The Pearson correlation coefficient showed that both wavelet amplitude and phase coherence are significantly correlated to the cognitive function of the prefrontal cortex. Therefore, brain FC is an available method to evaluate cognitive structure alteration in knowledge transfer. We also discussed why the dorsolateral prefrontal cortex (DLPFC) and occipital face area (OFA) distinguish themselves from the other brain areas in the M-WCST experiment. As an exploratory study in NeuroManagement, these findings may provide neurophysiological evidence about the functional brain network of knowledge transfer while engineering problem-solving.As a complex cognitive activity, knowledge transfer is mostly correlated to cognitive processes such as working memory, behavior control, and decision-making in the human brain while engineering problem-solving. It is crucial to explain how the alteration of the functional brain network occurs and how to express it, which causes the alteration of the cognitive structure of knowledge transfer. However, the neurophysiological mechanisms of knowledge transfer are rarely considered in existing studies. Thus, this study proposed functional connectivity (FC) to describe and evaluate the dynamic brain network of knowledge transfer while engineering problem-solving. In this study, we adopted the modified Wisconsin Card-Sorting Test (M-WCST) reported in the literature. The neural activation of the prefrontal cortex was continuously recorded for 31 participants using functional near-infrared spectroscopy (fNIRS). Concretely, we discussed the prior cognitive level, knowledge transfer distance, and transfer performance impacting the wavelet amplitude and wavelet phase coherence. The paired  Simulating the thinking pattern of the human brain is an attainable way to break through the bottleneck of artificial intelligence  has been widely used in FC in complex cognitive processing . We discussed the prior cognitive level and transfer distance affecting functional brain connectivity in knowledge transfer. Wavelet amplitude and WPCO were applied to evaluate the FC. Transfer performance analysis showed that the FC trustworthily assessed the cognitive level of subjects. The three groups of hypotheses are as follows:H1: The distance of knowledge transfer is significantly correlated to FC;H1a: The distance of knowledge transfer is significantly correlated to the wavelet amplitude of FC;H1b: The distance of knowledge transfer is significantly correlated to the WPCO of FC;H2: Prior cognitive level is significantly correlated to FC;H2a: Prior cognitive level is significantly correlated to the wavelet amplitude of FC;H2b: Prior cognitive level is significantly correlated to the WPCO of FC;H3: The transfer performance is significantly correlated to FC.H3a: The transfer performance is significantly correlated to the wavelet amplitude of FC;H3b: The transfer performance is significantly correlated to the WPCO of FC;A total of 33 subjects were recruited at the School of Mechanical Engineering, Shanghai Jiao Tong University, China. The experiment was finished by 31 subjects (age: 21.0526 ± 1.8995) , of which 24 are males and 7 are females. All participants satisfied the following criteria: (1) no structural abnormalities, (2) no neurological or psychiatric disorders, (3) no use of medication, (4) right-handed, and (5) healthy vision. Before the experiment, all participants signed an informed consent approved by the Institutional Review Board (IRB) of the Shanghai Jiao Tong University. It was in accordance with the ethical standards specified by the Helsinki Declaration of 1975 (revised in 2008). Anonymous information on the subjects was recorded before the test, such as gender and age.Handbook of Machine Design and Hydrodynamics and Hydraulic Transmission. Therefore, all the stimulus materials exhibited on the screen were knowledge concepts about engineering design, and all the concept-sorting tests were the specific problems to be solved for the subjects.The M-WCST experiment assessed the functional brain network of knowledge transfer while engineering problem-solving. It was divided into three phases, namely, prior technological paradigms (TP), near-transferred TP, and far-transferred TP, each phase taking about 30 min. In each phase, the subjects needed to solve specific design problems about three engineering products. The engineering products are as follows: a cylindrical speed-reducer gearbox (prior TP), a planetary speed-increaser gearbox (near-transferred TP), and an involute gear pump (far-transferred TP) . After the data pre-processing, the FC was calculated using the wavelet transform (wavelet amplitude and phase coherence). Pearson correlation analysis sustained the relevance between transfer performance and functional connectivity.The experiment of knowledge transfer was conducted in an enclosed and quiet laboratory environment, as shown in The brain regions covered by fNIRS are shown in The pre-processing of the cerebral oxygen signal will eliminate outliers and increase the signal-to-noise ratio so that the overall filtered signal is convenient for subsequent calculation and analysis. First, like all experimental instruments or equipment, the fNIRS equipment chose in this experiment (Shimadzu LIGHTNIRS) also has high-frequency noise during data acquisition, such as system noise and ambient light interference. Second, the subject's head movement and other reasons will bring low-frequency noise to the signal. Hence signal pre-processing also aims to detrend drift noise and movement artifacts, and the filtered signal can be used as the actual fNIRS signal. In this study, the raw data acquired by fNIRS was pre-processed through the NIRS_SPM toolbox of MATLAB R2013b, which included:(1) registration of MNI coordinates;(2) construction of the design matrix based on General Linear Model (GLM);(3) low-pass filter based on hemodynamic response function (HRF) with time derivative;(4) high-pass filter based on Discrete Cosine Transform (DCT) detrending algorithm.Afterward, SPSS 22.0 software supports statistical analysis and hypothesis tests to behavioral and pre-processed data.The different frequency intervals of blood oscillation signify different physiological connotations, specifically in the frequency intervals (0.0095–2.0 Hz). To extract the target signals from the filtered fNIRS signals, the spontaneous blood oscillation signal was divided into six frequency intervals  at a certain frequency ωk ∈ {I, VI} and a certain moment tn ∈  from different channels measured by fNIRS, we can get its complex spectral function through wavelet transform.Previous studies reported the wavelet transform method in detail, transforming non-stationary blood oxygen signals from the time domain to the time-frequency domain  and xj, one gets two corresponding instantaneous phases ϕi and ϕj in Equation 2. Then, the relative phase difference Δϕk, n = ϕj − ϕi can be computed. Subsequently, the trigonometric coefficients cosΔϕk, n and sinΔϕk, n are averaged in the time domain for the whole time series. Finally, the time-averaged WPCO was defined asThe amplitude-independent WPCO is assessed in this section  ≤ 1.WPCO(ωk) can assess the strength of phase coherence between two signals in different brain regions. If the coherence coefficient is close to zero, then, the two regions are uncorrelated. WPCO(ωk) = 1 would correspond to complete coherence between the two regions.0 ≤ WPCO(ωk) does not accurately indicate the synchronization of the two signals since it is easily disturbed by frequency. Concretely, in a signal with finite length, the low-frequency component can be represented by fewer periods than the high-frequency component  is defined asTo ensure the consistency between the WPCO and the synchronization of two signals, the amplitude adjusted Fourier-transform (AAFT) method was used to produce alternative signals to verify the coherence coefficients values . The coherence curves  from one subject are shown in WPCO(ωk) between the two channels separately; (3) generating alternative signals using the AAFT method, and checking the valid(ωk) of WPCO in Equation (5).whenever ωvalid(ωk) > 0, the WPCO of the brain regions is the mean of the WPCO of the related channels. Contrarily, if valid(ωk) ≤ 0, the WPCO of the brain regions is 0. The heatmaps of wavelet phase coherence and functional brain network of brain regions (subject #12) are shown in As mentioned above, we obtained the valid coefficients of WPCO between the two channels. If In The five functional regions are divided into 10 ROIs in the left and right brain. As shown in t-test was used to contrast the near-transferred TP group with far-transferred TP group. The significant differences in wavelet amplitude under different transfer distances are shown in According to the distance of knowledge transfer in M-WCST, we analyzed the wavelet amplitude and WPCO of blood oxygen signals in the near-transferred TP and far-transferred TP. For all subjects, the functional brain network of near transfer is shown in LDLPFC  under different transfer distances. It indicates that far transfer distances decreased the activation of the partial brain regions.Comparing the near-transferred and far-transferred groups, we found significant difference in the wavelet amplitude of LOFA-ROFA , LIPFG-RDLPFC , and RFOA-RDLPFC  were significantly different. It indicated that the transfer distance impacted the elaboration of the brain network in the PFC.Comparing the WPCO of the two groups above, we found that Notably, the DLPFC had significant activation under both near and far knowledge transfer. Cognitive results also illustrated a similar neurophysiological mechanism in both near and far transfer when the engineers were solving design problems since their activated brain regions partially overlap in different transfer distances.t-test. The significant differences in wavelet amplitude under different prior cognitive levels are shown in According to the cognitive level in the prior TP of M-WCST, the subjects were divided into the high cognitive level  and low cognitive level . We analyzed the wavelet amplitude and WPCO in the two groups. For all