Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UKbased ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.

Mitochondrial diseases collectively represent the most common cause of inherited metabolic disease. They are estimated to affect at least 1 in 8,000 adults and at least 1 in 250 adults carry a disease-causing genetic mutation. They comprise a heterogeneous group of disorders caused by mutations in either the nuclear or mitochondrial genome, which ultimately result in dysfunction of the critical cellular energy producing mitochondrial respiratory chain. Owing to the key role of mitochondria in energy production, mitochondrial disorders predominantly manifest in tissues with high metabolic demand. However, they demonstrate significant phenotypic and genotypic variability, often rendering the diagnostic process protracted and challenging. Since Luft's first description of mitochondrial disease nearly 60 years ago, substantial evolution in diagnostic techniques have simultaneously improved the diagnosis and understanding of mitochondrial disease and biology, but the standard diagnostic approach has failed to evolve at the same pace. Although sequencing technologies and analysis for the diagnosis of mitochondrial disease continue to evolve, advances to date, our expanding understanding of mitochondrial diseases and the increasing affordability of these new technologies justify a paradigm shift in the diagnostic approach. We review the progression, impact and challenges of diagnosing mitochondrial diseases and propose a minimally invasive "genetics first" approach incorporating stratification using non-invasive biomarkers, followed by non-targeted next-generation sequencing, such as whole genome sequencing. Such an approach may improve diagnostic yield and streamline diagnosis, leaving invasive investigations to address diagnostic challenges and functional validation of novel variants.

Accentuated blood pressure (BP) fluctuation and low cerebral blood flow (CBF) response to CO2 increases the risk of transient ischemic attack (TIA) recurrence and stroke in TIA patients. Improving cardio- and cerebrovascular function may reduce stroke risk. We found dietary nitrate lowered dynamic blood pressure variability (BPV) in rats, and improved cerebrovascular CO2 reactivity in healthy individuals. In thirty TIA patients, we examined the effects of a 7-day supplementation of dietary nitrate (0.1mmol/kg/day) on cerebrovascular function using a randomized, single-blinded, placebo-controlled study design. We hypothesized that 7-day dietary nitrate supplementation would decrease variabilities in BP and CBF and improve CBF-CO2 slope and cerebral autoregulation (CA). We assessed beat-to-beat middle cerebral artery blood velocity (MCAv, index of CBF) and BP at rest and during CO2 breathing. Transfer function analysis was performed on beat-to-beat MCAv and BP to determine CA parameters (gain, phase and coherence). Irrespective of treatment, high and low frequency BP-MCAv gain and MCAv-CO2 slope increased 7 days following TIA onset, while low frequency BPV decreased (p<0.05 vs. baseline). At follow-up, dietary nitrate elevated plasma nitrate concentration by ˜547% (p<0.001) and moderately lowered BPV (d=0.6, p=0.011), MCAv variability (d = 0.7, p = 0.018) and BP-MCAv coherence (d=0.7, p=0.008) in the very-low frequency range (0.02-0.07 Hz), while MCAv-CO2 slope and arterial stiffness were unaffected (p>0.05). Concurrent with standard treatment, dietary nitrate supplementation reduces BP and CBF fluctuation and improve cerebral autoregulation in TIA patients, without affecting cerebrovascular CO2 reactivity.

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