Improving Cloud Middlebox Infrastructure for Online Services

Middleboxes are an indispensable part of the datacenter networks that provide high availability, scalability and performance to the online services. Using load balancer as an example, this thesis shows that the prevalent scale-out middlebox designs using commodity servers are plagued with three fundamental problems: (1) The server-based layer-4 middleboxes are costly and inflate round-trip-time as much as 2x by processing the packets in software. (2) The middlebox instances cause traffic detouring en route from sources to destinations, which inflates network bandwidth usage by as much as 3.2x and can cause transient congestion. (3) Additionally, existing cloud providers do not support layer-7 middleboxes as a service, and third-party proxy-based layer-7 middlebox design exhibits poor availability as TCP state stored locally on middlebox instances are lost upon instance failure. This thesis examines the root causes of the above problems and proposes new cloud-scale middlebox design principles that systemically address all three problems. First, to address the performance problem, we make a key observation that existing commodity switches have resources available to implement key layer-4 middlebox functionalities such as load balancer, and by processing packets in hardware, switches offer low latency and high capacity benefits, at no additional cost as the switch resources are idle. Motivated by this observation, we propose the design principle of using idle switch resources to accelerate middlebox functionailites. To demonstrate the principle, we developed the complete L4 load balancer design that uses commodity switches for low cost and high performance, and carefully fuses a few software load balancer instances to provide for high availability. Second, to address the high network overhead problem from traffic detouring through middlebox instances, we propose to exploit the principles of locality and flexibility in placing the middlebox instances and servers to handle the traffic closer to the sources and reduce the overall traffic and link utilization in the network. Third, to provide high availability in a layer 7 middleboxes, we propose a novel middlebox design principle of decoupling the TCP state from middlebox instances and storing it in persistent key-value store so that any middlebox instance can seamlessly take over any TCP connection when middlebox instances fail. We demonstrate the effectiveness of the above cloud-scale middlebox design principles using load balancers as an example. Specifically, we have prototyped the three design principles in three cloud-scale load balancers: Duet, Rubik, and Yoda, respectively. Our evaluation using a datacenter testbed and large scale simulations show that Duet lowers the costs by 12x and latency overhead by 1000x, Rubik further lowers the datacenter network traffic overhead by 3x, and Yoda L7 Load balancer-as-a-service is practical; decoupling TCP state from load balancer instances has a negligible

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke).

BACKGROUND: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. METHODS: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. RESULTS: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients ( CONCLUSIONS: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640

The oral health status, behaviours and knowledge of patients with cardiovascular disease in Sydney Australia: a cross-sectional survey

Abstract Background Periodontal disease is a risk factor for atherosclerotic cardiovascular disease and it is recommended internationally that patients with cardiovascular disease should engage in preventative oral health practices and attend regular dental care visits. This study aimed to explore the oral health status, behaviours and knowledge of patients with cardiovascular disease. Methods A cross-sectional questionnaire containing 31 items was administered to patients with cardiovascular disease from cardiac rehabilitation and outpatient clinics in Sydney Australia in 2016–2017. Results Of the 318 patients surveyed, 81.1% reported having at least one oral health problem. Over a third (41.2%) of participants had not seen a dentist in the preceding 12 months and 10.7% had received any oral healthcare information in the cardiac setting. Those with valvular conditions were more likely to have received information compared to those with other cardiovascular conditions (40.6% versus 7.4%, p < 0.001). Only half of the participants had adequate oral health knowledge. Conclusions Despite a high incidence of reported oral health problems, many patients lacked knowledge about oral health, were not receiving oral health information from cardiac care providers and had difficulty accessing dental services. Further research is needed to develop oral health strategies in this area

Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide

In the 1950s the drug thalidomide administered as a sedative to pregnant women led to the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and its derivatives lenalidomide and pomalidomide (together known as Immunomodulatory Drugs: IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) E3 ubiquitin ligase and promote the ubiquitination of Ikaros/Aiolos transcription factors by CRL4(CRBN). Here we present the crystal structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes CRBN as a CRL4(CRBN) substrate receptor, which enantioselectively binds IMiDs. Through an unbiased screen we identify the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) when recruiting Ikaros/Aiolos for degradation. This dual activity implies that small molecules can principally modulate a ligase to up- or down-regulate the ubiquitination of proteins

Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries: a multicentre, international, observational cohort study

OBJECTIVES: Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs. DESIGN: A multicentre, international, collaborative cohort study. SETTING: 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020. PARTICIPANTS: Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, Wilms' tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer. MAIN OUTCOME MEASURE: All-cause mortality at 30 days and 90 days. RESULTS: 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001). CONCLUSIONS: The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally

Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke: Primary Results of the STRATIS Registry.

BACKGROUND AND PURPOSE: Mechanical thrombectomy with stent retrievers has become standard of care for treatment of acute ischemic stroke patients because of large vessel occlusion. The STRATIS registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) aimed to assess whether similar process timelines, technical, and functional outcomes could be achieved in a large real world cohort as in the randomized trials. METHODS: STRATIS was designed to prospectively enroll patients treated in the United States with a Solitaire Revascularization Device and Mindframe Capture Low Profile Revascularization Device within 8 hours from symptom onset. The STRATIS cohort was compared with the interventional cohort of a previously published SEER patient-level meta-analysis. RESULTS: A total of 984 patients treated at 55 sites were analyzed. The mean National Institutes of Health Stroke Scale score was 17.3. Intravenous tissue-type plasminogen activator was administered in 64.0%. The median time from onset to arrival in the enrolling hospital, door to puncture, and puncture to reperfusion were 138, 72, and 36 minutes, respectively. The Core lab-adjudicated modified Thrombolysis in Cerebral Infarction ≥2b was achieved in 87.9% of patients. At 90 days, 56.5% achieved a modified Rankin Scale score of 0 to 2, all-cause mortality was 14.4%, and 1.4% suffered a symptomatic intracranial hemorrhage. The median time from emergency medical services scene arrival to puncture was 152 minutes, and each hour delay in this interval was associated with a 5.5% absolute decline in the likelihood of achieving modified Rankin Scale score 0 to 2. CONCLUSIONS: This largest-to-date Solitaire registry documents that the results of the randomized trials can be reproduced in the community. The decrease of clinical benefit over time warrants optimization of the system of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02239640