the subjects, the functional brain network in the high-level group is shown in ROFA  under different prior cognitive levels. It indicated that the two groups with different prior cognitive levels had different activation in brain areas. While facing some complicated problems in the concept-sorting test, the subjects with a high cognitive level could utilize more brain regions to learn knowledge than those with weak basic skills.Comparison between the high-level and low-level groups showed a significant difference in the wavelet amplitudes of RFOA-LOFA , LFOA-LOFA , LFOA-LDLPFC  were significantly different. The statistical results showed that the WPCO of the functional connectivity was significantly different depending on the prior cognitive level. It indicated that subjects with high prior cognitive levels usually hold complex brain networks in the PFC while engineering problem-solving.Comparing the WPCO of the two groups above, we found that To verify the effectiveness of FC and explore the neurocognitive underpinnings of knowledge transfer, the Pearson correlation coefficient analyzed the associations among wavelet amplitude, WPCO, and transfer performance. As shown in LOFA  and LPTBA  showed significant positive correlation. Moreover, significant positive correlation was observed in the performance and WPCO of LIPFG-RIPFG , LPTBA-RIPFG , and LFOA-LIPFG . Correlation analysis also revealed that the performance was significantly negatively correlated with the WPCO of LFOA-RPTBA  and RFOA-LDLPFC . These statistical results certified that the procedure of knowledge transfer for engineering problem-solving involves the activation and inhibition of partial brain interconnectedness.The transfer performance and wavelet amplitude of This section interprets the results of the wavelet amplitude and WPCO of FC in the M-WCST experiment while engineering problem-solving (near transfer and far transfer). We discuss whether the functional brain network is an efficacious and trustworthy evaluation tool to study the neurocognitive underpinnings of knowledge transfer.H1a and H1b cannot be rejected, i.e., FC is significantly different due to different knowledge transfer distances.Different Distances of Knowledge Transfer section shows that the wavelet amplitude and WPCO of FC are significantly different with the altering transfer distance. Therefore, the hypothesis Transfer distance disturbs the process of information extraction and the attention time to the effective stimulus materials of subjects, thereby affecting the brain functional connectivity  of the self-directed learning readiness scale (SDLRS)  of Shanghai Jiao Tong University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.XL and LB designed the study and edited the manuscript. FW designed the study, analyzed the data, and drafted the manuscript. YJ performed the experiment and statistical analysis. ZJ administrated this project. All authors contributed to the article and approved the submitted version.This research was supported by the National Natural Science Foundation of China (No. 71671113).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.


Diabetic retinopathy (DR) is the major cause of visual impairment and blindness in the working-age population. Conventional management for nonproliferative diabetic retinopathy (NPDR) without diabetic macular edema (DME) is derived from the findings of the Early Treatment Diabetic Retinopathy Study (ETDRS). Although the ETDRS protocol basically includes observation, selected cases of severe NPDR may undergo scatter laser photocoagulation. Post-hoc analysis of recent trials has shown that patients with NPDR receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) for DME would experience improvement in the DR severity scale (DRSS). In addition, recent randomized trials (PANORAMA and Protocol W) have revealed that early intervention with intravitreal aflibercept in eyes with moderately severe to severe NPDR is associated with significant improvement in DRSS and reduced vision-threatening complications of DR. Based on recent studies, it seems that the therapeutic approach to NPDR may undergo a substantial change and a paradigm shift toward considering early intervention with the administration of intravitreal anti-VEGF injections. However, the long-term results and the duration of adherence to anti-VEGF therapy for eyes with NPDR are not yet defined. It is also not apparent whether improvement in DRSS is a true disease modification. Studies showed that DRSS improvement is not associated with retinal reperfusion. In addition, DRCR.net Protocol W showed no visual acuity benefit with the early intravitreal aflibercept injection in moderate to severe NPDR as compared with performing observation plus intravitreal aflibercept applied only after progression to proliferative DR or vision-impairing DME. The cost–benefit ratio is also a challenge. Herein, we look at different aspects of early anti-VEGF application and discuss its pros and cons in the process of treating NPDR. One of the most common microvascular complications of DM is diabetic retinopathy (DR), which is reported to be the leading cause of visual impairment in the working-age population.,3 Diabetic retinopathy is classically categorized into two types: nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). Diabetic macular edema (DME) is another important manifestation of DR, which may be experienced across all DR severity stages. While approaches to the patients with PDR or DME is straightforward, the therapeutic approach to NPDR patients with no DME has not been well established.According to the recent report of the International Diabetes Federation (IDF), about 400 million people live with diabetes mellitus (DM) worldwide; this prevalence is estimated to approach 600 million individuals by 2035. includes observation for mild and moderate NPDR. Most cases of severe NPDR are also followed closely; however, selected cases may undergo scatter laser photocoagulation. Post-hoc analysis of recent trials has shown that patients with NPDR receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) drugs for DME would experience amelioration in the DR severity scale (DRSS).,6 In addition, more recent randomized controlled trials (PANORAMA study and DRCR.net Protocol W) have revealed that early intervention with intravitreal injection of aflibercept in eyes with moderately severe to severe NPDR may be associated with significant improvement in DRSS and reduced vision-threatening complications although the effect on visual acuity has not been significantly different compared to proper follow-up with timely treatment of complications.,8 Based on recent studies, the therapeutic approach toward treating NPDR may undergo a significant change and paradigm shift to early intervention with intravitreal anti-VEGF injections that may substitute the conventional approach. However, the long-term results of anti-VEGF therapy for eyes with NPDR are not yet determined, and it is not clear how durable this approach will be and whether it is connected with enhanced visual functions and improved quality of life (QoL). The cost–benefit ratio is also a challenge that needs to be addressed. Herein, we review the different aspects of NPDR management and the early application of anti-VEGF therapy.Conventional management for NPDR without DME, which is derived from the findings of the Early Treatment Diabetic Retinopathy Study (ETDRS)Management of NPDR patients without DME involves all interventions that prevent occurrence of vision-threatening complications including PDR and DME. This goal can be achieved by both systemic and ocular interventions.,10 These results have been supported in other studies.,13 As an observation in the DCCT and UKPDS, the people in the early intensive glycemic control group had a significantly lower risk for long-term retinopathy progression and microvascular disorders regardless of the glycemic condition in the later course of the diabetes.,15 The American Diabetes Association (ADA) recommends a hemoglobin A1c (HbA1c) of Control of hyperglycemia remains the basis of care in diabetic patients. Intensive glycemic control evaluated in two landmark trials, the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), assisted in reducing the risk of developing retinopathy and slowing the DR progression in both type 1 and type 2 DM,18,19,20 Generally, blood pressure control has been recommended as a principal part of the standard care in diabetic patients, primarily because of its known beneficial effect on macro-vascular complications of DM rather than for its effect on DR. However, blood pressure control may also reduce the damage to endothelial cells, through which slowing of DR progression may be achieved. The available evidence does not support the idea that blood pressure control alone can inhibit or slow the progression of DR.Several studies have investigated the role of blood pressure regulation in the incidence and progression of DR. Some of these studies have demonstrated a positive effect from the intensive control of blood pressure, whereas no beneficial effect on the incidence and progression of DR has been observed in others. However, Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS II) reported a threefold increase in the risk of DR progression to PDR stage in patients with higher triglycerides levels. The ACCORD Eye Study has confirmed that fenofibrate benefits patients with DR. Furthermore, the FIELD study confirmed that fenofibrate could prevent the progression of DR independent of serum lipids' levels. It is postulated that the role of fenofibrate is more effective via iron chelation rather than hyperlipidemia treatment. Given the role of iron in retinal damages via oxidative pathways, iron chelation with fenofibrate may play a protective role in reducing retinal damage in DR. In the Collaborative Atorvastatin Diabetes Study and the Heart Protection Study, the progression of DR did not differ between patients treated with statins and those who received placebo.,30The effects of dyslipidemia on DR incidence and progression have been controversial. In a new meta-analysis, no significant difference in lipid profile was observed between patients with and without DR.,32 Some studies have suggested that lower hemoglobin levels may be linked to progression of DR.,34 Dietary modification, regular monitoring of anemia, and treatment with supplements may stop the progression of DR.Anemia is considered a risk factor of the microvascular complications of diabetic patients. Recently, it has been postulated that vitamin D3 exerts protective effects against retinal cell apoptosis and vascular damage in DR patients via an anti-inflammatory mechanism.A meta-analysis has revealed an association between vitamin D deficiency and increased risk of DR in type 2 DM. