Sympathetic-transduction in untreated hypertension.

Transduction of muscle sympathetic nerve activity (MSNA) into vascular tone varies with age and sex. Older normotensive men have reduced sympathetic transduction so that a given level of MSNA causes less arteriole vasoconstriction. Whether sympathetic transduction is altered in hypertension (HTN) is not known. We investigated whether sympathetic transduction is impaired in untreated hypertensive men compared to normotensive controls. Eight untreated hypertensive men and 10 normotensive men (age 50 ± 15 years vs. 45 ± 12 years (mean ± SD); p = 0.19, body mass index (BMI) 24.7 ± 2.7 kg/m2 vs. 26.0 ± 4.2 kg/m2; p = 0.21) were recruited. MSNA was recorded from the peroneal nerve using microneurography; beat-to-beat blood pressure (BP; Finapres) and heart rate (ECG) were recorded simultaneously at rest for 10 min. Sympathetic-transduction was quantified using a previously described method. The relationship between MSNA burst area and subsequent diastolic BP was measured for each participant with the slope of the regression indicating sympathetic transduction. MSNA was higher in the hypertensive group compared to normotensives (73 ± 17 bursts/100 heartbeats vs. 49 ± 19 bursts/100 heart bursts; p = 0.007). Sympathetic-transduction was lower in the hypertensive versus normotensive group (0.04%/mmHg/s vs. 0.11%/mmHg/s, respectively; R = 0.622; p = 0.006). In summary, hypertensive men had lower sympathetic transduction compared to normotensive individuals suggesting that higher levels of MSNA are needed to cause the same level of vasoconstrictor tone.

Wave Reflection and Ventriculo-Arterial Coupling in Bicuspid Aortic Valve Patients With Repaired Aortic Coarctation.

BACKGROUND: Ventriculo-arterial (VA) coupling in bicuspid aortic valve (BAV) patients can be affected by the global aortopathy characterizing BAV disease and the presence of concomitant congenital lesions such as aortic coarctation (COA). This study aimed to isolate the COA variable and use cardiovascular magnetic resonance (CMR) imaging to perform wave intensity analysis non-invasively to shed light on VA coupling changes in BAV. The primary hypothesis was that BAV patients with COA exhibit unfavorable VA coupling, and the secondary hypothesis was that BAV patients with COA exhibit increased wave speed as a marker of reduced aortic distensibility despite successful surgical correction. METHODS: Patients were retrospectively identified from a CMR database and divided into two groups: isolated BAV and BAV associated with repaired COA. Aortic and ventricular dimensions, global longitudinal strain (GLS), and ascending aortic flow data and area were collected and used to derive wave intensity from CMR data. The main variables for the analysis included all wave magnitudes (forward compression/expansion waves, FCW and FEW, respectively, and reflected backward compression wave, BCW) and wave speed. RESULTS: In the comparison of patients with isolated BAV and those with BAV associated with repaired COA (n = 25 in each group), no differences were observed in left ventricular ejection fraction, GLS, or ventricular volumes, whilst significant increases in FCW and FEW magnitude were noted in the BAV and repaired COA group. The FCW inversely correlated with age and aortic size. Whilst the BCW was not significantly different compared with that in patients with/without COA, its magnitude tends to increase with a lower COA index. Patients with repaired COA exhibited higher wave speed velocity. Aortic wave speed (inversely related to distensibility) was not significantly different between the two groups. CONCLUSION: In the absence of a significant restenosis, VA coupling in patients with BAV and COA is not negatively affected compared to patients with isolated BAV. A reduction in the magnitude of the early systolic FCW was observed in patients who were older and with larger aortic diameters.

A Snapshot of the Response from UK-based Clinical Trials of Investigational Medicinal Products to COVID-19.

