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Sec. Antimicrobials, Resistance and Chemotherapy
Volume 9 - 2018 | https://doi.org/10.3389/fmicb.2018.01613
Challenges of NTM Drug Development
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, United States
Discovery and development of antibiotics active against the environmental opportunistic non-tuberculous mycobacteria (NTM) have been retarded by innate antibiotic-resistance of NTM cells and methodological challenges in the laboratory. The basis for the innate resistance of NTM cells is its lipid rich outer membrane that results in hydrophobic cells and the outer membrane’s impermeability, and the residence of NTM cells in phagocytic cells, and the slow growth and dormancy of NTM. Laboratory challenges include: the choice of species and strains for screening and measurement of anti-NTM activity, the high frequency colony switching between antibiotic-susceptible and resistant variants, the preference of NTM to adhere to surfaces and form biofilms, and the aggregation of NTM cells. Understanding these challenges can guide and inform our approaches to discovery and development of antibiotics with activity against NTM.
Introduction to the Non-Tuberculous Mycobacteria (NTM)
The term non-tuberculous mycobacteria (NTM) encompass a large number (>150) Mycobacterium species that are environmental opportunistic pathogens causing pulmonary disease and skin infections in adults and cervical lymphadenitis in children (Marras and Daley, 2002). There is growing awareness of the emergence of NTM as causative agents of nosocomial infections (Marras and Daley, 2002). In the United States the species most commonly reported as causing disease are Mycobacterium avium subsp. hominissuis, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium kansasii, and Mycobacterium abscessus complex. Proven sources of infection include NTM from drinking water, potting soils, and medical equipment. Routes of infection include aerosols from water, dusts from soil, and water and soil contact with abraded or injured skin (Falkinham, 2015).
Humans are surrounded by NTM. NTM have been shown to be normal residents of drinking water distribution systems and premise plumbing; in fact, they grow in distribution systems between the treatment plant and buildings (Falkinham et al., 2001). Premise plumbing is an ideal habitat for the NTM. The water is heated and the low concentration of organic carbon is sufficient to support NTM growth. Although NTM can be grown on rich laboratory medium, they are oligotrophs able to grow on the small amount of organic matter in drinking water (George et al., 1980; Norton et al., 2004). Periods of water stagnation brought about by increased water age and oxygen consumption do not limit NTM growth, as they can grow at 12% oxygen as well as in air (21% oxygen) and can even grow, albeit at half the rate, at 6% oxygen (Lewis and Falkinham, 2015). Finally, NTM cells are surrounded by a lipid-rich outer membrane (Brennan and Nikaido, 1995) that makes NTM cells hydrophobic (van Oss et al., 1975) and impermeable (Jarlier and Nikaido, 1994). Hydrophobicity leads to the preferential attachment of NTM cells to the walls of any container or pipe, so the slowly growing NTM cells cannot be washed out. Surveys of household plumbing of M. avium patients showed that in 50% of the households the NTM isolates from the houses were of the same species and shared the same rep-PCR DNA fingerprint patterns (Falkinham, 2011). It is important to note that later work has shown that VNTR-RFLP is more discriminatory than rep-PCR (Iakhiaeva et al., 2016). Further, M. avium was common in plumbing of homes with a water heater temperatures of 125° F (50° C) or less, but rare if the water heater temperature was 130° F (55° C) or higher. That has led to a current study of the role of water heaters in increasing numbers of M. avium in premise plumbing. All the factors listed above undoubtedly contributed to the colonization and growth of M. chimaera in heater-coolers that have been shown to generate M. chimaera-laden aerosols and infected patients undergoing cardiac surgery (Sax et al., 2015).
Challenges to Development of Anti-NTM Antibiotics
The foregoing brief introduction to the NTM is necessary before discussion of how NTM physiologic and genetic features of NTM are challenges to antibiotic development. The challenges fall into two categories: those involving difficulties in overcoming innate genetic and physiologic traits of NTM (Table 1) and difficulties in measuring anti-NTM antibiotic activity in the laboratory (Table 2). The approach that follows focuses first on laboratory challenges of susceptibility measurements and then turns to challenges due to innate NTM resistance to antibiotics. In a number of instances, it will be clear that a single NTM feature drives antibiotic resistance and laboratory measurement problems. Finally, a table is included to suggest possible solutions to the challenges (Table 3).
TABLE 1. Non-tuberculous mycobacteria (NTM) antibiotic development challenges for NTM due to laboratory measurement of antibiotic susceptibility.
TABLE 2. Non-tuberculous mycobacteria antibiotic development challenges due to innate traits of NTM.
NTM Strain Selection
When searching among libraries of synthetic or nature compounds for anti-mycobacterial activity the choice of Mycobacterium spp. strains is of paramount importance. First, do not use strains of Mycobacterium smegmatis as indicators of potential anti-NTM activity by novel compounds in spite of their rapid rate of growth and ease of handling. Current isolates of M. smegmatis have been linearly cultivated for so long, that they do not resemble the original ATCC deposit. Most of the M. smegmatis isolates being used are derivatives of ATCC strain 607, and those lab-adapted strains have lost many unique characteristics – slow growth, hydrophobicity, and impermeability – that directly increase antibiotic susceptibility. Thus, measurements of minimal inhibitory concentrations (MIC) are not useful to guide compound selection as the M. smegmatis strains in use are unusually susceptible to a wide range of antibiotics. Prolonged, linear cultivation of NTM isolates selects for variants that can grow faster, have lost hydrophobicity and impermeability. Even employing M. smegmatis as a primary screen can be misleading, as some compounds that do not display anti-M. smegmatis inhibition has activity against M. avium, M. intracellulare, or M. abscessus. It is best to identify the ultimate target NTM species (e.g., M. avium) and measure MICs against representatives of that species (Table 3).