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), smoking was not significantly associated with the progression of DR in a 4-year and 10-year follow-up period. Although the relationship between smoking and progression of DR remains inconclusive, there is evidence that suggests that smoking encourages macro-vascular complications associated with DM. As a result, it is recommended that patients who suffer with DM be strongly advised to cease smoking.A new meta-analysis discovered that the risk of DR was greater in smokers with type 1 diabetes; while in those patients who suffered with type 2 diabetes, the risk of PDR significantly decreased in smokers in comparison with nonsmokers. Nevertheless, the question remains: Can retinal photocoagulation for patients with nonproliferative stages of DR decrease the risk of visual impairment by preventing the progression to PDR stage?As DR reaches proliferative stage, retinal photocoagulation is applied to preserve the vision. This indication was derived from the presentation of two landmark studies, Diabetic Retinopathy Study (DRS) and ETDRS, where the findings convinced ophthalmologists to reach consensus on laser photocoagulation as a gold standard procedure for high-risk PDR (HRPDR). One eye of each patient was randomly assigned to laser photocoagulation and the second eye was considered as the control group. The two-year risk of severe visual loss in eyes with severe NPDR was 3.2% and 2.8% in the control and laser photocoagulation groups, respectively. The four-year rates were 12.8% and 4.3%, respectively. Although the researchers found that 50% of the eyes with severe NPDR who were in the control group developed new vessels in one year, after considering the small risk of severe visual loss in the control group and the possible side effects of laser photocoagulation they did not recommend laser photocoagulation for all NPDR patients. Nevertheless, the DRS offered laser photocoagulation in NPDR eyes in some instances: one eye of a patient with severe NPDR in both eyes, presence of severe retinal ischemia, when the patient was pregnant or there was coexisting disorders such as renal failure that might accelerate the course of DR.Patients with either PDR in at least one eye or severe NPDR in both eyes were included in the DRS. Patients with moderate to severe NPDR or early PDR were included. Early photocoagulation was randomly performed in one eye of each patient and the other eye was assigned to deferred photocoagulation. In the latter, patients underwent laser therapy when high-risk PDR was detected. In the deferred photocoagulation group who had severe NPDR, the rate of PDR development was 51%, 71%, and 79% in the first-, third-, and fifth-year visits, respectively. Compared to deferred photocoagulation, early photocoagulation decreased progression to high-risk PDR by 25% and 50% with full scatter and mild scatter photocoagulation, respectively. However, the rate at the five-year visit determined that severe visual loss was low and comparable among the study groups .The ETDRS remains the only study addressing the question of the suitable time for starting laser photocoagulation. They found that earlier PRP at the severe NPDR stage was less costly and more effective than administering PRP to patients with high-risk PDR. It meant that fewer patients in the earlier PRP group progressed to more advanced stages of DR.A recent survey built a Markov model to explore whether it would be cost-effective either to apply panretinal photocoagulation (PRP) at the NPDR stage or to wait until HRPDR developed.,45 Fong et al have reported that visual field defects may occur in almost half of the treated patients, and the incidence is correlated with the intensity of the laser therapy. A recent study based on optical coherence tomography angiography (OCT-A) has reported that in laser-treated severe NPDR eyes, ocular blood flow is significantly reduced, which may be associated with decreased visual acuity in these patients.The most common complications of PRP are decreased visual field and exacerbation of macular edema.,49 According to the results of retrospective studies, anti-VEGF treatment can improve the DRSS and reduce the rate of PDR development.Intravitreal anti-VEGF therapy for NPDR is an evolving concept. Clinical data show that VEGF contributes to the pathogenesis of both NPDR and PDR.P Furthermore, it has been noted that the cumulative probability of DR progression was 34% in the sham-treated patients and 11.2–11.5% in the ranibizumab-treated patients by month 24. In addition, it has been reported that intravitreal ranibizumab in patients of RISE and RIDE trials slowed the progression of retinal non-perfused areas.RISE and RIDE were two phase-III, double-blind randomized clinical trials of intravitreal ranibizumab versus sham in patients with DME. In an exploratory analysis of RISE and RIDE trials, among the eyes with baseline ETDRS severity level of 53 (severe NPDR) or less, monthly intravitreal ranibizumab injection administered for 24 months was associated with a P In addition, the proportion of patients who developed PDR was significantly less in those who received intravitreal aflibercept as compared with the sham-treated group  compared with those treated with laser (13%) achieved a  There were no statistically significant differences among the three commercially available anti-VEGFs in terms of inducing the regression of DR.DRCR.net Protocol T compared the efficacy of intravitreal aflibercept, ranibizumab, and bevacizumab in the treatment of DME. Based on a post hoc analysis of the Protocol T, 25%, 22% and 31% of NPDR eyes receiving aflibercept, bevacizumab, and ranibizumab for DME demonstrated improvement in DRSS at two-year follow-up, respectively.P Furthermore, the proportion of eyes that developed vision-threatening complications and/or CI-DME were 50.4%, 16.3%, and 18.7% in the sham group, every 16 weeks and every 8 weeks aflibercept groups, respectively  and center-involved (CI) DME in patients with moderately severe to severe NPDR without DME. In this phase-3 clinical trial, 402 patients were randomly assigned to sham versus aflibercept administered every 8 weeks after 5 monthly loading doses versus aflibercept administered every 16 weeks after 3 monthly loading doses. At two-year follow-up, the proportion of eyes with 2-step or more improvement in DRSS was 12.8%, 62.2%, and 50% in the sham group, every 16 weeks aflibercept group and every 8 weeks (converted to pro re nata [PRN] in the second year) aflibercept group, respectively  versus sham in reducing vision-threatening complications in eyes with moderate to severe NPDR.Monte Carlo simulation of a real-world cohort of treatment-naive patients with NPDR from the IBMⓇ ExplorysⓇ database suggested that severe NPDR treatment with anti-VEGF would significantly decrease the probability of progression to PDR by 51.7% at the five-year follow-up period. Furthermore, the incidences of sustained blindness in severe NPDR patients were reduced with anti-VEGF therapy by 57.7% over a 10-year follow-up period. At the six-month follow-up period, among the patients who were treatment-naïve, 2-steps or greater improvement in the DRSS was achieved in 12.2%, 27.7%, and 38.6% of eyes in the 0.3 mg ranibizumab, 1.5 mg Faricimab, and 6 mg Faricimab groups, respectively.The phase-2 BOULEVARD trial compared the efficacy of Faricimab, a bispecific antibody, inhibiting both VEGF-A and angiopoietin-2, with ranibizumab in the treatment of patients with DME. Recently, there has been increasing evidence that anti-VEGF treatments would improve DRSS and decrease the risk of vision-threatening complications such as PDR and DME,,8 raising an important question: Is it recommended to target the DR at the nonproliferative stage by administering intravitreal anti-VEGF injections to prevent the disease progression and reduce the risk of vision threatening complications? There are pros and cons for this evolving approach.Conventional management of NPDR without DME included observation along with controlling the systemic condition. The ETDRS showed that in one year, 26% of eyes with moderately severe NPDR and 52% of eyes with severe NPDR in the deferred photocoagulation group would progress to PDR, a vision-threatening complication of DR. The rate of progression to PDR reached 66% and 75–81% at the five-year follow-up period. At the end of the second year, data were also emphasized in the DRCR.net W protocol, where the risk of vision-threatening complications was 16.3% and 43.5% for the aflibercept and the sham groups, respectively.There is increasing evidence in favor of administering intravitreal anti-VEGF injection in nonproliferative stages of DR without DME. The PANORAMA study showed that intravitreal aflibercept reduces the risk of vision-threatening complications by 77% and 83% in every 16 weeks and every 8 weeks (PRN in the second year) groups, respectively, as compared with the sham group at 100 weeks. However, a small interventional cohort with short term follow-up showed that anti-VEGF induced improvement of DRSS could occur without any retinal reperfusion.Extension of non-perfusion areas is the major pathology in DR. Diabetic retinopathy leads to upregulation of VEGF and contributes to further progression of non-perfusion areas as a vicious cycle. It was demonstrated that anti-VEGF therapy slows the development and progression of retinal non-perfusion in patients with DME. Furthermore, a cross-sectional study showed that vision-related