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.

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.

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.

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.

The comparative pharmacokinetics of physical manipulation by crushing of Xtampza® ER compared with OxyContin®.

AIM: To further characterize the pharmacokinetics of Xtampza® ER. SUBJECTS & METHODS: This was an open-label, randomized, active-controlled, five-treatment, five-period, naltrexone-blocked, cross-over study. Healthy subjects received five equivalent oxycodone doses: Xtampza ER (intact or crushed), OxyContin® (intact or crushed) or immediate-release (IR) oxycodone (crushed). Blood samples were collected to assess oxycodone concentrations. RESULTS: Crushed and intact Xtampza ER resulted in lower peak plasma concentrations compared with crushed oxycodone IR; crushed and intact Xtampza ER were bioequivalent. Crushed OxyContin exhibited a rapid increase in plasma oxycodone and was bioequivalent to crushed oxycodone IR. CONCLUSION: This second pharmacokinetic study demonstrated that Xtampza ER maintains its ER properties after crushing, unlike OxyContin, which failed to retain its ER properties after crushing. ANZCTR registration number: ACTRN12614000613606.

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.

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.

Changes in pain and concurrent pain medication use following compounded topical analgesic treatment for chronic pain: 3- and 6-month follow-up results from the prospective, observational Optimizing Patient Experience and Response to Topical Analgesics study.

BACKGROUND: Opioids and other controlled substances prescribed for chronic pain are associated with abuse, addiction, and death, prompting national initiatives to identify safe and effective pain management strategies including topical analgesics. METHODS: This prospective, observational study evaluated changes from baseline in overall mean severity and interference scores on the Brief Pain Inventory scale and the use of concurrent pain medications at 3- and 6-month follow-up assessments in chronic pain patients treated with topical analgesics. Changes in pain severity and interference and medication usage were compared between treated patients and unmatched and matched controls. RESULTS: The unmatched intervention group (unmatched-IG) included 631 patients who completed baseline and 3-month follow-up surveys (3-month unmatched-IG) and 158 who completed baseline and 6-month follow-up assessments (6-month unmatched-IG). Baseline and 3-month follow-up data were provided by 76 unmatched controls and 76 matched controls (3-month unmatched-CG and matched-CG), and 51 unmatched and 36 matched patients completed baseline and 6-month follow-up surveys (6-month unmatched-CG and matched-CG). Baseline demographic characteristics and mean pain severity and interference scores were similar between groups. There were statistically significant decreases from baseline in mean pain severity and interference scores within the 3- and 6-month unmatched-IG (all P<0.001). Significantly greater decreases in the mean change from baseline in pain severity and interference scores were evident for the 3- and 6-month unmatched-IG versus unmatched-CG (all P<0.001), with similar results when the 3- and 6-month matched-IG and matched-CG were compared. A higher percentage of the 3- and 6-month unmatched-IG and matched-IG de-escalated use of concurrent pain medications (all P<0.001), while significantly higher percentages of the unmatched-CG and matched-CG escalated medication use. Side effects were reported by <1% of the unmatched-IG. CONCLUSION: Topical analgesics appear to be effective and safe for the treatment of chronic pain, with randomized controlled trials needed to confirm these findings.

Application of a whole blood mycobacterial growth inhibition assay to study immunity against Mycobacterium tuberculosis in a high tuberculosis burden population.

The determinants of immunological protection against Mycobacterium tuberculosis (M.tb) infection in humans are not known. Mycobacterial growth inhibition assays have potential utility as in vitro surrogates of in vivo immunological control of M.tb. We evaluated a whole blood growth inhibition assay in a setting with high burden of TB and aimed to identify immune responses that correlate with control of mycobacterial growth. We hypothesized that individuals with underlying M.tb infection will exhibit greater M.tb growth inhibition than uninfected individuals and that children aged 4 to 12 years, an age during which TB incidence is curiously low, will also exhibit greater M.tb growth inhibition than adolescents or adults. Neither M.tb infection status, age of the study participants, nor M.tb strain was associated with differential control of mycobacterial growth. Abundance and function of innate or T cell responses were also not associated with mycobacterial growth. Our data suggest that this assay does not provide a useful measure of age-associated differential host control of M.tb infection in a high TB burden setting. We propose that universally high levels of mycobacterial sensitization (through environmental non-tuberculous mycobacteria and/or universal BCG vaccination) in persons from high TB burden settings may impart broad inhibition of mycobacterial growth, irrespective of M.tb infection status. This sensitization may mask the augmentative effects of mycobacterial sensitization on M.tb growth inhibition that is typical in low burden settings.

