical device was extensively explained, patients were not directly observed during the self-administration of Tonimer Lab Panthexyl 800 spray at home. In order to maximize virucidal efficacy, topical formulations against respiratory viruses should target the nasopharynx, the main infection settlement for SARS-CoV-2. If the nozzle of the medical device is inserted in the nose almost vertically, the deposition of drug droplets in the nasopharynx may be suboptimal. Therefore, after an initial vertical insertion to the top of the nostril, the medical device should be bent horizontally slightly toward the cheeks, to penetrate 5 mm into the nasal airspace.Information on PCR cycle threshold (CT) would have been more accurate to assess the nasopharyngeal negativization than antigenic test. Nonetheless, in a subset of 60 patients (34 treated with Tonimer and 26 controls) randomly selected, a negative antigenic test result was followed by a confirmatory RT-PCR, showing full concordance between the two tests.Although specific information on SARS-CoV-2 sub-lineages infecting each patient was not available, only Omicron BA.2 was known to be circulating in Treviso area during the study period, and hence we do not expect any difference in viral sub-variants between patients treated with Tonimer Lab Panthexyl 800 and controls. Moreover, the resulting molecule HOCl is highly reactive and highly virucidal when dissolved in water, regardless of the change in amino acids of the viral proteins. Given evidence from clinical studies, HOCl dissolved in water is still recommended for hand washing by the United States Environmental Protection Agency (USEPA) as an effective disinfectant against COVID-19, notwithstanding the continuous emergences of new SARS-CoV-2 sub-lineages .Inhibition of viral replication. SARS-CoV-2 replication is reportedly dose-dependently inhibited by saline solutions (0.8–1.7% NaCl). Inhibition of viral replication already started from a concentration of 0.6%, increasing up to 50% at 0.9%  and reaching 100% at 1.5%  [olution) . Saline,olution) .Shift of myeloperoxidase (MPO) activity in epithelial or phagocytic cells. This metabolic route yields hypochlorous acid (HOCl). Inhibition of viral replication in presence of chloride and halide salts was first reported in the 1960s [p < 0.05) were found in naso-oropharyngeal samples of SARS-CoV-2 patients. Over-expression of MPO may produce HOCl in excess, thereby damaging nasopharyngeal tissues [he 1960s . HOCl hahe 1960s . Signifi tissues .The most relevant pharmacological effects of hypertonic saline/seawater against SARS-CoV-2 are the following :InhibitiThe first part of the results of the present study likely agrees with both the above mechanistic hypotheses. Nasal spray with seawater and other additives achieves an early negativization of an initial positive swab test against SARS-CoV-2 through inhibition of viral replication  and shifThere were no similar findings for comparison.dynamical system” that is simply a function of possible outputs which can also be inputs [The second part of the results, exhibiting no apparent pattern, could be interpreted as a “e inputs . It is we inputs , possible inputs .−) or the amino acid taurine or both substances to a hypertonic saline solution. The highly reactive molecule HOCl, which also exhibits promiscuous reaction chemistry , oxidizes SCN− into OSCN− (hypothiocyanite) and, separately, taurine into N-chlorotaurine (NCT) [− and NCT—are less reactive but more selective  than HOCl. For example, OSCN− oxidized the thiol moiety R–SH essential for the activity of numerous enzymes and proteins, thereby inhibiting bacterial glycolysis, respiration, and glucose transport. A recent in vitro study showed that micromolar concentrations of OSCN− exhibited dose- and time-dependent virucidal activity against SARS-CoV-2, without toxicity on Vero cells [For this purpose, we suggest a formulation including either thiocyanate  . These pne (NCT) . The lacne (NCT) . Both prro cells . On the ro cells .In the present study, we employed an already existing treatment including xylitol and panthenol as excipients of the hypertonic saline solution. Xylitol is a naturally occurring chemical compound with inherent antimicrobial properties. A systematic review was recently conducted on five RCTs where xylitol was compared to a nasal saline additive for the treatment of sinonasal disease, using as the primary outcome the difference in the 22-item Sinonasal Outcome Test (SNOT-22). Compared to a predefined Minimal Clinically Important Difference score of 8.9, the post-surgical Endoscopic Sinus Surgery (ESS) subgroup met this threshold, whereas the non-surgical subgroup failed to meet the threshold. In conclusion, xylitol may be an effective agent for the treatment of sinonasal disease in post-surgical ESS patients . On the Once a person is infected, the median “latent period”, preceding the communicability window of SARS-CoV-2 infection, is ≈3 days followed by ≈4 days of close to maximal infectiousness ,42.According to the standard behavior of upper respiratory viruses, if symptoms deteriorate in five days after disease onset or persist beyond 10 days, it is likely that there is a secondary bacterial infection requiring clinical evaluation .The UK Health Security Agency allows healthcare workers (HCWs) to return to work if they test negative on both days 5 and 6 (undertaken 24 h apart) after the date of the initial positive RT-PCR swab test .Current occupational guidelines by the European Centre for Disease Prevention and Control (ECDC) for HCWs testing positive for SARS-CoV-2 recommend a standard isolation of six days for vaccinated versus 10 days for individuals unvaccinated against COVID-19 .Our data support the suggestion to consider five days of treatment in future clinical trials . This deIf confirmed in further clinical trials, the present findings could support the reduction of the communicability window of SARS-CoV-2 infection by 2–3 days in the community. This intervention could also arguably support a return to work of asymptomatic individuals from COVID-19 isolation 2–3 days earlier.Since the communicability of SARS-CoV-2 is considerable , especiaNasal spray with Tonimer Lab Panthexyl 800 was effective against SARS-CoV-2, stopping viral shedding in the treatment arm two days earlier than controls. No evidence of adverse effects was found. The treatment should be continued for at least five days, since there is no contraindication to extend it beyond.