functional burden is significantly greater in patients with severe NPDR or PDR versus those with no retinopathy.Epidemiological studies have shown that DR has an adverse effect on the quality of life (QoL). A recent longitudinal and observational study showed that QoL significantly decreases with aggravation of DR severity from mild NPDR to PDR. Kaplan-Meier's analysis of a recent epidemiological study has shown that eyes with moderate NPDR, severe NPDR, and PDR were 2.6, 3.6, and 4 times, respectively, more likely to develop sustained blindness, as compared to eyes with mild NPDR, after two years of follow-up.Longitudinal population-based studies have shown that more advanced DR at diagnosis is associated with higher risk of developing sustained blindness. This shows that nearly half of the patients who have NPDR will not progress to PDR or develop DME despite not receiving any intraocular injection.At the end of two-year follow-up in the PANORAMA study, 49.6% of eyes in the sham group did not develop vision-threatening complications and/or CI-DME.,61 The most devastating complication is infectious endophthalmitis. The prevalence of endophthalmitis following intravitreal injections is estimated to be 0.01–0.26%.Some complications have been reported regarding the use of intravitreal anti-VEGF injections. Common complications are the incidence of floaters and the rise of IOP.P = 0.47).It is not clear whether intravitreal anti-VEGF for severe NPDR can be associated with enhanced visual function and improved QoL. DRCR.net Protocol W, during a two-year period, showed no visual benefit of the preventive intravitreal aflibercept treatment in eyes with moderate to severe NPDR as compared with those eyes that underwent observation plus aflibercept which was administered only after progression to PDR or vision-impairing CI-DME. The mean change of visual acuity was –0.9 and –2.0 ETDRS letters in aflibercept and sham groups, respectively  study, nearly 40% of eyes that did not receive any more ranibizumab injections during the OLE experienced 2-steps or more worsening in the DRSS.The long-term real-world benefits of anti-VEGF therapy for eyes with NPDR are not yet determined. It is not clear how durable the treatment is and how long the patients should receive anti-VEGF treatment. In the second year of the PANORAMA study, those patients who initially received aflibercept every eight weeks transitioned to PRN. Concomitantly the rate of 2-steps or more improvement in DRSS reduced from 79.9% to 50%. In addition, Bonnin et al showed that after administering anti-VEGF injections in DR eyes, the improvement in the DRSS score based on color fundus photograph could occur without retinal reperfusion on UWF FA. In an OLE of RISE/RIDE study, it was shown that patients with anti-VEGF injection induced moderate NPDR were more prone to DR progression compared to patients with moderate NPDR at enrollment who were randomized to the sham group.It is not apparent whether improvement in the DRSS following intravitreal injections of anti-VEGFs is a true disease modification. In a case series by Couturier et al, no reflow of vessels or reperfusion of capillary bed was found in non-perfusion areas using ultra-widefield (UWF) fluorescein angiography (FA) and swept-source widefield (SS-WF) OCT-A in eyes with DR after 3 anti-VEGF injections.The cost–benefit ratio is also a challenge that needs to be addressed. Answering this question requires more time and further studies.Inhibition of the VEGF independent pathways may also affect the course of DR. There is some evidence that angiopoietin/Tie2 and Rho-associated kinase (ROCK) play an influential role in retinal perfusion. Inhibition of angiopoietin 2 may enhance the effects of VEGF inhibition in improving the DRSS.,67 An in vivo study showed that fasudil (a specific ROCK inhibitor) decreased vasoconstriction, improved retinal flow, and could potentially reduce the retinal ischemia. Intravitreal ripasudil also decreased the retinal non-perfusion areas and improved retinal blood flow in a murine model of retinal vein occlusion. Ahmadieh et al reported that a combination of intravitreal bevacizumab and fasudil in eyes with persistent DME and macular ischemia was associated with significantly more visual improvement as compared with solely administering intravitreal bevacizumab. This significant visual improvement could be due to improved perfusion induced by the ROCK inhibitor. Further research is needed to determine the role of ROCK inhibitors in ameliorating diabetes-induced retinal microvascular damage and improving DRSS.Expression of Rho-associated kinase (ROCK) is increased in diabetic eyes and activation of ROCK-1 induces focal retinal vasoconstriction and subsequent retinal ischemia.The concept of slowing the progressive course of DR and preventing the vision-threatening complications of this potentially blinding disease may represent the initial sign of a paradigm shift from the observation, which has been the standard care for patients with NPDR to a new strategy comprising intravitreal anti-VEGF injections. However, there is not enough evidence supporting this paradigm shift at present. A new classification may help improving the management of NPDR based on recent progress in understanding of the pathophysiology and advances in treatment of DR and addresses the need to possible paradigm shift in the future.The authors declare that they did not receive any fund for the current manuscript or any research relevant to the present study.The authors have no conflicts of interest to declare.


The mechanical properties of aerospace carbon fiber/graphene nanoplatelet/epoxy hybrid composites reinforced with pristine graphene nanoplatelets (GNP), highly concentrated graphene oxide (GO), and Functionalized Graphene Oxide (FGO) are investigated in this study. By utilizing molecular dynamics data from the literature, the bulk-level mechanical properties of hybrid composites are predicted using micromechanics techniques for different graphene nanoplatelet types, nanoplatelet volume fractions, nanoplatelet aspect ratios, carbon fiber volume fractions, and laminate lay-ups . For the unidirectional hybrid composites, the results indicate that the shear and transverse properties are significantly affected by the nanoplatelet type, loading and aspect ratio. For the cross-ply and angle ply hybrid laminates, the effect of the nanoplate’s parameters on the mechanical properties is minimal when using volume fractions and aspect ratios that are typically used experimentally. The results of this study can be used in the design of hybrid composites to tailor specific laminate properties by adjusting nanoplatelet parameters. The development of the next generation of high-performance composite materials has been motivated by increasing performance demands in applications such as aerospace and wind energy. One route to producing composites with improved properties over state-of-the-art systems involves the use of nanoparticle reinforcement inside traditional fiber-reinforced thermosetting resins. Nanoparticles such as carbon nanotubes and graphene have extraordinary mechanical properties, and thus these hybrid nanoparticle and fiber-reinforced composites can potentially achieve greater stiffness, strength, and toughness relative to traditional fiber-reinforced composites ,9,10,11.A significant number of studies have addressed the fabrication, characterization, and testing of hybrid composite materials ,22,23,24There are a few multiscale computational options for developing novel, high-performance hybrid composites. The finite element method (FEM) is a powerful technique capable of the multiscale modeling of hybrid polymer composites. A wide variety of variables can be investigated when using FEM to model polymer composites, including dispersion, waviness, agglomeration, and nanoparticle loading . It is aAnother computational option for understanding the structure–property relationships of hybrid composites is a multi-scale approach comprising molecular dynamics (MD) simulation and micromechanics theory. MD simulation is an accurate and efficient computational method for predicting the mechanical properties of polymers and their composites ,32,33,34The interaction between the nanoparticle and polymer matrix dictates the level of reinforcement load transfer, and therefore significantly affects the composite’s mechanical properties. The nanoparticle–polymer interface can be strengthened by functionalizing the nanoparticle . FunctioThe objective of this research is to utilize multiscale modeling to determine the structural behavior of CF/graphene nanoplatelet/epoxy hybrid composite laminates for different levels of nanoplatelet functionalization, aspect ratio, and loading, as well as CF loading and layup. The monograph is intended to produce a useful database for experimentalists and/or manufacturers, which will help to reduce the time, cost, and effort involved in developing these composite materials. Such comprehensive data are not currently available in the literature for this material and level of accuracy. The results provide predictions of the laminate-level response of hybrid composites based on nanoscopic, microscopic, and macroscopic material parameters. First, the modeling methods will be described, followed by a comprehensive discussion of the results.The details of the simulated material and the modeling procedures are presented in this section. The modeling described herein builds off of two multiscale modeling studies: one on dispersed and agglomerated CF/graphene nanoplatelet/epoxy hybrid composites , and anoMAC/GMC is a comprehensive, user-friendly, and efficient computer code developed at NASA’s Glenn Research Center. The computational approach in this code is based on the High-Fidelity Generalized Method of Cells (HFGMC) micromechanics theory. HFGMC is more accurate and efficient in predicting the local stress and strain fields relative to the standard GMC. This improvement is essential to providing accurate predictions and more detailed analyses of composite materials. Specifically, the availability of accurate local stress and strain fields is