Another problem concerns selection of isolates from patients for measurement of MIC to guide and select antibiotics for therapy. More than a single isolate needs to be selected and its susceptibility measured (CSLI, 2011), as it has been shown that colonies of M. avium from AIDS patients having identical morphology, yielded different patterns of susceptibility to antibiotics (von Reyn et al., 1995). Further, as NTM-infected patients may be infected by more than a single NTM species as detected directly (Wallace et al., 1998) or evidenced by relapse (Boyle et al., 2016), selection of single colonies may lead to an incorrect assessment of the antibiotic of choice.
NTM Colonial Variation
Another problem associated with strain choice is that NTM strains can display alternative colonial variants. For M. avium and M. intracellulare, isolates exhibit either a transparent or opaque colony form (McCarthy, 1970; Stormer and Falkinham, 1989). Likewise, M. abscessus complex isolates can exhibit either a rough and smooth colonial morphology (Howard et al., 2006). In M. avium and M. intracellulare the transparent (T) “Mexican Hat” colony morphology is found upon primary culture from patients. The transparent (T) variant is slow-growing, hydrophobic, virulent, and antibiotic-resistant compared to the opaque (O) variant that emerges during laboratory medium cultivation (Schaefer et al., 1970). The opaque (O) variants are faster growing, less hydrophobic, and antibiotic-sensitive compared to the isogenic transparent (T) variants. In M. avium, single colony isolates switch between the T and O forms; colony variation is fully reversible (McCarthy, 1970). The frequency of colony variants of the opposite type amongst isolates of M. avium is approximately 1 in 1,000 (Stormer and Falkinham, 1989). Thus, in a barely turbid culture of one-hundred million (108) M. avium (T) variant cells, there are approximately one-hundred thousand (105 O) cells. Thus, special care must be taken to sample every culture to ensure that the frequency of colonies of the opaque (O) type are always less than or equal to 1 in 1,000 (Table 3).
As the alternative colonial variants have different susceptibilities to antibiotics (McCarthy, 1970; Stormer and Falkinham, 1989), measurement of MIC values may not provide the guidance to direct either chemotherapy or selection of promising novel anti-mycobacterial compounds. For example, as transparent (T) colony variants predominate in patients, selection of an isogenic opaque (O) variant for MIC measurement will lead to choice of an antibiotic that may lack activity against the patient’s transparent (T) variant. This may be the basis, in part, for the lack of any correlation between MIC measurements and prediction of therapeutic success (Sison et al., 1996; Van Engen et al., 2010; Schön and Chryssanthou, 2017). It might also result in the advancement of a compound for further testing based on MIC values from an opaque (O) variant, that will be ineffective in patients as the transparent variant (T) is resistant to the compound.
NTM Hydrophobicity and Measurement of Antibiotic Susceptibility
Non-tuberculous mycobacteria hydrophobicity also creates problems in measuring MICs to guide compound selection or patient therapy. As NTM are hydrophobic, they prefer surface attachment and growth rather than replicating in aqueous suspension. That means that the NTM cells are not in suspension, but rather adhere to the walls of the individual wells in 96-well plates used to measure MICs as recommended by Clinical and Laboratory Standards Institute (CSLI, 2011). Measurements of NTM cells adhering to the walls of water heaters and pipes in households and hospitals, in medical equipment (e.g., heater-coolers), and in test tubes in the laboratory shows that the majority of NTM cells (>99%) are surface-attached (Falkinham et al., 2001; Falkinham, 2011). This observation alone provides a reason why measurement of antibiotic susceptibility in tubes or 96-well plates has not provided guidance for therapeutic efficacy in patients (Sison et al., 1996; Van Engen et al., 2010; Schön and Chryssanthou, 2017). Simply, measurement of turbidity of cell suspensions does not accurately reflect the number of total cells; most are not in suspension but adhering to the wells or tubes. The solution is to use methods to measure MIC of biofilm-grown cells in biofilms (Table 3).
Non-tuberculous mycobacteria preference for adherence and biofilm-formation (Falkinham et al., 2001; Falkinham, 2011) also explain why disinfection of hospital pipes and medical equipment generally fails. The NTM cells in the biofilms survive disinfection and can re-inoculate the water.
A second hydrophobicity-driven problem reducing the utility of standard methods of MIC measurement (CSLI, 2011) is the spontaneous aggregation of NTM cells. Typically, early growth of NTM cells in laboratory medium (e.g., M7H9 broth) can be followed by increases in turbidity, but upon reaching the mid to late exponential phase of growth turbidity disappears and visible aggregates of various dimensions appear. Thus, for many NTM isolates, antibiotic susceptibility cannot be measured with accuracy. Aggregation between NTM cells is driven by hydrophobicity, just as hydrophobicity drives the adherence of NTM to the walls of tubes and wells (van Oss et al., 1975). The best solution to this problem is to measure MIC of isolates during the early phases of cell growth, before aggregation occurs (Table 3). This may require amplification, such as PCR or dyes, to increase the signal from the low cell numbers.
