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Synaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca2+-binding to Synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to Synaptotagmin-1 and complexins. However, the nature of this state and the steps leading to membrane fusion are unclear, in part because of the difficulty of studying this dynamic process experimentally. To shed light into these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two flat bilayers or a vesicle and a flat bilayer with or without fragments of Synaptotagmin-1 and/or complexin-1. Our results need to be interpreted with caution because of the limited simulation times and the absence of key components, but suggest mechanistic features that may control release and help visualize potential states of the primed Synaptotagmin-1-SNARE-complexin-1 complex. The simulations suggest that SNAREs alone induce formation of extended membrane-membrane contact interfaces that may fuse slowly, and that the primed state contains macromolecular assemblies of trans-SNARE complexes bound to the Synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration that prevents premature membrane merger and formation of extended interfaces, but keeps the system ready for fast fusion upon Ca2+ influx.

Languages such as C and C++ use unsafe manual memory management, allowing simple bugs (i.e., accesses to an object after deallocation) to become the root cause of exploitable security vulnerabilities. This paper proposes Watchdog, a hardware-based approach for ensuring safe and secure manual memory management. Inspired by prior software-only proposals, Watchdog generates a unique identifier for each memory allocation, associates these identifiers with pointers, and checks to ensure that the identifier is still valid on every memory access. This use of identifiers and checks enables Watchdog to detect errors even in the presence of reallocations. Watchdog stores these pointer identifiers in a disjoint shadow space to provide comprehensive protection and ensure compatibility with existing code. To streamline the implementation and reduce runtime overhead: Watchdog (1) uses micro-ops to access metadata and perform checks, (2) eliminates metadata copies among registers via modified register renaming, and (3) uses a dedicated metadata cache to reduce checking overhead. Furthermore, this paper extends Watchdog's mechanisms to detect bounds errors, thereby providing full hardware-enforced memory safety at low overheads.

A multiprocessor's memory consistency model imposes ordering constraints among loads, stores, atomic operations, and memory fences. Even for consistency models that relax ordering among loads and stores, ordering constraints still induce significant performance penalties due to atomic operations and memory ordering fences. Several prior proposals reduce the performance penalty of strongly ordered models using post-retirement speculation, but these designs either (1) maintain speculative state at a per-store granularity, causing storage requirements to grow proportionally to speculation depth, or (2) employ distributed global commit arbitration using unconventional chunk-based invalidation mechanisms. In this paper we propose InvisiFence, an approach for implementing memory ordering based on post-retirement speculation that avoids these concerns. InvisiFence leverages minimalistic mechanisms for post-retirement speculation proposed in other contexts to (1) track speculative state efficiently at block-granularity with dedicated storage requirements independent of speculation depth, (2) provide fast commit by avoiding explicit commit arbitration, and (3) operate under a conventional invalidation-based cache coherence protocol. InvisiFence supports both modes of operation found in prior work: speculating only when necessary to minimize the risk of rollback-inducing violations or speculating continuously to decouple consistency enforcement from the processor core. Overall, InvisiFence requires approximately one kilobyte of additional state to transform a conventional multiprocessor into one that provides performance-transparent memory ordering, fences, and atomic operations.

The C programming language is at least as well known for its absence of spatial memory safety guarantees (i.e., lack of bounds checking) as it is for its high performance. C's unchecked pointer arithmetic and array indexing allow simple programming mistakes to lead to erroneous executions, silent data corruption, and security vulnerabilities. Many prior proposals have tackled enforcing spatial safety in C programs by checking pointer and array accesses. However, existing software-only proposals have significant drawbacks that may prevent wide adoption, including: unacceptably high run-time overheads, lack of completeness, incompatible pointer representations, or need for non-trivial changes to existing C source code and compiler infrastructure. Inspired by the promise of these software-only approaches, this paper proposes a hardware bounded pointer architectural primitive that supports cooperative hardware/software enforcement of spatial memory safety for C programs. This bounded pointer is a new hardware primitive datatype for pointers that leaves the standard C pointer representation intact, but augments it with bounds information maintained separately and invisibly by the hardware. The bounds are initialized by the software, and they are then propagated and enforced transparently by the hardware, which automatically checks a pointer's bounds before it is dereferenced. One mode of use requires instrumenting only malloc, which enables enforcement of perallocation spatial safety for heap-allocated objects for existing binaries. When combined with simple intraprocedural compiler instrumentation, hardware bounded pointers enable a low-overhead approach for enforcing complete spatial memory safety in unmodified C programs.

