Diabetes, Drug Treatment, and Mortality in COVID-19: A Multinational Retrospective Cohort Study.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of severe coronavirus disease 2019 (COVID-19) outcomes possibly because of dysregulated inflammatory responses. Glucose-regulating medications, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and pioglitazone, are known to have anti-inflammatory effects that may improve outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a multinational retrospective cohort study, we used the TriNetX COVID-19 Research Network of 56 large health care organizations to examine these medications in relation to the incidence of hospital admissions, respiratory complications, and mortality within 28 days after a COVID-19 diagnosis. After matching for age, sex, race, ethnicity, BMI, and significant comorbidities, use of GLP-1R agonists and/or pioglitazone was associated with significant reductions in hospital admissions (GLP-1R: 15.7% vs. 23.5%, risk ratio [RR] 0.67 [95% CI 0.57-0.79; P < 0.001]; pioglitazone: 20.0% vs. 28.2%; RR 0.71 [95% CI 0.54-0.93; P = 0.01]). Use of GLP-1R agonists was also associated with reductions in respiratory complications (15.3% vs. 24.9%, RR 0.62 [95% CI 0.52-0.73]; P < 0.001) and incidence of mortality (1.9% vs. 3.3%, RR 0.58 [95% CI 0.35-0.97]; P = 0.04). Use of DPP-4 inhibitors was associated with a reduction in respiratory complications (24.0% vs. 29.2%, RR 0.82 [95% CI 0.74-0.90]; P < 0.001), and continued use of DPP-4 inhibitors after hospitalization was associated with a decrease in mortality compared with those who discontinued use (9% vs. 19%, RR 0.45 [95% CI 0.28-0.72]; P < 0.001). In conclusion, use of glucose-regulating medications, such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone, may improve COVID-19 outcomes for patients with T2DM; randomized clinical trials are needed to further investigate this possibility.

The role of neutrophils in mediating stroke injury in the diabetic db/db mouse brain following hypoxia-ischemia.

Diabetic mice exhibit increased mortality and morbidity following stroke. Recent studies from our laboratory have indicated that increased morbidity in diabetic db/db mice relative to their non-diabetic db/+ littermates is associated with increased levels of MMP-9 protease activity, increased blood-brain barrier (BBB) permeability, and greater neutrophil infiltration following hypoxic/ischemic (H/I) insult. Neutrophils are a major source of proteases and reactive oxygen species and studies have reported neutrophil depletion/inhibition is protective in certain models of experimental stroke. The objective of the current study is to determine the role of neutrophils in the increased morbidity seen in db/db mice following acute ischemic stroke. In this study, we found a significant increase in circulating neutrophils in the db/db mice at 4 h post H/I, which bound to endothelial cells in the ipsilateral hemisphere and infiltrated into brain tissue by 24 h of recovery. Depletion of circulating neutrophils resulted in reduced neutrophil concentrations in blood and in the ipsilateral hemispheres of the brain of both db/+ and db/db mice and decreased the levels of MMP-9 within the infarcted area. This resulted in smaller infarct size in the db/db mice compared to non-treated controls but did not affect stroke outcome in db/+ mice. While there was a significant correlation between neutrophil number and the levels of MMP-9 in the ipsilateral hemisphere of control and diabetic mice, surprisingly, neutrophil depletion had no effect on BBB permeability in either group. Thus, the current study suggests that neutrophil depletion reduces MMP-9 protease levels and improves stroke outcome in db/db mice but not in their db/+ counterparts.

Current status and future prospects of pathophysiology-based neuroprotective drugs for the treatment of vascular dementia.

Vascular dementia (VaD) is a progressive neurocognitive clinical syndrome that is caused by a decrease in cerebral blood flow and damage to the neurovascular unit. Given increasing life expectancy, VaD is emerging as one of the leading health problems in society. Despite the high global prevalence of cognitive impairment associated with VaD, diagnosis and treatment still remain limited because of the complexity of mechanisms of neuronal loss. Therefore, advances in our understanding of the pathophysiological mechanisms involved is crucial for the development of new therapeutic strategies. In this review, we highlight the pathophysiology, current pharmacology-based primary and secondary prevention strategies and emerging treatment options for VaD.

Clinical outcomes of moderate to severe acute ischemic stroke in a telemedicine network.