There are no other current useful approaches to reduce the aggregation of NTM cells, as the use of detergent reduces cell-surface hydrophobicity and abolishes aggregation, but increases NTM permeability and growth rate, and thereby the susceptibility to antibiotics. Selection of non-aggregating variants of NTM isolates is not a solution, as the non-aggregating variants have reduced cell hydrophobicity and altered outer membrane composition. Thus, the cells are not representative of those recovered from the patient. This is represented by the laboratory-culture-induced selection of opaque (O) variants of the transparent (T) variants that are isolated from patients.
NTM Adherence and Biofilm Formation
Non-tuberculous mycobacteria cells prefer surface adherence to residence in suspension, whether in humans, in water, or in laboratory growth medium. Surface attachment allows NTM cells to reduce the interaction of their hydrophobic surfaces with the positive and negative charges in aqueous suspension. Once the NTM cells adhere, they can grow to form a biofilm that consists of NTM and other microbial cells within a polymeric matrix consisting of polysaccharide, lipid, DNA, and protein (Mullis and Falkinham, 2013). The layers of cells within the matrix are relatively impermeable to antibiotics and disinfectants. There are significant differences in the susceptibility to chlorine (Falkinham, 2003; Steed and Falkinham, 2006) or antibiotics (Falkinham, 2007) of M. avium cells grown and exposed in biofilms compared to suspension-grown and exposed cells. The increased resistance of M. avium cells in biofilms to antimicrobial agents, compared to those grown and exposed in suspension, prevents obtaining an accurate measurement of disinfectant- or antibiotic-susceptibility for guidance in water treatment or patient care. Again, the solution to biofilm formation is to measure MICs of NTM cells grown in biofilms (Table 3).
That is not the only problem of NTM biofilm formation. Surprisingly, cells of M. avium grown in biofilms, yet harvested and exposed as single cell suspensions were significantly more tolerant of chlorine or antibiotics than cells grown and exposed in suspension (Steed and Falkinham, 2006; Falkinham, 2007). That tolerance was transient, as cells lost the increased resistance to chlorine or antibiotics exhibited by suspension-grown cells following overnight growth in fresh medium (Steed and Falkinham, 2006; Falkinham, 2007). I speculate that such a physiologic adaptation (adaptation, because cells are not permanently altered in susceptibility) is a consequence of growth of NTM-cells in a biofilm.
NTM-dormancy has been demonstrated in a variety of NTM species, particularly in M. avium (Archuleta et al., 2005). M. avium cells subjected to nutrient starvation entered a dormant stage in which cells are effectively non-growing and thereby resistant to any antibiotic challenge (Archuleta et al., 2005). Whether such NTM-dormant cells are in patient tissue or in the wells of an antibiotic-containing medium, such non-growing cells would be expected to be resistant to most antibiotics, as the antibiotics do not actively destroy cell components.
As demonstrated by the studies of Larry Wayne, the slow decrease in oxygen levels as M. tuberculosis triggers the formation of lung tubercles, points out that dormancy of M. tuberculosis is triggered by the absence of oxygen. Those dormant cells can, under certain conditions, be triggered to grow again. The discovery of proteins that can induce growth in such dormant cells, suggests an approach to measurement of MIC of cells suspected to be dormant; namely resuscitate the dormant cells (Wivagg and Hung, 2012) and measure the MIC following the subsequent growth (Table 3).
NTM Residence in Phagocytic Cells
Non-tuberculous mycobacteria cells are not only found within phagocytic cells in infected individuals, but also in granulomas in infected organs like the lungs and liver. NTM-cells in granulomas have not only the NTM outer membrane to protect them, but they also have the layers of host, human cells that make up the granuloma. When considering that it is likely that the majority of NTM-cells are located within mammalian phagocytic cells in infected individuals, a problem of permeability re-appears. Here, it is not the NTM cell’s impermeability that is the only factor, but rather the impermeability of the phagocytic cell’s membrane now plays a role. Recognition of that fact led David Yajko and his colleagues to measure antibiotic susceptibility of NTM cells in human macrophages (Yajko et al., 1991). However, as discussed above, impermeability can be possibly overcome using combinations of agents; namely, one agent to increase the permeability of the phagocytic cell’s membrane to achieve bacteriostatic or bactericidal concentrations within those cells and a second for killing or inhibiting the growth of the NTM cells (Table 3). Documentation that the MICs of the intracellular NTM cells were higher than those of the NTM cells alone, forces us to consider this approach.
Innate Resistance of NTM to Antibiotics
NTM Hydrophobicity and Impermeability and NTM Susceptibility to Antibiotics
Both the hydrophobic and impermeable NTM outer membrane are major and independent contributors to the lack of susceptibility of NTM to commonly used antibiotics (Rastogi et al., 1981; Jarlier and Nikaido, 1994; Brennan and Nikaido, 1995). NTM are the most hydrophobic of bacteria (van Oss et al., 1975), due to the fact that cells are surrounded by the lipid-rich outer membrane that comprises 30% of the cell mass (Brennan and Nikaido, 1995). Hydrophobicity, measured as water droplet contacts angles on filters covered with NTM cells are high (≥75°) almost resembling water droplets on a freshly waxed automobile. The non-polar cell surface prevents the adherence or binding of antibiotics that carry positive or negative charges.