Background/Aims Coronavirus Disease 2019 (COVID-19) has presented an unprecedented challenge for non-COVID related clinical trials of investigational medicinal medicines (CTIMPs). These challenges are considerable for trials run in high -risk groups, such as older adults. Clinical trials must ensure the safety of their participants, whilst also considering the potential, and often long-term, benefits of the trial intervention to public health. Here we sought to provide a brief perspective on the response and conduct of CTIMPs relevant to older adults and neurology in the UK to the COVID-19 pandemic. Methods We performed a cross-sectional study, surveying CTIMP teams running trials broadly relevant to older adults and neurology in the UK, as well as sponsors and Clinical Trials Units (CTU), to understand the response and preparedness to the pandemic. Results Due to the pandemic, active recruitment has been suspended in more than half of the trials. The primary driver for the temporary halt of recruitment activity was considerations of patient safety. Interestingly, the majority of trials, sponsors and CTUs did not consider pandemic or epidemic outbreaks in their risk assessments before January 2020. Conclusion These findings support the need to re-evaluate the risk-management approach whereby clinical trials establish contingency plans for predicted but rare events to minimise the disruption to recruitment and clinical trial delivery.

Validity and Reliability of the German Quality of Life-Alzheimer's Disease (QoL-AD) Self-Report Scale.

BACKGROUND: The Quality of Life-Alzheimer's Disease (QoL-AD) scale is a widely used measure of quality of life (QoL) in dementia. Although the instrument has been validated in several languages, the psychometric properties of the German self-report version have not yet been analyzed. OBJECTIVE: This study examines the internal consistency, test-retest reliability, and construct validity of the German QoL-AD self-report scale. METHODS: The sample included 30 patients suffering from mild to moderate Alzheimer's disease or vascular dementia (19 females; mean age 77.3 years; mean Mini-Mental State Examination (MMSE) score 19.7 points). To determine test-retest reliability, the QoL-AD self-report scale was re-administered four to seven days apart. For construct validity analysis, the Dementia Quality of Life instrument (DQoL), Geriatric Depression Scale (GDS), MMSE, and an adapted short form of the Neuropsychiatric Inventory (NPI) were used. RESULTS: The German QoL-AD self-report scale shows an internal consistency of α= 0.79 and a test-retest reliability of r = 0.75 (p < 0.01). Regarding construct validity, there was a significant positive correlation between the total scores of the QoL-AD and DQoL (r = 0.47, p < 0.05). The analysis revealed no significant correlations with the GDS or the adapted NPI. No association could be observed between the QoL-AD and the MMSE (r = 0.01), confirming divergent validity. CONCLUSION: The results indicate that the German QoL-AD self-report scale is a suitable instrument for assessing QoL in patients suffering from mild to moderate dementia, thus supporting its use in clinical practice and research.

Value of Eye-Tracking Data for Classification of Information Processing-Intensive Handling Tasks: Quasi-Experimental Study on Cognition and User Interface Design.

BACKGROUND: In order to give a wide range of people the opportunity to ensure and support home care, one approach is to develop medical devices that are as user-friendly as possible. This allows nonexperts to use medical devices that were originally too complicated to use. For a user-centric development of such medical devices, it is essential to understand which user interface design best supports patients, caregivers, and health care professionals. OBJECTIVE: Using the benefits of mobile eye tracking, this work aims to gain a deeper understanding of the challenges of user cognition. As a consequence, its goal is to identify the obstacles to the usability of the features of two different designs of a single medical device user interface. The medical device is a patient assistance device for home use in peritoneal dialysis therapy. METHODS: A total of 16 participants, with a subset of seniors (8/16, mean age 73.7 years) and young adults (8/16, mean age 25.0 years), were recruited and participated in this study. The handling cycle consisted of seven main tasks. Data analysis started with the analysis of task effectiveness for searching for error-related tasks. Subsequently, the in-depth gaze data analysis focused on these identified critical tasks. In order to understand the challenges of user cognition in critical tasks, gaze data were analyzed with respect to individual user interface features of the medical device system. Therefore, it focused on the two dimensions of dwell time and fixation duration of the gaze. RESULTS: In total, 97% of the handling steps for design 1 and 96% for design 2 were performed correctly, with the main challenges being task 1 insert, task 2 connect, and task 6 disconnect for both designs. In order to understand the two analyzed dimensions of the physiological measurements simultaneously, the authors propose a new graphical representation. It distinguishes four different patterns to compare the eye movements associated with the two designs. The patterns identified for the critical tasks are consistent with the results of the task performance. CONCLUSIONS: This study showed that mobile eye tracking provides insights into information processing in intensive handling tasks related to individual user interface features. The evaluation of each feature of the user interface promises an optimal design by combining the best found features. In this way, manufacturers are able to develop products that can be used by untrained people without prior knowledge. This would allow home care to be provided not only by highly qualified nurses and caregivers, but also by patients themselves, partners, children, or neighbors.

