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Introduction: Concerns exist that a potential mechanism for harm from upright activity (sitting, standing, and walking) early after an acute ischaemic stroke could be the reduction of cerebral perfusion during this critical phase. We aimed to estimate the effects of upright positions (sitting and standing) on cerebral hemodynamics within 48 h and later, 3-7 days post-stroke, in patients with strokes with and without occlusive disease and in controls. Methods: We investigated MCAv using transcranial Doppler in 0° head position, then at 30°, 70°, 90° sitting, and 90° standing, at <48 h post-stroke, and later at 3-7 days post-stroke. Mixed-effect linear regression modeling was used to estimate differences in MCAv between the 0° and other positions and to compare MCAv changes across groups. Results: A total of 42 stroke participants (anterior and posterior circulation) (13 with occlusive disease, 29 without) and 22 controls were recruited. Affected hemisphere MCAv decreased in strokes with occlusive disease (<48 h post-stroke): from 0° to 90° sitting (-9.9 cm/s, 95% CI[-16.4, -3.4]) and from 0° to 90° standing (-7.1 cm/s, 95%CI[-14.3, -0.01]). Affected hemisphere MCAv also decreased in strokes without occlusive disease: from 0° to 90° sitting (-3.3 cm/s, 95%CI[-5.6, -1.1]) and from 0° to 90° standing (-3.6 cm/s, 95%CI [-5.9, -1.3]) (p-value interaction stroke with vs. without occlusive disease = 0.07). A decrease in MCAv when upright was also observed in controls: from 0° to 90° sitting (-3.8 cm/s, 95%CI[-6.0, -1.63]) and from 0° to 90° standing (-3 cm/s, 95%CI[-5.2, -0.81]) (p-value interaction stroke vs. controls = 0.85). Subgroup analysis of anterior circulation stroke showed similar patterns of change in MCAv in the affected hemisphere, with a significant interaction between those with occlusive disease (n = 11) and those without (n = 26) (p = 0.02). Changes in MCAv from 0° to upright at <48 h post-stroke were similar to 3-7 days. No association between changes in MCAv at <48 h and the 30-day modified Rankin Scale was found. Discussion: Moving to more upright positions <2 days post-stroke does reduce MCAv in the affected hemisphere; however, these changes were not significantly different for stroke participants (anterior and posterior circulation) with and without occlusive disease, nor for controls. The decrease in MCAv in anterior circulation stroke with occlusive disease significantly differed from without occlusive disease. However, the sample size was small, and more research is warranted to confirm these findings.
RESUMO
BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. CONCLUSION: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.