Anti-PD-1/PD-L1 immunotherapy reactivates T-cell activity to boost the antitumor effect and may trigger autoimmune toxicity in various organ systems involving eyeball and periocular structures at the same time. The rarity of ocular immune-related adverse events should not prevent us from paying attention to this issue because of the bad consequences of visual impairment. This is the first case report of anti-PD-1 sintilimab-induced bilateral optic neuropathy in a 76-year-old man with squamous non-small cell lung cancer (NSCLC). The patient presented with sudden vision blurring without pain in both eyes after three therapeutic cycles of sintilimab plus chemotherapy. Based on the ophthalmic examination, laboratory, and radiological results, our patient was diagnosed with optic neuropathy complication secondary to anti-PD-1 sintilimab treatment. Consequently, sintilimab was held and systemic steroids were administered. The follow-up review showed that the vision recovered and the size of the primary tumor continued to decrease with the response assessment as the partial response. In conclusion, this case report suggested that patients with NSCLC undergoing anti-PD-1/PD-L1 therapy should be closely monitored for ophthalmic assessment and alert to the occurrence of sintilimab-induced optic neuropathy. Non-small cell lung cancer (NSCLC) is one of the most prevalent and aggressive malignant tumors, which causes the most cancer-related death worldwide . Next toThe PD-1/PD-L1 blocking antibodies disturb the binding of PD-L1 to PD-1 on T cells, thus reversing T-cell exhaustion and boosting antitumor immunity . An indiWith the widespread use of immunotherapy in cancer therapy globally, immunotherapeutic toxicities have become a very critical topic that requires immediate diagnosis and treatment . MeanwhiA comprehensive review reported that ophthalmoplegia (40.51%), uveitis (20.25%), dry eye 17.72%), retinopathy (5.06%), conjunctivitis (5.06%), and optic neuritis (3.80%) were the most common immune checkpoint inhibitor (ICI)-related ocular adverse events in lung cancer .72%, ret. Sintili2. The Karnofsky score was 90. His past medical issues included appendectomy (9 years ago), cataract phacoemulsification and intraocular lens implantation in both eyes (5 years ago), and type 2 diabetes mellitus . He had no relevant previous comorbidities, and no previous history of liver disease, hepatitis, alcohol abuse, or smoking. Meanwhile, there was no medical history of autoimmune diseases and endocrinopathies. The positron emission tomography-computed tomography (PET-CT) scan showed that irregular soft tissue masses (approximately 8.7 × 6.0 × 7.7 cm) in the dorsal segment of the left upper lobe and lower lobe of the left lung are lobulated, growing across the interlobular fissures, local bronchial occlusion, and abnormally increased standard uptake value (SUV) activity, which is consistent with lung cancer manifestations  was 20.5 kg/mTreatment with sintilimab (200 mg) plus paclitaxel liposome (270 mg) was initiated on 5 May 2021. He then received two cycles of therapy including sintilimab plus paclitaxel liposome (270 mg) and nedaplatin (120 mg) on 2 June 2021 and 30 June 2021. Three weeks after the third infusion of sintilimab, he presented with sudden vision blurring in his both eyes without redness, eye pain, swelling, or other discomforts. No special treatment was performed outside. Approximately 2 weeks after he first developed vision blurring, the patient was referred to the Department of Ophthalmology  reported that the common three classes of ICIs  have the potential to induce optic neuritis . The immA case report showed that a 64-year-old man with stage IV NSCLC received the third-line anti-PD-L1 antibody (atezolizumab) treatment for about 12 months, which decreased tumor burden. The anti-PD-L1 therapy was withdrawn because of the general fatigue, anorexia, diarrhea, and bilateral upper limb pain, then the visual loss was noted in the left eye without eye movement pain 1 week later . FurtherMoreover, some previous studies suggested that irAEs might be related to stronger antitumor immunity and better tumor control, which could serve as a predictive surrogate marker of clinical benefit , 33. A rThis is the first case report that conveyed anti-PD-1 sintilimab-induced bilateral optic neuropathy characterized by painless vision decline in a patient with squamous NSCLC receiving three cycles of sintilimab injection. Visual function improved with sintilimab cessation and systemic steroids while the primary tumor showed an ongoing trend to reduce with the response assessment as PR .The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patient provided their written informed consent to participate in this study and consent for publication of this case report and any accompanying images.JW, XW, and RZ collected the clinical information and wrote the manuscript. XX, XD, and GW contributed to revising the manuscript critically for important intellectual content. XW and RZ coordinated the patient’s care and provided the clinical data. RZ supervised this study. All authors contributed to the article and approved the submitted version.We would like to thank the patient in this study and all the clinicians for providing care to the patient.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Twenty-one percent of the COVID+ participants were discharged to inpatient rehabilitation (7% of the COVID− participants). Of note, pre-existing pulmonary disease was more prevalent in the COVID− group . Within the COVID+ group, when compared to participants discharged home, those who required inpatient rehabilitation had worse peripheral oxygen saturation (SpO2) on admission  and longer median LOS . Despite having less people with pre-existing pulmonary disease, the COVID+ group required more care and rehabilitation than the COVID− group. In the COVID+ group, SpO2 on hospital presentation was associated with LOS, critical care needs, mechanical ventilation duration and the need for inpatient rehabilitation.↔This study aims to compare the characteristics, in-hospital data and rehabilitation needs between those who tested positive versus negative for COVID-19 during hospitalisation with suspected COVID-19. In this cross-sectional study, a convenience sample of adults admitted to Western Australian tertiary hospitals with suspected COVID-19 was recruited. Participants were grouped according to their polymerase chain reaction (PCR) test result into COVID-19 positive (COVID+) and COVID-19 negative (COVID−) groups. Between-group comparisons of characteristics of the participants and hospital admission data were performed. Sixty-five participants were included . Participants in the COVID+ group had greater acute hospital length of stay (LOS) (median [25–75th percentile] 10 [5–21] vs. 3 [2–5] days;  Throughout the COVID-19 pandemic, emergency departments (ED) were filled with people being treated for COVID-19. A challenge created by COVID-19 is that no specific clinical features discern the disease from other respiratory illnesses ,3,4,5. IApproximately 15% of symptomatic COVID-19 cases develop severe disease requiring oxygen support . Simple The primary aim of this study was, for adults who presented with suspected COVID-19 in EDs, to compare characteristics and in-hospital data between those who tested positive versus negative for COVID-19. The secondary aim was, in those who tested positive for COVID-19, to explore factors linked to discharge destination. In this group, we also provided details of the assessment of physical function.This report presents the combined data and outcomes of the hospitalised cohort recruited in the Life AfTER COVID-19 (LATER-19) trial ,28 and aA convenience sample of consecutive patients admitted to respiratory wards was used. As per policy of the time, all those presenting to hospital with symptoms of respiratory illness took a PCR test. Participants who were confirmed to have a positive result by laboratory PCR test formed the COVID+ group. Those who returned a negative result formed the COVID− group.Under sister trial provisions, admission and emergency department (ED) data from participants were captured when recruited to the WA node of the ISARIC Trial. Data collected during the LATER-19 study were extracted as per protocol  and link2) on room air, oxygen flow rate (L/min) and device required to stabilise SpO2); (ii) factors during admission , ICU admission, mechanical ventilation, days ventilated, discharge destination); and (iii) critical care needs, defined as the need for any of the following during admission: low-flow O2 therapy ≥10 L/min, high-flow O2 therapy, non-invasive ventilation (NIV) or mechanical ventilation . Comparison between participants in the COVID+ and COVID− group (group comparison 1) as well the comparison of COVID+ participants according to their discharge destination  were performed using Chi-squared tests, independent samples The results of the recruitment process for the LATER-19 trial are described elsewhere . A totalp < 0.05). In the COVID+ group, there was a trend towards a greater critical care need, and participants were more likely to be admitted to an ICU and receive mechanical ventilation (p < 0.05). The median LOS-acute of those in the COVID+ group was a week longer than those in the COVID− group (p < 0.05).Participants in the COVID+ (n = 38) and COVID− (n = 27) group were balanced for sex, age and BMI . The COVtilation . Ten par2 on admission  and longer median LOS .The comparison of COVID+ participants grouped according to their discharge destination is presented in 2 on room air and oxygen flow required to stabilise, appear to differ by LOS-acute and critical care needs  had the opportunity to complete repeated 1STS during acute hospital admission. The characteristics of this subgroup of participants are described in In this study of patients hospitalised with suspected COVID-19, those with COVID+ and COVID− demonstrated similar baseline characteristics and respiratory compromise at ED presentation. Although those who were COVID− had higher rates of pre-existing pulmonary disease, those who were COVID+ demonstrated higher care needs during admission via higher rates of ICU admission, mechanical ventilation, RIB (IMS < 2), and LOS-acute. It is notable that, when comparing critical care needs rather than ICU admission, although the rate of critical needs within the COVID+ group remains higher, the difference between groups is less. This difference in results may acknowledge the presence of instances of pre-existing clinical frailty barring admission to an ICU, as well as accounting for those prophylactically admitted to an ICU for monitoring. Both groups were admitted under the same jurisdictional conditions early in the pandemic in a health care system that was not overwhelmed . This re2 < 90% on RA, requiring oxygen > 3 L/min to stabilise, were more likely to need mechanical ventilation and/or inpatient rehabilitation, whereas factors of age, comorbidity or BMI had less impact on care trajectory. The duration of mechanical ventilation correlated with a need for inpatient rehabilitation, in keeping with the known impact of ICU-AW, irrespective of the effects of COVID-19 [For those with COVID+, the results for the impact of respiratory compromise at the point of admission on critical care needs, including mechanical ventilation, echo those of much larger studies ,18. SpecCOVID-19 ,26. ThisCOVID-19 ,35,36. ICOVID-19 . The chaCOVID-19 .This study demonstrates a successful completion of the 1STS without adverse events by those with COVID+ in an inpatient setting. Those completing the 1STS appear to have a greater disease burden than the larger COVID+ group; however, this comparison could not be made formally due to the small group size. This success does offer some value for assessing the response to exercise in the acute period. Given that the frequency of physiotherapy intervention during COVID-19 illness can improve the likelihood of discharge home , and theTo our knowledge, this is the first study to provide a comparison group for exploring the trajectory of critical care and rehabilitation needs for COVID-19 patients. To our knowledge, it is also the first study to assess the response to exercise within acute hospitalisation with COVID-19 using repeated measures of a standardised exercise test (1STS).Low case numbers limited the intended prospective analysis and generalisability of results regardless of the PCR results. Low case numbers also impacted the capacity of matching sub-cohorts by comorbidities and the depth of subsequent between groups comparisons. For instance, exploring types of comorbidities  and association with dyspnoea would clarify the needs of COVID+ patients. Future studies would also benefit by controlling for prevalence of comorbidities, such as cardiac and chronic pulmonary disease, to clarify the care needs specifically related to COVID-19. Including a marker of clinical frailty could assist in establishing a functional baseline. The analysis of early mobilisation could be improved by quantifying mobility over repeated measures in conjunction with movement accelerometers to gather more comprehensive movement data.2 on hospital presentation was associated with LOS, critical care needs, mechanical ventilation duration and the need for inpatient rehabilitation. Given the well-established lifetime burden of care required by those with chronic pulmonary disease, this study provides a base that future larger studies may draw from in assessing long-term burden of care in COVID-19.Those with COVID+ required more care and rehabilitation than the COVID− group, despite lower rates of a pre-existing pulmonary disease. In the COVID+ group, SpOThe 1STS can be safely performed as repeated exercise during acute COVID-19 illness with established physiological parameters. This result could benefit from applications in a larger population to more thoroughly explore responses to exercise and the effect of early intervention during acute COVID-19.


