Use of PVDF Wire Sensors for Leakage Localization in a Fluid-Filled Pipe.

The detection and location of pipeline leakage can be deduced from the time difference between the arrival leak signals measured by sensors placed at the pipe access points on either side of a suspected leak. Progress has been made in this area to offer a potential improvement over the conventional cross-correlation method for time delay estimation. This paper is concerned with identifying suitable sensors that can be easily deployed to monitor the pipe vibration due to the propagation of leak noise along the pipeline. In response to this, based on the low-frequency propagation characteristics of leak noise in our previous study, polyvinylidene fluoride (PVDF) wire sensors are proposed as a potential solution to detect the pipeline leak signals. Experimental investigations were carried out at a leak detection pipe rig built in the Chinese Academy of Sciences. Their performances for leak detection were shown in comparison with hydrophones. It is suggested that with special considerations given to aspects pertaining to non-intrusive deployment and low cost, the PVDF wire sensors are of particular interest and may lead to a promising replacement for commercial leak noise transducers.

Adaptive Phase Transform Method for Pipeline Leakage Detection.

In leak noise correlation surveys, time delay estimation (TDE) is of great importance in pinpointing a suspected leak. Conventional TDE methods involve pre-filtering processes prior to performing cross-correlation, based on a priori knowledge of the leak and background noise spectra, to achieve the desired performance. Despite advances in recent decades, they have not proven to be capable of tracking changes in sensor signals as yet. This paper presents an adaptive phase transform method based on least mean square (LMS) algorithms for the determination of the leak location to overcome this limitation. Simulation results on plastic water pipes show that, compared to the conventional LMS method, the proposed adaptive method is more robust to a low signal-to-noise ratio. To further verify the effectiveness of the proposed adaptive method, an analysis is carried out on field tests of real networks. Moreover, it has been shown that by using the actual measured data, improved performance of the proposed method for pipeline leakage detection is achieved. Hence, this paper presents a promising method, which has the advantages of simple implementation and ability to track changes in practice, as an alternative technique to the existing correlation-based leak detection methods.

The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination.

The genome of Mycobacterium tuberculosis, the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex.

PE and PPE Genes: A Tale of Conservation and Diversity.

PE and PPE are two large families of proteins typical of mycobacteria whose structural genes in the Mycobacterium tuberculosis complex (MTBC) occupy about 7% of the total genome. The most ancestral PE and PPE proteins are expressed by genes that belong to the same operon and in most cases are found inserted in the esx clusters, encoding a type VII secretion system. Duplication and expansion of pe and ppe genes, coupled with intragenomic and intergenomic recombination events, led to the emergence of the polymorphic pe_pgrs and ppe_mptr genes in the MTBC genome. The role and function of these proteins, and particularly of the polymorphic subfamilies, remains elusive, although it is widely accepted that PE and PPE proteins may represent a specialized collection used by MTBC to interact with the complex host immune system of mammals. In this chapter, we summarize what has been discovered since the identification of these genes in 1998, focusing on M. tuberculosis genetic variability, host-pathogen interaction and TB pathogenesis.

Association of Human Antibodies to Arabinomannan With Enhanced Mycobacterial Opsonophagocytosis and Intracellular Growth Reduction.

BACKGROUND: The relevance of antibodies (Abs) in the defense against Mycobacterium tuberculosis infection remains uncertain. We investigated the role of Abs to the mycobacterial capsular polysaccharide arabinomannan (AM) and its oligosaccharide (OS) fragments in humans. METHODS: Sera obtained from 29 healthy adults before and after primary or secondary bacillus Calmette-Guerin (BCG) vaccination were assessed for Ab responses to AM via enzyme-linked immunosorbent assays, and to AM OS epitopes via novel glycan microarrays. Effects of prevaccination and postvaccination sera on BCG phagocytosis and intracellular survival were assessed in human macrophages. RESULTS: Immunoglobulin G (IgG) responses to AM increased significantly 4-8 weeks after vaccination (P < .01), and sera were able to opsonize BCG and M. tuberculosis grown in both the absence and the presence of detergent. Phagocytosis and intracellular growth inhibition were significantly enhanced when BCG was opsonized with postvaccination sera (P < .01), and these enhancements correlated significantly with IgG titers to AM (P < .05), particularly with reactivity to 3 AM OS epitopes (P < .05). Furthermore, increased phagolysosomal fusion was observed with postvaccination sera. CONCLUSIONS: Our results provide further evidence for a role of Ab-mediated immunity to tuberculosis and suggest that IgG to AM, especially to some of its OS epitopes, could contribute to the defense against mycobacterial infection in humans.

Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation.

OBJECTIVE: Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy. METHODS: A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid-associated adverse events convened to discuss the literature on assessment methods used for opioid-induced constipation and reach consensus on each objective using the nominal group technique. RESULTS: Five validated assessment tools were evaluated: the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF-Diary). The 3-item BFI and 4-item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12-item PAC-SYM are most commonly used. The 11-item BF-Diary is highly relevant in opioid-induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC-SYM, and 28-item PAC-QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation. CONCLUSIONS: The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid-induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first-line interventions.

Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation.

The chromosome of Mycobacterium tuberculosis encodes five type VII secretion systems (ESX-1-ESX-5). While the role of the ESX-1 and ESX-3 systems in M. tuberculosis has been elucidated, predictions for the function of the ESX-5 system came from data obtained in Mycobacterium marinum, where it transports PPE and PE_PGRS proteins and modulates innate immune responses. To define the role of the ESX-5 system in M. tuberculosis, in this study, we have constructed five M. tuberculosis H37Rv ESX-5 knockout/deletion mutants, inactivating eccA(5), eccD(5), rv1794 and esxM genes or the ppe25-pe19 region. Whereas the Mtbrv1794ko displayed no obvious phenotype, the other four mutants showed defects in secretion of the ESX-5-encoded EsxN and PPE41, a representative member of the large PPE protein family. Strikingly, the MtbeccD(5) ko mutant also showed enhanced sensitivity to detergents and hydrophilic antibiotics. When the virulence of the five mutants was evaluated, the MtbeccD(5) ko and MtbΔppe25-pe19 mutants were found attenuated both in macrophages and in the severe combined immune-deficient mouse infection model. Altogether these findings indicate an essential role of ESX-5 for transport of PPE proteins, cell wall integrity and full virulence of M. tuberculosis, thereby opening interesting new perspectives for the study of this human pathogen.

Deciphering the proteome of the in vivo diagnostic reagent "purified protein derivative" from Mycobacterium tuberculosis.

Purified protein derivative (PPD) has served as a safe and effective diagnostic reagent for 60 years and is the only broadly available material to diagnose latent tuberculosis infections. This reagent is also used as a standard control for a number of in vitro immunological assays. Nevertheless, the molecular composition and specific products that contribute to the extraordinary immunological reactivity of PPD are poorly defined. Here, a proteomic approach was applied to elucidate the gene products in the U.S. Food and Drug Administration (FDA) standard PPD-S2. Many known Mycobacterium tuberculosis T-cell antigens were detected. Of significance, four heat shock proteins (HSPs) (GroES, GroEL2, HspX, and DnaK) dominated the composition of PPD. The chaperone activities and capacity of these proteins to influence immunological responses may explain the exquisite solubility and immunological potency of PPD. Spectral counting analysis of three separate PPD reagents revealed significant quantitative variances. Gross delayed-type hypersensitivity (DTH) responses in M. tuberculosis infected guinea pigs were comparable among these PPD preparations; however, detailed histopathology of the DTH lesions exposed unique differences, which may be explained by the variability observed in the presence and abundance of early secretory system (Esx) proteins. Variability in PPD reagents may explain differences in DTH responses reported among populations.

Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein.

