Untargeted Metabolomic Profiling Reveals Differentially Expressed Serum Metabolites and Pathways in Type 2 Diabetes Patients with and without Cognitive Decline: A Cross-Sectional Study.

Diabetes is recognized as a risk factor for cognitive decline, but the underlying mechanisms remain elusive. We aimed to identify the metabolic pathways altered in diabetes-associated cognitive decline (DACD) using untargeted metabolomics. We conducted liquid chromatography-mass spectrometry-based untargeted metabolomics to profile serum metabolite levels in 100 patients with type 2 diabetes (T2D) (54 without and 46 with DACD). Multivariate statistical tools were used to identify the differentially expressed metabolites (DEMs), and enrichment and pathways analyses were used to identify the signaling pathways associated with the DEMs. The receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of a set of metabolites. We identified twenty DEMs, seven up- and thirteen downregulated in the DACD vs. DM group. Chemometric analysis revealed distinct clustering between the two groups. Metabolite set enrichment analysis found significant enrichment in various metabolite sets, including galactose metabolism, arginine and unsaturated fatty acid biosynthesis, citrate cycle, fructose and mannose, alanine, aspartate, and glutamate metabolism. Pathway analysis identified six significantly altered pathways, including arginine and unsaturated fatty acid biosynthesis, and the metabolism of the citrate cycle, alanine, aspartate, glutamate, a-linolenic acid, and glycerophospholipids. Classifier models with AUC-ROC > 90% were developed using individual metabolites or a combination of individual metabolites and metabolite ratios. Our study provides evidence of perturbations in multiple metabolic pathways in patients with DACD. The distinct DEMs identified in this study hold promise as diagnostic biomarkers for DACD patients.

Blood-Based Proteomic Profiling Identifies Potential Biomarker Candidates and Pathogenic Pathways in Dementia.

Dementia is a progressive and debilitating neurological disease that affects millions of people worldwide. Identifying the minimally invasive biomarkers associated with dementia that could provide insights into the disease pathogenesis, improve early diagnosis, and facilitate the development of effective treatments is pressing. Proteomic studies have emerged as a promising approach for identifying the protein biomarkers associated with dementia. This pilot study aimed to investigate the plasma proteome profile and identify a panel of various protein biomarkers for dementia. We used a high-throughput proximity extension immunoassay to quantify 1090 proteins in 122 participants (22 with dementia, 64 with mild cognitive impairment (MCI), and 36 controls with normal cognitive function). Limma-based differential expression analysis reported the dysregulation of 61 proteins in the plasma of those with dementia compared with controls, and machine learning algorithms identified 17 stable diagnostic biomarkers that differentiated individuals with AUC = 0.98 ± 0.02. There was also the dysregulation of 153 plasma proteins in individuals with dementia compared with those with MCI, and machine learning algorithms identified 8 biomarkers that classified dementia from MCI with an AUC of 0.87 ± 0.07. Moreover, multiple proteins selected in both diagnostic panels such as NEFL, IL17D, WNT9A, and PGF were negatively correlated with cognitive performance, with a correlation coefficient (r2) ≤ -0.47. Gene Ontology (GO) and pathway analysis of dementia-associated proteins implicated immune response, vascular injury, and extracellular matrix organization pathways in dementia pathogenesis. In conclusion, the combination of high-throughput proteomics and machine learning enabled us to identify a blood-based protein signature capable of potentially differentiating dementia from MCI and cognitively normal controls. Further research is required to validate these biomarkers and investigate the potential underlying mechanisms for the development of dementia.

Brucellosis in older person: a case report from Qatar.