The lipid-rich outer membrane is also impermeable. Measurement of rates of uptake of compounds showed the uptake of charged antibiotics, nutrients, metals, oxyanions, and disinfectants was only 1% of the rate measured in rapidly growing bacteria such as Escherichia coli (Jarlier and Nikaido, 1994). Thus, not only is adherence of charged compounds reduced, but the rate of transport though the outer membrane is greatly reduced. Therefore, it is not surprising that NTM exhibit resistance to most commonly used antibiotics. That having been stated, it is important to point out that the targets for antibiotic action, for example the 23S rRNA for the erythromycin-family antibiotic clarithromycin, are intact and resemble those in other bacteria. That can be shown by exposing NTM cells to antibiotics or other anti-microbial compounds in the presence of detergent. Detergent disrupts the outer membrane, reducing hydrophobicity and increasing permeation, artificially creating phenocopy cells that are antibiotic-susceptible.
One successful route to development of anti-NTM antibiotics is to synthesize hydrophobic derivatives of existing antibiotics. That approach was taught in a paper describing the synthesis of effective anti-NTM drugs through the addition of hydrophobic groups, starting with an ineffective and hydrophilic drug (Rastogi et al., 1988). Although those drugs are not in use, there is the example of synthesizing hydrophobic derivatives of erythromycin, a common antibiotic with little activity against NTM. Hydrophobic derivatives of erythromycin, namely clarithromycin and azithromycin have been shown effective in treating NTM-infected patients whether suffering from NTN pulmonary disease or NTM bacteremia. Following that rational for anti-NTM antibiotic development, a family of Amphipathic dendritic amphiphiles were synthesized and their anti-NTM activity measured (Table 3). These compounds consist of a fatty acid tail linked to (Williams et al., 2007; Falkinham et al., 2012). A number of these compounds displayed strong antibiotic activity against M. avium, M. intracellulare, and M. abscessus with MICs all below 10 μg/mL (Williams et al., 2007; Falkinham et al., 2012).
Another successful approach to overcoming the hydrophobic barrier of the NTM outer membrane is through combinations of antibiotics (Table 3). For example, the antibiotic ethambutol is an inhibitor of formation of the arabinogalactan polymer that links the NTM outer membrane to the peptidoglycan cell wall. Although ethambutol is not a first line drug, it acts synergistically with other antibiotics with targets within cells. Ethambutol reduces the hydrophobic and impermeable outer membrane barrier resulting in increased transport of the second drug (Yajko et al., 1988). That demonstrated example of rational synergism, suggests that the search for anti-NTM antibiotics includes screening methods to identify those that target and disrupt the outer membrane and then measure MICs of those compounds in combination with drugs whose targets are intracellular. Adoption of this view strongly suggests that screening natural and synthetic compounds for anti-NTM activity include all possible combinations and screening in combination with known, albeit low, anti-NTM active antibiotics such as ethambutol.
NTM Slow Growth and Adaptation
The unique structural feature of the mycobacteria; namely the presence of a long chain lipid and wax-rich outer membrane, is the major determinant of their physiology, growth, ecology, and epidemiology (Brennan and Nikaido, 1995). As the outer membrane makes up 30% of the total mycobacterial cell weight, its synthesis reduces energy available for production of new cells. Consequently, NTM grow slowly with a generation time of 1 doubling per day under nutrient-rich conditions at 37°C. However, it is important to point out that the NTM do not replicate slowly because of a slow rate of metabolism. NTM metabolism, as reflected by oxygen uptake and ATP production, is as active as that of rapidly growing bacteria; the NTM simply expend a great deal of energy making the outer membrane. That rapid rate of metabolism means that NTM cells can induce gene products that protect against environmental stress before cells divide.
In M. avium, growth rate modulates antibiotic susceptibility. The susceptibility of M. avium cells to antibiotics or chlorine is greater in medium that supports more rapid growth compared to a minimal, nutrient-poor medium (Falkinham, 2003). In measuring antibiotic MICs of NTM isolates, it is valuable to examine and identify MICs on a daily basis (Table 3). For example, inspection of MICs for the antibiotic clarithromycin against strains of Mycobacterium abscessus identified some whose MIC values increased over time. Significantly, the MIC measured after 3 days incubation was significantly lower than that measured at 7 days (Nash et al., 2009). Further examination of that behavior led to the discovery of an erythromycin methylase that protected cells from inhibition of protein synthesis due to its induction and synthesis leading to methylation of the 23S rRNA target of clarithromycin (Nash et al., 2009).
The studies of Maaløe and Kjeldgaard (1966) taught microbiologists the concept of “balanced” and “unbalanced” growth and the relationship of growth rate to the efficacy of antibiotics. Growth of microorganisms in the absence of antibiotics leads to “balanced” conditions where the increases in the amount of DNA, RNA, protein, and cell walls are proportionate with the growth rate. Exposure of cells growing under “balanced” conditions to an antibiotic unbalances growth. For example, as antibiotics have a single target (e.g., DNA polymerase), it follows that exposure to an antibiotic that inhibits the activity of DNA polymerase would lead to an “unbalanced” condition where increases in of DNA, are not proportionate with increases in cell mass. “Unbalanced” growth of microbial cells leads to death, particularly in rapidly dividing cells (e.g., E. coli). However, unlike E. coli, NTM cells can react to antibiotic stress by synthesizing proteins and other cell constituents able to protect the cells before they are forced to divide (24 h/generation).