critical for accurately modeling the interphase region between composite constituents. This level of accuracy is necessary to analyze composite material damage and failures, such as matrix inelasticity and fiber–matrix debonding. Via this micromechanics approach, the microscale architecture of constituents was characterized using a doubly and triply periodic repeating unit cell (RUC) to model the mechanical behavior and response. The RUC is composed of a number of subcells. Each subcell can be used to represent a single phase of heterogeneous or composite materials. Thus, the code can be used to analyze a wide range of material constitutive models. The constitutive model of the material could be isotropic, transversely isotropic, or completely anisotropic. Studies on polymer-based nanocomposites reinforced with graphene nanoplatelets have referred to a critical problem, represented by the difficulty of preserving the perfect dispersion of the graphene nanoplatelets within the polymer matrix. This is because graphene nanoplatelets have a natural tendency to agglomerate and form particles of stacked graphene layers within the polymer matrix. This problem is referred to as the agglomeration phenomenon, and is triggered by the noncovalent Van der Waals forces and pi-conjugation. It is an unfavorable phenomenon because it impedes the dispersion of graphene nanoplatelets in polymer matrices ,49,50,51Given the discussion mentioned above, four different graphene nanoplatelet types were considered in this study: pristine well-dispersed graphene nanoparticles (GNP), agglomerated nanoparticles (4GNP), graphene nanoparticles functionalized with oxygen groups (GO), and graphene nanoparticles functionalized with oxygen and amine groups (FGO). Molecular dynamics (MD) images of these four nanoplatelet types and the corresponding nanoplatelet/epoxy MD models are shown in Al Mahmud et al. ,42 used For the current study, using the nanoplatelet/epoxy homogenized mechanical properties that were predicted as described above, a second MAC/GMC script was developed to simulate the CF/nanoplatelet/epoxy hybrid composite systems. The predicted mechanical properties of the CF/nanoplatelet/epoxy hybrid composites are described in this section. The predictions for the unidirectional plies are presented first, followed by the laminates.,The simulation for the unidirectional CF-based hybrid composites was performed as illustrated in 3 GNP aspect ratio. Clearly, the greatest improvement can be observed in the shear moduli with To better discern the reinforcing effect of the GNP on each mechanical property of the hybrid composite, the mechanical properties were normalized and plotted together in one graph. For the reinforcing effect caused by increasing the GNP aspect ratio, 3 aspect ratio for various values of 4GNP content. Once again, the reinforcing effects of the 4GNP on At lower levels of GNP dispersion, the mechanical responses of unidirectional CF/4GNP/epoxy hybrid composites exhibit a similar trend to that observed for the unidirectional CF/GNP/epoxy.  E11 see . In gene3 aspect ratio for various nanoplatelet contents. To emphasize the reinforcing effect, each predicted mechanical property was normalized by its initial magnitude. In general, the reinforcing effect of GNP is the greatest among all the nanoplatelets. While the reinforcing effect of the 4GNP is slightly lower than that of GNP, FGO followed by GO have the lowest reinforcing effect. This is true for the aspect ratio range 102–104. For aspect ratios less than 102, which are most common in nanocomposites, all the nanoplatelet types involve a comparable reinforcing function. Interestingly, at very high aspect ratios (>104), the predicted reinforcing effect of 4GNP slightly surpasses that of GNP.Symmetric balanced cross-ply laminated composite plate (eight layers)s ≡ CP-8;[0/90/0/90/90/0/90/0] ≡ [0/90/0/90]Symmetric balanced angle-ply laminated composite plate (eight layers) s ≡ AP-8;[45/0/−45/90/90/−45/0/45] ≡ [45/0/−45/90]Symmetric balanced angle-ply laminated composite plate (six layers)s ≡ AP-6.[60/−60/0/0/−60/60] ≡ [60/−60/0]The mechanical response prediction of three different stacking orders of laminated CF/nanoplatelet/epoxy hybrid composites is explored herein. The stacking order of each laminate is:The hybrid composite laminate structures were modeled using MAC/GMC. The modeling approach involves two steps, as shown in 11), the bending stiffness (D11), the in-plane elastic modulus (Exx = Eyy), and the in-plane Poisson’s ratio (νxy). The reinforcement effect is greater for the cross-ply laminates in terms of the shear modulus (Gxy). To better illustrate the reinforcing effect of each of the four nanoplatelet types on the mechanical response of the laminated hybrid composite plates, 11) values of the CP-8-laminated hybrid composite plate, along with the normalized values shown in 11 values is based on the nanoplatelet type and content with an aspect ratio of 100. 11 values for the same laminated hybrid composite plate, along with the normalized values shown in 11 values using each of the four nanoplatelet types follows the order of GNP > 4GNP > FGO ≥ GO. However, this rule does not hold true at conditions with a low nanoplatelet content (<1 wt%) and aspect ratio (< 100), for which there are nearly identical reinforcing effects. Another exception to this rule occurs in the rare instance when the aspect ratio is greater than 104, at which point the reinforcing effect of 4GNP surpasses that of GNP  values of the CP-8-laminated hybrid composite plate, along with the normalized values, which are shown in 11 values is based on the nanoplatelet type and content with a constant aspect ratio of 100. 11 values for the same laminated hybrid composite plate, and the normalized values are shown in 11 values using each of the four nanoplatelet types also follows the order of GNP > 4GNP > FGO ≥ GO. Similar trends can be observed for the predicted D11 values of the AP-8- and AP-6-laminated hybrid composites shown in In the same manner, xx = Eyy) values of the CP-8-laminated hybrid composite plate, along with the normalized values shown in xx values is based on the nanoplatelet type and content, with a constant aspect ratio of 100. xx values for the same laminated hybrid composite plate, along with the normalized values shown in xx values using each of the four nanoplatelet types follows the order of GNP > 4GNP > FGO ≥ GO. Similar trends can be observed for the predicted Exx values of the AP-8- and AP-6-laminated hybrid composites, as shown in xx values are more likely to be close or identical at nanoplatelet aspect ratio values less than 100.xy) values of the CP-8-laminated hybrid composite, along with the normalized values shown in xy values is based on the nanoplatelet type  with various nanoplatelet contents and an aspect ratio of 100. xy values for the same laminated hybrid composite plate, along with the normalized values shown in xy values using each of the four nanoplatelet types follows the order of GNP > 4GNP > FGO ≥ GO. Similar trends can be observed for the predicted Gxy values of the AP-8- and AP-6-laminated hybrid composites shown in xy values are more likely to be close or identical at nanoplatelet aspect ratio values less than 100.xy) values of the CP-8-laminated hybrid composite, along with the normalized values shown in xy values is based on the nanoplatelet type content with an aspect ratio of 100. xy values for the same laminated hybrid composite plate, along with the normalized values shown in xy, identical νxy values  can be observed for the inclusion of FGO and GO nanoplatelets. Similarly, xy values predicted for the AP-8 and AP-6 composites, respectively. The plots show a general decrease in the predicted νxy as the nanoplatelet content and aspect ratio are increased. For aspect ratio values < 100, nearly identical responses can be observed for the predicted νxy with 4GNP, FGO, and GO. However, the decrease in the predicted νxy with 4GNP is close to that predicted with GNP, with aspect ratio values > 100. The νxy values predicted with GNP registered the highest drop among the nanoplatelets, except at very large aspect ratio values, where the drop in νxy with 4GNP surpassed that with GNP. Finally, A parametric computational study was performed to assess the mechanical performance of aerospace epoxy composites reinforced with carbon fiber and functionalized graphene nanoplatelets. Four types of graphene nanoplatelets were considered , and a wide range of nanoplatelet loadings and aspect ratios were also used as adjustable parameters. Micromechanical modeling methods were used to predict the effects of these parameters on the overall laminate properties for unidirectional, cross-ply, and angle-ply layups. For the unidirectional CF/nanoplatelet/epoxy hybrid composites, the predicted mechanical properties indicate that the axial mechanical response is dominated by the CF. However, there is an improvement in the transverse mechanical response owing to the nanoplatelet reinforcing effect. For the cross-ply and angle-ply hybrid laminates, the reinforcing effect of the nanoplatelets is rather insignificant in terms of the in-plane mechanical response. This is because the in-plane mechanical properties are highly governed by the angle or orientation of the CF within each lamina. Based upon the engineering application or the mechanical function of the structural component, this comparative study can provide insight for designing and fabricating hybrid laminated composite structures using graphene nanoplatelets. The results of these models can be utilized to optimize the mechanical behavior of the laminated hybrid composite by controlling the parameters that affect the mechanical response. These controlling parameters can be adjusted according to the component function within the structure. The CF angle/direction in each lamina and the number of laminas and their stacking sequence are fundamental to determining the mechanical response of the constructed laminated composite. The nanoplatelet content and its aspect ratio are additional important factors that can be considered in fabricating laminated hybrid composite plates.