The Wisconsin Multifacet Project has created a simulation toolset to characterize and evaluate the performance of multiprocessor hardware systems commonly used as database and web servers. We leverage an existing full-system functional simulation infrastructure (Simics [14]) as the basis around which to build a set of timing simulator modules for modeling the timing of the memory system and microprocessors. This simulator infrastructure enables us to run architectural experiments using a suite of scaled-down commercial workloads [3]. To enable other researchers to more easily perform such research, we have released these timing simulator modules as the Multifacet General Execution-driven Multiprocessor Simulator (GEMS) Toolset, release 1.0, under GNU GPL [9].

Many future shared-memory multiprocessor servers will both target commercial workloads and use highly-integrated "glueless" designs. Implementing low-latency cache coherence in these systems is difficult, because traditional approaches either add indirection for common cache-to-cache misses (directory protocols) or require a totally-ordered interconnect (traditional snooping protocols). Unfortunately, totally-ordered interconnects are difficult to implement in glueless designs. An ideal coherence protocol would avoid indirections and interconnect ordering; however, such an approach introduces numerous protocol races that are difficult to resolve.We propose a new coherence framework to enable such protocols by separating performance from correctness. A performance protocol can optimize for the common case (i.e., absence of races) and rely on the underlying correctness substrate to resolve races, provide safety, and prevent starvation. We call the combination Token Coherence, since it explicitly exchanges and counts tokens to control coherence permissions.This paper develops TokenB, a specific Token Coherence performance protocol that allows a glueless multiprocessor to both exploit a low-latency unordered interconnect (like directory protocols) and avoid indirection (like snooping protocols). Simulations using commercial workloads show that our new protocol can significantly outperform traditional snooping and directory protocols.

We develop an availability solution, called SafetyNet, that uses a unified, lightweight checkpoint/recovery mechanism to support multiple long-latency fault detection schemes. At an abstract level, SafetyNet logically maintains multiple, globally consistent checkpoints of the state of a shared memory multiprocessor (i.e., processors, memory, and coherence permissions), and it recovers to a pre-fault checkpoint of the system and re-executes if a fault is detected. SafetyNet efficiently coordinates checkpoints across the system in logical time and uses "logically atomic" coherence transactions to free checkpoints of transient coherence state. SafetyNet minimizes performance overhead by pipelining checkpoint validation with subsequent parallel execution.We illustrate SafetyNet avoiding system crashes due to either dropped coherence messages or the loss of an interconnection network switch (and its buffered messages). Using full-system simulation of a 16-way multiprocessor running commercial workloads, we find that SafetyNet (a) adds statistically insignificant runtime overhead in the common-case of fault-free execution, and (b) avoids a crash when tolerated faults occur.

CMOS scaling trends have led to an inflection point where thermal constraints (especially in mobile devices that employ only passive cooling) preclude sustained operation of all transistors on a chip --- a phenomenon called "dark silicon." Recent research proposed computational sprinting --- exceeding sustainable thermal limits for short intervals --- to improve responsiveness in light of the bursty computation demands of many media-rich interactive mobile applications. Computational sprinting improves responsiveness by activating reserve cores (parallel sprinting) and/or boosting frequency/voltage (frequency sprinting) to power levels that far exceed the system's sustainable cooling capabilities, relying on thermal capacitance to buffer heat. Prior work analyzed the feasibility of sprinting through modeling and simulation. In this work, we investigate sprinting using a hardware/software testbed. First, we study unabridged sprints, wherein the computation completes before temperature becomes critical, demonstrating a 6.3x responsiveness gain, and a 6% energy efficiency improvement by racing to idle. We then analyze truncated sprints, wherein our software runtime system must intervene to prevent overheating by throttling parallelism and frequency before the computation is complete. To avoid oversubscription penalties (context switching inefficiencies after a truncated parallel sprint), we develop a sprint-aware task-based parallel runtime. We find that maximal-intensity sprinting is not always best, introduce the concept of sprint pacing, and evaluate an adaptive policy for selecting sprint intensity. We report initial results using a phase change heat sink to extend maximum sprint duration. Finally, we demonstrate that a sprint-and-rest operating regime can actually outperform thermally-limited sustained execution.