To explain NTM-adaptation further, what follows are the results of a study of M. avium heat-adaptation. My students and I have found heat-tolerance in M. avium isolates recovered from plumbing biofilm samples collected from homes of M. avium-infected patients. The isolates are able to survive exposure to 60°C for 3 h without any loss in colony-forming units; they are only killed at 65°C. This data is in contrast to published data on heat-susceptibility of NTM species (Schulze-Röbbecke and Buchholtz, 1992). As the patient, plumbing, and water-provider M. avium isolates shared an identical VNTR-RFLP DNA fingerprint patterns (Iakhiaeva et al., 2016) and heat-tolerance was an adaptation, we hypothesized that passage through the home’s water heater may have triggered an adaptive response leading to increased heat-tolerance. Accordingly, we grew the household M. avium strains at 25°, 30°, 35°, and 42° (the latter the highest temperature of growth for M. avium) and measured their susceptibilities to 55°, 60°, and 65°C. Further, we measured the cell concentration of trehalose that has been shown to be a modulator of temperature-susceptibility. Compared to cells grown at 25°C, cells grown at 42°C had 10-times more trehalose/cell protein. Further, cells grown at 42°C were significantly more tolerant to survival at 60°C compared to those grown at 25°C.
The foregoing information provides strong support for the notion that the search for novel anti-NTM antibiotics will continue to be difficult. It is already well-established that laboratory measures of antibiotic MICs of suspension-grown NTM cells do not provide guidance for therapy (Sison et al., 1996; Van Engen et al., 2010; Schön and Chryssanthou, 2017). The challenges involve both methods of measuring antibiotic susceptibility of NTM strains in the laboratory (Table 1) as well as developing novel anti-NTM antibiotics that can overcome innate characters of these waterborne opportunistic pathogens (Table 2). I have suggested several solutions to these problems (Table 3), but further approaches are needed.
First, identification of suitable novel anti-NTM antibiotics requires development of accurate laboratory measures of NTM antibiotic susceptibility. That requires choice of species and strains coupled with the development of accurate measures of suspension-, biofilm-, and intracellular- (e.g., macrophage) NTM susceptibility (Table 1). Those in vitro measures must be supplemented with ways to prevent NTM cell aggregation, without altering NTM susceptibility.
The second challenge facing development of anti-NTM antibiotics involves efforts to overcome NTM cell surface hydrophobicity and outer membrane impermeability (Table 2). A starting point might be the realization that successful anti-NTM drug therapy involves synergistic combinations; one antibiotic to disrupt or inhibit the outer membrane, and a second antibiotic to inhibit a critical cellular process (i.e., DNA, RNA, or protein and outer membrane synthesis) and hence unbalance growth. For such an approach, high throughput screening involving pairs or compounds seems the likely tool.
JF researched, practiced, and wrote the article.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Van Engen, J., van der Laan, T., Dekhuijzen, R., Boeree, M., and van Soolingen, D. (2010). In vitro drug susceptibility of 2275 clinical non-tuberculous Mycobacterium isolates of 49 species in the Netherlands. Int. J. Antimicrob. Agents 35, 169–173. doi: 10.1016/j.ijantimicag.2009.09.023
van Oss, C. J., Gillman, C. F., and Neumann, A. W. (1975). Phagocytic Engulfment and Cell Adhesiveness as Cellular Phenomena. New York, NY: Marcel Dekker.
von Reyn, C. F., Jacobs, N. J., Arbeit, R. D., Maslow, J. N., and Niemczyk, S. (1995). Polyclonal Mycobacterium avium infections in patients with AIDS: variations in antimicrobial susceptibilities of different strains of M. avium isolated from the same patient. J. Clin. Microbiol. 33, 1008–1010.
Wallace, R. J. Jr., Zhang, Y., Brown, B. A., Dawson, D., Murphy D. T., Wilson, R., et al. (1998). Polyclonal Mycobacterium avium complex infections in patients with nodular bronchiectasis. Am. J. Respir. Crit. Care Med. 158, 1235–1244. doi: 10.1164/ajrccm.158.4.9712098
Williams, A. A., Sugandhi, E. W., Macri, R. V., Falkinham, J. O., and Gandour, R. D. (2007). Antimicrobial activity of long-chain, water-soluble, dendritic tricarboxylato amphiphiles. J. Antimicrob. Chemother. 59, 451–458. doi: 10.1093/jac/dkl503
Wivagg, C. N., and Hung, D. T. (2012). Resuscitation-promoting factors are required for β-lactam tolerance and the permeability barrier of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56, 1591–1594. doi: 10.1128/AAC.06027-11
Yajko, D. M., Nassos, P. S., Sanders, C. A., and Hadley, W. K. (1991). Effects of antimicrobial agents on survival of Mycobacterium avium complex inside alveolar macrophages obtained from patients with human immunodeficiency virus infection. Antimicrob. Agents Chemother. 35, 1621–1625. doi: 10.1128/AAC.35.8.1621
Yajko, D. M., Kirihara, J., Sanders, C., Nassos, P., and Hadley, W. K. (1988). Antimicrobial synergism against Mycobacterium avium complex strains Isolated from patients with acquired immune deficiency syndrome. Antimicrob. Agents Chemother. 32, 1392–1395. doi: 10.1128/AAC.32.9.1392
Keywords: slow growth, rapid metabolism, adaptation, impermeable, hydrophobic, dormancy, biofilms, intracellular
Citation: Falkinham JO III (2018) Challenges of NTM Drug Development. Front. Microbiol. 9:1613. doi: 10.3389/fmicb.2018.01613
Received: 11 April 2018; Accepted: 28 June 2018;
Published: 18 July 2018.
Edited by:Thomas Dick, Rutgers, The State University of New Jersey, United States
Reviewed by:David E. Griffith, The University of Texas Health Science Center at Tyler, United States
César de la Fuente, Massachusetts Institute of Technology, United States
Copyright © 2018 Falkinham. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Joseph O. Falkinham III, email@example.com