COVID-19 in older people: a rapid clinical review.

INTRODUCTION: the COVID-19 pandemic poses a high risk to older people. The aim of this article is to provide a rapid overview of the COVID-19 literature, with a specific focus on older adults. We frame our findings within an overview of the disease and have also evaluated the inclusion of older people within forthcoming clinical trials. METHODS: we searched PubMed and bioRxiv/medRxiv to identify English language papers describing the testing, treatment and prognosis of COVID-19. PubMed and bioRxiv/medRxiv searches took place on 20 and 24 March 2020, respectively. RESULTS: screening of over 1,100 peer-reviewed and pre-print papers yielded n = 22 on COVID-19 testing, n = 15 on treatment and n = 13 on prognosis. Viral polymerase chain reaction (PCR) and serology are the mainstays of testing, but a positive diagnosis may be increasingly supported by radiological findings. The current evidence for the effectiveness of antiviral, corticosteroid and immunotherapies is inconclusive, although trial data are largely based on younger people. In addition to age, male gender and comorbidities, specific laboratory and radiology findings are important prognostic factors. Evidence suggests that social distancing policies could have important negative consequences, particularly if in place for an extended period. CONCLUSION: given the established association between increasing age and poor prognosis in COVID-19, we anticipate that this rapid review of the current and emergent evidence might form a basis on which future work can be established. Exclusion of older people, particularly those with comorbidities, from clinical trials is well recognised and is potentially being perpetuated in the field of current COVID-19 research.

Retrograde blood flow in the internal jugular veins of humans with hypertension may have implications for cerebral arterial blood flow.

OBJECTIVES: To use multi-parametric magnetic resonance imaging (MRI) to test the hypothesis that hypertensives would have higher retrograde venous blood flow (RVBF) in the internal jugular veins (IJV) vs. normotensives, and that this would inversely correlate with arterial inflow and gray matter, white matter, and cerebrospinal fluid volumes. METHODS: Following local institutional review board approval and written consent, a prospective observational 3-T MRI study of 42 hypertensive patients (53 ± 2 years, BMI 28.2 ± 0.6 kg/m2, ambulatory daytime systolic BP 148 ± 2 mmHg, ambulatory daytime diastolic BP 101 ± 2 mmHg) and 35 normotensive patients (48 ± 2 years, BMI 25.2 ± 0.8 kg/m2, ambulatory daytime systolic BP 119 ± 3 mmHg, ambulatory daytime diastolic BP 90 ± 2 mmHg) was performed. Phase contrast imaging calculated percentage retrograde venous blood flow (%RVBF), brain segmentation estimated regional brain volumes from 3D T1-weighted images, and pseudo-continuous arterial spin labeling measured regional cerebral blood perfusion. Statistical analysis included two-sample equal variance Student's T tests, two-way analysis of variance with Tukey's post hoc correction, and permutation-based two-group general linear modeling (p < 0.05). RESULTS: In the left IJV, %RVBF was higher in hypertensives (6.1 ± 1.5%) vs. normotensives (1.1 ± 0.3%, p = 0.003). In hypertensives, there was an inverse relationship of %RVBF (permutation-based general linear modeling) to cerebral blood flow in several brain regions, including the left occipital pole and the cerebellar vermis (p < 0.01). Percentage retrograde flow in the left IJV correlated inversely with the total matter volume (gray plus white matter volume) in hypertensives (r = - 0.49, p = 0.004). CONCLUSION: RVBF in the left IJV is greater in hypertensives vs. normotensives and is linked to regional hypoperfusion and brain total matter volume. KEY POINTS: • Hypertensive humans have higher retrograde cerebral venous blood flow, associated with regional brain hypoperfusion and lower tissue volume, compared with controls. • Cerebral retrograde venous blood flow may add further stress to already hypoperfused tissue in hypertensive patients. • The amount of retrograde venous blood flow in hypertensive patients may predict which patients might be at higher risk of developing cerebral pathologies.