Acute ischemic strokes (AIS) with severe neurologic deficits are associated with poor short- and long-term prognosis. Thrombectomy alone or in combination with thrombolysis is used for reperfusion in patients with moderate-to-severe AIS. However, the best therapeutic approach within the setting of telemedicine networks needs to be elucidated further. The objective of this study was to analyze clinical and imaging based outcomes of moderate to severe stroke following treatment with thrombolysis, thrombectomy or a combination of both in a telemedicine network. Data of this retrospective study was abstracted from the institutional telestroke database. Patients with a National Institute of Health Stroke Scale score (NIH-SS ≥ 10) were included into the study. Primary outcome measure was the difference in NIH-SS at admission compared to discharge from the hospital. Secondary outcome measure was the discharge disposition defined as favorable (discharge to home or rehabilitation) versus unfavorable disposition (discharge to hospice/death). Furthermore, outcome was analyzed based on reperfusion status following thrombectomy using the Thrombolysis in Cerebral Infarction (TICI) scale. The NIH-SS improved in all three groups, independent of treatment subtype, with a trend towards best outcomes following thrombolysis and combined treatment therapy compared to thrombectomy alone. In addition, reperfusion rates were higher in the combination group compared to the thrombectomy only group. The number of favorable discharges was similar in all three groups. The present study stresses the benefits of tele-stroke networks in allowing to early identify and treat even patients with severe strokes and benefit from different treatment modalities.

Impaired Retinal Vasoreactivity: An Early Marker of Stroke Risk in Diabetes.

Diabetes is a common cause of small vessel disease leading to stroke and vascular dementia. While the function and structure of large cerebral vessels can be easily studied, the brain's microvasculature remains difficult to assess. Previous studies have demonstrated that structural changes in the retinal vessel architecture predict stroke risk, but these changes occur at late disease stages. Our goal was to examine whether retinal vascular status can predict cerebral small vessel dysfunction during early stages of diabetes. Retinal vasoreactivity and cerebral vascular function were measured in 78 subjects (19 healthy controls, 22 subjects with prediabetes, and 37 with type-2 diabetes) using a new noninvasive retinal imaging device (Dynamic Vessel Analyzer) and transcranial Doppler studies, respectively. Cerebral blood vessel responsiveness worsened with disease progression of diabetes. Similarly, retinal vascular reactivity was significantly attenuated in subjects with prediabetes and diabetes compared to healthy controls. Subjects with prediabetes and diabetes with impaired cerebral vasoreactivity showed mainly attenuation of the retinal venous flicker response. This is the first study to explore the relationship between retinal and cerebral vascular function in diabetes. Impairment of venous retinal responsiveness may be one of the earliest markers of vascular dysfunction in diabetes possibly indicating subsequent risk of stroke and vascular dementia.

Impaired coronary and retinal vasomotor function to hyperoxia in Individuals with Type 2 diabetes.

PURPOSE: Adults with diabetes are at a high risk of developing coronary heart disease. The purpose of this study was to assess coronary artery vascular function non-invasively in individuals with and without Type 2 diabetes and to compare these coronary responses to another microvascular bed (i.e. retina). We hypothesized that individuals with diabetes would have impaired coronary reactivity and that these impairments would be associated with impairments in retinal reactivity. METHODS: Coronary blood velocity (Transthoracic Doppler Echocardiography) and retinal diameters (Dynamic Vessel Analyzer) were measured continuously during five minutes of breathing 100% oxygen (i.e. hyperoxia) in 15 persons with Type 2 diabetes and 15 age-matched control subjects. Using fundus photographs, retinal vascular calibers were also measured (central retinal arteriole and venule equivalents). RESULTS: Individuals with diabetes compared to controls had impaired coronary (-2.34±16.64% vs. -14.27±10.58%, P=0.03) and retinal (arteriole: -0.04±3.34% vs. -3.65±5.07%, P=0.03; venule: -1.65±3.68% vs. -5.23±5.47%, P=0.05) vasoconstrictor responses to hyperoxia, and smaller central arteriole-venule equivalent ratios (0.83±0.07 vs. 0.90±0.07, P=0.014). Coronary reactivity was associated with central retinal arteriole equivalents (r=-0.516, P=0.005) and retinal venular reactivity (r=0.387, P=0.034). CONCLUSION: Diabetes impairs coronary and retinal microvascular function to hyperoxia. Impaired vasoconstrictor responses may be part of a systemic diabetic vasculopathy, which may contribute to adverse cardiovascular events in individuals with diabetes.

Impaired retinal vasodilator responses in prediabetes and type 2 diabetes.