domain: health


text:
NeNe explains why she was so upset with the other 'Wives for being late.
NeNe opens up about being a glam-mother.
NeNe didn't feel a connection between Kenya and Walter during the Anguilla trip.
NeNe sums up her thoughts on Kim's departure from the show.
NeNe was surprised to hear what Phaedra had to say about Cynthia.
Nene Leakes addresses Kim and Kandi's negative comments towards her.
NeNe explains how Ryan Murphy has changed her life.
NeNe knew that the ladies were going to target her at the reunion.

domain: celebrity


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This Massachusetts City is Super Popular with Gen Z
One Massachusetts city is attracting the youngest adults in America, meaning those in Generation Z. Really, Gen Z is all the talk right now, which is interesting, because for at least a decade, it seemed everyone was buzzing about the Millennials. Technically, those in Gen Z are born from the mid-to-late 1990s to the early 2010s. They tend to be the children of older Millennials or Generation X. So, which Massachusetts city is super popular with Gen Z?
The new study is from Thisoldhouse.com. In it, they talk about moving trends among Americans. Roughly 8.2 million people moved states in 2022, according to the latest U.S. Census Bureau data. That’s about 4% higher than in 2021. It appears moving to different states is becoming a trend, too, when you look at the last decade of data. “Interestingly, the cities Americans are moving to and from vary greatly between generations,” they state. “For example, while Seattle was a top choice for millennials, it wasn’t even in the top 10 cities where Generation Zers moved in 2022.”
Before we get to Massachusetts, let’s look at the city in America that’s attracting the most Gen Z residents. It’s Washington, D.C. Another interesting trend is that Gen Z is moving more to big cities, while other generations are moving out of big cities. “Gen Z flocked to D.C. and Chicago in droves, while thousands of millennials, Generation X, and baby boomers chose to leave those cities in 2022,” the article states. “Millennials are on the move because they’re in favor of more midsize, tech-hub cities.”
The Massachusetts city that’s super popular with Gen Z is Boston. It’s No. 3 on the list of cities that are bringing in the most people from that generation. In 2002, the net migration to Boston was 12,794. It was 10,271 in 2021. So, if your new neighbor looks extra young, now you know why. Find the full study here.

domain: geography


MPC(reg) moldable phenolic composite material is for molding components that must endure high heat cycling and stress, yet provide resistance to cracking. This glass-reinforced material is targeted for molding powertrain and electric motor components where these components need to resist creep, maintain high strength and elastic stiffness, withstand high temperatures, and provide resistance to the chemicals found in automotive environments.
A simple new chemical method for repairing and recycling notoriously difficult carbon fiber composites has been developed by the Fraunhofer Institute for Applied Polymer Research. An entire component can be completely recycled, including reclaiming its expensive carbon fibers for reuse.
In today’s connected world we are seeing the beginning of connected homes, smart grids, self-driving automobiles, drones, and many other amazing devices. Out of all the soon-to-be connected devices, which device poses the greatest dangerous to its users and society?
Focus on Fundamentals consists of 45-minute on-line classes that cover a host of technologies. You learn without leaving the comfort of your desk. All classes are taught by subject-matter experts and all are archived. So if you can't attend live, attend at your convenience.


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PATHEIN — Seventeen townships across the Irrawaddy Delta are still flooded in the wake of the August deluge, with the divisional government estimating that damage to crops, homes and businesses exceeds 18 billion kyats (US$15.4 million).
More than 400,000 people in Irrawaddy Division alone have now been affected by the floods, according to government officials in Pathein. Townships across Pathein, Hinthada and Maubin districts remain inundated.
“We are monitoring the water levels of rivers and creeks in Irrawaddy Division around the clock and making sure embankments are OK. We are also sending relief supplies and rice reserves to flood-hit areas,” said Khin Maung Lay, a divisional government spokesman.
At least 37 relief camps have opened up in Thabaung, one of the hardest hit townships in the delta.
“There are over 7,000 people taking shelter at the camps, while more than 4,000 others have had to build scaffolds inside their homes and live on them,” Thabaung Township administrator Soe Min Htut told The Irrawaddy.
Floods have inundated more than 260,000 acres of rice paddy fields, and over 1,200 schools have been closed indefinitely.
“In the face of the flood crisis, the division government has exempted its ministers from going to their offices and assigned them to supervise relief works in their home areas,” said Khin Maung Lay. “The most important thing is to make sure there are no casualties, the second is to make sure there is no more losses of property and the third is to make immediate relief responses in flooded areas.”
Independent relief workers claimed that the government failed to take prompt actions to handle flood crisis.
On a visit to Irrawaddy Division on Aug. 9, President Thein Sein announced he would donate 300 million kyats ($257,000) from his presidential fund for relief and rehabilitation works, in addition to 10,000 gallons of diesel and 10,000 gallons of petrol.
Members of Burma’s opposition National League for Democracy (NLD) said that government aid had not gone far enough to assist those in need.
“I haven’t seen any helpful assistance by the government to flood victims,” said Thein Tun, chairman of the Thabaung NLD office. “The departments are just transporting the donors to flood-ravaged areas. People have to live on scaffolds as soon as floods come in and if they cannot do that, they have to stay at monasteries.”
Despite the fact that floods are receding in most areas, water remains above the danger level in 10 townships, according to the divisional Department of Meteorology and Hydrology.