Artificial intelligence outperforms human students in conducting neurosurgical audits.

OBJECTIVES: Neurosurgical audits are an important part of improving the safety, efficiency and quality of care but require considerable resources, time, and funding. To that end, the advent of the Artificial Intelligence-based algorithms offered a novel, more economically viable solution. The aim of the study was to evaluate whether the algorithm can indeed outperform humans in that task. PATIENTS & METHODS: Forty-six human students were invited to inspect the clinical notes of 45 medical outliers on a neurosurgical ward. The aim of the task was to produce a report containing a quantitative analysis of the scale of the problem (e.g. time to discharge) and a qualitative list of suggestions on how to improve the patient flow, quality of care, and healthcare costs. The Artificial Intelligence-based Frideswide algorithm (FwA) was used to analyse the same dataset. RESULTS: The FwA produced 44 recommendations whilst human students reported an average of 3.89. The mean time to deliver the final report was 5.80 s for the FwA and 10.21 days for humans. The mean relative error for factual inaccuracy for humans was 14.75 % for total waiting times and 81.06 % for times between investigations. The report produced by the FwA was entirely factually correct. 13 out of 46 students submitted an unfinished audit, 3 out of 46 made an overdue submission. Thematic analysis revealed numerous internal contradictions of the recommendations given by human students. CONCLUSION: The AI-based algorithm can produce significantly more recommendations in shorter time. The audits conducted by the AI are more factually accurate (0 % error rate) and logically consistent (no thematic contradictions). This study shows that the algorithm can produce reliable neurosurgical audits for a fraction of the resources required to conduct it by human means.

Feasibility of Wave Intensity Analysis in Patients With Conotruncal Anomalies Before and After Pregnancy: New Physiological Insights?

Background: Conotruncal anomalies (CTA) are associated with ongoing dilation of the aortic root, as well as increased aortic stiffness, which may relate to intrinsic properties of the aorta. Pregnancy hormones lead to hemodynamic changes and remodeling of the tunica media, resulting in the opposite effect, i.e., increasing distensibility. These changes normalize post-pregnancy in healthy women but have not been fully investigated in CTA patients. Methods: We examined aortic distensibility and ventriculo-arterial coupling before and after pregnancy using cardiovascular magnetic resonance (CMR)-derived wave intensity analysis (WIA). Pre- and post-pregnancy CMR data were retrospectively analyzed. Aortic diameters were measured before, during, and after pregnancy by cardiac ultrasound and before and after pregnancy by CMR. Phase contrast MR flow sequences were used for calculating wave speed (c) and intensity (WI). A matched analysis was performed comparing results before and after pregnancy. Results: Thirteen women (n = 5, transposition of the great arteries; n = 6, tetralogy of Fallot; n = 1, double outlet right ventricle, n = 1, truncus arteriosus) had 19 pregnancies. Median time between delivery and second CMR was 2.3 years (range: 1-6 years). The aortic diameter increased significantly after pregnancy in nine (n = 9) patients by a median of 4 ± 2.3 mm (range: 2-7.0 mm, p = 0.01). There was no difference in c pre-/post-pregnancy (p = 0.73), suggesting that increased compliance, typically observed during pregnancy, does not persist long term. A significant inverse relationship was observed between c and heart rate (HR) after pregnancy (p = 0.01, r = 0.73). There was no significant difference in cardiac output, aortic/pulmonary regurgitation, or WI peaks pre-/post-pregnancy. Conclusions: WIA is feasible in this population and could provide physiological insights in larger cohorts. Aortic distensibility and wave intensity did not change before and after pregnancy in CTA patients, despite an increase in diameter, suggesting that pregnancy did not adversely affect coupling in the long-term.

