Clinical Laboratory Assessment of \u3cem\u3eMycoplasma genitalium\u3c/em\u3e Transcription-Mediated Amplification Using Primary Female Urogenital Specimens

Following analysis of primary cervix, vagina, and first-void female urine specimens for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis via commercial transcription-mediated amplification (TMA), residual material was subjected to Mycoplasma genitalium research-use-only TMA. Representation within a 2,478-specimen retrospective study set was established by comparison to a 6-month audit of clinical C. trachomatis TMA (12,999 specimens) on the basis of the C. trachomatis detection rate, specimen source distribution, clinic location, and age. M. genitalium was detected in 282 (11.4%) patients. This rate was higher than those seen with T. vaginalis (9.0%; P _ 0.005), C. trachomatis (6.2%), and N. gonorrhoeae (1.4%). Positive M. genitalium results were confirmed by repeat testing or alternative-target TMA at a rate of 98.7%. The mean age of the M. genitalium-infected females (24.7 years) was lower than that of the T. vaginalis-infected females (mean, 30.1 years; P\u3c0.0001) and higher than that of the C. trachomatis-infected females (mean, 23.8 years; P_0.003). Of 566 patient encounters positive for at least one sexually transmitted infection (STI), 35.9% exhibited sole detection of M. genitalium (P \u3c 0.0004 versus sole detection of other STI agents) and 26.1% were solely positive for T. vaginalis (P \u3c 0.0002 versus C. trachomatis). The M. genitalium and T. vaginalis detection rates among 755 patients at urban emergency departments were 14.6% and 13.0%, respectively (P _ 0.37). A 10.0% M. genitalium detection rate from other facilities exceeded that of T. vaginalis (7.2%; P _ 0.004). Incorporation of M. genitalium TMA into comprehensive testing programs would detect M. genitalium in a significant proportion of females, particularly those in outpatient obstetrics and gynecology (OB/GYN) settings

The long-term impact of the MEMA kwa Vijana adolescent sexual and reproductive health intervention: effect of dose and time since intervention exposure.

BACKGROUND: Despite recent decreases in HIV incidence in many sub-Saharan African countries, there is little evidence that specific behavioural interventions have led to a reduction in HIV among young people. Further and wider-scale decreases in HIV require better understanding of when behaviour change occurs and why. The MEMA kwa Vijana adolescent sexual and reproductive health intervention has been implemented in rural Mwanza, Tanzania since 1999. A long-term evaluation in 2007/8 found that the intervention improved knowledge, attitudes to sex and some reported risk behaviours, but not HIV or HSV2 prevalence. The aim of this paper was to assess the differential impact of the intervention according to gender, age, marital status, number of years of exposure and time since last exposure to the intervention. METHODS: In 2007, a cross-sectional survey was conducted in the 20 trial communities among 13,814 young people (15-30 yrs) who had attended intervention or comparison schools between 1999 and 2002. Outcomes for which the intervention had an impact in 2001 or 2007 were included in this subgroup analysis. Data were analysed using cluster-level methods for stratified cluster-randomised trials, using interaction tests to determine if intervention impact differed by subgroup. RESULTS: Taking into account multiplicity of testing, concurrence with a priori hypotheses and consistency within the results no strong effect-modifiers emerged. Impact on pregnancy knowledge and reported attitudes to sex increased with years of exposure to high-quality intervention. CONCLUSIONS: The desirable long-term impact of the MEMA kwa Vijana intervention did not vary greatly according to the subgroups examined. This suggests that the intervention can have an impact on a broad cross-section of young people in rural Mwanza. TRIAL REGISTRATION: ClinicalTrials.gov NCT00248469

CheriRTOS: A Capability Model for Embedded Devices

Embedded systems are deployed ubiquitously among various sectors including automotive, medical, robotics and avionics. As these devices become increasingly connected, the attack surface also increases tremendously; new mechanisms must be deployed to defend against more sophisticated attacks while not violating resource constraints. In this paper we present CheriRTOS on CHERI-64, a hardware-software platform atop Capability Hardware Enhanced RISC Instructions (CHERI) for embedded systems. Our system provides efficient and scalable task isolation, fast and secure inter-task communication, fine-grained memory safety, and real-time guarantees, using hardware capabilities as the sole protection mechanism. We summarize state-of-the-art se- curity and memory safety for embedded systems for comparison with our platform, illustrating the superior substrate provided by CHERI’s capabilities. Finally, our evaluations show that a capability system can be implemented within the constraints of embedded systems

The HIV care cascade among female sex workers in Zimbabwe: results of a population-based survey from the Sisters Antiretroviral therapy Programme for Prevention of HIV, an Integrated Response (SAPPH-IRe) Trial.