domain: news


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Pax Christi International signs onto Joint Oral Statement on Right to Development
For the 33rd Regular Session of the Human Rights Council, 13-30 September 2016, Pax Christi International has joined with 16 other NGOs in issuing a joint oral statement on the "Right to Development". The statement is entitled, "Right to Development at 30: Time to act!" The statement begins:
- The 2030 Agenda has been informed by the Declaration on the Right to Development and provides a new impetus for realizing its vision. For the SDGs to be successfully achieved, States should focus on strengthening the Means of Implementation (SDG17) and creating an enabling and equitable global order.
- In implementing and monitoring the SDGs, it is necessary to adopt a Right to Development approach that focus not only on the outcomes but also on the processes through which those outcomes must be achieved.
- The right to development expresses, at the highest level, the values of the United Nations Charter. Its achievement is necessary for the protection, respect and fulfilment of the economic, social and cultural rights as well as civil and political rights...

domain: law


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McDonald’s website lists more than 30 ingredients in its mozzarella sticks, but it apparently forgot the most important one: the cheese. Customers are flipping out over the lack of mozzarella cheese, resulting in fried and hollowed-out logs of bread crumbs. So, they’re complaining on social media with some people using the hashtag #wheresthecheese.
#wheresthecheese @McDonalds pic.twitter.com/zGN5oVG17B
— Dennis Guerra (@coachdguerra) January 28, 2016
@Reachout_mcd @McDonaldsCorp new cheese sticks are perfect for the lactose intolerant #dairyfree #wheresthecheese pic.twitter.com/AeqLWOWNEG — Lisa (@lisa_sparkles) January 25, 2016
You have read the maximum number of free articles.
This content is available exclusively to Digiday+ members.
— DerekB (@punkrockmohawks) January 29, 2016
So, how did this happen?
In a statement, McDonald’s said that while a “low volume” number of people were affected, the anger was enough to provoke an explanation. “In these instances, we believe the cheese melted out during the baking process in our kitchens and shouldn’t have been served,” McDonald’s said.
Obviously, this isn’t the biggest furor emanating from social media that McDonald’s has had to endure, but it’s a minor blow for its fledgling 2 for $2 value meal. Earlier this week, Wendy’s and Burger King went at it on Twitter over who had the best deal. Both of those brands have remained silent on the issue, so far.
McDonald’s customers who ordered mozzarella sticks are in for a rude surprise. #WheresTheCheese
Posted by Digiday on Friday, January 29, 2016
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domain: food


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KLEIN TOOLS J2000-9NECLX
Limited Edition 160th Anniversary Side Cutters
Be the envy of your friends and coworkers with these limited edition High-Leverage Side-Cutters. Created to honor Klein's 160th Anniversary, they are engraved with the American flag, Klein's 160th Anniversary logo and feature unique red, white and blue Journeyman handles. 2000 Series heavy-duty cutting knives cut ACSR, screws, nails, most hardened wire and are induction hardened for long life. The high-leverage design provides 46% greater cutting and gripping power than other plier designs. Exclusive handle tempering absorbs the “snap” when cutting wire. Available in the USA only.

domain: design


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Tom Ellis was born on November 17, 1978 in Cardiff, Wales as Thomas Paul Ellis. He is an actor, known for Lucifer (2015), Miranda (2009) and Buffalo Soldiers (2001). He was previously married to Tamzin Outhwaite.
|Movie Name||Release Date|
|Isn’t It Romantic||February 13, 2019|


