Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Intraoperative Opioid Waste and Association of Intraoperative Opioid Dose with Postoperative Adverse Outcomes: A Hospital Registry Study.

INTRODUCTION: Perioperative opioid use has been associated with adverse clinical outcomes. Additionally, opioid disposal carries significant costs, due to the waste of pharmaceutical products and the time needed by skilled labor to report the waste. In this study, we aimed to estimate costs and predict factors of opioid-associated intraoperative product waste, as well as to evaluate whether higher intraoperative opioid doses are associated with increased risk of adverse postoperative outcomes. METHODS: We included 170,607 patients undergoing general anesthesia and receiving intraoperative fentanyl, hydromorphone, or morphine at Beth Israel Deaconess Medical Center, Boston, MA, USA, between January 2010 and June 2020. We estimated product waste-associated costs based on various opioid syringe sizes and determined predictors of opioid waste. Further, we evaluated whether higher opioid doses were associated with postoperative adverse events according to the severity-indexed, incident report-based medication error-reporting program classification. The primary outcome included post-extubation desaturation, postoperative nausea or vomiting, or postoperative somnolence or sedation. RESULTS: The use of the smallest syringe sizes (50 mcg for fentanyl, 0.2 mg for hydromorphone, and 2 mg for morphine) resulted in the lowest product waste-associated costs. The main predictor of opioid waste was the administration of more than one intraoperative opioid (adjusted odds ratio [aOR] = 7.64, 95% CI 7.40-7.89, P < 0.001). Intraoperative doses of fentanyl > 50-100 mcg (aOR = 1.17 [1.10-1.25], P < 0.001, adjusted risk difference [ARD] 2%) and > 100 mcg (aOR = 1.24 [1.16-1.33], P < 0.001, ARD 3%), hydromorphone > 1 mg (aOR = 1.13 [1.06-1.20], P < 0.001, ARD 2%), and morphine > 2-4 mg (aOR = 1.26 [1.02-1.56], P = 0.04, ARD 3%) and > 4 mg (aOR = 1.45 [1.18-1.77], P < 0.001, ARD 5%) were associated with higher risk of the primary outcome. CONCLUSION: Smaller syringe sizes of intraoperative opioids may help to reduce product waste and associated costs, as well postoperative adverse events through utilization of lower intraoperative opioid doses.

Centering the Inner Experience of Autism: Development of the Self-Assessment of Autistic Traits.

Current tools for identifying autism are critiqued for their lack of specificity and sensitivity, especially in autistic people who are older, have higher verbal ability or significant compensatory skills, and are not cisgender boys. This may reflect the following: the historical focus of autism research on White (cisgender) male, upper and middle class children; limited interest in the inner, lived experience of autism; and the predominance of a deficit-based model of autism. We report here on the first attempt of which we are aware to develop a clinical self-report measure of autistic traits as described by autistic people. We believe this is an advance in methodology because prior work in the development of autistic trait/diagnostic measures has prioritized the perspectives of nonautistic clinicians and scientists. The measure was developed under the leadership of two autistic researchers and constructed by leveraging descriptions of autism by autistic people to generate items designed to encompass the range of the autistic experience, using strength-based, accessible language. The team utilized iterative feedback from a panel of autistic experts to refine and enhance the measure, called the Self Assessment of Autistic Traits (SAAT). It is intended for people 16 years or older and uses a format that is designed to increase its accessibility and acceptability for autistic respondents. Future work will report on the preliminary psychometrics of the SAAT, with a long-term goal of advancing our understanding of the inner autistic experience and enhancing the clinical and scientific assessment of autism.

Why is this topic important?: Some people, especially older people, and those who can "mask" their autism, are missed by the current autism assessment tools. This can keep them from getting supports or getting connected to autistic communities. This can harm their well-being and independence. The tools we currently have to assess autism are important, but they were not developed with people who represent the full range of genders, ages, abilities, and cultural identities that characterize autism. Furthermore, current tools emphasize behaviors that other people observe, for example, making eye contact, and do not fully explore the lived or inner experience of autism. What is the purpose of this article?: This article describes the first attempt we know of to begin developing a self-report measure of autistic traits as described by autistic people. What did the authors do?: The authors started by reading what autistic people had to say about autism. They used those readings to come up with initial ideas about autistic experience. Then they used those ideas to write questions for a questionnaire about autistic traits. They asked autistic experts to review the questionnaire and made changes based on what they said. How did the authors work together?: This project was led by two autistic researchers who worked with a team of nonautistic researchers experienced in different research methods. A panel of autistic experts, including both autistic scientist and community leaders, also provided important input. Some of those methods were community-based research, Delphi panels, cognitive interviewing, and measure development. The research team made decisions together. The autistic researchers made the final decisions if there was disagreement. What did they produce?: They produced a preliminary version of the Self Assessment of Autistic Traits (SAAT). The SAAT is a questionnaire that asks if a person has common autistic experiences and traits. It has 58 items that are written with the aim of being respectful and using accessible language. The questionnaire is designed to work with common autistic thinking styles. How will this help autistic adults now or in the future?: The long-term goal is to create a reliable and valid self-report questionnaire that people 16 years old and older can complete to measure their autistic traits. We believe that this could be an important tool for advancing our understanding of the inner autistic experience of autism. This could improve how we assess autistic adults and how we research and think about autism.

