A Branch Predictor Directed Data Cache Prefetcher for Out-of-order and Multicore Processors

Modern superscalar pipelines have tremendous capacity to consume the instruction stream. This has been possible owing to improvements in process technology, technology scaling and microarchitectural design improvements that allow programs to speculate past control and data dependencies in the superscalar architecture. However, the speed of the memory subsystem lags behind due to physical constraints in bringing in huge amounts of data to the processor core. Cache hierarchies have subdued the impact of this speed gap; however, there is much that can be still done in improving microarchitecture. Data prefetching techniques bring in memory content significantly before the instruction stream actually witnesses demand misses. However, a majority of the techniques proposed so far depend upon an initial demand miss that initiates a stream of previously identified prefetches. In this thesis, we propose a novel prefetching algorithm, which leverages branch prediction to facilitate deep memory system speculation. The branch predictor directed lookahead mechanism builds a speculative control flow path for the instruction stream about to be fetched by the main superscalar pipeline. Prefetches are generated along this speculative path from a condensed representation of the memory instructions, leveraging register index based correlation. The technique integrates eloquently with the main pipeline's branch predictor to filter out prefetches along invalid speculative paths. Impact of the prefetching scheme is analyzed using out- of-order model of the Gem5 cycle accurate simulator. Evaluation shows that on a set of 13 memory intensive SPEC CPU2006 benchmarks, our prefetching technique improves performance by an average of 5.6% over the baseline out-of-order processor

Hypoxia-inducible factor (HIF): fuel for cancer progression

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygenindependent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors

The poly dA helix: a new structural motif for high performance DNA-based molecular switches

We report a pH-dependent conformational transition in short, defined homopolymeric deoxyadenosines (dA15) from a single helical structure with stacked nucleobases at neutral pH to a double-helical, parallel-stranded duplex held together by AH+-H+A base pairs at acidic pH. Using native PAGE, 2D NMR, circular dichroism (CD) and fluorescence spectroscopy, we have characterized the two different pH dependent forms of dA15. The pH-triggered transition between the two defined helical forms of dA15 is characterized by CD and fluorescence. The kinetics of this conformational switch is found to occur on a millisecond time scale. This robust, highly reversible, pH-induced transition between the two well-defined structured states of dA15 represents a new molecular building block for the construction of quick-response, pH-switchable architectures in structural DNA nanotechnology

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Third-Year Nursing Student’s Physiological Knowledge Retention

There is a growing concern that medical, allied health & nursing students struggle to retain & apply physiological knowledge in the subsequent years of their disciplines (Narnaware & Neumeier, 2020). However, physiological knowledge retention has not been studied as extensively as anatomical knowledge retention in healthcare, with very few studies focusing on nursing students (Aari et al., 2004). The present study evaluates physiological knowledge retention in third-year nursing students. Students were quizzed on ten major organ systems using an online platform, Kahoot (Kahoot, Inc. Oslo, Norway). The results show that the mean class average in the first year was 64.9 ± 10.5 (±SD), which significantly (P<0.05) decreased to 50.95 ± 9.2 (±SD) in the third year. This equates to a knowledge retention rate of 88.1% or 11.9% knowledge loss within three years. Organ-specific knowledge retention was the highest for inflammation (100%), respiratory physiology (99.10%), and vascular physiology (95.01%), followed by blood (89.16%), digestive physiology (86.28%), endocrinology (83.76%), defences (82.50%) and renal physiology (82.19%). Retention was comparatively lower for fluid and electrolyte balance (79.36%) and reproductive physiology (77.54%). Although organ-specific knowledge retention was found, this study identifies the potential gaps in knowledge retention, which helps develop an effective and robust interventional strategy to improve knowledge retention in nursing students. Faculty Mentors: Dr. Raj Narnaware & Melanie Neumeie

Intraoperative neurocytology of primary central nervous system neoplasia: A simplified and practical diagnostic approach

Intraoperative consultations may pose considerable diagnostic challenge to the neuropathologist in diagnosing primary and metastatic neoplasms of the central nervous system (CNS). Cytological preparations in the form of squash, touch, imprint or smears are few of the available modalities in addition to the frozen section (FS). Although the latter is superior in providing both histologic patterns and cytomorphologic details yet smears are of vital importance when tissue available is limited (stereotactic biopsy), scrutinisation of intercellular matrix (astrocytoma versus oligodendroglioma) and evaluation of discohesive cells (lymphoma, pituitary adenoma) and in inflammatory lesions. This review is intended to emphasize the value, applicability and limitations of neurocytology aiming to expedite the intraoperative smear-based diagnoses of CNS neoplasia as per the World Health Organization (WHO) classification. We recommend that whenever possible, both smears and FS should be examined concomitantly and in a correlative manner. In the unlikely event of a mismatch between the findings on smear and FS, intraoperative diagnosis is primarily based on FS, if adequate tissue is available. However, each case must be evaluated on its own merit and in difficult cases relevant differential diagnoses should be offered to facilitate surgical decisions and optimally triage patient management