Post-stroke fatigue is frequently present in young adults, but its underlying mechanism is still unclear. The aim of the study was to investigate the association between lesion location, network efficiency and chronic post-stroke fatigue based on voxel-based lesion-symptom mapping and structural network connectivity analysis.One hundred and thirty five young patients, aged 18–50 years, with a first-ever transient ischemic attack or cerebral infarction from the Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation (FUTURE) study, underwent 1.5T MRI and were assessed for fatigue using the self-report Checklist Individual Strength. Stroke lesions were manually segmented, and structural network efficiency was calculated using the diffusion MRI-based brain networks and graph theory for each patient. Univariate and multivariate analyses was performed to study the associations between MRI parameters and chronic post-stroke fatigue. In addition, we used voxel-based lesion-symptom mapping to analyze the relationship between the lesion location and chronic post-stroke fatigue.Mean age at index event was 39.0 years (SD ± 8.2), and mean follow-up duration was 11.0 years (SD ± 8.0). 50 patients (37%) had post-stroke fatigue. Voxel-based lesion-symptom mapping showed no significant relation between stroke lesions and the presence of chronic post-stroke fatigue. Furthermore, there were no significant associations between the lesion size or network efficiency, and the presence of chronic post-stroke fatigue.We did not find any association between stroke characteristics (lesion location and size) and chronic post-stroke fatigue (CIS20-R), nor associations between structural brain network connectivity and post-stroke fatigue on the long term in young stroke patients. Stroke in young adults (18–50 years) has a high socioeconomic impact due to amongst other the lifelong post-stroke consequences including post-stroke fatigue (PSF) –4. FurthDespite its importance, little is known about the underlying mechanisms of PSF. Lesion location may be an important determinant of PSF, but the associations between stroke topology and PSF remain unclear, as most studies did not show any associations between stroke side, location, and size and PSF –8. One oAn alternative explanation is that PSF is not primarily determined by the location of the stroke lesions, but rather by the brain networks affected by stroke. Recent studies have shown that cognitive and behavioral functions are distributed in the brain via several interconnected brain regions , 13. NetThe aim of this study was to investigate the association between the location of stroke lesions, network efficiency, and chronic PSF by using VLSM and structural network connectivity analysis based on DTI. We hypothesized that lesion location is not an important determinant of chronic PSF, but that lower structural network efficiency is associated with chronic PSF in young ischemic stroke patients.n = 2, and lack of T1 scans n = 3), yielding a total sample size of 135 patients for this study. The 135 patients included in this study had higher NIHSS-scores at admission [median 4 (IQR 2–10)] than patients excluded from the study (n = 376)  and more often had aphasia  based on NIHSS evaluated by the treating clinicians. Patients included in the study were also younger at the time of the index event compared to patients excluded from the study . No significant differences were found in clinical outcome at follow-up based on mRS.This study is part of the Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation (FUTURE) study, which is a prospective cohort study in which the etiologies and consequences of young stroke were investigated . InclusiThe presence of fatigue was assessed with the fatigue subscale of the self-report Checklist Individual Strength CIS20-R) , 20, a q-R , 20, We defined depressive symptoms and anxiety using the Hospital Anxiety and Depression Scale (HADS) . The Dut2).Images were acquired on a 1.5T S Magneton Sonata scanner . The scanning protocol included (1) whole brain 3D T1 magnetization-prepared rapid gradient-echo (MPRAGE) sequence , (2) Fluid-attenuated inversion recovery (FLAIR) pulse sequences , (3) gradient echo susceptibility weighted imaging sequence , (4) DTI . All lesion borders were checked by an experienced clinician (EB). We manually segmented stroke lesion and the adjacent glial scars. After lesion segmentation, we registered the lesion masks non-linearly to a standard space. To this end, the Functional MRI of the Brain non-linear registration tool (FNIRT) was used to non-linearly register the skull-stripped T1-weighted images to Montreal Neurological Institute (MNI) 152 template. Next, we registered both the masks of the stroke lesions and the FLAIR images to the standard space using the transformation matrix of T1-weighted images to standard space after linearly registering to T1-weighted image using Functional MRI of the brain linear image registration tool (FLIRT). We used FSL 5.0.5 tools .We defined network nodes  using the Automated Anatomical Labeling (AAL) template , which rWe defined our network edges  by the following procedures. First, we used “PATCH” on the raw diffusion data to correct for cardiac and head motion artifacts and for eddy currents . Second,post-hoc analysis in which the network measures were calculated from the unaffected hemisphere.We assessed graph-theoretical network measures using the Brain Connectivity Toolbox . We calc2-tests or Fisher's exact tests for categorical variables and t-test for the continuous variables, where appropriate. To investigate the relationship between lesion location and the presence of chronic PSF, we used voxel-based lesion mapping (VLSM)  false discovery rate (FDR) correction (https://github.com/neurolabusc/NiiStat). We also analyzed group differences for imaging variables, including lesion location, lesion volume and network measures. For significant associations, we additionally adjusted for possible confounders; age at follow-up, education, depressive symptoms, anxiety, and mRS score during follow-up. In case of multiple comparisons, we used the Bonferroni correction to adjust for multiple comparisons. Furthermore, we investigated whether a specific subnetwork for chronic PSF could be found by analyzing group differences for nodal efficiency of each brain region, by using unpaired t-tests, corrected for multiple comparisons using BH FDR correction. All statistical analyses were carried out in the statistical software IBM SPSS Statistics 26 and Matlab R2021a.We analyzed group differences between fatigued and non-fatigued patients for demographic, clinical variables using χg (VLSM)  implemeng (VLSM)  and a t-rrection . Next, wWe included 135 patients with a mean age of 39.0 years (SD ± 8.2) at index event. Mean follow-up duration was 11.0 years (SD ± 8.0). The mean CIS20-R-score was 30.3 (SD ± 13.3) and 50 patients (37%) patient fulfilled the criteria of severe PSF. Depression and anxiety were significantly more present in the fatigued group than in the non-fatigued group. The demographic and clinical variables are shown in p = 0.06).The results of the univariate and multivariate analyses are shown in q < 0.05). This was further confirmed by the multivariate VLSM, while correcting for the potential confounders.post-hoc analysis, network measures from the unaffected hemisphere were also not significantly associated with the presence of chronic PSF. Furthermore, we found no significant differences in the nodal efficiency of each brain region between the fatigued group compared to the non-fatigued group after correcting for multiple testing.Whole brain network strength, network density, global efficiency and local efficiency were not significantly associated with the presence of chronic PSF . In the In this study, we found no association between stroke characteristics  and chronic PSF (based on CIS20-R), nor between structural network connectivity and chronic PSF in young stroke patients. These findings indicate that structural brain measures  are not important determinants of PSF on the long term in young stroke patients.We performed VLSM to investigate the relationship between stroke location and chronic PSF in a more robust manner than previous studies. Our analysis did not show any differences in (damaged) brain structures in young stroke patients with chronic PSF compared to patients without PSF. Our findings are comparable to previous studies showing no associations between either visible stroke lesions or lesions detected with VLSM and PSF in patients during the chronic stage of stroke –36. ThisHowever, we did not find associations between structural network connectivity and chronic PSF. These results are in line with findings in the general stroke population showing no associations between chronic PSF and structural network measures or lesion characteristics . A recenConsistent with previous studies, we found that chronic PSF was associated with depressive symptoms and anxiety , 45, 46.Strengths of our study include the large sample size of young stroke patients, the long follow-up duration of 11 years and the single-centre design. Furthermore, to the best of our knowledge, this is the first study to investigate the relationship between structural brain measures and chronic PSF using VLSM and structural network analysis in young stroke patients who are free from other neurological disorders.However, there are several limitations to be mentioned. First, we do not have information about predisposing factors . In a coChronic PSF in young stroke patients seems to be a multi-dimensional and multifactorial symptom, which is not associated with stroke characteristics and structural network measures. Future studies are needed to better understand the mechanisms of PSF, focusing more on the role of predisposing factors of fatigue and its different subtypes, and the role of stroke lesions in the acute phase.