PE_PGRS33 is the most studied member of the unique PE family of mycobacterial proteins. These proteins are composed of a PE domain (Pro-Glu motif), a linker region and a PGRS domain (polymorphic GC-rich-repetitive sequence). Previous studies have shown that PE_PGRS33 is surface-exposed, constitutively expressed during growth and infection, involved in creating antigenic diversity, and able to induce death in transfected or infected eukaryotic cells. In this study, we showed that PE_PGRS33 co-localizes to the mitochondria of transfected cells, a phenomenon dependent on the linker region and the PGRS domain, but not the PE domain. Using different genetic fusions and chimeras, we also demonstrated a direct correlation between localization to the host mitochondria and the induction of cell death. Finally, although all constructs localizing to the mitochondria did induce apoptosis, only the wild-type PE_PGRS33 with its own PE domain also induced primary necrosis, indicating a potentially important role for the PE domain. Considering the importance of primary necrosis in Mycobacterium tuberculosis dissemination during natural infection, the PE_PGRS33 protein may play a crucial role in the pathogenesis of tuberculosis.

Methylation-dependent T cell immunity to Mycobacterium tuberculosis heparin-binding hemagglutinin.

Although post-translational modifications of protein antigens may be important componenets of some B cell epitopes, the determinants of T cell immunity are generally nonmodified peptides. Here we show that methylation of the Mycobacterium tuberculosis heparin-binding hemagglutinin (HBHA) by the bacterium is essential for effective T cell immunity to this antigen in infected healthy humans and in mice. Methylated HBHA provides high levels of protection against M. tuberculosis challenge in mice, whereas nonmethylated HBHA does not. Protective immunity induced by methylated HBHA is comparable to that afforded by vaccination with bacille Calmette et Guérin, the only available anti-tuberculosis vaccine. Thus, post-translational modifications of proteins may be crucial for their ability to induce protective T cell-mediated immunity against infectious diseases such as tuberculosis.

On the detection of objects buried at a shallow depth using seismic wave reflections.

This paper concerns the detection of shallow (of the order 1 m) buried objects using seismic excitation. Time-extended signals are used to generate a compressional wave using a shaker attached to the ground. The wave propagates through the ground, reflects off a buried object and is captured by an array of geophones on the surface. The envelopes of the cross-correlation functions between the measured ground velocities and the excitation signal are calculated and summed to generate a cross-sectional image of the ground. The wide cross-correlation peaks caused by high ground attenuation are partially compensated for by using the generalized cross-correlation function called the phase transform. Simple simulations are conducted to demonstrate the method, and some field experiments have been carried out aimed at the detection of a buried concrete pipe. In the experiments the pipe could be detected using the method proposed, with experimental and simulated data producing good agreement.

PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX-5.

ESX-5 is one of the five type VII secretion systems found in mycobacteria. These secretion systems are also known as ESAT-6-like secretion systems. Here, we have determined the secretome of ESX-5 by a proteomic approach in two different strains of Mycobacterium marinum. Comparison of the secretion profile of wild-type strains and their ESX-5 mutants showed that a number of PE_PGRS and PPE-MPTR proteins are dependent on ESX-5 for transport. The PE and PPE protein families are unique to mycobacteria, are highly expanded in several pathogenic species, such as Mycobacterium tuberculosis and M. marinum, and certain family members are cell surface antigens associated with virulence. Using a monoclonal antibody directed against the PGRS domain we showed that nearly all PE_PGRS proteins that are recognized by this antibody are missing in the supernatant of ESX-5 mutants. In addition to PE_PGRS and PPE proteins, the ESX-5 secretion system is responsible for the secretion of a ESAT-6-like proteins. Together, these data show that ESX-5 is probably a major secretion pathway for mycobacteria and that this system is responsible for the secretion of recently evolved PE_PGRS and PPE proteins.

The role of urine drug testing for patients on opioid therapy.