PURPOSE: In diabetes, endothelial dysfunction and subsequent structural damage to blood vessels can lead to heart attacks, retinopathy and strokes. However, it is unclear whether prediabetic subjects exhibit microvascular dysfunction indicating early stages of arteriosclerosis and vascular risk. The purpose of this study was to examine whether retinal reactivity may be impaired early in the hyperglycaemic continuum and may be associated with markers of inflammation. METHODS: Individuals with prediabetes (n = 22), type 2 diabetes (n = 25) and healthy age and body composition matched controls (n = 19) were studied. We used the Dynamic Vessel Analyzer to assess retinal vasoreactivity (percentage change in vessel diameter) during a flickering light stimulation. Fasting highly sensitive c-reactive protein (hs-CRP), a marker of inflammation, was measured in blood plasma. RESULTS: Prediabetic and diabetic individuals had attenuated peak vasodilator and relative amplitude changes in retinal vein diameters to the flickering light stimulus compared with healthy controls (peak dilation: prediabetic subjects 3.3 ± 1.8%, diabetic subjects 3.3 ± 2.1% and controls 5.6 ± 2.6%, p = 0.001; relative amplitude: prediabetic subjects 4.3 ± 2.2%, diabetic subjects 5.0 ± 2.6% and control subjects 7.2 ± 3.2%, p = 0.003). Similar findings were observed in retinal arteries. Levels of hs-CRP were not associated with either retinal vessel response parameters. CONCLUSION: Retinal reactivity was impaired in prediabetic and type 2 diabetic individuals in parallel with reduced insulin sensitivity but not associated with levels of hs-CRP. Retinal vasoreactivity measurements may be a sensitive tool to assess early vascular risk.

Correction: Diagnostic Potential of the NMDA Receptor Peptide Assay for Acute Ischemic Stroke.

[This corrects the article DOI: 10.1371/journal.pone.0042362.].

Diagnostic potential of the NMDA receptor peptide assay for acute ischemic stroke.

BACKGROUND: The acute assessment of patients with suspected ischemic stroke remains challenging. The use of brain biomarker assays may improve the early diagnosis of ischemic stroke. The main goal of the study was to evaluate whether the NR2 peptide, a product of the proteolytic degradation of N-methyl-D-aspartate (NMDA) receptors, can differentiate acute ischemic stroke (IS) from stroke mimics and persons with vascular risk factors/healthy controls. A possible correlation between biomarker values and lesion sizes was investigated as the secondary objective. METHODS AND FINDINGS: A total of 192 patients with suspected stroke who presented within 72 h of symptom onset were prospectively enrolled. The final diagnosis was determined based on clinical observations and radiological findings. Additionally gender- and age-matched healthy controls (n = 52) and persons with controlled vascular risk factors (n = 48) were recruited to compare NR2 peptide levels. Blinded plasma was assayed by rapid magnetic particles (MP) ELISA for NR2 peptide within 30 min and results for different groups compared using univariate and multivariate statistical analyses. There was a clinical diagnosis of IS in 101 of 192 (53%) and non-stroke in 91 (47%) subjects. The non-stroke group included presented with acute stroke symptoms who had no stroke (n = 71) and stroke mimics (n = 20). The highest NR2 peptide elevations where found in patients with IS that peaked at 12 h following symptom onset. When the biomarker cut off was set at 1.0 ug/L, this resulted in a sensitivity of 92% and a specificity of 96% to detect IS. A moderate correlation (r(s) = 0.73) between NR2 peptide values and acute ischemic cortical lesions (<200 mL) was found. CONCLUSIONS: This study suggests that the NR2 peptide may be a brain specific biomarker to diagnose acute IS and may allow the differentiation of IS from stroke mimics and controls. Additional larger scale clinical validation studies are required.

Comparison of retinal vasodilator and constrictor responses in type 2 diabetes.

PURPOSE: The retinal blood vessels provide a unique way to directly examine the human microvasculature, which is frequently damaged in individuals with diabetes. Previous studies have demonstrated that retinal flickering light-induced vasodilation and hyperoxia-induced vasoconstriction may operate by enhancing or reducing similar vasoregulatory factor(s), but a comparison between these two provocative stimuli in individuals with diabetes has not been studied. The purpose of the study was to examine the association between retinal flickering light-induced vasodilation and retinal hyperoxia-induced vasoconstriction in type 2 diabetic subjects and in healthy controls. METHODS: Twenty men and women with type 2 diabetes and 10 men and women without diabetes between 21 and 75 years of age were recruited. Changes in retinal artery and vein diameters to flickering light and during hyperoxia (100% oxygen) stimuli were measured on the same visit using a noninvasive retinal imaging device (Dynamic Vessel Analyzer, Imedos Inc., Germany). RESULTS: Compared with controls, diabetic subjects had impaired arterial vasodilator and vasoconstrictor responses to both flickering light and hyperoxia, respectively (both p<0.001). Merging both groups, an inverse correlation (r=-0.56; p=0.003) between the retinal artery's responses to flickering light-induced vasodilation and hyperoxia-induced vasoconstriction was demonstrated independent of glucose or insulin levels. CONCLUSION: This suggests that both responses are attenuated to a similar degree in diabetic subjects and that the attenuation to both stimuli can be observed in retinal arteries and veins. This would suggest that similar vasoregulatory factor(s) might in part help to explain the retinal diameter responses between the two stimuli. One suggested common vasoregulator of vascular tone is nitric oxide; however, other factor(s) may be involved, which contribute to this association and require further research.