Clinical neuroimaging in intracerebral haemorrhage related to cerebral small vessel disease: contemporary practice and emerging concepts.

INTRODUCTION: About 80% of all non-traumatic intracerebral hemorrhage (ICH) are caused by the sporadic cerebral small vessel diseases deep perforator arteriopathy (DPA, also termed hypertensive arteriopathy or arteriolosclerosis) and cerebral amyloid angiopathy (CAA), though these frequently co-exist in older people. Contemporary neuroimaging (MRI and CT) detects an increasing spectrum of hemorrhagic and non-hemorrhagic imaging biomarkers of small vessel disease which may identify the underlying arteriopathies. AREAS COVERED: We discuss biomarkers for cerebral small vessel disease subtypes in ICH, and explore their implications for clinical practice and research. EXPERT OPINION: ICH is not a single disease, but results from a defined range of vascular pathologies with important implications for prognosis and treatment. The terms 'primary' and 'hypertensive' ICH are poorly defined and should be avoided, as they encourage incomplete investigation and classification. Imaging-based criteria for CAA will show improved diagnostic accuracy, but specific imaging biomarkers of DPA are needed. Ultra-high-field 7 T-MRI using structural and quantitative MRI may provide further insights into mechanisms and pathophysiology of small vessel disease. We expect neuroimaging biomarkers and classifications to allow personalized treatments (e.g. antithrombotic drugs) in clinical practice and to improve patient selection and monitoring in trials of targeted therapies directed at the underlying arteriopathies.

Sex Differences in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis.

Background: Cerebral small vessel disease (SVD) is a common cause of stroke, mild cognitive impairment, dementia and physical impairments. Differences in SVD incidence or severity between males and females are unknown. We assessed sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution, and severity of SVD features. Methods: We assessed four recent systematic reviews on SVD and performed a supplementary search of MEDLINE to identify studies reporting M:F ratio in covert, stroke, or cognitive SVD presentations (registered protocol: CRD42020193995). We meta-analyzed differences in sex ratios across time, countries, SVD severity and presentations, age and risk factors for SVD. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and three mixed studies published between 1989 and 2020, more males were recruited in hospital-based than in community-based studies [M:F = 1.16 (0.70) vs. M:F = 0.79 (0.35), respectively; p < 0.001]. More males had moderate to severe SVD [M:F = 1.08 (0.81) vs. M:F = 0.82 (0.47) in healthy to mild SVD; p < 0.001], and stroke presentations where M:F was 1.67 (0.53). M:F did not differ for recent (2015-2020) vs. pre-2015 publications, by geographical region, or age. There were insufficient sex-stratified data to explore M:F and risk factors for SVD. Conclusions: Our results highlight differences in male-to-female ratios in SVD severity and amongst those presenting with stroke that have important clinical and translational implications. Future SVD research should report participant demographics, risk factors and outcomes separately for males and females. Systematic Review Registration: [PROSPERO], identifier [CRD42020193995].

Associations Between White Matter Hyperintensity Burden, Cerebral Blood Flow and Transit Time in Small Vessel Disease: An Updated Meta-Analysis.

Cerebral small vessel disease (SVD) is a major contributor to stroke and dementia, characterized by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 systematic review, identifying 30 new studies, 27 cross-sectional (n = 2,956) and 3 longitudinal (n = 440). Cross-sectionally, 10/27 new studies (n = 1,019) included sufficient data for meta-analysis, which we meta-analyzed with 24 previously reported studies (n = 1,161), total 34 (n = 2,180). Our meta-analysis showed that patients with lower CBF had worse WMH burden (mean global CBF: standardized mean difference (SMD): -0.45, 95% confidence interval (CI): -0.64, -0.27). Longitudinally, associations between baseline CBF and WMH progression varied: the largest study (5 years, n = 252) found no associations, while another small study (4.5 years, n = 52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found that CBF was lower in WMH than in normal-appearing white matter in an additional meta-analysis (5 cross-sectional studies; n = 295; SMD: -1.51, 95% CI: -1.94, -1.07). These findings highlight that relationships between resting CBF and WMH are complex. Further longitudinal studies analyzing regional CBF and subsequent WMH change are required to determine the role of CBF in SVD progression.

A survey of healthcare providers' knowledge and attitudes regarding pain relief in labor for women in Ethiopia.

BACKGROUND: To explore healthcare providers' knowledge and attitudes to the need for pain relief for women in labor. METHODS: A structured questionnaire (n = 200) distributed to healthcare providers working in the obstetric departments, including theatres, of three public hospitals in different settings (rural, peri-urban and urban) in Ethiopia. Descriptive analysis was performed using Excel 2013 and SPSS version 22 for associations. RESULTS: The response rate was 81.5% with 164 questionnaires completed. The majority, 79% of respondents, understood that women can feel moderate to severe pain in labor and 77% were of the opinion that labor pain should be relieved. However, common practices included only supportive measures such as breathing and relaxation exercises, back massage and support from family. The general attitude of healthcare providers is that labor is a natural process, women should be able to cope and that pain relief is not a priority for women in labor. More than half, 52% of healthcare providers had safety concerns with using pharmacological methods to relieve pain in labor. CONCLUSION: The majority of healthcare providers understand that women suffer significant pain during labor. However, providing effective pain relief is currently not provided as part of routine intra-partum care in Ethiopia.