The world is facing serious health and economic threats from the global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The burden of disease has been significant, with tens of millions of cases and more than 1.5 million deaths reported globally. .  and protection of vulnerable populations . There has been significant international collaboration to develop responses to COVID-19. If the increased awareness of the importance of public health can lead to a greater focus on developing responses to mosquito-borne disease, there may be a positive outcome from the current situation. Although there may be competing public health priorities, especially for COVID-19, authorities must maintain the programmes designed to reduce the burden of malaria and dengue.


A ratio of the mean epithelial reflectivity to stromal reflectivity of >1.29 corresponded with a high sensitivity (91.7%) and specificity (98.75%); while a mean superficial vascular density score of >0.38 corresponded with a sensitivity of 97.9% and specificity of 73.8%. In conclusion, HR-OCT/A as a non-invasive imaging modality could prove to be a useful tool for confirming the diagnosis of LSCD, with potential clinical and research applications.This study aimed to identify the anterior segment high-resolution optical coherence tomography (HR-OCT) and HR-OCT angiography (HR-OCTA) features suggestive of limbal stem cell deficiency (LSCD) as confirmed by both impression cytology (IC) and in vivo confocal microscopy (IVCM). This was a single-centre prospective cross-sectional study including 24 eyes of 22 patients with clinical suspicion of LSCD based on peripheral superficial corneal vascularisation and scarring. On IC and IVCM, performed and interpreted by blinded observers, 12 eyes each were diagnosed with and without LSCD. Additionally, 10 eyes of 5 healthy volunteers with no ocular pathology were also imaged. The 136 HR-OCT/A images of these 34 eyes were analysed with respect to 12 imaging parameters; the parameters most suggestive of LSCD were identified and the sensitivity and specificity were calculated. In the LSCD group, the most common aetiology was ocular chemical burns (83%), whereas in the non-LSCD group, the most common aetiology was viral keratitis (67%). Multiple logistic regression analysis revealed that mean epithelial reflectivity, mean stromal reflectivity, and mean superficial vascular density were the parameters that were diagnostic of LSCD on HR-OCT/A ( The cornea is an optically transparent structure and is responsible for three-fourths of the refractive power of the eye. Regularity of the surface epithelium is an important factor for maintaining this transparency. This continuous process of corneal epithelial cell renewal is normally sustained throughout life due to the presence of epithelial stem cells at the limbus . The limThe confirmation of the diagnosis of LSCD is the first critical step in managing this condition . HistoriOver the last decade, high-resolution optical coherence tomography (HR-OCT) has emerged as a popular method of imaging for the anterior segment. The HR-OCT imaging of the cornea is a rapid, non-contact technique, with low operator dependence and provides instantaneous output and analysis with good histopathological correlation ,12. PrevThis was a prospective cross-sectional imaging study done at the L.V. Prasad Eye Institute, Hyderabad, India between 1 August 2018 and 30 June 2019. All adult patients with peripheral corneal vascularisation and scarring with a clinical suspicion of LSCD in at least one eye were eligible to be included along with age and sex-matched healthy normal volunteers. All patients and volunteers underwent a comprehensive ocular examination including slit-lamp examination with fluorescein staining of the ocular surface. Next, all recruited patients underwent IC, IVCM, HR-OCT and HR- OCTA at baseline by single observers who were blinded to the clinical diagnosis during the initial sitting. Based on the findings noted on slit lamp photomicrographs, IC and IVCM, the patients were divided into 2 groups (i) LSCD and (ii) non-LSCD. Patients who refused to undergo all the required investigations, uncooperative patients, and patients in whom good quality imaging or sampling could not be performed were excluded from the study. Additionally, patients who underwent IC and IVCM but had discordance in the results between IC and IVCM and where LSCD or non-LSCD could not be confirmed, were excluded from this study. The HR-OCT/A images of the patients in the LSCD and non LSCD groups were then processed and analysed by observers who were blinded to the clinical diagnosis (one observer for each of the tests). Slit-lamp photographs were captured before and after application of fluorescein-dye using cobalt blue light. Corneal IC was then performed, and the technique used has been described in detail previously . Specime2 and analysed using FIJI software [IVCM was performed with the Confoscan 4 , Italy). Confocal imaging of the central cornea, paracentral cornea and four locations of limbus was performed. Morphologic characteristics of the corneal epithelium and the nerves in the subbasal nerve plexus were studied. The limbus was examined for the presence of palisades of Vogt (poV). High-contrast digital images of all the corneal layers and limbus were acquired with a field of view of 300 × 300 mmsoftware . Cornealsoftware ,10.HR-OCT was performed in all eyes on the central and paracentral cornea . The cross-line scan mode was used to obtain the images of the central cornea. HR-OCTA was performed by a technician using the AngioVue OCTA system  in all four limbal quadrants  with adjoining bulbar conjunctiva. The technique of HR-OCTA imaging that the authors performed has been explained by the authors previously . Twelve Images were analysed in en-face custom mode by two settings: total vascular density and superficial vascular density. Further details of image analysis for these two settings are mentioned in MedCalc  statistical software was used for data analysis. A two-tailed P value less than 0.05 was considered statistically significant. Descriptive statistics using mean ± standard deviation, median ± inter-quartile range (IQR) and mode were used to elucidate the demographic data. Multiple logistic regression analysis using Akaike’s information criteria (AIC) with step wise elimination modelling was used to identify the HR-OCT angiography parameters significantly associated with the confirmed diagnosis of LSCD. To ensure that the study was adequately powered for multiple regression analysis, the sample size was calculated as a minimum of 20 eyes with 10 eyes in each group (LSCD and non-LSCD). Subsequently, a Receiver Operating Characteristic (ROC) curve analysis was performed to detect the threshold value for optimal sensitivity and specificity (using criterion corresponding with highest Youden index) of diagnosis of LSCD for each parameter identified by multiple logistic regression modelling. Positive and negative predictive values for the threshold scores were also calculated along with 95% confidence intervals.This study included 24 eyes of 22 patients with clinical suspicion of LSCD. On IC and IVCM, 12 eyes of 11 patients were diagnosed to have LSCD (both IC and IVCM positive for LSCD) while 12 eyes of 11 patients were diagnosed to not have LSCD . Additionally, ten eyes of five volunteers were imaged that had no ocular pathology . Among the LSCD group, there were nine males (82%) and two females (18%). The mean age of patients in this group was 26.8 ± 8.7 years. The most common aetiology for LSCD was ocular chemical burns (10/12 eyes: 83%) with BCVA ranging from 20/30 to hand movement. In the non-LSCD group, there were eight males (73%) and three females (27%). The mean age of patients in this group was 38.45 ± 15.6 years. The most common aetiology was corneal vascularisation and scarring secondary to viral keratitis  with BCVA ranging from 20/20 to counting fingers at 1 metre. Out of five normal subjects, three (60%) were male while two (40%) were female. The mean age of patients in this group was 27.6 years ± 2.9 years. A total of 136 quadrants of 34 eyes were analysed by HR-OCTA imaging, out of which 48 quadrants (35%) had confirmed LSCD while 88 quadrants (65%) belonged to non-LSCD eyes.p < 0.0001), more details about individual parameters are mentioned in Multiple logistic regression analysis of the 12 imaging parameters, revealed three parameters to be significantly different in eyes with LSCD as compared to the non-LSCD group and normal eyes  were highly predictive of the diagnosis of LSCD. The field of limbal biology, limbal imaging and limbal stem cell transplantation for the treatment of LSCD is rapidly evolving . HR-OCT The current gold standards for LSCD diagnosis are IC and IVCM, however they are not routinely available in a cornea clinic. IC requires specialised techniques for staining and requires trained staff and a fully equipped laboratory to process and evaluate the specimens. The evaluation is time-consuming, thus delaying the diagnosis. Additionally, the probability of false positive or false negative results is high due to tissue contamination while obtaining or processing the samples. IVCM is an expensive machine, not commonly