The Cross-Species Mycobacterial Growth Inhibition Assay (MGIA) Project, 2010-2014.

The development of a functional biomarker assay in the tuberculosis (TB) field would be widely recognized as a major advance in efforts to develop and to test novel TB vaccine candidates efficiently. We present preliminary studies using mycobacterial growth inhibition assays (MGIAs) to detect Mycobacterium bovis BCG vaccine responses across species, and we extend this work to determine whether a standardized MGIA can be applied in characterizing new TB vaccines. The comparative MGIA studies reviewed here aimed to evaluate robustness, reproducibility, and ability to reflect in vivo responses. In doing so, they have laid the foundation for the development of a MGIA that can be standardized and potentially qualified. A major challenge ahead lies in better understanding the relationships between in vivo protection, in vitro growth inhibition, and the immune mechanisms involved. The final outcome would be a MGIA that could be used with confidence in TB vaccine trials. We summarize data arising from this project, present a strategy to meet the goals of developing a functional assay for TB vaccine testing, and describe some of the challenges encountered in performing and transferring such assays.

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.

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.

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.

PE_PGRS33 Contributes to Mycobacterium tuberculosis Entry in Macrophages through Interaction with TLR2.

PE_PGRS represent a large family of proteins typical of pathogenic mycobacteria whose members are characterized by an N-terminal PE domain followed by a large Gly-Ala repeat-rich C-terminal domain. Despite the abundance of PE_PGRS-coding genes in the Mycobacterium tuberculosis (Mtb) genome their role and function in the biology and pathogenesis still remains elusive. In this study, we generated and characterized an Mtb H37Rv mutant (MtbΔ33) in which the structural gene of PE_PGRS33, a prototypical member of the protein family, was inactivated. We showed that this mutant entered macrophages with an efficiency up to ten times lower than parental or complemented strains, while its efficiency in infecting pneumocytes remained unaffected. Interestingly, the lack of PE_PGRS33 did not affect the intracellular growth of this mutant in macrophages. Using a series of functional deletion mutants of the PE_PGRS33 gene to complement the MtbΔ33 strain, we demonstrated that the PGRS domain is required to mediate cell entry into macrophages, with the key domain encompassing position 140-260 amino acids of PE_PGRS33. PE_PGRS33-mediated entry into macrophages was abolished in TLR2-deficient mice, as well as following treatment with wortmannin or an antibody against the complement receptor 3 (CR3), indicating that PE_PGRS33-mediated entry of Mtb in macrophages occurs through interaction with TLR2.

Opioid abuse-deterrent strategies: role of clinicians in acute pain management.

Opioid abuse is a healthcare and societal problem that burdens individuals, their families and the healthcare professionals who care for them. Restricting access to opioid analgesics is one option to deter abuse, but this may prevent pain patients in need from obtaining effective analgesics. Therefore, strategies that mitigate the risk of opioid abuse while maintaining access are being pursued by several stakeholders including federal agencies, state governments, payors, researchers, the pharmaceutical industry and clinicians. Federal agency efforts have included required licensure and documentation for prescribing opioids, implementation of risk evaluation and mitigation strategies, and guidance on assessment and labeling of opioid abuse-deterrent formulations. In addition, state governments and payors have enacted monitoring programs, and pharmaceutical companies continue to develop abuse-deterrent opioid formulations. Strategies for clinicians to mitigate opioid abuse include comprehensive patient assessment and universal precautions (e.g. use of multimodal analgesia and abuse-deterrent opioid formulations, urine toxicology screening, participation in prescription drug monitoring and risk evaluation and mitigation strategy programs).

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.