Opioid analgesics must be prescribed with discernment and their appropriate use should be periodically assessed. Urine drug testing, although not designed specifically for this role, is a widely available and familiar method for monitoring opioid use in chronic pain patients. Urine drug testing can help track patient compliance and expose possible drug misuse and abuse. We sought to evaluate current attitudes and practices regarding the use of urine drug testing among chronic pain patients taking opioids. To the best of our knowledge, this is one of the first such attempts in the literature to examine and document the practice patterns of urine drug testing in this context. A total of 99 attendees at the American Congress of Pain Medicine were surveyed in 2008 about their urine testing practices for patients on opioid therapy. Surprisingly, more urine testing was motivated by a desire to detect undisclosed substances than to evaluate appropriate opioid use. Some respondents never urine-tested their opioid patients, and about two-thirds of respondents had no formal training in urine testing of patients on opioid therapy. The literature does not thoroughly address the role of urine drug testing in this patient population. Most respondents did random rather than scheduled testing; few had any urine testing protocol. The study found motivations for urine testing and testing practices varied widely, and urine testing, despite its clinical utility, is not used consistently.

The prescription opioid conundrum: 21st century solutions to a millennia-long problem.

Health-care professionals are faced with a daunting task: balancing appropriate care for chronic pain with their responsibility to keep patients and others safe from treatment-related harm. Whereas opioids have historically been considered an effective tool in the analgesic armamentarium, the rise of opioid abuse has caused the pendulum to swing away from prescribing opioids to an emphasis on safety. This paradigm shift risks neglecting the very real consequences of untreated/undertreated pain. Using data from the medical literature, this review examines influences on the real and perceived benefit-to-risk ratio for opioids and provides clinicians with a practical approach to prescribing opioids that minimizes the risk for abuse/misuse. There is appreciable clinical trial and observational evidence of efficacy/effectiveness with opioids used for pain management over the short or long term when considered in the context of pharmacologic alternatives. Enhancing the relative safety and minimizing the risk for abuse/misuse may be achieved through proactive prescription practices that include careful patient selection, risk assessment, individualized and multimodal treatment plans with established goals, initiating opioid treatment cautiously with an exit plan in place, ongoing assessments of response to therapy, and routine patient monitoring. Additionally, prescribing opioids with a lower potential for abuse or misuse (e.g. abuse-deterrent formulations) may provide a benefit. Using a pragmatic approach to prescribing practices, we postulate that the balance between benefit and risk can be favorable for opioid therapy in select patients, even for long-term treatment of chronic pain.

Mycobacterium tuberculosis PE_PGRS16 and PE_PGRS26 genetic polymorphism among clinical isolates.

The Mycobacterium tuberculosis PE_PGRS multigene family is thought to be involved in antigenic variation, which can be generated by differential regulation of expression and a high frequency of genetic polymorphism. PE_PGRS16 and PE_PGRS26 are inversely regulated during persistent M. tuberculosis infection, suggesting that differential regulation of the expression of these two PE_PGRS genes may have a role in latency. To understand how genetic diversity, in addition to differential regulation, contributes to antigenic variability, we investigated the sequence variations in the PE_PGRS16 and PE_PGRS26 genes among 200 clinical M. tuberculosis strains, in comparison to the sequenced laboratory strain H37Rv, using PCR and DNA sequencing. Among the 200 strains, 102 (51%) and 100 (50%) had sequence variations within the PE_PGRS16 gene and the PE_PGRS26 gene, respectively. In-frame insertions and deletions, frameshifts, and SNPs were observed in both the PE_PGRS16 gene and the PE_PGRS26 gene. However, the frequency of frameshifts and in-frame deletions differed between the two PE_PGRS genes. Examining the profile of the PE_PGRS16, PE_PGRS26, and the previously investigated PE_PGRS33 amino acid sequences for each of the 200 strains, 72 different profiles were observed with frequencies ranging from 0.5% to 13%. In conclusion, a remarkable level of genetic diversity exists in the PE_PGRS16 and PE_PGRS26 genes of M. tuberculosis clinical strains. The significant sequence variations in the two PE_PGRS genes observed in this study could impact the function of these two PE_PGRS proteins and be associated with differences in the ability of the tubercle bacilli to remain persistent within the host.

Retrospective accounts of initial subjective effects of opioids in patients treated for pain who do or do not develop opioid addiction: a pilot case-control study.