BACKGROUND: Brucellosis is a multisystem disease with a broad spectrum of non-specific symptoms that generally occur within three weeks but sometimes up to 3 months after inoculation. Human brucellosis is quite uncommon in Elderly in Qatar. CASE REPORT: This report describes a case of Brucellosis in acute geriatric unit under Rumailah Hospital in Qatar. The patient was an 81-year-old Qatari Gentle man, functionally able to walk with minimal assistance and had mild cognitive impairment who presented with high-grade fever with chills, anorexia, low back pain and arthralgia for 10 days. The above complaints occurred often for 1 month and had fever intermittently. Lab investigations revealed as high CRP 117 mg/l, low Hb 9.1 g/dl and mild elevation in ALP (151 µ/l) with normal leukocyte and platelet count. His blood culture positive for Brucella melitensis with high brucella Antibody titter 1:1280. The diagnosis made as Brucellosis. DISCUSSION: The clinical manifestations of Brucellosis are fever, night sweating, chills, arthralgia and loss of appetite. It seems pyrexia of unknown origin without other symptoms is most common presentation of Brucellosis in old age. The confirmation of Brucellosis made with serological tests, with significantly high titer, in the presence or absence of blood culture. Brucella antibody titers (≥1:160) are suggestive of active infection. Anemia and raised CRP and liver enzymes were the most prominent laboratory abnormalities in our patients. Previous study from Qatar reported that 41.7% had a history of raw milk consumption and 12.5% had a history of animal contact. The objectives of Brucellosis treatment include the prevention of complications and relapse. CONCLUSION: Our case presented with classical symptoms and received appropriate treatment on time. However, atypical clinical presentation and lack of specific history taking can delay diagnosis and treatment; it leads to serious clinical disease progression with increased complications. From this case study, we would contribute to optimal assessment and to keep differential diagnosis for unknown cause of fever can be Brucellosis in geriatric population.

Implementation of pressure ulcer prevention and management in elderly patients: a retrospective study in tertiary care hospital in Qatar.

OBJECTIVE: Preventing pressure ulcers is an essential part of patient care and it is important to be aware of the best way to prevent it. Hence, the present study aims to look for the demographics, clinical characteristics, and risk factors in patients with and without pressure ulcer among elderly patients. METHODS: A retrospective longitudinal study was conducted in elderly (above 65 years) patients from a period of October 2014 to October 2015 in the medical ward under acute Geriatric care at Hamad General Hospital in Qatar. RESULTS: Overall, a total of 90 patients were included with an average age of 79 ± SD 11.3 years of which 45 patients developed pressure ulcer. There was male (64.4%) preponderance in the study population. Most common comorbidity was hypertension (77.8%). Anemia correction (91%), high protein diet supplementation (1.5 g/kg body wt.) (100%), and 2 h repositioning (100%) were implemented for majority of the pressure ulcer patients as preventive intervention. CONCLUSIONS: From the study finding, it is observed that, anemia correction, high protein diet supplementation and 2 h repositioning are the best practices for the management of pressure ulcer. Hence, these best practices are recommended for the early prevention of pressure ulcer among elderly.

A wearable wound moisture sensor as an indicator for wound dressing change: an observational study of wound moisture and status.

Wound moisture is known to be a key parameter to ensure optimum healing conditions in wound care. This study tests the moisture content of wounds in normal practice in order to observe the moisture condition of the wound at the point of dressing change. This study is also the first large-scale observational study that investigates wound moisture status at dressing change. The WoundSense sensor is a commercially available moisture sensor which sits directly on the wound in order to find the moisture status of the wound without disturbing or removing the dressing. The results show that of the 588 dressing changes recorded, 44·9% were made when the moisture reading was in the optimum moisture zone. Of the 30 patients recruited for this study, 11 patients had an optimum moisture reading for at least 50% of the measurements before dressing change. These results suggest that a large number of unnecessary dressing changes are being made. This is a significant finding of the study as it suggests that the protocols currently followed can be modified to allow fewer dressing changes and less disturbance of the healing wound bed.

Need for evidence synthesis for quality control of healthcare decision-making.