Novel licensure pathways for expeditious introduction of new tuberculosis vaccines: a discussion of the adaptive licensure concept.

The ultimate goal of vaccine development is licensure of a safe and efficacious product that has a well-defined manufacturing process resulting in a high quality product. In general, clinical development and regulatory approval occurs in a linear, sequential manner: Phase 1 - safety, immunogenicity; Phase 2 - immunogenicity, safety, dose ranging and preliminary efficacy; Phase 3 - definitive efficacy, safety, lot consistency; and, following regulatory approval, Phase 4 - post-marketing safety and effectiveness. For candidate TB vaccines, where correlates of protection are not yet identified, phase 2 and 3 efficacy of disease prevention trials are, by necessity, very large. Each trial would span 2-5 years, with full licensure expected only after 1 or even 2 decades of development. Given the urgent unmet need for a new TB vaccine, a satellite discussion was held at the International African Vaccinology Conference in Cape Town, South Africa in November 2012, to explore the possibility of expediting licensure by use of an "adaptive licensure" process, based on a risk/benefit assessment that is specific to regional needs informed by epidemiology. This may be appropriate for diseases such as TB, where high rates of morbidity, mortality, particularly in high disease burden countries, impose an urgent need for disease prevention. The discussion focused on two contexts: licensure within the South African regulatory environment - a high burden country where TB vaccine efficacy trials are on-going, and licensure by the United States FDA --a well-resourced regulatory agency where approval could facilitate global licensure of a novel TB vaccine.

Inhibition of mycobacterial growth in vitro following primary but not secondary vaccination with Mycobacterium bovis BCG.

Despite the widespread use of the Mycobacterium bovis BCG vaccine, there are more than 9 million new cases of tuberculosis (TB) every year, and there is an urgent need for better TB vaccines. TB vaccine candidates are selected for evaluation based in part on the detection of an antigen-specific gamma interferon (IFN-γ) response. The measurement of mycobacterial growth in blood specimens obtained from subjects immunized with investigational TB vaccines may be a better in vitro correlate of in vivo vaccine efficacy. We performed a clinical study with 30 United Kingdom adults who were followed for 6 months to evaluate the abilities of both a whole-blood- and a novel peripheral blood mononuclear cell (PBMC)-based mycobacterial growth inhibition assay to measure a response to primary vaccination and revaccination with BCG. Using cryopreserved PBMCs, we observed a significant improvement in mycobacterial growth inhibition following primary vaccination but no improvement in growth inhibition following revaccination with BCG (P < 0.05). Mycobacterial growth inhibition following primary BCG vaccination was not correlated with purified protein derivative (PPD) antigen-specific IFN-γ enzyme-linked immunospot (ELISPOT) responses. We demonstrate that a mycobacterial growth inhibition assay can detect improved capacity to control growth following primary immunization, but not revaccination, with BCG. This is the first study to demonstrate that an in vitro growth inhibition assay can identify a difference in vaccine responses by comparing both primary and secondary BCG vaccinations, suggesting that in vitro growth inhibition assays may serve as better surrogates of clinical efficacy than the assays currently used for the assessment of candidate TB vaccines.

Update on prescription extended-release opioids and appropriate patient selection.

Chronic pain is largely underdiagnosed, often undertreated, and expected to increase as the American population ages. Many patients with chronic pain require long-term treatment with analgesic medications, and pain management may involve use of prescription opioids for patients whose pain is inadequately controlled through other therapies. Yet because of the potential for abuse and addiction, many clinicians hesitate to treat their patients with pain with potentially beneficial agents. Finding the right opioid for the right patient is the first - often complicated - step. Ensuring that patients continue to properly use the medication while achieving therapeutic analgesic effects is the long-term goal. Combined with careful patient selection and ongoing monitoring, new formulations using extended-release technologies incorporating tamper-resistant features may help combat the growing risk of abuse or misuse, which will hopefully reduce individual suffering and the societal burden of chronic pain. The objective of this manuscript is to provide an update on extended-release opioids and to provide clinicians with a greater understanding of which patients might benefit from these new opioid formulations and how to integrate the recommended monitoring for abuse potential into clinical practice.