The clinical diagnosis of pulmonary embolism (PE) remains difficult despite years of investigation. The clinical signs and symptoms of pulmonary embolism are numerous, but they are not diagnostically accurate. Radionuclide ventilation perfusion imaging (VQ) has become an important adjunct in screening patients for suspected PE. This study re-evaluates the predictive capabilities of various clinical signs and symptoms in a population of patients in whom angiography was thought to be necessary because of clinical concern for PE. One hundred one patients with suspected PE were retrospectively identified. Clinical information on them was complete, and laboratory studies, VQ imaging, and pulmonary angiography were performed. Thirty-seven clinical signs, symptoms, and other characteristics were individually compared for patients whose angiographic results were positive or negative for PE. Modifying or interactive effects on PE were then examined with logistic regression analysis. Several clinical conditions, including immobilization and recent surgery, were significantly associated with PE. Shortness of breath and history of smoking were significantly associated with negative results on pulmonary angiography. A "high probability" VQ scan was highly predictive (P.0001) of positive results on angiography. When interactive factors for PE were examined, lack of shortness of breath and arterial pHor = 7.45, lack of shortness of breath and respiratory rate23, diaphoresis in a nonsmoker and immobilized female, were significantly associated with PE. This study again documents the difficulty in using clinical criteria--including signs, symptoms, and laboratory determinations--to predict PE accurately, even in a population in which PE was of clinical concern irrespective of the VQ scan results.(ABSTRACT TRUNCATED AT 250 WORDS)

Over the past decade there has been a surge of academic and industrial interest in optimistic concurrency, i.e. the speculative parallel execution of code regions that have the semantics of isolation. This work analyzes scalability bottlenecks of workloads that use optimistic concurrency. We find that one common bottleneck is updates to auxiliary program data in otherwise non-conflicting operations, e.g. reference count updates and hashtable occupancy field increments. To eliminate the performance impact of conflicts on such auxiliary data, this work proposes RETCON, a hardware mechanism that tracks the relationship between input and output values symbolically and uses this symbolic information to transparently repair the output state of a transaction at commit. RETCON is inspired by instruction replay-based mechanisms but exploits simplifying properties of the nature of computations on auxiliary data to perform repair without replay. Our experiments show that RETCON provides significant speedups for workloads that exhibit conflicts on auxiliary data, including transforming a transactionalized version of the Python interpreter from a workload that exhibits no scaling to one that exhibits near-linear scaling on 32 cores.

Hardware transactional memory has great potential to simplify the creation ofcorrect and efficient multithreaded programs, allowing programmers to exploitmore effectively the soon-to-be-ubiquitous multi-core designs. Several recentproposals have extended the original bounded transactional memory to unboundedtransactional memory, a crucial step toward transactions becoming ageneral-purpose primitive. Unfortunately, supporting the concurrent executionof an unbounded number of unbounded transactions is challenging, and as aresult, many proposed implementations are complex. This paper explores a different approach. First, we introduce thepermissions-only cache to extend the bound at which transactions overflow toallow the fast, bounded case to be used as frequently as possible. Second, wepropose OneTM to simplify the implementation of unbounded transactional memoryby bounding the concurrency of transactions that overflow the cache. Thesemechanisms work synergistically to provide a simple and fast unboundedtransactional memory system. The permissions-only cache efficiently maintains the coherencepermissions-but not data-for blocks read or written transactionally thathave been evicted from the processor's caches. By holding coherencepermissions for these blocks, the regular cache coherence protocol can be usedto detect transactional conflicts using only a few bits of on-chip storage peroverflowed cache block.OneTM allows only one overflowed transaction at a time, relying on thepermissions-only cache to ensure that overflow is infrequent. We present twoimplementations. In OneTM-Serialized, an overflowed transaction simply stallsall other threads in the application. In OneTM-Concurrent, non-overflowedtransactions and non-transactional code can execute concurrently with theoverflowed transaction, providing more concurrency while retaining OneTM's coresimplifying assumption.