Systematic reviews that are out-of-date delay policymaking, create controversy, and can erode trust in research. To avoid this issue, it is preferable to keep summaries of the study evidence. Living evidence is a synthesis approach that provides up-to-date rigorous research evidence summaries to decision-makers. This strategy is particularly useful in rapidly expanding research domains, uncertain existing evidence, and new research that may impact policy or practice, ensuring that physicians have access to the most recent evidence. Addressing global challenges - ranging from public health crises to climate change or political instability - requires evidence-based judgements. An obsolete, biased, or selective information poses risks of poor decisions and resource misallocation. The relatively nascent practice of living evidence proves invaluable in maintaining continuous interest and team engagement. The concept of living evidence has been particularly relevant during the COVID-19 pandemic due to the rapidly evolving nature of the virus, the urgent need for timely information, and the continuous emergence of new research findings. Although the COVID-19 pandemic accelerated the adoption of evidence systems, researchers and funders of research should rigorously test the living-evidence model across diverse domains to further advance and optimize its methodology.

Profiling the autoantibody repertoire reveals autoantibodies associated with mild cognitive impairment and dementia.

Background: Dementia is a debilitating neurological disease affecting millions of people worldwide. The exact mechanisms underlying the initiation and progression of the disease remain to be fully defined. There is an increasing body of evidence for the role of immune dysregulation in the pathogenesis of dementia, where blood-borne autoimmune antibodies have been studied as potential markers associated with pathological mechanisms of dementia. Methods: This study included plasma from 50 cognitively normal individuals, 55 subjects with MCI (mild cognitive impairment), and 22 subjects with dementia. Autoantibody profiling for more than 1,600 antigens was performed using a high throughput microarray platform to identify differentially expressed autoantibodies in MCI and dementia. Results: The differential expression analysis identified 33 significantly altered autoantibodies in the plasma of patients with dementia compared to cognitively normal subjects, and 38 significantly altered autoantibodies in the plasma of patients with dementia compared to subjects with MCI. And 20 proteins had significantly altered autoantibody responses in MCI compared to cognitively normal individuals. Five autoantibodies were commonly dysregulated in both dementia and MCI, including anti-CAMK2A, CKS1B, ETS2, MAP4, and NUDT2. Plasma levels of anti-ODF3, E6, S100P, and ARHGDIG correlated negatively with the cognitive performance scores (MoCA) (r2 -0.56 to -0.42, value of p < 0.001). Additionally, several proteins targeted by autoantibodies dysregulated in dementia were significantly enriched in the neurotrophin signaling pathway, axon guidance, cholinergic synapse, long-term potentiation, apoptosis, glycolysis and gluconeogenesis. Conclusion: We have shown multiple dysregulated autoantibodies in the plasma of subjects with MCI and dementia. The corresponding proteins for these autoantibodies are involved in neurodegenerative pathways, suggesting a potential impact of autoimmunity on the etiology of dementia and the possible benefit for future therapeutic approaches. Further investigations are warranted to validate our findings.

Corneal nerve loss predicts dementia in patients with mild cognitive impairment.

OBJECTIVES: This study compared the utility of corneal nerve measures with brain volumetry for predicting progression to dementia in individuals with mild cognitive impairment (MCI). METHODS: Participants with no cognitive impairment (NCI) and MCI underwent assessment of cognitive function, brain volumetry of thirteen brain structures, including the hippocampus and corneal confocal microscopy (CCM). Participants with MCI were followed up in the clinic to identify progression to dementia. RESULTS: Of 107 participants with MCI aged 68.4 ± 7.7 years, 33 (30.8%) progressed to dementia over 2.6-years of follow-up. Compared to participants with NCI (n = 12), participants who remained with MCI (n = 74) or progressed to dementia had lower corneal nerve measures (p < 0.0001). Progressors had lower corneal nerve measures, hippocampal, and whole brain volume (all p < 0.0001). However, CCM had a higher prognostic accuracy (72%-75% vs 68%-69%) for identifying individuals who progressed to dementia compared to hippocampus and whole brain volume. The adjusted odds ratio for progression to dementia was 6.1 (95% CI: 1.6-23.8) and 4.1 (95% CI: 1.2-14.2) higher with abnormal CCM measures, but was not significant for abnormal brain volume. INTERPRETATION: Abnormal CCM measures have a higher prognostic accuracy than brain volumetry for predicting progression from MCI to dementia. Further work is required to validate the predictive ability of CCM compared to other established biomarkers of dementia.