: Female sex workers (FSW) in sub-Saharan Africa have a higher prevalence of HIV than other women of reproductive age. Social, legal, and structural barriers influence their access to care. Little is known about the HIV diagnosis and care cascade in most countries in Southern Africa. We aimed to describe the HIV diagnosis and care cascade among FSW in Zimbabwe. : We conducted cross-sectional respondent driven sampling (RDS) surveys of FSW in 14 sites across Zimbabwe as the baseline for a cluster-randomised controlled trial investigating a combination HIV prevention and care package. We administered a questionnaire, tested women for HIV and measured viral load. We report the mean, minimum, and maximum respondent-driven sampling-2 weighted site values. : The survey included 2722 women, approximately 200 per site. The mean HIV prevalence was 57.5% (42.8-79.2 site minimum and maximum). Of HIV-positive women, 64.0% (51.6-73.7) were aware of their status, 67.7% (53.4-84.1) of these reported taking antiretroviral therapy, and 77.8% (64.4-90.8) of these had a suppressed HIV viral load (&lt;1000 copies/mL). Among all HIV-positive women, 49.5% had a viral load &lt; 1000 copies/mL. : Although most HIV-positive women aware of their status are accessing antiretroviral therapy, 36.0% of HIV-positive women are unaware of their status and 29.3% of all FSW have an unsuppressed HIV viral load. Investigation and investment into models of testing, treatment, and care are necessary to reach UNAIDS targets for HIV elimination.<br/

Efficient tagged memory

We characterize the cache behavior of an in-memory tag table and demonstrate that an optimized implementation can typically achieve a near-zero memory traffic overhead. Both industry and academia have repeatedly demonstrated tagged memory as a key mechanism to enable enforcement of powerful security invariants, including capabilities pointer integrity, watchpoints, and information-flow tracking. A single-bit tag shadowspace is the most commonly proposed requirement, as one bit is the minimum metadata needed to distinguish between an untyped data word and any number of new hardware-enforced types. We survey various tag shadowspace approaches and identify their common requirements and positive features of their implementations. To avoid non-standard memory widths, we identify the most practical implementation for tag storage to be an in-memory table managed next to the DRAM controller. We characterize the caching performance of such a tag table and demonstrate a DRAM traffic overhead below 5\% for the vast majority of applications. We identify spatial locality on a page scale as the primary factor that enables surprisingly high table cache-ability. We then demonstrate tag-table compression for a set of common applications. A hierarchical structure with elegantly simple optimizations reduces DRAM traffic overhead to below 1\% for most applications. These insights and optimizations pave the way for commercial applications making use of single-bit tags stored in commodity memory

Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats

R-loops have been described at immunoglobulin class switch sequences, prokaryotic and mitochondrial replication origins, and disease-associated (CAG)n and (GAA)n trinucleotide repeats. The determinants of trinucleotide R-loop formation are unclear. Trinucleotide repeat expansions cause diseases including DM1 (CTG)n, SCA1 (CAG)n, FRAXA (CGG)n, FRAXE (CCG)n and FRDA (GAA)n. Bidirectional convergent transcription across these disease repeats can occur. We find R-loops formed when CTG or CGG and their complementary strands CAG or CCG were transcribed; GAA transcription, but not TTC, yielded R-loops. R-loop formation was sensitive to DNA supercoiling, repeat length, insensitive to repeat interruptions, and formed by extension of RNA:DNA hybrids in the RNA polymerase. R-loops arose by transcription in one direction followed by transcription in the opposite direction, and during simultaneous convergent bidirectional transcription of the same repeat forming double R-loop structures. Since each transcribed disease repeat formed R-loops suggests they may have biological functions

Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans

Decellularization of pancreata and repopulation of these non-immunogenic matrices with islets and endothelial cells could provide transplantable, endocrine Neo- Pancreata. In this study, rat pancreata were perfusion decellularized and repopulated with intact islets, comparing three perfusion routes (Artery, Portal Vein, Pancreatic Duct). Decellularization effectively removed all cellular components but conserved the pancreas specific extracellular matrix. Digital subtraction angiography of the matrices showed a conserved integrity of the decellularized vascular system but a contrast emersion into the parenchyma via the decellularized pancreatic duct. Islets infused via the pancreatic duct leaked from the ductular system into the peri- ductular decellularized space despite their magnitude. TUNEL staining and Glucose stimulated insulin secretion revealed that islets were viable and functional after the process. We present the first available protocol for perfusion decellularization of rat pancreata via three different perfusion routes. Furthermore, we provide first proof-of-concept for the repopulation of the decellularized rat pancreata with functional islets of Langerhans. The presented technique can serve as a bioengineering platform to generate implantable and functional endocrine Neo-Pancreata

Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich’s ataxia

Friedreich’s ataxia (FRDA) is caused by biallelic expansion of GAA repeats leading to the transcriptional silencing of the frataxin (FXN) gene. The exact molecular mechanism of inhibition of FXN expression is unclear. Herein, we analyze the effects of hyperexpanded GAA repeats on transcription status and chromatin modifications proximal and distal to the GAA repeats. Using chromatin immunoprecipitation and quantitative PCR we detected significant changes in the chromatin landscape in FRDA cells relative to control cells downstream of the promoter, especially in the vicinity of the GAA tract. In this region, hyperexpanded GAAs induced a particular constellation of histone modifications typically associated with heterochromatin-like structures. Similar epigenetic changes were observed in GFP reporter construct containing 560 GAA repeats. Furthermore, we observed similar levels of FXN pre-mRNA at a region upstream of hyperexpanded GAA repeats in FRDA and control cells, indicating similar efficiency of transcription initiation. We also demonstrated that histone modifications associated with hyperexpanded GAA repeats are independent of initiation and progression of transcription. Our data provide strong evidence that FXN deficiency in FRDA patients results from a block of transition from initiation to a productive elongation of FXN transcription due to heterochromatin-like structures formed in the proximity of the hyperexpanded GAAs

Cornucopia: Temporal safety for CHERI heaps

Use-after-free violations of temporal memory safety continue to plague software systems, underpinning many high-impact exploits. The CHERI capability system shows great promise in achieving C and C++ language spatial memory safety, preventing out-of-bounds accesses. Enforcing language-level temporal safety on CHERI requires capability revocation, traditionally achieved either via table lookups (avoided for performance in the CHERI design) or by identifying capabilities in memory to revoke them (similar to a garbage-collector sweep). CHERIvoke, a prior feasibility study, suggested that CHERI’s tagged capabilities could make this latter strategy viable, but modeled only architectural limits and did not consider the full implementation or evaluation of the approach. Cornucopia is a lightweight capability revocation system for CHERI that implements non-probabilistic C/C++ temporal memory safety for standard heap allocations. It extends the CheriBSD virtual-memory subsystem to track capability flow through memory and provides a concurrent kernel-resident revocation service that is amenable to multi-processor and hardware acceleration. We demonstrate an average overhead of less than 2% and a worst-case of 8.9% for concurrent revocation on compatible SPEC CPU2006 benchmarks on a multi-core CHERI CPU on FPGA, and we validate Cornucopia against the Juliet test suite’s corpus of temporally unsafe programs. We test its compatibility with a large corpus of C programs by using a revoking allocator as the system allocator while booting multi-user CheriBSD. Cornucopia is a viable strategy for always-on temporal heap memory safety, suitable for production environments.This work was supported by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory (AFRL), under contracts FA8750-10-C-0237 (“CTSRD”) and HR0011-18-C-0016 (“ECATS”). We also acknowledge the EPSRC REMS Programme Grant (EP/K008528/1), the ABP Grant (EP/P020011/1), the ERC ELVER Advanced Grant (789108), the Gates Cambridge Trust, Arm Limited, HP Enterprise, and Google, Inc