Background: The operative management of children with combined gastroesophageal reflux and delayed gastric emptying is controversial. This study measures the long-term follow-up of gastric emptying in children who have undergone gastroesophageal fundoplication combined with antroplasty. Methods: Fifteen randomly selected children with gastroesophageal reflux and scintigraphically demonstrated delayed gastric emptying underwent fundoplication and antroplasty. Each patient had another gastric emptying scintigraphic study performed an average of 3.6 years postoperation. Results: All patients reported improvement of their symptoms compared with before the operation, and none required further medical therapy for gastroesophageal reflux or experienced dumping syndrome. Eleven of the 15 patients had significant long-term improvement of their gastric emptying postoperatively. The mean percent of isotope meal remaining in the stomach at 90 minutes improved from 72% preoperatively to 40% postoperatively ( P = 0.0005). Conclusions: Gastric emptying in children with gastroesophageal reflux and delayed gastric emptying is significantly improved for several years in three-fourths of patients after fundoplication and antroplasty. Fundoplication and concomitant antroplasty are recommended for symptomatic children with documented gastroesophageal reflux and delayed gastric emptying.

Destination-set prediction can improve the latency/bandwidth tradeoff in shared-memory multiprocessors. The destination set is the collection of processors that receive a particular coherence request. Snooping protocols send requests to the maximal destination set (i.e., all processors), reducing latency for cache-to-cache misses at the expense of increased traffic. Directory protocols send requests to the minimal destination set, reducing bandwidth at the expense of an indirection through the directory for cache-to-cache misses. Recently proposed hybrid protocols trade-off latency and bandwidth by directly sending requests to a predicted destination set.This paper explores the destination-set predictor design space, focusing on a collection of important commercial workloads. First, we analyze the sharing behavior of these workloads. Second, we propose predictors that exploit the observed sharing behavior to target different points in the latency/bandwidth tradeoff. Third, we illustrate the effectiveness of destination-set predictors in the context of a multicast snooping protocol. For example, one of our predictors obtains almost 90% of the performance of snooping while using only 15% more bandwidth than a directory protocol (and less than half the bandwidth of snooping).

The UCLA Hospital experience with indium-111 labeled white blood cells was reviewed. There were a total of 345 consecutive cases covering a broad range of clinical indications. The overall sensitivity of the method was 79%, specificity was 62%, and accuracy was 73%. The sensitivity for suspected osteomyelitis cases was 84%, with a specificity of 65% and an accuracy of 75%. For other cases sensitivity was 77%, specificity was 60%, and accuracy was 72%. Furthermore, patterns of normal distribution were reviewed.

Technetium 99m sulfide colloid can be prepared rapidly and conveniently by precipitation from pertechnetate eluted from a Tc99m generator, using rhenium as a carrier, through the action of sodium thiosulfate. The use of presterilized reagents yields a sterile product, which is ready for use without further processing. Gelatin is added as a protective colloid. No toxic materials or odoriferous gases are used. The product contains virtually no soluble technetium and no macroaggregates. Preparation time is less than 10 minutes, and can be done in a small area of any radioisotope clinic. Liver scans of high resolution and excellent counting statistics can be obtained with minimal patient radiation dose.

Since the imaging pattern of 67Ga-citrate is well known, it can be the benchmark for evaluation of potential tumor imaging agents. Tritium labeled 5-fluorouracil, Adriamycin, (doxorubicin/Adria) and Methotrexate/Lederle were compared at 2 h to 67Ga-citrate at 2 and 48 h by percent uptake per gram of various tissues and tumor in rats implanted with Walker 256 carcinosarcoma. 67Ga at 48 h showed approximately three times more uptake in the tumor than 5 fluorouracil and eight times more than the others. 5 Fluorouracil showed approximately three times greater uptake than Methotrexate or doxorubicin and 1.4 times the 2 h uptake of 67Ga. 5 Fluorouracil shows potential as an imaging agent especially where the waiting time between injection and imaging must be short.

Symmetric muultiprocessor (SMP) servers provide superior performance for the commercial workloads that dominate the Internet. Our simulation results show that over one-third of cache misses by these applications result in cache-to-cache transfers, where the data is found in another processor's cache rather than in memory. SMPs are optimized for this case by using snooping protocols that broadcast address transactions to all processors. Conversely, directory-based shared-memory systems must indirectly locate the owner and sharers through a directory, resulting in larger average miss latencies.This paper proposes timestamp snooping, a technique that allows SMPs to i) utilize high-speed switched interconnection networks and ii) exploit physical locality by delivering address transactions to processors and memories without regard to order. Traditional snooping requires physical ordering of transactions. Timestamp snooping works by processing address transactions in a logical order. Logical time is maintained by adding a few bits per address transaction and having network switches perform a handshake to ensure on-time delivery. Processors and memories then reorder transactions based on their timestamps to establish a total order.We evaluate timestamp snooping with commercial workloads on a 16-processor SPARC system using the Simics full-system simulator. We simulate both an indirect (butterfly) and a direct (torus) network design. For OLTP, DSS, web serving, web searching, and one scientific application, timestamp snooping with the butterfly network runs 6-28% faster than directories, at a cost of 13-43% more link traffic. Similarly, with the torus network, timestamp snooping runs 6-29% faster for 17-37% more link traffic. Thus, timestamp snooping is worth considering when buying more interconnect bandwidth is easier than reducing interconnect latency.