The Global, Regional, and National Burden of Adult Lip, Oral, and Pharyngeal Cancer in 204 Countries and Territories: A Systematic Analysis for the Global Burden of Disease Study 2019.

Importance: Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning. Objective: To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates. Evidence Review: The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019. Findings: In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia. Conclusions and Relevance: In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Abnormal corneal nerve morphology and brain volume in patients with schizophrenia.

Neurodevelopmental and neurodegenerative pathology occur in Schizophrenia. This study compared the utility of corneal confocal microscopy (CCM), an ophthalmic imaging technique with MRI brain volumetry in quantifying neuronal pathology and its relationship to cognitive dysfunction and symptom severity in schizophrenia. Thirty-six subjects with schizophrenia and 26 controls underwent assessment of cognitive function, symptom severity, CCM and MRI brain volumetry. Subjects with schizophrenia had lower cognitive function (P ≤ 0.01), corneal nerve fiber density (CNFD), length (CNFL), branch density (CNBD), CNBD:CNFD ratio (P < 0.0001) and cingulate gyrus volume (P < 0.05) but comparable volume of whole brain (P = 0.61), cortical gray matter (P = 0.99), ventricle (P = 0.47), hippocampus (P = 0.10) and amygdala (P = 0.68). Corneal nerve measures and cingulate gyrus volume showed no association with symptom severity (P = 0.35-0.86 and P = 0.50) or cognitive function (P = 0.35-0.86 and P = 0.49). Corneal nerve measures were not associated with metabolic syndrome (P = 0.61-0.64) or diabetes (P = 0.057-0.54). The area under the ROC curve distinguishing subjects with schizophrenia from controls was 88% for CNFL, 84% for CNBD and CNBD:CNFD ratio, 79% for CNFD and 73% for the cingulate gyrus volume. This study has identified a reduction in corneal nerve fibers and cingulate gyrus volume in schizophrenia, but no association with symptom severity or cognitive dysfunction. Corneal nerve loss identified using CCM may act as a rapid non-invasive surrogate marker of neurodegeneration in patients with schizophrenia.

The burden of injury in Central, Eastern, and Western European sub-region: a systematic analysis from the Global Burden of Disease 2019 Study.

BACKGROUND: Injury remains a major concern to public health in the European region. Previous iterations of the Global Burden of Disease (GBD) study showed wide variation in injury death and disability adjusted life year (DALY) rates across Europe, indicating injury inequality gaps between sub-regions and countries. The objectives of this study were to: 1) compare GBD 2019 estimates on injury mortality and DALYs across European sub-regions and countries by cause-of-injury category and sex; 2) examine changes in injury DALY rates over a 20 year-period by cause-of-injury category, sub-region and country; and 3) assess inequalities in injury mortality and DALY rates across the countries. METHODS: We performed a secondary database descriptive study using the GBD 2019 results on injuries in 44 European countries from 2000 to 2019. Inequality in DALY rates between these countries was assessed by calculating the DALY rate ratio between the highest-ranking country and lowest-ranking country in each year. RESULTS: In 2019, in Eastern Europe 80 [95% uncertainty interval (UI): 71 to 89] people per 100,000 died from injuries; twice as high compared to Central Europe (38 injury deaths per 100,000; 95% UI 34 to 42) and three times as high compared to Western Europe (27 injury deaths per 100,000; 95%UI 25 to 28). The injury DALY rates showed less pronounced differences between Eastern (5129 DALYs per 100,000; 95% UI: 4547 to 5864), Central (2940 DALYs per 100,000; 95% UI: 2452 to 3546) and Western Europe (1782 DALYs per 100,000; 95% UI: 1523 to 2115). Injury DALY rate was lowest in Italy (1489 DALYs per 100,000) and highest in Ukraine (5553 DALYs per 100,000). The difference in injury DALY rates by country was larger for males compared to females. The DALY rate ratio was highest in 2005, with DALY rate in the lowest-ranking country (Russian Federation) 6.0 times higher compared to the highest-ranking country (Malta). After 2005, the DALY rate ratio between the lowest- and the highest-ranking country gradually decreased to 3.7 in 2019. CONCLUSIONS: Injury mortality and DALY rates were highest in Eastern Europe and lowest in Western Europe, although differences in injury DALY rates declined rapidly, particularly in the past decade. The injury DALY rate ratio of highest- and lowest-ranking country declined from 2005 onwards, indicating declining inequalities in injuries between European countries.

Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

Investigation of a COVID-19 Outbreak and Its Successful Containment in a Long Term Care Facility in Qatar.

Introduction: The objective of this study is to investigate the COVID-19 outbreak and its successful containment in a long-term care facility, Qatar. Materials and Methods: It was a retrospective case series of 24 COVID-19 positive patients inclusive of elderly, patient attenders, and front-liners from 06th to 18th June 2020. Laboratory, radiological, and treatment findings were assessed from electronic records. Results: The outbreak management team concluded that despite all the pre-existing preventive measures implemented at the start of the pandemic, there was still evidence of lapses in infection control practices such as breach of infection control protocols like improper use of personal protective equipment. The infection prevention and control team promptly reassessed and implemented more stringent infection control methods and practices that successfully contained the outbreak on July 1, 2020. Among the seven elderly patients, the average age was 76.28 years ± SD25.5 and all were females. 57% of the patients were symptomatic. The most common comorbidities were Dementia (57%), Diabetes mellitus (43%), Coronary Artery Disease (43%), and Seizures (43%). Ground glass appearances in the lungs were found in 29% of the patients. Among the three deceased patients, Dementia and Coronary Artery Disease were the common comorbidities. Persistent elevation in blood glucose levels was observed among all patients during this period of infection. Conclusion: Elderlies in long-term care facilities are with certain pre-existing comorbidities which makes them more prone to develop COVID-19 complications. Thus, intensive infection control measures like ongoing education and awareness, staff compliance monitoring, quick contact tracing, visitor policy revision, ongoing patient and caregivers monitoring are inevitable recommendations for effective outbreak prevention and management.

Epidemiologic characteristics, clinical management, and public health implications of Coronavirus Disease 2019 (COVID-19) in pregnancy: A Systematic Review and Meta-analysis.

BACKGROUND: The novel Coronavirus Disease 2019 (COVID-19) outbreak, caused by the pathogenic severe acute respiratory syndrome-2 (SARS-CoV-2) virus, is exponentially spreading across the globe. METHODS: The current systematic review was performed utilising the following electronic databases PubMed, MEDLINE and EMBASE. We searched for the keywords "COVID-19 AND "pregnancy" between January 1, 2020 until December 31, 2020. RESULTS: Out of 4005 records which were identified, 36 original studies were included in this systematic review. Pooled prevalence of vertical transmission was 10%, 95% CI: 4-17%. Pooled prevalence of neonatal mortality was 7%, 95% CI: 0-21%. CONCLUSION: The contemporary evidence suggests that the incubation period of COVID-19 is 2-14 days, and this infection could be transmitted even from the infected asymptomatic individuals. It is found that the clinical presentation of pregnant women with COVID-19 infection is comparable with the infected non-pregnant females, and the frequent symptoms were fever, cough, myalgia, sore throat and malaise. Some cases have severe maternal morbidity and perinatal deaths secondary to COVID-19 infection. Under these circumstances, pregnant women should focus on maintaining personal hygiene, proper nutrition and extreme social distancing to reduce the risk of COVID-19. Therefore, systematic data reporting for evidence based clinical assessment, management and pregnancy outcomes is essential for preventing of COVID-19 infection among pregnant women.

Corneal nerve loss as a surrogate marker for poor pial collaterals in patients with acute ischemic stroke.