Validation of the German Version of the Transsexual Voice Questionnaire for Male-to-Female Transsexuals.

OBJECTIVE: The purpose of this study was to examine the psychometric properties of the German translation of the Transsexual Voice Questionnaire for Male-to-Female Transsexuals (TVQMtF), an instrument assessing the voice-related quality of life (VrQoL) in trans women. STUDY DESIGN: This is a cross-sectional study. METHOD: The conducted online survey contained the TVQMtF as well as a generic measurement of VrQoL (Voice Handicap Index) and items on transition. Data of 127 trans women were analyzed computing coefficients of reliability and convergent validity. Additionally, confirmatory factor analysis and model modification were performed. RESULTS: Analyses revealed excellent internal consistency (α = 0.97), split-half reliability (rSB = 0.95) and good convergent validity. Significant associations were found between the total scores of the German TVQMtF and the Voice Handicap Index (r = 0.88; P < 0.001) as well as the vocal self-perception (r = -0.57; P < 0.001). An acceptable model with a two-factor structure including 22 of the 30 items was found. CONCLUSIONS: The TVQMtF is the first German reliable and valid measurement of VrQoL for trans women. Therefore, its utilization can be recommended for clinical and research purposes in the fields of voice therapy and surgery.

Cerebral Blood Flow Response to Simulated Hypovolemia in Essential Hypertension: A Magnetic Resonance Imaging Study.

Hypertension is associated with raised cerebral vascular resistance and cerebrovascular remodeling. It is currently unclear whether the cerebral circulation can maintain cerebral blood flow (CBF) during reductions in cardiac output (CO) in hypertensive patients thereby avoiding hypoperfusion of the brain. We hypothesized that hypertension would impair the ability to effectively regulate CBF during simulated hypovolemia. In the present study, 39 participants (13 normotensive, 13 controlled, and 13 uncontrolled hypertensives; mean age±SD, 55±10 years) underwent lower body negative pressure (LBNP) at -20, -40, and -50 mmHg to decrease central blood volume. Phase-contrast MR angiography was used to measure flow in the basilar and internal carotid arteries, as well as the ascending aorta. CBF and CO decreased during LBNP (P<0.0001). Heart rate increased during LBNP, reaching significance at -50 mmHg (P<0.0001). There was no change in mean arterial pressure during LBNP (P=0.3). All participants showed similar reductions in CBF (P=0.3, between groups) and CO (P=0.7, between groups) during LBNP. There was no difference in resting CBF between the groups (P=0.36). In summary, during reductions in CO induced by hypovolemic stress, mean arterial pressure is maintained but CBF declines indicating that CBF is dependent on CO in middle-aged normotensive and hypertensive volunteers. Hypertension is not associated with impairments in the CBF response to reduced CO.

Diagnostic accuracy of frontotemporal dementia. An artificial intelligence-powered study of symptoms, imaging and clinical judgement.

PURPOSE: Frontotemporal dementia (FTD) is a neurodegenerative disorder associated with a poor prognosis and a substantial reduction in quality of life. The rate of misdiagnosis of FTD is very high, with patients often waiting for years without a firm diagnosis. This study investigates the current state of the misdiagnosis of FTD using a novel artificial intelligence-based algorithm. PATIENTS & METHODS: An artificial intelligence algorithm has been developed to retrospectively analyse the patient journeys of 47 individuals diagnosed with FTD (age range 52-80). The algorithm analysed the efficiency of patient pathways by utilizing a reward signal of ‒1 to +1 to assess the symptoms, imaging techniques, and clinical judgement in both behavioural and language variants of the disease. RESULTS: On average, every patient was subjected to 4.93 investigations, of which 67.4% were radiological scans. From first presentation it took on average 939 days for a firm diagnosis. The mean time between appointments was 204 days, and the average patient had their diagnosis altered 7.37 times during their journey. The algorithm proposed improvements by evaluating the interventions that resulted in a decreased reward signal to both the individual and the population as a whole. CONCLUSIONS: The study proves that the algorithm can efficiently guide clinical practice and improve the accuracy of the diagnosis of FTD whilst making the process of auditing faster and more economically viable.