The detection of musculoskeletal sepsis, especially following joint replacement, continues to be a challenging problem. Often, even with invasive diagnostic evaluation, the diagnosis of infection remains uncertain. This is a report on the first 55 Indium-111 white blood cell (WBC) images performed in 39 patients for the evaluation of musculoskeletal sepsis. There were 40 negative and 15 positive Indium-111 WBC images. These were correlated with operative culture and tissue pathology, aspiration culture, and clinical findings. Thirty-eight images were performed for the evaluation of possible total joint sepsis (8 positive and 30 negative images); 17 for the evaluation of nonarthroplasty-related musculoskeletal sepsis (7 positive and 10 negative images). Overall, there were 13 true-positive, 39 true-negative, two false-positive, and one false-negative images. Indium-111 WBC imaging is a sensitive and specific means of evaluating musculoskeletal sepsis, especially following total joint replacement.

BACKGROUND: Despite prognostic improvements in ST-elevation myocardial infarction (STEMI), patients presenting with cardiogenic shock (CS) have still high mortality. Which are the relevant early prognostic factors despite revascularization in this high-risk population is poorly investigated. METHODS: We analyzed STEMI patients treated with primary percutaneous coronary intervention (PCI) and enrolled at the University Hospital of Trieste between 2012 and 2018. A decision tree based on data available at first medical contact (FMC) was built to stratify patients for 30-day mortality. Multivariate analysis was used to explore independent factors associated with 30-day mortality. RESULTS: Among 1222 STEMI patients consecutively enrolled, 7.5% presented with CS. CS compared with no-CS patients had worse 30-day mortality (33% vs 3%, P 3 h and 21 min were at the highest mortality risk, with a 30-day mortality of 85.7%. In CS, age (OR 1.246; 95% CI 1.045-1,141; P = 0.003), final TIMI flow 2-3 (OR 0.058; 95% CI 0.004-0.785; P = 0.032) and Ischemia Time (OR = 1.269; 95% CI 1.001-1.609; P = 0.049) were independently associated with 30-day mortality. CONCLUSIONS: In a contemporary real-world population presenting with CS due to STEMI, age is a relevant negative factor whereas an early and successful PCI is positively correlated with survival. However, a subgroup of elderly patients had severe prognosis despite revascularization. Whether pPCI may have an impact on survival in a very limited number of irreversibly critically ill patients remains uncertain and the identification of irreversibly shocked patients remains nowadays challenging.

Background and Objectives B-cell MALT lymphoma is a well-recognized entity and its characterization as low-grade (LG) and high-grade (HG) lymphoma has been widely accepted. In the present study we reviewed a series of 95 surgical specimens of primary gastric MALT lymphoma selected between 1979 and 1998. Immunohistochemical expression of p53, bcl-2, and Ki67 and Helicobacter pylori (Hp) infection was evaluated, along with a correlation with clinical outcome. Methods A morphologic and immunohistochemical analysis, including p53, bcl-2, and Ki67 expression, was carried out in all cases. A complete follow-up was obtained in 49 patients and in these cases a survival analysis was performed. Results bcl-2 protein was highly expressed in 25 of 25 assessed LG tumors and in 20 of 24 assessed HG tumors. p53 protein was expressed in 13 of 25 assessed LG tumors and in 21 of 24 assessed HG tumors. High proliferation rate as expressed by Ki67 was detected in 15 of 25 assessed LG tumors and in 23 of 24 assessed HG tumors. Hp infection was detected in 11 of 16 assessed LG tumors and 2 of 10 assessed HG tumors. Median survival rates were 72 months for LG tumors and 24 months for HG tumors. Conclusions A significant inverse relationship between Hp infection and histological grade was found. High p53 expression and high-proliferation rate correlated with HG tumors. However, a correlation between p53, bcl-2, and Ki67 expression with clinical outcome was not found. J. Surg. Oncol. 2003;83:106–111. © 2003 Wiley-Liss, Inc.