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Ethics Committee Region Arnhem-Nijmegen. The patients/participants provided their written informed consent to participate in this study.SC, EB, and AT were involved in data analysis and wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.AT was a junior staff member of the Dutch Heart Foundation (Grant No. 2016T044). F-EL has received the Innovational Research Incentive grant (016-126-351) and the Clinical established investigator Dutch Heart Foundation grant (2014 T060).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The coronavirus disease (COVID-19) can cause acute respiratory distress syndrome with dyspnea, anosmia, fever, and cough. Few studies describing ocular findings have been reported. The current case series, reports the clinical findings and natural history of patients with retinal vascular occlusion after COVID-19 infection.Patients from multiple Brazilian hospitals who had clinical and laboratory diagnoses of COVID-19 with retinal vein or arterial occlusion were analyzed retrospectively. The baseline demographics, clinical presentations of COVID-19, comorbidities, risk factors for thromboembolic events, and use of anticoagulant drugs were reviewed. The relevant clinical findings associated with the retinal vascular occlusive event, management, and outcomes were reported. Fourteen cases of retinal vascular occlusion within 3 months of the laboratory confirmed COVID-19 infection were identified. Three of which required hospitalization for COVID-19 management. Eight cases had central retinal vein occlusion, three branch retinal vein occlusion, one hemispheric retinal vein occlusion, and two central arterial occlusion. The mean patient age at presentation was 48 years; the visual acuity ranged from light perception to 20/20. Nine patients received intravitreal injections of anti-angiogenic drugs and one received ketorolac tromethamine drops for the management of secondary macular edema; four were untreated.COVID-19 patients may rarely have ocular manifestations of the disease. It was presented a case series of vascular occlusion events that may be related to COVID-19 infection, since these thrombotic events are actively involved in the disease pathophysiology. These cases emphasize the need for further investigation of ocular complications associated with this disease. An outbreak of coronavirus disease COVID-19) was first reported as a pneumonia case in Wuhan, China, in December 2019 [9 was firThe most common symptoms of COVID-19 include dyspnea, anosmia, fever, and cough. The ocular findings described in the literature include conjunctivitis , intraocAlthough few cases of retinal vascular occlusion in patients with COVID-19 have been reported in the literature, the explanation for such an association is unknown. We report 14 patients with retinal vascular occlusion. The current study both reports a unique and large series of retinal vascular occlusion cases, including arterial and venous vessels, in relatively young patients with COVID-19 and forwards some hypotheses for this occurrence .The data were collected retrospectively from multiple Brazilian centers from public and private hospitals, by members of the Brazilian Retina and Vitreous Society. The present study was approved by the Research Ethics Committee of the Fundacao Universidade Regional de Blumenau .Data were collected regarding the treatment of COVID, the presence of retinal vein or arterial occlusion, included reverse transcriptase-polymerase chain reaction (RT-PCR) positivity, age, sex, comorbidities, initial and final visual acuities (VAs), hospitalization, necessity for anticoagulant drugs, time after infection when the VA decreased, and the treatments of the occlusions administered, i.e., none, anti-inflammatory non-hormonal drops, antivascular endothelial growth factor (VEGF) injections or dexamethasone intravitreal implant. Patients were excluded who had previous decompensated hypertension, diabetes, thromboembolic phenomena, and cardiovascular disease.All data from patients in whom a retinal vascular occlusion developed after COVID-19 were collected between August 15, 2020, and October 30, 2020, after the patients provided informed consent.The patients were divided into four groups: 1, those with central retinal vein occlusion (CRVO); 2, those with hemispheric retinal vein occlusion (HRVO); 3, those with branch retinal vein occlusion (BRVO); and 4, those with central retinal arterial occlusion (CRAO).A total of 14 cases of retinal vascular occlusion following COVID-19 infections that were confirmed by RT-PCR were identified. The mean patient age was 47.97 years and most patients (85.72%) had no previous history of systemic hypertension or thrombotic events.The severity of the retinal vascular occlusive events in the present case series varied from mild retinal vein occlusion with a BCVA exceeding 20/60 in eight cases, severe retinal vein occlusion with a BCVA worse than 20/60 in three cases, and retinal arterial occlusion in 2 cases.Eight patients  with CRVO were identified. Five patients had a VA of 20/40 better and four had a VA below 20/40 . Patient 5, was an emblematic case. No previous medical history, with 27 years old who presented with CRVO had D-dimer of 1232 ng/mL and PCR of 1,9 mg/L, the remain laboratory workup was unremarkable. Protein C, S and antiphospholipid antibody were normal. Six patients were treated with intravitreal anti-VEGF drugs. Two patients with a VA of 20/20 were followed clinically. The VA improved in all treated patients; three patients achieved 20/20.A 43-year-old Caucasian man without comorbidities had HRVO. He presented with a painless decrease in VA in his right eye to 20/50 during 10 days of hospitalization to treat the COVID-19 infection. Biomicroscopy was unremarkable. Fundus examination of the right eye showed widespread hemorrhages and axonal congestion of the hemispheric superior retina  had BRVO. None had severe COVID-19 requiring hospitalization. The retinal vein branch involved was superotemporal in two cases and inferotemporal in one case. The mean central foveal thickness at presentation was 441 microns.One of these patients was a 36-year-old man diagnosed with BRVO in the right eye about 3 months after mild symptomatic COVID-19 confirmed by serologic testing (IgM-IgG rapid test). His VA was 20/30 in the right eye. He was treated with one intravitreal injection of bevacizumab  and due to the prompt clinical response and the VA improvement to 20/20 he opted to not continue with anti-angiogenic treatment.A 64-year-old man was seen 7 days after the onset of COVID-19 symptoms. The best-corrected VA (BCVA) was 20/20 in the right eye and counting fingers in the left eye. The pupillary reflexes were normal, and biomicroscopy of the anterior and posterior segments did not reveal cells in either eye. Color fundus photography showed exudates and intraretinal hemorrhages in the posterior pole, including the macular area, and fluorescein angiography revealed hypo- and hyper-fluorescence on the topography of the macular area of the left eye, indicating retinal non-perfusion and vascular leakage, respectively. After the intravitreal bevacizumab injection, there was a marked reduction in the amount of macula edema in the left eye at 1-month follow-up at which time the VA was 20/200.Two patients had CRAO. A healthy 47-year-old man and a 73-year-old man with systemic hypertension and diabetes were both hospitalized with severe COVID-19. Both had a similar history of painless visual loss to the level of light perception 7 days after COVID-19 was diagnosed. Fundus examination showed diffuse paleness and a cherry-red spot in the macula Fig. . The worThe initial and final VAs and treatments are shown in Table The National Institutes of Health (NIH) classified adults with SARS-Cov-2 infection into the following severity of illness categories: asymptomatic (0), mild illness with any of signs or symptoms, without dyspnea or abnormal chest imaging ( +), moderate illness lower respiratory disease or imaging and SpO2 > 94% (++), severe illness SatpO2 < 94%, respiratory rate > 30 breaths/min or lung infiltrates > 50% (+++) and critical illness: individual with respiratory failure, septic shock and/or multiple organ dysfunction (++ ++). Table 1Most patients had no history of systemic hypertension or thrombotic events. Only one 41-year-old patient with CRVO used medication to treat dyslipidemia and hypertriglyceridemia, and one patient in the CRAO group had systemic hypertension and controlled diabetes mellitus.The pathogenesis of COVID-19 remains poorly understood, although there is increasing evidence that an inflammatory cytokine storm and viral evasion of cellular immune responses play a fundamental role in disease severity and progression . COVID-1Endothelial alterations and endotheliitis are important determinants of microvascular dysfunction, which disrupts the vascular balance toward vasoconstriction, ischemia, tissue edema, and a procoagulant state. Concurrent with the altered coagulation, an exacerbated proinflammatory cytokine response has been observed in patients with COVID-19 , although the cause of this cytokine storm remains unclear. The