available in most cornea clinics, highly operator dependent, and obtaining good quality images in eyes with LSCD may be a significant challenge in eyes with significant corneal scarring or conjunctivalisation. Being a semi-contact method of imaging, it requires patient cooperation in image acquisition. Thus, to overcome these limitations most cornea specialists rely on clinical slit lamp examination for diagnosis. Our study was unique because the preliminary diagnosis of LSCD was not made on clinical examination alone, but IC and IVCM were considered as gold standard diagnostic tools for diagnosis of LSCD.Out of the three parameters of HR-OCT angiography discussed above, epithelial and stromal reflectivity can be detected easily without any need for complex data processing. These values can also be obtained using HR-OCT machines that are not necessarily equipped to perform angiography. Mean epithelial reflectivity is a better parameter than stromal reflectivity. Furthermore, when the ratio of these two parameters is taken into consideration, a steep improvement is observed in the sensitivity and specificity of the test E. ConjunIn a non-LSCD eye with peripheral corneal vascularisation and scarring, the epithelium is unaffected and has normal epithelial reflectivity on OCT. However, there is contrasting increase in signal intensity of the stroma due to scarring. We found that measuring reflectivity can be an efficient way to differentiate eyes with LSCD from other aetiologies which may seem similar to LSCD. Previously, Karp et al. utilised epithelial hyperreflectivity on OCT to diagnose cases of ocular surface squamous neoplasia . AdditioConjunctivalisation of the cornea is a hallmark of LSCD. The blood vessels within the fibrovascular pannus that grows over the cornea in eyes with LSCD are derived from the superficial episcleral vascular plexus, which also supplies the conjunctiva. These pathological vessels are superficial in location and can be differentiated from deeper vascularisation of the peripheral cornea, which is unrelated to LSCD. When HR-OCT angiographic images are segmented for the superficial layers, there is minimal change in vascular density in cases of true LSCD . HoweverThe strengths of our study include the fact that we compared the HR-OCT and HR-OCTA parameters in eyes with LSCD to eyes with LSCD mimickers, and in eyes of healthy volunteers. Additionally, our study included more typical causes of LSCD such as ocular chemical burns. The main limitations of our study include lack of clinical staging of LSCD, and relatively modest number of eyes included per group. Some inherent limitations also exist with the OCTA imaging technology for the anterior segment, such as longer image acquisition time as compared to posterior segment and need for good co-operation from the patient. No clock hour demarcation settings exist in the software for accurate 360 degree scanning of limbus and the cross-sectional limbal images taken at the site of vascular imaging have a low resolution. Additionally, as the in-built software is custom built for retina, the settings need to be modified before imaging and image analysis. Currently it takes about 5 min for the reflectivity measurement and another 5–10 min for the vascular density measurement. Hopefully with further advances in HR-OCT platforms there will be automated settings for the anterior segment angiography scans and integrated software for reflectivity and vascular density assessment, which will significantly reduce the post-processing time and improve the applicability of this modality. Previous studies have shown good repeatability and reproducibility for measuring parameters such as central corneal thickness using HR-OCT . HoweverIn conclusion, this study aimed to identify the HR-OCT angiography features that are most reliably diagnostic of LSCD as compared to the current gold-standards of a combination of clinical examination, IC, and IVCM. Since HR-OCT angiography is a non-contact, non-invasive, real time, and high-resolution imaging modality with low operator dependence, it can potentially be very useful both for the objective diagnosis of LSCD as well as for monitoring the success of different stem cell-based therapies in clinical trials.


We read the review article about herpes zoster and COVID-19 infection with great interest . This asDexamethasone has become commonplace in the treatment protocols for management of more severe cases of COVID-19 infection . A standWhen we performed a search on the PubMed website, looking for articles on dexamethasone treatment of COVID-19, we retrieved 788 titles. A brief survey of these articles included an estimation that during 2020, as many as 50% of patients with severe COVID-19 disease received corticosteroids. For example, in a large controlled open-label trial carried out in the United Kingdom by the Recover Collaborative Group, the investigators concluded that the use of dexamethasone resulted in a lower 28-day mortality among COVID-19 patients who were receiving either invasive mechanical ventilation or oxygen alone at randomization [As cited in the review , most pa


This randomized clinical trial aimed to compare the short-term postsurgical symptoms after insertion of one or two implants for retention of a mandibular overdenture. This study investigated whether the less invasive single-implant approach results in lower postoperative symptoms compared to the conventional two-implant overdenture.n = 23), or the lateral incisor-canine area bilaterally (n = 24). Patient-reported postoperative symptoms were measured in a 0–100 visual analogue scale concerning pain in the surgical area, pain when chewing, bleeding, swelling, and unpleasantness. Data collection occurred 24 h and 7 and 21 days after surgery. Demographic and clinical features , osteotomy for alveolar bone reduction, and surgery time were tested as predictors of symptom levels.Patients received new complete dentures and were randomly assigned to groups receiving one or two single-stage, early-loaded hydrophilic implants, inserted in the midline (p < 0.001), similarly in both groups. None of the clinical predictors was significantly associated with the changes in symptoms.Overall reported symptoms were mild and self-limited, with high rates of complete remission after the early loading period of 3 weeks. Progressive improvement of symptoms occurred from the 24-h to the 7-day and 21-day follow-ups (Findings suggest that the insertion of one or two implants may result in similar postoperative outcomes.The severity of short-term postoperative symptoms may not be a critical factor for the decision between overdenture treatment with one or two implants. There is a widely accepted consensus that a mandibular overdenture retained by two implants is the first implant treatment choice for edentulous subjects, resulting in better chewing function, comfort, and patient satisfaction when compared to the conventional complete denture . HoweverSince surgical anxiety is one of the main factors influencing patients’ refusal of dental implants , 4, reduPatient report of postoperative pain after surgical placement of dental implants is considered to be mild to moderate , 7 with Considering that a single-implant overdenture is assumed to be less extensive and invasive than a 2-implant overdenture, we hypothesized that it could be associated with reduced tissue manipulation, shorter surgical time, and lower incidence and severity of postoperative bleeding, pain, and discomfort. Hence, this study aimed to compare the short-term patient-reported postsurgical outcomes after implant surgery for treatment with mandibular overdenture retained by one or two implants. The underlying study question is whether 1-IOD surgery results in lower postsurgical symptoms compared to the 2-IOD.This study reports the short-term postsurgical symptoms as part of a randomized clinical trial comparing the treatment with mandibular overdentures retained by a single (1-IOD group) or two implants (2-IOD group) opposing to a conventional maxillary complete denture. The study protocol was previously registered (NCT03691285) and approved by the local ethical research committee (CAEE 65240617.5.0000.5083). A detailed description of the randomized clinical trial is previously published , which iParticipants were fully edentulous subjects needing replacement of old complete dentures and implant intervention for retention of the mandibular denture. Eligibility criteria included favorable general health and sufficient bone dimensions for placement of an implant at least 8-mm length in the potential implant sites (midline and canine regions), assessed using a panoramic radiograph. The exclusion criteria comprised any general or local contra-indication for implant treatment, presence of oral conditions that demand additional treatments, subjects with significant cognitive decline, and those who disagreed to be randomly assigned to one of the two study groups. Subjects who did not meet the inclusion and exclusion criteria were referred for appropriate treatment in other clinical settings of the dental school. The study sample size was calculated within the context of the main study  and compAfter complete denture treatment, participants were randomly assigned