Virtuoso: An Open-Source, Comprehensive and Modular Simulation Framework for Virtual Memory Research

Virtual memory is a cornerstone of modern computing systems.Introduced as one of the earliest instances of hardware-software co-design, VM facilitates programmer-transparent memory man agement, data sharing, process isolation and memory protection. Evaluating the efficiency of various virtual memory (VM) designs is crucial (i) given their significant impact on the system, including the CPU caches, the main memory, and the storage device and (ii) given that different system architectures might benefit from various VM techniques. Such an evaluation is not straightforward, as it heavily hinges on modeling the interplay between different VM techniques and the interactions of VM with the system architecture. Modern simulators, however, struggle to keep up with the rapid VM research developments, lacking the capability to model a wide range of contemporary VM techniques and their interactions. To this end, we present Virtuoso, an open-source, comprehensive and modular simulation framework that models various VM designs to establish a common ground for virtual memory research. We demonstrate the versatility and the potential of Virtuoso with four new case studies. Virtuoso is freely open-source and can be found at https://github.com/CMU-SAFARI/Virtuoso

Pulmonary Rehabilitation and Exercise in Pulmonary Arterial Hypertension: An Underutilized Intervention

Pulmonary arterial hypertension (PAH) is a rare and devastating disease characterized by progressive increases in pulmonary arterial pressure and pulmonary vascular resistance which eventually leads to right ventricular failure and death. Early thought process was that exercise and increased physical activity may be detrimental to PAH patients however many small cohort trials have proven otherwise. In addition to the many pharmaceutical options, exercise and pulmonary rehabilitation have also been shown to increase exercise capacity as well as various aspects of psychosomatic health. As pulmonary and exercise rehabilitation become more widely used as an adjuvant therapy patient outcomes improve and physicians should consider this in the therapeutic algorithm along with pharmacotherapy

Methamphetamine and emerging drugs of concern: A training needs analysis of Australian alcohol and other drug helplines

Introduction: Fielding greater than 100,000 calls annually, telephone helplines are an important point of entry to alcohol and other drug (AOD) support and services in Australia. Methamphetamine and emerging drugs can present a particular challenge for this workforce. We sought to identify training needs for these services, so that appropriate targeted resources can be developed. Methods: We distributed an anonymous, online, cross-sectional survey to helpline staff from New South Wales, Queensland, South Australia, Victoria and Western Australia. Based on the WHO Hennessy-Hicks training needs analysis tool, participants were asked: to rate on a 7-point likert scale the importance of a topic to their practice and how well they perform in relation to the topic; open-ended questions specifying their own self-perceived training needs; and demographic data. Results: Of 50 participants, 29 completed the full survey (median age 49 [IQR 30–57.5]; median time working in AOD sector 6 years [IQR 1–20]). The results identified a need for: practical community-informed population relevant information for culturally and linguistically diverse populations and Aboriginal and Torres Strait Islander peoples for calls relating to methamphetamine and emerging drugs of concern; training and resources with a particular focus on families and friends of people who use methamphetamine and emerging drugs; and readily accessible up-to-date information on new and emerging drugs and treatment of related disorders. Discussion and Conclusions: This training needs analysis provides a structured approach to supporting the first-line AOD counsellors to provide up-to-date and accurate information to assist Australians seeking information, support and advice

Effects of long-term fertilization on the fertility of erosion-affected soils from the Moldavian Plateau

The paper presented the results of investigations concerning the influence of long-term fertilization (43 years) on some chemical characteristics of Cambic Chernozem from the Moldavian Plain and on the maize yield. On slope lands, the high rate fertilization of maize crop (N140P100) has determined, in the latest ten years, an average yield increase of 103% (3373 kg/ha), against the control, and applying a rate of N70P70+40 t/ha manure resulted in getting a very close yield increase (99%, 3258 kg/ha). The minimum supply level of mobile phosphorus in soil (37-72 ppm) in pea-wheat-maize rotation (37 ppm) was maintained in case of annual application of a rate of N100P80. The total carbon content in Cambic Chernozem from the Moldavian Plain has registered significant increases at higher rates than N140P100 and in case of organo-mineral fertilization. The annual fertilization of wheat and maize, at the rate of 70 kg N + 70 kg P2O5/ha + 6 t/ha stalks of wheat, has determined, compared to the unfertilized variant, the increase in the content of organic carbon from soil by 14.5% (2.4 g organic C/kg) on weakly eroded soils, and by 29.5% (4.2 g organic C/kg) on highly eroded soils. During the long-term fertilizing of wheat and maize with high rates of mineral fertilizers (N140P100), on highly eroded lands, the total content of carbon has increased by 16.9% (2.4 g organic C/kg soil), against the unfertilized control. Applying moderate rates of mineral fertilizers (N70P70), together with 60 t/ha manure, has determined, after 43 years of testing, the increase by 32% (5.3 g organic C/kg) in the content of organic carbon from soil, on weakly eroded soils, and by 42.3% (6.0 g organic C/kg soil) on highly eroded soils, compared to the unfertilized control. On 16% slope arable lands from the Moldavian Plateau, the mean annual soil losses by erosion, registered during 1986-2007, were of 1.640 t/ha in winter wheat, 4.618 t/ha in beans, 1.89 t/ha in the field cultivated with perennial grasses and legumes on the second year of vegetation, 9.176 t/ha in maize and 9.6 t/ha in sunflower