SARS-CoV-2 cytokine storm precipitates the onset of a systemic inflammatory response syndrome, resulting in activation of the coagulation cascade that induces to a hypercoagulable state. However, whether the virus directly activates the coagulation cascade or whether this is the result of local or systemic inflammation is not completely understood. These findings are consistent with the close connection between thrombosis and inflammation [The severity of the retinal vascular occlusive events in the present case series varied from mild retinal vein occlusion with a BCVA exceeding 20/60 in eight cases, severe retinal vein occlusion with a BCVA worse than 20/60 in three cases, and retinal arterial occlusion in 2 cases. Individual factors or the severity of the COVID-19 infection might explain the variable presentations of the retinal vascular phenomenon.The occurrence of CRVO in adults under 60 years of age has been reported to be considerably less common than in older patients. Systemic hypertension was the most prevalent risk factor for CRVO in young patients, followed by diabetes mellitus and hyperlipidemia . NeverthIn the current case series, the mean patient age was 47.97 years and most patients (85.72%) had no previous history of systemic hypertension or thrombotic events. The only common patient background was the previous COVID-19 infection. It is not possible to identify a direct cause and effect of the viral infection and retinal vascular occlusion. However, understanding the pathophysiology of the SARS CoV-2 infection, the COVID-19 can be viewed as a prothrombotic disease and may justify this retinal vascular disease in such young patients.Two major possible mechanisms might explain vascular damage in COVID-19 disease, first a pseudo-vasculitis state as a result of a viral infiltration of the endothelial cells, and second, a hypercoagulable condition, characterized by a disseminated intravascular coagulation-like scenario. These mechanisms might explain the association between the potential impact of COVID-19 on the retinal vascular circulation and the occurrence of a retinal vascular disease as seen in the current cases.The effect on the retinal circulation in patients with COVID-19 has been suggested previously and reinforces the idea that the effect is not coincidental but rather a disease consequence. The presentation of unilateral CRVO in our young, healthy patients without any identifiable hypercoagulability risk factors shortly after recovery from COVID-19, may imply that CRVO or CRAO in our patients was related to the thromboembolic state associated with the SARS-CoV-2 infection .Most patients experience a non-arteritic CRAO. In non-arteritic CRAO, the retinal artery is occluded from a platelet–fibrin thrombus or embolism from an atherosclerotic lesion or hypercoagulable state such as with COVID-19 . Some stAl-Moujahed et al.  publisheThis study has some limitation in that it is an uncontrolled case series, the time until symptom onset varied considerably , and we did not compare the incidence of the retinal vascular occlusion to a similar timeframe (2018/2019), but it is a first step for future confirmatory controlled studies to show an association between COVID-19 infection and retinal vascular occlusion.This is the largest case series thus far that describes 14 patients with retinal vascular occlusion after a COVID-19 infection. It well known that patients with COVID-19 are at risk of presenting with venous and arterial thrombotic events, and these thrombotic events are actively involved in the disease pathophysiology. The three main factors involved in the pathogenesis of coagulopathy in patients with COVID-19 are endotheliitis, which causes mechanical problems through vasoconstriction; hyper-inflammation and a cytokine storm that activate clotting factors; and stasis and hypoxia that also activate coagulation mechanisms. Clinicians and ophthalmologists must be aware of the effect of COVID-19 beyond the involvement of the ocular surface that occurs in the intermediate stages of COVID-19 and that there may be an increased incidence in the number of patients with ocular vascular diseases due to the hyper-inflammatory and hypercoagulable state triggered by a SARS-CoV-2 infection.


Increasing awareness, treatment, andcontrol of hypertension is predicated on the accessibility and responsiveness of thehealth system to the needs of its population. Vertically aligned health programmes and apersistent shortage of trained physicians along with their disproportionateconcentration in urban as opposed to rural areas have hampered routine periodicscreening for non-communicable diseases in most low-income and middle-income countries.Effective hypertension control is thus multifactorial and requires a recalibration ofthe health system.2Hypertension is the leading preventable cause of death and disability worldwide,accounting for 19·2% (10·8 million) of all deaths globally and16·4% (2 million) of all deaths in low-income and middle-incomecountries.3 In thiscluster-randomised trial among 30 communities in Bangladesh, Pakistan, and Sri Lanka, amulticomponent hypertension management programme was evaluated for the budget that isrequired to scale up the programme and its cost-effectiveness.4 The intervention was locally adapted, withtargeted education, training of providers, regular blood pressure monitoring andreferral, and a financing model to support additional service provision by communityhealth workers. From the health system (public payer) perspective, the investigatorsfound the first-year costs per participant to be US$10·65 for Bangladesh,$10·25 for Pakistan, and $6·42 for Sri Lanka, and recurrent costs perparticipant ranged from $5·70 (Pakistan) to $6·52 (Bangladesh).Incremental cost-effectiveness ratios ranged from $2270 (in Pakistan) to $4080 (in SriLanka) per cardiovascular disease-associated disability-adjusted life-year averted.The COBRA-BPS study provides useful information on the effectiveness of a complexintervention programme led by community health workers in combating hypertension inrural areas.5 The feasibility and success of a programmedelivered by community health workers does pose several potential challenges,however.6 The effectiveness ofthe intervention is highly dependent on many health system factors such as availability,funding, and retention of an appropriately sized team of community health workers;adequate training, supervision, and monitoring of community health workers; thedevelopment of context-specific protocols for screening, diagnosing, referring, andtreating patients; availability and access to affordable medicines; and clear careerpathways for the community health workers. Many community health workers are oftenalready overloaded with multiple responsibilities and are poorly remunerated, leading topoor motivation and job attrition. Designing a programme that is culturally and sociallyacceptable is a crucial factor that drives the success of the task-sharing strategy; forinstance, many community health workers are women, and gender barriers in somecommunities might impair the effective rollout of a programme led by community healthworkers.Community health workers have traditionally been involved in the delivery ofmaternal and child health services in most low-income and middle-income countries aswell as in HIV/AIDS programmes. Task sharing for hypertension control by communityhealth workers offers a cost-effective way of addressing the community burden ofhypertension. A 2019 meta-analysis showed a significant reduction in blood pressure whenhypertension care was provided by non-physician health-care workers.4 fills an important gap in informing health-careprofessionals and governments on how to improve hypertension care in rural communities.Progressively more rigorous methods have been used to generate evidence on thecost-effectiveness of interventions for hypertension control. Trial-basedcost-effectiveness analyses along with budget impact analyses, as used by Finkelsteinand colleagues,4 generally provide amore robust estimate of cost-effectiveness than decision-based models.7 Despite the remarkably lowper-participant cost reported in the trial,4 expanding the COBRA programme could require a considerable increasein the health-care budget by at least 20–30% across the three countries. Anincrease in the out-of-pocket expenditure for pharmacotherapy for hypertension couldalso affect the willingness to seek and continue care. It is, therefore, important tounderstand how the COBRA-BPS intervention is valued from the patients, serviceproviders, and societal perspectives in public and private facilities. With theincreased implementation of health insurance models by governments in south Asia,further economic data will help to examine how different payers value interventions ledby community health workers.Compared with the enormous effort spent on research to identify cost-effectivetreatments in clinical trials, there have been few efforts to integrate new strategiesin routine clinical practice. The study by Finkelstein and colleagues8However, despite all the implementation challenges and available cost-effectivenessevidence, task sharing among physicians and health workers should be viewed as anessential and key element for hypertension control in low-income and middle-incomecountries. The risk is as Toni Morrison said in her epic novel Song ofSolomon: “If we don’t create the future, the present extendsitself”.Relative to overall budgets and estimated gains, there are other cost-effectivestrategies to manage hypertension.