to the study groups (1-IOD and 2-IOD groups) using block randomization and stratification by gender, aiming to reduce allocation bias and to achieve a balance of participants in the two groups. To avoid selection bias, each participant’s assignment group was labeled and concealed in sealed black envelopes, and the group identification was only revealed at the time of the implant surgery.A new set of complete dentures was provided to all participants. They were scheduled for implant treatment planning after reporting being adapted to denture use with no major complaints, except the perceived need to improve the mandibular denture retention and stability.Implant surgery planning included the clinical assessment of the residual alveolar dimensions in the midline and bilateral canine areas and panoramic radiograph for confirmation of sufficient bone height for placement of one or two regular diameter implants with 8-, 10-, or 12-mm length. Preoperative care included verification of vital signs, medication with antibiotic prophylaxis with amoxicillin 2 g or clindamycin 600 mg, paracetamol 750 mg, and dexamethasone 8 mg in cases of alveolar ridge reduction .At the time of the surgery, the group assignment for each participant was disclosed to the patient and the surgeon. Implant surgery procedures initiated infiltration anesthesia with articaine hydrochloride with 1:100,000 epinephrine, crestal incision allowing a full-thickness flap elevation to expose the implant site extending between canine regions for the 1-IOD group and immediately beyond the mental foramen bilaterally for the 2-IOD group. When needed, alveolar bone reduction was performed for preparation of the implant site with a straight surgical handpiece and a tungsten drill under sterile saline irrigation. In all cases, a surgical guide was obtained by duplication of the mandibular denture, which served as a reference for correct implant positioning.Tissue level Straumann® Standard Plus SLActive® regular neck implants  were inserted in the mandible midline (1-IOD group) or the lateral incisor-canine area bilaterally (2-IOD group). Drilling sequence and implant insertion were performed according to the manufacturer’s protocol. The final insertion torque was checked with a torque wrench adjusted to 25 N cm. After implant placement and healing abutment connected to the implants, tissues were sutured, and the mandibular denture was relieved and relined with temporary soft relining material . The patient’s postoperative care included paracetamol 750 mg in case of pain (every 6 h for up to 3 days), a soft diet, and 0.12% chlorhexidine mouthwash rinse for 1 week. Sutures were removed after 7 days.After the implant surgery, postoperative pain and discomfort were measured by questionnaires using graduated visual analogue scales (VAS) from 0 to 100 mm. Each participant was asked to rate the value that corresponds to their perception of the following aspects: (1) pain in the surgical area, (2) pain when chewing, (3) bleeding in the surgical area, (4) swelling of the surgical area, and (5) perception of the unpleasantness of the surgery . Data weData concerning participants’ demographic (age and sex) and clinical features were collected. Clinical characteristics included smoking habit, classification of the residual ridges  , and proThe mucosal width and thickness at the implant sites were evaluated before the surgical procedures to record the keratinized tissue width (KTW) and vertical mucosa thickness (VMT). The KTW was measured by identifying the mucogingival junction at the buccal, lingual, and crestal sites using a calibrated probe and the rolling technique. Measurements were categorized as wide (> 2 mm) or narrow (≤ 2 mm) . For assThe surgery duration was recorded in minutes, ranging from the local infiltrative anesthesia until tissue suture. The need for osteotomy for alveolar bone reduction was also recorded.Z/√N).Descriptive statistics and between-group comparisons were performed to test differences in baseline characteristics of the two groups. Then, we tested the effect of the different follow-up times on the patient’s perceived outcomes after surgery in the two overdenture groups. The Shapiro-Wilk test was used for testing the normality of data. Non-normal distribution measurement data were expressed as median (interquartile range) and analyzed by non-parametric comparison tests—Mann-Whitney test for between-group comparisons, and the Wilcoxon signed rank test for within-group comparisons. The effect size for longitudinal comparisons was calculated (ES = c = 10) to all observations “Y”, so that Y + c > 0, preventing the exclusion of the corresponding case in the analysis. GEE models were also tested considering the remission of symptoms (score = 0) for outcome measure, using binary logistic regression. The follow-up period, overdenture group, and clinical features were used as fixed predictor variables in the GEE models. The maximum likelihood estimates were used to calculate the regression parameters, and the Wald statistics were used to test the significance of the model effects. The IBM-SPSS was used for data analysis, and the 0.05 level of significance was considered for statistical inferences.Since each subject gave multiple responses in a repeated-measures design, the assumption of independence of ratings was violated, due to an idiosyncratic factor that affects all responses from the same subject, thus rendering these different responses inter-dependent (correlated) rather than independent. Therefore, a generalized estimating equations (GEE) regression was performed for each of the postsurgical outcomes, considering the combined subject and time-point variables as the within-subject variable to identify the repeated measures across the dataset. The gamma with Log-link was selected as the distribution-link function combination for the dependent variables due to the skewed distribution of data. Due to the excessive occurrence of zero values in the outcome variable (zero-inflated data), added a positive constant (p = 0.040) and for the lingual mucosa thickness .The complete participant flowchart is detailed in Fig. p = 0.638). The duration of the surgery was longer for the 2-IOD group (1:34 h ± 0:11) compared to the 1-IOD group (1:09 h ± 0:17), representing a mean 26.6% longer time for insertion of the two implants (p < 0.001).During the follow-up period after implant placement, three participants of the 2-IOD group had early implant failure, one implant failure for each participant, and a new implant was inserted after 3 months. For data analysis, only the first implant surgery and 3-week healing period were considered for analysis. Implant surgery included osteotomy for alveolar bone reduction in 19 cases (82.6%) of the 1-IOD group and 21 cases (87.5%) of the 2-IOD group (p = 0.045). No difference between the 1- and 2-IOD groups was found for the overall patient scores that encompass the mean value of all perceived surgical outcomes.Figure Conversely, Table p > 0.05). Nevertheless, as expected, progressive improvement of symptoms occurred from the 24-h to the 7-day and 21-day follow-ups (p < 0.001). Similar results were found for the progression to the complete remission of symptoms concerning the evidence of no difference between groups and progressive improvement in the 7-day and 21-day follow-ups , suture removal (7 days), and implant loading (21 days) and not demanding additional visits for the patient for data collection.Regarding implant surgery outcomes, three implant failures occurred in the 2-IOD group, which were attributed to low primary stability and excessive trauma due to the denture’s use during the healing period. However, the failures were detected only during the removal of the healing caps for insertion of the overdenture abutment 3 weeks after implant insertion. They were not associated with higher pain levels by patient reporting. The higher incidence of implant failure in the 2-IOD group could be related to the lateral position of the implants, more prone to higher functional distress than the midline region.Finally, this study provides additional information on the comparative effectiveness of the 1-IOD compared to the 2-IOD. Although previous studies have shown positive aspects and similar outcomes using both treatment strategies, clinical decisions regarding selecting one treatment over another may rely on comprehensive factors that include patient preferences and expectations, treatment costs, and specific clinical characteristics. Therefore, the option for a single-implant overdenture may be justified by the patient’s preference for a treatment that is less invasive, less costly, and easy to maintain over time. The current body of evidence on this topic may guide the decision-making process for the individual patient and subside clinical practice in various settings, and further research.Within the limits of this short-term clinical trial, it was concluded that, although the 1-IOD may be potentially associated with lower surgical time, more conservative bone drilling, and flap extension, it seems not to be significantly advantageous from the patient perspective regarding the level of postsurgical symptoms and may not be a determinant factor in treatment decision-making.