This pilot case-control study retrospectively assessed between-groups differences in subjective opioid effects in patients treated for the first time with opioids for chronic pain. Cases were individuals in an inpatient substance abuse treatment center for primary prescription opioid addiction whose initial exposure to prescription opioids was reported for chronic pain. Controls had not developed prescription opioid addiction as measured in part by close monitoring on long-term opioid therapy at a pain management center. Twenty subjects in each group completed a battery of measures to capture data related to the individual's first exposure to prescription opioids. The Morphine Benzedrine Group subscale of an adapted 49-item Addiction Center Research Inventory (ARCI), designed to measure euphoria and other drug effects, showed an average score of 8.70 (+/-4.18) in cases versus 2.55 (+/-3.36) in controls (p<0.001), indicating a significantly greater "euphoric" effect of opioids in the cases compared to the controls. Differences in the subjective response to opioids suggest that: (1) a subgroup of patients does develop euphoria when taking opioids for pain, which may be a risk factor for eventual development of prescription opioid addiction; and (2) subjective effects predictive of eventual addiction may include stimulation and other experiences not typically associated with opioids.

Reduction of opioid use and improvement in chronic pain in opioid-experienced patients after topical analgesic treatment: an exploratory analysis.

OBJECTIVE: There is a need to identify safe and effective opioid-sparing multimodal alternative treatment strategies and approaches, including topical analgesics, for opioid-experienced chronic pain patients to mitigate the risk of addiction, misuse, and abuse of opioids. METHODS: This subset analysis from a prospective, observational study evaluated changes in opioid use, other concurrent medication use, and pain severity and interference in opioid-experienced patients (OEP) treated with topical analgesics for chronic pain with measures obtained at baseline and 3- and 6- month follow-up. RESULTS: The 3-month opioid-experienced patient (3-month OEP) group included 121 patients who completed baseline and 3-month follow-up assessments; 27 opioid-experienced patients completed baseline and 6-month follow-up assessments (6-month OEP). Demographic characteristics, and mean pain severity and interference scores were similar between groups at baseline. After treatment with topical analgesics, 49% of patients in the 3-month and 56% of patients in the 6-month group reported they had completely discontinued use of opioids. In addition, 31% of patients at the 3-month assessment and 30% at the 6-month assessment reported that they were no longer taking any pain medication. Other concurrent medications decreased by 65% after 3 months, and 74% after 6 months. There were statistically significant decreases from baseline in pain severity and interference scores within the 3- (CI:0.7-1.4, 1.4-2.2) and 6-month (CI:0.7-2.4 (severity); CI:1.2-3.5 (interference)) OEP groups. CONCLUSIONS: Opioid use and other concurrent medications decreased among opioid-experienced chronic pain patients after 3- and 6- months of treatment with topical analgesics. Pain severity and interference scores also decreased. The topical analgesics were reported to be effective and safe for the treatment of chronic pain, with randomized controlled trials needed to confirm these findings.

A New Whooping Cough Vaccine That May Prevent Colonization and Transmission.

This article is a Letter to the Editor. The major purpose of this Letter is to highlight the development of a new genetically altered whooping cough vaccine. Recently a baboon model has been used to show that this next generation pertussis vaccine can prevent colonization, as well as disease, and elicit antibodies against major pertussis antigens. Two phase I clinical trials have been performed, showing that this new vaccine is safe in humans, and a phase II trial will be performed in the US in 2018.

Strategies for Combating Opioid-Induced Constipation: Targeted Mechanisms to Maintain Pain Control Without Compromise.

Opioid-induced constipation (OIC) is a common side effect of opioid use and can occur from the outset of opioid therapy (Online access: http://courses.elseviercme.com/aapmr2016/638e). OIC has been reported to interfere with pain management, increase health care costs, decrease work productivity and daily activities, and significantly affect patient quality of life. It can also lead to bowel obstruction. Assessing and managing OIC is important for establishing maximum function for patients. Several pharmacologic approaches, with different mechanisms of action, are available or in development.