This scoping review reports on studies that collect survey data using quantitative research to measure self-reported oral health status outcome measures. The objective of this review is to categorize measures used to evaluate self-reported oral health status and oral health quality of life used in surveys of general populations.The review is guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) with the search on four online bibliographic databases. The criteria include (1) peer-reviewed articles, (2) papers published between 2011 and 2021, (3) only studies using quantitative methods, and (4) containing outcome measures of self-assessed oral health status, and/or oral health-related quality of life. All survey data collection methods are assessed and papers whose methods employ newer technological approaches are also identified.Of the 2981 unduplicated papers, 239 meet the eligibility criteria. Half of the papers use impact scores such as the OHIP-14; 10% use functional measures, such as the GOHAI, and 26% use two or more measures while 8% use rating scales of oral health status. The review identifies four data collection methods: in-person, mail-in, Internet-based, and telephone surveys. Most (86%) employ in-person surveys, and 39% are conducted in Asia-Pacific and Middle East countries with 8% in North America. Sixty-six percent of the studies recruit participants directly from clinics and schools, where the surveys were carried out. The top three sampling methods are convenience sampling (52%), simple random sampling (12%), and stratified sampling (12%). Among the four data collection methods, in-person surveys have the highest response rate (91%), while the lowest response rate occurs in Internet-based surveys (37%). Telephone surveys are used to cover a wider population compared to other data collection methods. There are two noteworthy approaches: 1) sample selection where researchers employ different platforms to access subjects, and 2) mode of interaction with subjects, with the use of computers to collect self-reported data.The study provides an assessment of oral health outcome measures, including subject-reported oral health status and notes newly emerging computer technological approaches recently used in surveys conducted on general populations. These newer applications, though rarely used, hold promise for both researchers and the various populations that use or need oral health care.The online version contains supplementary material available at 10.1186/s12903-022-02399-5. A fundamentally different approach is currently needed to address the oral health of populations worldwide namely by considering the perspective of patients or populations and not only dental professionals' views . It seemThe literature on oral health and dental-related scoping and systematic reviews includes studies that use specific populations in terms of disease or clinical conditions, treatments, political or social status and typically do not explore oral health status outcome measures –15. ThesThe objective of this review is to categorize measures used to evaluate self-reported oral health status and oral health quality of life used in surveys of general populations.This work is implemented following the framework of scoping reviews –19 and iA health science librarian assisted in the development of a search strategy that identified papers concerning subject-reported oral health status surveys. The search terms consisted of three broad categories, including survey methods, subject-reported outcomes, and oral health and disease  for title-and-abstract screening, which implies almost perfect agreement . After fTable The four main data collection methods include in-person N = 206, 86.2%), mail-in , Internet-based , and telephone-based  surveys. The characteristics of the various data collection methods are summarized in Table 06, 86.2%The majority of the studies using in-person surveys have high response rates with an average of 90.6%. Those studies using in-person survey methods represent half 55.8% of the studies employ face-to-face interviews, while 35.4% used a paper-and-pencil approach. Participants for 58.7% of the studies are recruited directly from clinics , hospitaThe mail-in survey method is used by 15 studies and may be more cost-effective than in-person delivery, though these were the two main sources, via post (80%) and by carriers (20%). Mail-in surveys have a relatively high response rate averaging 72%, especially when children or other respondents bring surveys home to complete. Similar to in-person surveys, mail-in surveys can incorporate additional resources, such as photographs and explanations of clinical conditions and treatments , 31.Only six studies are identified as using an Internet-based survey, mainly through computer-assisted web interviews (4 studies), and email (2 studies). Three papers employ direct recruitment and another three papers recruit participants through websites and databases. The average response rate is as low as 36.7% for this method with small sample sizes with a median of 259 participants.Three studies use a telephone survey method covering large populations compared to other survey methods with more responders on average. Two of these studies recruit participants through an existing database, and all surveys used interviewers. Computer-Assisted Telephone Interviews (CATI)  and VoicIn addition to the data collection methods, we further categorize the measures found in the 239 articles. Table There is a total of 63 papers using more than one type of measure. Either combining functional and impact measures (36 and 15%) or self-rating OHS and one or more of the other measures (27 or 11%). The group of single impact measures is 50% of the overall and also represents where two or more measures were used. The single measure, GOHAI, based on function is only 9% of all measures but also played a role in combination with other measures. Finally, the self-reported OHS as a single measure represents 8% of the studies. Its role is mainly in combination with other measures and represented another 15% of the articles. In total. children's oral health measures form a considerable portion of the self-reported oral health outcome research papers, representing 16% of all studies. There are additional studies where children’s measures are used in combination with adults.Currently, the use of technological approaches emerged in the field of survey research to improve the quality and quantity of data collection. After reviewing and charting all qualified 239 articles, twelve studies that employ technological approaches are summarized in Table This scoping review provides an overview of data collection methods used for subject-reported surveys to measure oral health outcomes. Studies are characterized by four survey methods  and by summarized dimensions and attributes of data collection for each method, such as technological approaches, survey population or sampling methods. Studies typically employ in-person surveys and more studies were conducted in Asia-Pacific and Middle East countries than in any other world region. Most studies recruit participants directly from study sites. Both probability and non-probability sampling methods employ typically convenience sampling, simple random sampling, and stratified sampling. Studies that achieve the highest response rate on average use in-person surveys, while the lowest rate occurs in Internet-based surveys. Telephone surveys are used to cover a wider population compared to other data collection methods. Many studies, especially those using in-person and mail-in data collection methods, incorporate supplemental data types and technological approaches. Outcome measures are frequently used to evaluate impacts caused by functional limitations related to physical, psychological, and social factors.Frequently used self-reported oral health status and OHRQoL measures are OHIP-14, an impact measure, and the GOHAI, a functional measure. Children’s oral health outcomes measures form a considerable portion of the self-reported oral health outcome research papers. Although OHIP-14 is the most utilized single measure, many other papers use only portions of this measure, while adding other outcome measures, such as dental care needs, satisfaction, oral health status, and so on. The validity of these measures is therefore compromised and could not provide insight into the degree that the studies are measuring self-reported oral health status or quality of life , 57. TheThis review identifies research that employs more conventional methods. The face-to-face interview and the pencil and paper format are conventionally used in many studies along with a clinical dental exam. While offering unique flexibility and easier administration, in-person approaches are more labor-intensive and normally take more time compared to other methods. Countries, such as Brazil, rely for years on these techniques to develop national epidemiological oral health surveys , 58, 59.The use of Internet-based surveys is increasingly common in the medical field. Although these surveys end with potentially lower response rates, this approach is normally more cost-effective . InterneTwo noteworthy approaches to survey research methodology emerge from this review, particularly in: (1) sample selection, and (2) mode of interaction with research subjects. North American researchers found different platforms to access subjects for their studies. Canadian studies use random digit dialing to recruit and conduct computer-assisted interviews . In the An innovative technological approach worth noting is the use of OralCam to perform self-examination using a smartphone camera . The stuThis scoping review is limited to oral health survey-based studies in peer-reviewed journals and MedRxiv published in English between 2011 to 2021. A further limitation is that many of the reviewed papers do not adequately describe the methods they use to collect data. Publications using secondary data from national studies are excluded, The exclusion is based on the fact that these researchers are not engaged in designing the methods or conducting the data collection. Often, the publications refer to the original study to describe the method used. Also, the original data collection may have occurred before the time frame of this review. The fifteen papers that use secondary data published over this study’s time frame represent only about six percent of the reviewed papers. Thus, the overall impact of this exclusion is minimal on this scoping review’s results.This scoping review provides an assessment of oral health outcome measures, including subject-reported oral health status, and notes newly emerging computer technological approaches recently used in surveys conducted on general populations. Such technological approaches, although rarely used in the reviewed studies, hold promise for both researchers and the various populations that use or need oral health care. Future studies employing more developed computer applications for survey research to boost recruitment and participation of study subjects with wide and diverse backgrounds from almost unlimited geographic areas can then provide a broader perspective on oral health survey methods and outcomes.Additional file 1. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist.Additional file 2. Search Terms.Additional file 3. Search Tool.Additional file 4. Data Charting Form.Additional file 5. Glossary of Terms.