Effects of temperature and doxorubicin exposure on keratinocyte damage in vitro

Cancer chemotherapy treatment often leads to hair loss, which may be prevented by cooling the scalp during drug administration. The current hypothesis for the hair preservative effect of scalp cooling is that cooling of the scalp skin reduces blood flow (perfusion) and chemical reaction rates. Reduced perfusion leads to less drugs available for uptake, whereas the reduced temperature decreases uptake of and damage by chemotherapy. Altogether, less damage is exerted to the hair cells, and the hair is preserved. However, the two mechanisms in the hypothesis have not been quantified yet. To quantify the effect of reduced drug damage caused by falling temperatures, we investigated the effect of local drug concentration and local tissue temperature on hair cell damage using in vitro experiments on keratinocytes. Cells were exposed for 4 h to a wide range of doxorubicin concentrations. During exposure, cells were kept at different temperatures. Cell viability was determined after 3 d using a viability test. Control samples were used to establish a concentration–viability curve. Results show that cell survival is significantly higher in cooled cells (T < 22° C) than in non-cooled cells (T = 37° C), but no significant differences are visible between T = 10° C and T = 22° C. Based on this result and previous work, we can conclude that there is an optimal temperature in scalp cooling. Further cooling will only result in unnecessary discomfort for the patient and should therefore be avoided

Paging on Complex Architectures

Advances in technology allow to build computer systems of ever increasing performances and capabilities. However, the effective use of such computational resources is often made difficult by the complexity of the system itself. Crucial to the performance of a computing device is the orchestration of the flow of data across the memory hierarchy. Specifically, given a fast but small memory (a cache) through which all the data that have to be processed must pass, it is necessary to establish a set of rules, then implemented by an algorithm, that define which data has to be evicted from such a memory to make room for new incoming data. The goal is that of minimizing the number of times that requested data is outside the cache (faults), since fetching data from farther levels of the memory hierarchy incurs high costs, in terms of time and also of energy. This thesis studies two generalizations of this problem, known as the paging problem. This problem is intrinsically online, as future data requests issued by a computer program are typically unknown. Motivated by the recent diffusion of multi-threaded and multi-core architectures, whereby several threads or processes can be executed simultaneously, and/or there are several processing units, and by the recent and rapidly growing interest in reducing power consumptions of computer systems, in the first part of the thesis we study a variation of paging which rewards the efficient usage of memory resources. In this problem the goal is that of minimizing a combination of both the number of faults and the cache occupancy of the process' data in fast memory. The main results of this part are two: the first is an impossibility result that indicates that, roughly speaking, online algorithms cannot compete in practice with algorithms that know in advance all the data requests issued by the process; the second is the design of an online algorithm that has almost the best performance among all the possible online algorithms. In the second part of the thesis we concentrate on the management of a cache shared among several concurrent processes. As outlined above, this has direct application in multi-threaded or multi-core architectures. In this problem the fast memory has to service a sequence of requests which is the interleaving of the requests issued by t different processes. Through its replacement decisions, the algorithm dynamically allocates the cache space among the processes, and this clearly impacts their progress. The main goal here is to minimize the time needed to complete the service of all the request sequences. We show tight lower and upper bounds on the performance of online algorithms for several variants of the problem

Repeated out-of-Africa expansions of Helicobacter pylori driven by replacement of deleterious mutations

Erratum in: Nat Commun. 2023 Mar 20;14(1):1539. doi: 10.1038/s41467-023-37302-5.Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori fromEurope and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying selection to remove them during admixture. Simulations show that population fitness can be restored after bottlenecks bymigration and subsequent admixture of small numbers of bacteria from non-bottlenecked populations. We conclude that recent spread of African DNA has been driven by deleterious mutations accumulated during the original out-of-Africa bottleneck.This work was supported by Sequencing Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (221S0002, 18KK0266, 19H03473, 21H00346 and 22H02871) to Y.Y. F.F.V. is financed by FCT through Assistant Researcher grant CEECIND/03023/2017 and a project grant PTDC/BTM-TEC/3238/ 2020. I.K. studentship was funded by the National Strategic Reference Framework Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020, project No. MIS5002486) and sequencing of strains was supported by the InfeNeutra Project (NSRF 2007-2013, project no. MIS450598) of the Ministry of Culture and Edu- cation, Greece. K.T. and the sequencing of KI isolates was supported by Erik Philip-Sörensen Foundation grant G2016-08, and Swedish Society for Medical research (SSMF). All primary bioinformatics and parts of the comparative genomics were performed on resources provided by Swedish National Infrastructure for Computing (SNIC) through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under projects snic2018-8-24 and uppstore2017270. Work by S.S. was supported by the German Research Foundation (DFG, project number 158 989 968–SFB 900/A1) and by the Bavarian Ministry of Sci- ence and the Arts in the framework of the Bavarian Research Network “New Strategies Against Multi-Resistant Pathogens by Means of Digital Networking—bayresq.net”. D.F. was supported by Shanghai Municipal Science and Technology Major Project No. 2019SHZDZX02.info:eu-repo/semantics/publishedVersio