Imaging the carotid atherosclerotic plaque.

This mini review provides a concise overview of imaging techniques that are currently used to image the atheroscletoric plaque in the carotid artery in vivo. The main techniques include ultrasound imaging, X-ray imaging, magnetic resonance imaging and positron emission tomography imaging. Each technique has advantages and limitations and may be chosen depending on the availability, cost and clinical justification for its use. Common to all the imaging techniques presented here is the need for a skilled imaging professional to allow for high reliability and repeatability. While ultrasound-based imaging currently is regarded as a first line technique in clinical practice, the use of other techniques such as computed tomography angiography or magnetic resonance angiography need to be considered in the presence of significant stenosis with or without symptoms. Advancements in these two modalities, as well as in positron emission tomography imaging, are increasingly moving toward a better understanding of the risk-stratification and pre-interventional monitoring of patients at risk of plaque rupture as well as early identification of plaque development and better understanding of plaque composition (e.g. metabolic imaging).

Incidental Follow-up Imaging of Previous Ventricular Tuberculosis and Pneumoencephalography in a 57-year-old man.

We present a rare case of follow-up by neuroimaging in a 57-year-old man with a previous pneumoencephalography to evaluate ventricular tuberculosis (TB). Magnetic resonance imaging (MRI) of the whole head was performed at 3T using T1-weighted magnetization-prepared rapid gradient echo (T1-MPRAGE). A full quantitative sensory testing battery on the forearm was also performed, alongside a brief clinical examination. All test results were normal with the exception of the T1-MPRAGE which showed enlarged ventricles and a cyst-like focal changes, mistaken for a sign of old ischaemic infarct. The change, however, is consistent with the insertion of a cannula for the pneumoencephalogram. This is the first follow-up report with neuroimaging presented nearly 40 years after the diagnosis of ventricular TB.

The German Focus on the Outcomes of Communication Under Six (FOCUS-G): Reliability and Validity of a Novel Assessment of Communicative Participation.

Purpose: Our purpose was to explore the validity and reliability of the German Focus on the Outcomes of Communication Under Six (FOCUS-G; Thomas-Stonell, Oddson, Robertson, & Rosenbaum, 2010, 2012), which is an authorized adaptation of the Focus on the Outcomes of Communication Under Six (Thomas-Stonell et al., 2010) tool, which measures communicative participation in preschool children. Method: Parents of typically developing children (TDC) and of children with speech impairment (CSI) completed the FOCUS-G and the Questionnaire for Measuring Health-Related Quality of Life in Children (KiddyKINDL; Ravens-Sieberer & Bullinger, 2000). To determine test-retest reliability, the FOCUS-G was readministered to a subsample of parents 1 week later. Results: The FOCUS-G had high values for internal consistency (α = .959, Ω = .941), test-retest reliability (intraclass correlation coefficient = .974), and split-half reliability (r = .832). Total scores on the FOCUS-G and KiddyKINDL demonstrated significant associations. FOCUS-G total scores and subdomain scores for both samples showed significant correlations, indicating good construct validity. The discriminatory ability of the FOCUS-G was indicated by significantly higher mean scores for TDC (M = 6.03, SD = 0.65) than CSI (M = 5.47, SD = 1.02). Conclusion: The overall good psychometric properties of this novel assessment of communicative participation support its use by speech-language pathologists for clinical and research purposes with German-speaking children.

The German Intelligibility in Context Scale (ICS-G): reliability and validity evidence.