Multivariable linear regression analyses compared FMI at 18 years among the four MVPA&SED groups and among the four MVPA&TV groups, adjusting for socioeconomic status, energy intake, and baseline adiposity. The analysis results showed that SED or TV viewing time was not prospectively associated with adiposity in both active and inactive Brazilian adolescents. This study suggests that the association between specific sedentary behaviors, such as TV viewing, and adiposity may differ across societal settings—in this case, high-income vs. middle-income countries. A prior study conducted in high-income countries demonstrated that specific sedentary behavior, such as TV viewing, is prospectively associated with adiposity in both active and inactive adolescents. The aim of this study was to examine the joint associations of sedentary behaviors and moderate- and vigorous-intensity physical activity (MVPA) with adiposity among Brazilian adolescents. This prospective cohort study included 377 participants of the 1993 Pelotas (Brazil) Study who completed an accelerometry assessment at age 13 years and a dual-energy X-ray absorptiometry (DXA) assessment at age 18 years. Accelerometer-measured MVPA was dichotomized into high (≥60 min/day) and low (<60 min/day). Accelerometer-measured sedentary time (SED) was dichotomized into low (<49 min/h) and high (≥49 min/h) based on the median. Self-reported TV viewing time was also dichotomized into low (<3 h/day) and high (≥3 h/day) based on the median. We combined the two MVPA groups (high and low) and two SED groups (low and high) to form the four MVPA&SED groups: high&low, high&high, low&low, and low&high. We also created four MVPA&TV groups in the same manner. Fat mass index (FMI; kg/m Physical activity (PA) is well recognized to provide numerous health benefits in youth, including obesity prevention, cardiovascular health, and bone health . SedentaGriffiths et al.  examinedIn low- and middle-income countries (LMIC), studies about the effects of sedentary behavior on adiposity are scarce , althougThe purpose of this study was to prospectively examine the joint associations of MVPA and SED or TV viewing time with adiposity development among Brazilian adolescents. Compared to prior prospective cohort studies that examined the association between sedentary behavior and adiposity in youth, this investigation is unique in that it was designed to examine the association separately for adolescents who are active and those who are not, it used dual-energy X-ray absorptiometry (DXA)-derived fat mass as an adiposity indicator (as opposed to body mass index [BMI]), and its sample was from a middle-income country.This study used data obtained from the 1993 Pelotas (Brazil) cohort study. The 1993 Pelotas Study is a birth cohort study that recruited almost all new births (n = 5249) born from all maternity hospitals in the city of Pelotas, Brazil, in 1993 . The CitFor the current paper, we included 1993 Pelotas Study participants who completed an accelerometer assessment at age 13 years (the primary exposure) and a dual-energy X-ray absorptiometry (DXA) examination at age 18 years (the primary outcome). We excluded those were classified as obese (WHO BMI-for-age z-score ≥ 2.00) [Exposures: The main exposure variables were time spent in MVPA, SED, and TV viewing during adolescence. During each of the 11-, 13-, and 15-year study visits, participants self-reported TV viewing time in minutes on a weekday and a weekend day in face-to-face interviews . Daily TMVPA and SED were assessed using accelerometers. Accelerometers are widely used to assess child PA . Acceler2). Outcome: The primary outcome variable was the fat mass index (FMI) derived from DXA scans at age 18 years. DXA is a gold standard for fat mass assessment. During the 18-year study visit, participants were asked to participate in a DXA scan  . ParticiConfounding factors: Consistent with our prior study , we consAll analyses were conducted separately according to participant sex, using SAS 9.4 . Missing data were treated using a list-wise deletion method. MVPA at age 13 years was dichotomized into high ≥60 min/day) and low (<60 min/day) [0 min/dayDescriptive analyses, including frequency and distribution analyses, were conducted. We calculated the means of the main study variables according to wealth index quintiles. Multivariable linear regression analyses were conducted with a log link to compare FMI at 18 years among the four MVPA&SED groups, adjusted for BMI z-score at the 13-year assessment, and age, wealth index quintiles, and energy intake quintiles at the 18-year assessment. The regression analyses were repeated for the MVPA&TV groups. A significance level was set at 0.05 (two-sided). Of the 415 Pelotas Study participants who had accelerometry and DXA data, we excluded 38 participants (9.2%) with obesity at the 13-year assessment. A total of 377 Pelotas participants  were included for analysis. p < 0.05): 86 vs. 59 min/day for the lowest vs. highest wealth index quintile groups among males and 60 vs. 50 min/day for the lowest vs. highest wealth index quintile groups among females. In contrast, when participants were from a wealthier family, SED levels tended to be higher; however, the trends were not statistically significant. Average TV viewing time during adolescence tended to increase with higher wealth index among males, while it tended to decrease with higher wealth index among females ; howeverMales : When unWhen FMI was adjusted for the confounding factors, it was significantly higher in the low MVPA&high TV group  compared to the high MVPA&low TV group . However, no significant differences in the FMI were found among the four MVPA&SED groups.2 for high TV viewing vs. 7.9 kg/m2 for low TV viewing) and low MVPA (FMI = 8.4 kg/m2 for high TV viewing vs. 7.9 kg/m2 for low TV viewing) groups; however, the differences did not reach a statistical significance. When FMI was adjusted for the confounding factors, no significant FMI differences were found among the MVPA&SED groups or among the MVPA&TV groups. Females : The higThis study found that total sedentary time or TV viewing time was not prospectively associated with adiposity during adolescence in both active and inactive Brazilian adolescents. The present study also found that the relationships between socioeconomic status and MVPA, sedentary time, TV viewing, and adiposity in Brazilian adolescents are not linear, and are more complex than the relationships observed in high-income countries: i.e., inverse associations between socioeconomic status and unhealthy PA, sedentary time, and adiposity . This study found that, relative to adolescents in high-income countries, such as the UK and US ,28,29, BThis study found no prospective association between TV viewing and adiposity among Brazilian adolescents, which contradicts that which has been hypothesized and supported based on data from high-income counties ,30,31. FThe practical implications of this study include the fact that the potential harmful effects of TV viewing on excess body fat should not be generalized across settings, particularly in middle-income countries. While the current PAG by the WHO  should gThe strengths of this study include the use of DXA-derived fat mass as an adiposity indicator and the use of a middle-income country as a study setting. A limitation of this study is its relatively small sample size for the examination of the joint associations. Moreover, a single assessment of MVPA and total sedentary time at age 13 years may not represent MVPA and the total sedentary time during the entire adolescent period. Self-reported TV viewing time is subjective and prone to error. The results could have been biased due to unmeasured or poorly measured confounding factors. The results may not be generalized to other adolescent populations from different settings.Future research is guaranteed to gather empirical evidence for the roles of sedentary behaviors and socioeconomic status in adiposity in low- and middle-income countries, as the present study suggests that relationships between socioeconomic status and adiposity or obesogenic behaviors appear to be different in middle-income countries from those in high-income countries. Moreover, further research should identify specific types of sedentary behaviors  that influence adiposity. This study found that total sedentary time or TV viewing time was not prospectively associated with adiposity in both active and inactive Brazilian adolescents. This study suggests that the association between specific sedentary behaviors, such as TV viewing, and adiposity, may differ across societal settings, in this case, in high-income vs. middle-income countries.