In patients with acute ischemic stroke, pial collaterals play a key role in limiting neurological disability by maintaining blood flow to ischemic penumbra. We hypothesized that patient with poor pial collaterals will have greater corneal nerve and endothelial cell abnormalities. In a cross-sectional study, 35 patients with acute ischemic stroke secondary to middle cerebral artery (MCA) occlusion with poor (n = 12) and moderate-good (n = 23) pial collaterals and 35 healthy controls underwent corneal confocal microscopy and quantification of corneal nerve and endothelial cell morphology. In patients with MCA stroke, corneal nerve fibre length (CNFL) (P < 0.001), corneal nerve fibre density (CNFD) (P = 0.025) and corneal nerve branch density (CNBD) (P = 0.002) were lower compared to controls. Age, BMI, cholesterol, triglycerides, HDL, LDL, systolic blood pressure, NIHSS and endothelial cell parameters did not differ but mRS was higher (p = 0.023) and CNFL (p = 0.026) and CNBD (p = 0.044) were lower in patients with poor compared to moderate-good collaterals. CNFL and CNBD distinguished subjects with poor from moderate-good pial collaterals with an AUC of 72% (95% CI 53-92%) and 71% (95% CI 53-90%), respectively. Corneal nerve loss is greater in patients with poor compared to moderate-good pial collaterals and may act as a surrogate marker for pial collateral status in patients with ischemic stroke.

Development and implementation of a potential coronavirus disease 2019 (COVID-19) vaccine: A systematic review and meta-analysis of vaccine clinical trials.

BACKGROUND: To date, there is no comprehensive systematic review and meta-analysis to assess the suitability of COVID-19 vaccines for mass immunization. The current systematic review and meta-analysis was conducted to evaluate the safety and immunogenicity of novel COVID-19 vaccine candidates under clinical trial evaluation and present a contemporary update on the development and implementation of a potential vaccines. METHODS: For this study PubMed, MEDLINE, and Embase electronic databases were used to search for eligible studies on the interface between novel coronavirus and vaccine design until December 31, 2020. RESULTS: We have included fourteen non-randomized and randomized controlled phase I-III trials. Implementation of a universal vaccination program with proven safety and efficacy through robust clinical evaluation is the long-term goal for preventing COVID-19. The immunization program must be cost-effective for mass production and accessibility. Despite pioneering techniques for the fast-track development of the vaccine in the current global emergency, mass production and availability of an effective COVID-19 vaccine could take some more time. CONCLUSION: Our findings suggest a revisiting of the reported solicited and unsolicited systemic adverse events for COVID-19 candidate vaccines. Hence, it is alarming to judiciously expose thousands of participants to COVID-19 candidate vaccines at Phase-3 trials that have adverse events and insufficient evidence on safety and effectiveness that necessitates further justification.

Painful diabetic neuropathy is associated with increased nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control.

AIMS/INTRODUCTION: Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. MATERIALS AND METHODS: This exploratory substudy of an open-label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal-bolus insulin at baseline and 1-year follow up, and 18 controls at baseline only. RESULTS: Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain. CONCLUSIONS: This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy.

Association of Cerebral Ischemia With Corneal Nerve Loss and Brain Atrophy in MCI and Dementia.

INTRODUCTION: This study assessed the association of cerebral ischemia with neurodegeneration in mild cognitive impairment (MCI) and dementia. METHODS: Subjects with MCI, dementia and controls underwent assessment of cognitive function, severity of brain ischemia, MRI brain volumetry and corneal confocal microscopy. RESULTS: Of 63 subjects with MCI (n = 44) and dementia (n = 19), 11 had no ischemia, 32 had subcortical ischemia and 20 had both subcortical and cortical ischemia. Brain volume and corneal nerve measures were comparable between subjects with subcortical ischemia and no ischemia. However, subjects with subcortical and cortical ischemia had a lower hippocampal volume (P < 0.01), corneal nerve fiber length (P < 0.05) and larger ventricular volume (P < 0.05) compared to those with subcortical ischemia and lower corneal nerve fiber density (P < 0.05) compared to those without ischemia. DISCUSSION: Cerebral ischemia was associated with cognitive impairment, brain atrophy and corneal nerve loss in MCI and dementia.

Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study.

INTRODUCTION: To assess the effect of exenatide and pioglitazone or basal-bolus insulin on diabetic peripheral neuropathy (DPN) in patients with poorly controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This is a substudy of the Qatar Study, an open-label, randomized controlled trial. 38 subjects with poorly controlled T2D were studied at baseline and 1-year follow-up and 18 control subjects were assessed at baseline only. A combination of exenatide (2 mg/week) and pioglitazone (30 mg/day) or glargine with aspart insulin were randomly assigned to patients to achieve an HbA1c <53 mmol/mol (<7%). DPN was assessed with corneal confocal microscopy (CCM), DN4, vibration perception and sudomotor function. RESULTS: Subjects with T2D had reduced corneal nerves, but other DPN measures were comparable with the control group. In the combination treatment arm (n=21), HbA1c decreased by 35.2 mmol/mol (3.8 %) (p<0.0001), body weight increased by 5.6 kg (p<0.0001), corneal nerve branch density increased (p<0.05), vibration perception worsened (p<0.05), and DN4 and sudomotor function showed no change. In the insulin treatment arm, HbA1c decreased by 28.7 mmol/mol (2.7 %) (p<0.0001), body weight increased by 4.6 kg (p<0.01), corneal nerve branch density and fiber length increased (p≤0.01), vibration perception improved (p<0.01), and DN4 and sudomotor function showed no change. There was no association between the change in CCM measures with change in HbA1c, weight or lipids. CONCLUSIONS: Treatment with exenatide and pioglitazone or basal-bolus insulin results in corneal nerve regeneration, but no change in neuropathic symptoms or sudomotor function over 1 year.

Corneal Nerve and Brain Imaging in Mild Cognitive Impairment and Dementia.

BACKGROUND: Visual rating of medial temporal lobe atrophy (MTA) is an accepted structural neuroimaging marker of Alzheimer's disease. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic technique that detects neuronal loss in peripheral and central neurodegenerative disorders. OBJECTIVE: To determine the diagnostic accuracy of CCM for mild cognitive impairment (MCI) and dementia compared to medial temporal lobe atrophy (MTA) rating on MRI. METHODS: Subjects aged 60-85 with no cognitive impairment (NCI), MCI, and dementia based on the ICD-10 criteria were recruited. Subjects underwent cognitive screening, CCM, and MTA rating on MRI. RESULTS: 182 subjects with NCI (n = 36), MCI (n = 80), and dementia (n = 66), including AD (n = 19, 28.8%), VaD (n = 13, 19.7%), and mixed AD (n = 34, 51.5%) were studied. CCM showed a progressive reduction in corneal nerve fiber density (CNFD, fibers/mm2) (32.0±7.5 versus 24.5±9.6 and 20.8±9.3, p < 0.0001), branch density (CNBD, branches/mm2) (90.9±46.5 versus 59.3±35.7 and 53.9±38.7, p < 0.0001), and fiber length (CNFL, mm/mm2) (22.9±6.1 versus 17.2±6.5 and 15.8±7.4, p < 0.0001) in subjects with MCI and dementia compared to NCI. The area under the ROC curve (95% CI) for the diagnostic accuracy of CNFD, CNBD, CNFL compared to MTA-right and MTA-left for MCI was 78% (67-90%), 82% (72-92%), 86% (77-95%) versus 53% (36-69%) and 40% (25-55%), respectively, and for dementia it was 85% (76-94%), 84% (75-93%), 85% (76-94%) versus 86% (76-96%) and 82% (72-92%), respectively. CONCLUSION: The diagnostic accuracy of CCM, a non-invasive ophthalmic biomarker of neurodegeneration, was high and comparable with MTA rating for dementia but was superior to MTA rating for MCI.