BACKGROUND: In 2012 the Intelligibility in Context Scale (ICS) was published as a parent-report screening assessment that considers parents' perceptions of their children's functional intelligibility with a range of communication partners that differ in levels of authority and familiarity in real-life situations. To date, the ICS has been translated into 60 languages (including German). AIMS: To evaluate the psychometric properties of the German translation of the ICS ( = ICS-G), especially its reliability and validity, using four objective measures of speech sound disorder (SSD) severity: percentage of consonants correct (PCC); percentage of initial consonants correct (PICC); percentage of vowels correct (PVC); and percentage of phonemes correct (PPC). METHODS & PROCEDURES: Children who were typically developing (TD) and children with SSD (n = 181; 90 males, 81 females; mean age = 4.18 years, SD = 0.79 years, range = 3;0-5;11 years) were recruited through 13 kindergartens and 15 speech-language pathologists (SLPs) in Germany. All children's parents completed the ICS-G. To obtain an insight into the severity of SSD (n = 30), children's speech skills were assessed with PLAKSS-II. For the analysis of test-retest reliability the ICS-G was re-administered with a subsample of parents (n = 36) after 1 week. OUTCOMES & RESULTS: The ICS-G had high internal consistency (α = .95, p < .001) and high test-retest reliability (r = .998, p < .001). The ICS-G total scores and item scores for both samples showed significant correlations, indicating good construct validity. Analyses revealed low but significant correlations with external factors (e.g., age, social class). Criterion validity was established through significant correlations between the ICS-G and scores for PCC (r = .43), PICC (r = .43), PVC (r = .62) and PPC (r = .47). The discriminatory ability of the ICS-G was indicated by significantly higher mean scores for the TD group (mean = 4.49, SD = 0.47) than the SSD group (mean = 3.97, SD = 0.63). CONCLUSIONS & IMPLICATIONS: The overall good psychometric properties of the ICS-G support its use by SLPs for clinical and research purposes with German-speaking children.

Is High Blood Pressure Self-Protection for the Brain?

RATIONALE: Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular variants of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the pathogenesis of essential hypertension, which remains enigmatic in 95% of patients. OBJECTIVE: To evaluate the role of the cerebral circulation in the pathophysiology of hypertension. METHODS AND RESULTS: We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia, and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow, and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving antihypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension, suggesting that it may be a novel prognostic or diagnostic marker (n=126). CONCLUSIONS: Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore, lowering blood pressure may worsen cerebral perfusion in susceptible individuals.

Characterization of NS5A polymorphisms and their impact on response rates in patients with HCV genotype 2 treated with daclatasvir-based regimens.

OBJECTIVE: Daclatasvir (DCV) is a pan-genotypic non-structural protein 5A (NS5A) inhibitor that is approved for treatment of hepatitis C virus (HCV) genotype (GT)1 and GT3 in the USA and GT1, GT3 and GT4 in Europe. We set out to examine the impact of daclatasvir-based regimens on the sustained virologic response (SVR) in patients with GT2 infection with respect to GT2 subtype and NS5A polymorphisms at amino acid positions associated with daclatasvir resistance. METHODS: Analyses were performed on 283 GT2 NS5A sequences from five daclatasvir regimen-based clinical trials (ClinicalTrials.gov: NCT-01257204, NCT-01359644, NCT-02032875, NCT-02032888 and NCT-01616524) and 143 NS5A sequences from the Los Alamos HCV database. Susceptibility analyses of substitutions at amino acid positions associated with daclatasvir resistance and patient-derived NS5A sequences were performed using an in vitro HCV replication assay. RESULTS: Of 13 GT2 subtypes identified from 426 NS5A sequences, the most prevalent were GT2a (32%), GT2b (48%) and GT2c (10%). The most prevalent NS5A polymorphism was L31M (GT2a = 88%; GT2b = 59%; GT2c = 10%). Substitutions identified in 96% of GT2 NS5A sequences exhibited daclatasvir EC50 values ranging from 0.005 to 20 nM when tested in vitro. A similar range in daclatasvir EC50 values was observed for 16 diverse GT2 patient-derived NS5A sequences (EC50 = 0.005-60 nM). Depending on the daclatasvir-based regimen studied (daclatasvir/interferon-based or daclatasvir/sofosbuvir-based), SVR rates ranged from 90% to 100% in GT2 patients with the most prevalent baseline NS5A-L31M polymorphism, compared with from 96% to 100% without this polymorphism. CONCLUSIONS: High SVR rates were achieved in patients infected with GT2 treated with daclatasvir-based regimens irrespective of GT2 subtype or baseline NS5A polymorphisms.