A material-tailored special concrete composite that uses a synthetic fiber to make the concrete ductile and imposes strain-hardening characteristics with eco-friendly ingredients is known as an “engineered geopolymer composite (EGC)”. Mix design of special concrete is always tedious, particularly without standards. Researchers used several artificial intelligence tools to analyze and design the special concrete. This paper attempts to design the material EGC through an artificial neural network with a cross-validation technique to achieve the desired compressive and tensile strength. A database was formulated with seven mix-design influencing factors collected from the literature. The five best artificial neural network (ANN) models were trained and analyzed. A gradient descent momentum and adaptive learning rate backpropagation (GDX)–based ANN was developed to cross-validate those five best models. Upon regression analysis, ANN [2:16:16:7] model performed best, with 74% accuracy, whereas ANN [2:16:25:7] performed best in cross-validation, with 80% accuracy. The best individual outputs were “tacked-together” from the best five ANN models and were also analyzed, achieving accuracy up to 88%. It is suggested that when these seven mix-design influencing factors are involved, then ANN [2:16:25:7] can be used to predict the mix which can be cross-verified with GDX-ANN [7:14:2] to ensure accuracy and, due to the few mix trials required, help design the SHGC with lower costs, less time, and fewer materials. Engineered geopolymer composites (EGC) are a new class of ultrahigh ductile fiber–reinforced concrete composites with 100% eco-friendly binding materials . CombinaDesigning concrete composites to achieve the desired compressive strength is always tedious. The mix-design procedure of conventional concrete has been standardized such that the concrete can be designed to achieve the target compressive strength . ResearcThe artificial neural network (ANN) is one of the artificial intelligence tools widely applied in almost all kinds of research worldwide ,17,18. TIn the early stages of the developmental phase of advanced research on special concrete and in order to study the material’s behavior in relation to various properties such as high strength and durability, it is essential to preliminarily understand the material’s basic behavior. The paramount concern in designing any kind of concrete composite is the compressive strength. For the conventional type of concrete, standard mix-design procedures are available by which, with the available material properties such as specific gravity and gradation, among others, the concrete composite can be designed to achieve the desired compressive strength . For speTo overcome this, several advanced techniques are being adopted in concrete technology to standardize the procedure of design . Among tEGC is one of the types of special concrete for which standards have not been prescribed, and since it is in the initial phases of development, several advanced studies are being carried out worldwide ,38. The f (%), curing temperature x hours, and ambient curing days—were given as outputs. Several ANN models were created and analyzed to predict the seven mix-design factors, with only compressive strength and tensile strength values as inputs. Predicting seven outputs with only two inputs is a tedious task as per ANN   resulted in nominal values of material conditions and curing regimes. It was identified that the higher the number of hidden neurons, the higher its prediction accuracy. However, numbers greater than 16 (>16) was not considered since the training process failed upon regression.During the training stages, 70% of the dataset was used for training, 15% for self-validation, and 15% for self-testing as per the “In the next phase, two layers of hidden neurons were used. Under different combinations of hidden neurons, it was found that the first hidden layer with 16 neurons was more efficient than the other combinations. Keeping 16 neurons as constant for the first hidden layer, various numbers of hidden neurons upon hidden layers were tried and self-tested and it was found that the ANN [2:16:16:7] and ANN [2:16:25:7] models provided nominal results. Furthermore, various hidden neurons with three hidden layers were tried and found the best possible outcomes as ANN [2:16:16:8:7], ANN [2:16:16:25:7] and ANN [2:16:32:16:7] models. In this stage, the same 72 datasets were employed in the development of the ANN-II model to predict the compressive and tensile strengths. During the prediction of compressive strength with several mix-design factors, i.e., few outputs with several inputs, GDX based ANN performed best, as per the literature . Hence, ANN-I models were developed to predict the numerical mix-design factors that help develop the material SHGC for its desired compressive and tensile strength. The five best models were selected from several trained models. The analysis on the predicting ability of ANN models to mix-design factors does not primarily lie in regression analysis, unlike compressive strength. For instance, when predicting sensitive parameters such as compressive strength, variance beyond ±5% is not acceptable , whereas2) was performed for the predictions of mix-design obtained from the five best ANN-I models. The prediction results and the experimental literature database are summarized through The regression analysis with the coefficient of determination . For curing temperature x hours, ANN [2:16:16:25:7], and for ambient curing days, ANN [2:16:16:7] were chosen for its maximum accuracy. However, adjustments to the nominal values can be made wherever required, as described earlier. The tacked-together outputs of mix design are shown in The predicted mix design from ANN-I models (illustrated in The regression analysis with a coefficient determination of ANN-I models and the hybrid model upon cross-validation for compressive and tensile strength are illustrated in As discussed in As per The ANN model [2:16:25:7], which performed well upon compressive strength, was also found to be best upon the tensile strength, with the predictive ability of up to 90% with RMSE 0.27, which is phenomenal, as indicated in As far as the tacked-together model upon cross-validation is concerned, the combination of individual best results of ANN-I models as a mix also showed greater accuracy up to the level of 88% on compressive strength but showed accuracy of only 54% on tensile strength. Thus, it is also suggested to use the tacked-together output combinations of different trained ANN models to predict the mix-design of SHGC with proper nominal adjustments when compressive strength is the primary concern. It is also to be noted that the ANN-II model showed accuracy of 94% only, i.e., the coefficient of determination obtained from cross-validation may still have improved accuracy beyond the results obtained.The ANN technique was attempted to predict the mix-design of SHGC for its desired compressive and tensile strength including curing conditions. Five LM-based ANN models were developed to predict seven mix-design factors based on two inputs, compressive and tensile strengths. The predicted outputs of these five models were analyzed upon regression using a coefficient of determination. The best resulting outputs of those five best models were summarized and “tack-together mix-design” was framed and also analyzed. A GDX-based ANN model was developed, trained, and tested with 94% accuracy to predict the compressive strength for cross-validation. The outputs obtained from LM-based ANN models were fed as inputs to GDX-based ANN for cross-validation. The regression and cross-validation results were analyzed, from which the following conclusions have been summarized.This research study reveals that the basic mix-design parameters required to design the material EGC are feasible with few LM-based ANN models which can be cross-analyzed with GDX-based ANN and if only these seven mix-design influencing factors are involved, then ANN [2:16: 25:7] can be used to predict the mix which can be cross verified with GDX-ANN [7:14:2] for ensuring accuracy.The five best ANN models that can predict the mix-design of SHGC were LM-based ANN [2:16:16:7], ANN [2:16:25:7], ANN [2:16:16:25:7], ANN [2:16:16:8:7], and ANN [2:16:32:16:7], and the best model for cross-validation was GDX-based ANN [7:14:2].A few models, i.e., ANN [2:16:16:7], performed well on regression analysis, which failed to perform cross-validation. This insists on the importance of cross-validating since to predict the mix-design of composites, the performance of the combination of all the factors is the key concern and not the performance of individual factors/materials.Even though the ANN [2:16:25:7] model showed less accuracy upon regression analysis, it performed well on cross-validation with the accuracy of prediction up to 85% and 90% upon compressive and tensile strength.In addition to the identification of each best mix-design factor upon regression analysis, isolating and tacking-together also performed best with the accuracy of 88% upon cross-validation.Thus it is recommended to use those predictive models for the material design of EGC involving the aforesaid mix factors with fewer trial mixes. This would certainly reduce the cost and time of trial experiments. However, the models cannot be applied directly for EGC involving surplus mix-factors.The material EGC is in the developmental stage, so there may be the need for analytical and experimental studies in various aspects of EGC, such as material development, structural behaviors, micro-structural enhancements, etc. The utilization of such ANN models reduces the trial mixes in the methodology and finds its way to develop more accurate predictive models, as larger availability of data certainly strengthens the training stage of predictive models. This will allow researchers to develop more accurate predictive models with various other-computing techniques such as response surface methodology, gene expression programming, and other optimization techniques.