Retinal vasoreactivity as a marker for chronic ischemic white matter disease?

UNLABELLED: The cerebral microvasculature cannot be easily studied non-invasively. Because the retina and brain share embryological, anatomical and physiological similarities, studies of retinal blood vessels may prove to be useful as a surrogate marker for cerebrovascular disease. In epidemiological studies abnormal retinal arteriovenous ratios (AVRs) predict the risk of stroke and vascular dementia. However, the association between retinal vasoreactivity, cerebral small vessel ischemic disease, and cerebral blood vessel function remains unknown. STUDY GOALS: To examine (1) the association between cerebral ischemic white matter disease (WMD) and retinal microvessel behavior and (2) the relationship between retinal blood vessel reactivity and measures of cerebrovascular function. METHODS: Cohort study of 12 patients with ischemic WMD and 14 healthy controls. Retinal vasoreactivity was measured following high frequency flicker light stimulation. Middle cerebral artery (MCA) vasoreactivity was measured using transcranial Doppler ultrasound (TCD). Magnetic resonance imaging scans (MRIs) were reviewed for evidence of ischemic WMD. RESULTS: Patients with ischemic WMD had attenuated retinal venous (2.2% ± 0.27 SD, vs. controls 6% ± 0.7 SD, p=0.002, CI 95%) and arterial (1.9% ± 0.8 SD, vs. controls 4.9% ± 0.8 SD, p=0.004, CI 95%) vasoreactivity compared to controls. An attenuated retinal venous light flicker response was associated with a significant decrease of MCA vasoreactivity (r=0.45, p=0.05, CI 95%). Decreased AVRs, an indicator for altered retinal vessel architecture in patients with cerebral chronic ischemic WMD, were also significantly correlated with dysfunction of cerebral vasoreactivity (r=0.69, p=0.001, CI 95%). CONCLUSION: In this study functional and structural impairment of the retinal microvasculature were associated with ischemic WMD and measures of cerebral vascular function. Microvascular dysfunction in the eye may predict cerebral small vessel disease, but validation by larger studies is needed.

Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study.

BACKGROUND: Lipid-lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without mild cognitive impairment (MCI) at baseline. METHODS: A longitudinal, observational study was conducted of 3069 cognitively healthy elderly patients (≥75 years of age) who were enrolled in the Ginkgo Evaluation of Memory Study. The primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). The secondary outcome measure was the change in global cognitive function over time measured by scores from the Modified Mini-Mental State Exam (3MSE) and the cognitive subscale of the AD Assessment Scale (ADAS-Cog). RESULTS: Among participants without MCI at baseline, the current use of statins was consistently associated with a reduced risk of all-cause dementia (hazard ratio [HR], 0.79; 95% confidence interval [95% CI], 0.65-0.96; P = .021) and AD (HR, 0.57; 95% CI, 0.39-0.85; P = .005). In participants who initiated statin therapy, lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast, there was no significant association between LLM use (including statins), dementia onset, or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline, there was a trend for a neuroprotective effect of statins on cognitive decline. CONCLUSIONS: Statins may slow the rate of cognitive decline and delay the onset of AD and all-cause dementia in cognitively healthy elderly individuals, whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.

Stroke rehabilitation.

Despite improvements in prevention and acute management, stroke remains a common condition and a major cause of permanent disability. For patients who have had a stroke, an effective rehabilitation program is critical to maximize functional recovery and quality of life. Rehabilitation can occur in a number of different physical settings and is often coordinated by a comprehensive interdisciplinary team of professionals. Rehabilitation includes retraining to regain loss of function and teaching compensatory strategies when that is not possible. A number of interesting training approaches have been developed in recent years to supplement more traditional rehabilitation programs. A variety of adaptive devices is available to improve mobility and performance of self-cares, and these devices should be prescribed for appropriate patients. Physicians caring for patients during stroke rehabilitation must be aware of potential medical complications, as well as a number of special problems that may complicate recovery, including dysphagia, urinary incontinence, shoulder pain, spasticity, falls, and poststroke depression. Involvement of the patient and caregivers in the rehabilitation process is essential. It is important to train and educate these individuals in the physical aspects of poststroke care, the expectations for recovery, and secondary stroke prevention. Issues related to community reintegration, including driving and vocational aspects, should be addressed in appropriate patients. Stroke rehabilitation is an important part of the "stroke continuum of care," which includes prevention, acute management, rehabilitation, and secondary prevention.