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Get Rid Of Severe Health Issues Via Using Cbd Cream
Does Cbd Assist With Arthritis Ache?
Derived from uncooked hemp oil, this 150mg cream contains no THC , so you can rub it on joints or painful muscles without being toast at work. A distinctive combo of CBD, crisp menthol and moisturizing aloe delivers targeted pain aid to joints, muscle tissue and ligaments. In a newer 2020 examine, researchers evaluated CBD’s effects in 397 adults dwelling in New Zealand. The research members obtained medical CBD prescriptions for quite a lot of illnesses, including non-most cancers ache, most cancers-associated signs, neurological signs, and psychological health symptoms. For example, should you swallow drugs like aspirin or ibuprofen for pain aid, these medicine may cause abdomen problems if taken too long.
Now, you possibly can merely purchase CBD cream for your pals too to comfortably decreasing their health issues. The individual who desires to eliminate stress can purchase the CBD cream with no miss.
Some Common CBD Vaping Mistakes You Need to be Aware of
Pain is a universal experience, one many people are all too conversant in. The seek for ache reduction is one reason why cannabidiol , a non-psychoactive herbal remedy, is shortly gaining recognition. But with so many options available on the market it can be onerous to find a quality CBD product. In this text, we’ll look at the best CBD lotions for pain, which have been medically reviewed byAshley Jordan Ferira, PhD, RDN. If yes, then you can proceed with this article to know the clear element about the process of cbd cream.
It follows cGMPs for topical manufacturing, and its merchandise are formulated with soothing natural ingredients to alleviate ache sensations. Currently, the one CBD product accredited by the Food and Drug Administration is a prescription oil referred to as Epidiolex. The entire cbd cream is grown with full skilled care and produce the character of CBD cream setting-friendly, recyclable, and so on. The on-line CBD retailer has huge experience in a trading cbd body lotion aloe wide range of CBD creams with different types. The experience of the web CBD store expresses within the Availability of CBD cream with high quality, timely delivery, secure field, affordable value, and so forth. The individual who has purchase CBD cream from the web CBD retailer earns the assure of durability in addition to high quality.
How CBD Can Influence Our Metabolism?
These are some of the most important issues when choosing most CBD oil products, together with topicals like a CBD ache cream. When it involves marijuana, drug exams sometimes solely display screen for THC — the compound in cannabis that will get you “high” — or one of many compounds created when your physique metabolizes it. CBD cream can be used to deal with a really specific area of your physique that’s experiencing pain. If you’re taking CBD oil for a sore muscle, you’ll get a general ache aid all through your entire body, but the muscle ache itself might not utterly disappear. That stated, in case you have very sensitive skin, you could be allergic to a number of the elements, like olive oil, beeswax, or vitamin E oil. But, truthfully, these ingredients are good for your skin, so it’s unlikely that you simply’ll have any issues.
CBD is mostly considered secure; nonetheless, it could possibly nonetheless cause lightheadedness, sleepiness, dry mouth, and barely, liver problems. There may be uncertainty in regards to the potency or purity of CBD merchandise , and CBD can interact with different medicines. For pregnant ladies, concern has been raised about a attainable link between inhaled hashish and lower-birthweight babies; it’s not clear if this applies to CBD. Some ache specialists have issues that CBD might upset the physique’s natural system of ache regulation, resulting in tolerance , although the potential for addiction is generally thought of to be low. In addition, people experience ache and respond to treatment in numerous ways.
Need For The CBD Bath Bombs For Relaxing Your Body And Mind
The CBD cream is principally desired by those who need to give up smoking by boosting energy stage, bettering sleep, lowering stress and despair. Now, you’ll be able to achieve these health advantages with full thoughts by the engagement of CBD cream. The high quality CBD cream is majorly chosen by many as a result of they want to make use of these merchandise with a high quality conventional touch. Check out the web CBD retailer to buy apt size and high quality CBD cream at your doorstep quickly. From the above talked about scenario, now you have got the idea about the effective influence concerned in cbd cream in a prime notch method. Now it is time so that you can use the cream at the regular interval and remedy your skin problems fully.
- This pain aid cream expertly combines broad spectrum CBD extract and different useful ingredients to promote joint support and scale back irritation.
- Whether it’s sore muscular tissues from a exercise, or coping with neck pain from a nasty evening’s rest, CBD lotions and salves are serving to folks get well faster — and all-naturally.
- Pain is a universal experience, one many people are all too conversant in.
- There are tons of products on the market that promise ache relief, however many individuals are turning to the CBD trade for an answer to the aches they expertise in daily exercise.
There are tons of merchandise available on the market that promise ache reduction, but many individuals are turning to the CBD industry for an answer to the aches they expertise in day by day exercise. Whether it is sore muscle tissue from a exercise, or coping with neck ache from a nasty night time’s relaxation, CBD creams and salves are serving to individuals recover quicker — and all-naturally.
Tips On How To Use Cbd Lotions And Topicals
Any point out of products or services isn’t meant as a guarantee, endorsement, or advice of the merchandise, companies, or corporations. Reliance on any data offered is solely at your personal threat. Please discuss any choices together with your healthcare supplier. Don’t make CBD your first selection for ache reduction; it’s extra applicable to consider it if different treatments have not been effective sufficient. If you have chronic arthritis ache, you could be questioning about cannabidiol as a treatment. CBD, along with delta-9-tetrahydrocannabinol and different chemicals, is present in marijuana.
Because of the legally murky nature of marijuana, the FDA has not stepped in to control merchandise like CBD oil, Bonn-Miller said. States are struggling to place laws in place, but they do not have the deep pockets of the federal government. MONDAY, May 7, Cannabidiol oil has turn into the new new product in states that have legalized medical marijuana. Like other merchandise mentioned, this CBD cream uses a few of the finest ingredients out there, with Sunflower Oil, Glycerin, Peppermint and Menthol among the many issues working magic on all those sore muscle tissue of yours. OK, so this technically isn’t a CBD crream or salve, but the Biovelle CBD Coconut Oil is similar as some of these different merchandise mentioned, because it presents up quick reduction for ache — amongst different nicely-being solutions.
But with CBD cream, you don’t have to fret about this facet impact — or really any side impact, for that matter — as a result of the medication absorbs via your pores and skin and doesn’t have an opportunity to annoy your abdomen. CBD topicals are a fantastic herbal technique to help with localized aches and pains, and they are typically thought-about protected to use. However, the FDA has but to judge mainstream CBD skincare products, which is why you need to all the time do your research and goal to purchase from high-quality corporations. If you or the one you love are seeking the best CBD cream for ache, our suggestions are a great place to start out.
We’ll even reveal the benefits of CBD cream and show you the way to make your very own batch for pain relief. cbd canisun Before we do this, we’ll begin at the beginning with the building blocks of CBD cream. If you think you might have a medical emergency, call your healthcare provider or 911 immediately.
But unlike THC, CBD is not “psychoactive” — that’s, it does not trigger the intoxication or excessive related to marijuana use. The materials in this site is meant cbd coconut oil tincture to be of basic informational use and is not intended to constitute medical advice, probable analysis, or beneficial remedies.
These receptors are a part of the physique’sendocannabinoid system, or ECS, that governs features such asour capability to course of pain, as well as irritation, mood, and sleep. The hashish plant accommodates phytocannabinoids like CBD that work together with our ECS, which is why hemphas therapeutic properties.
Only purchase products from reputable manufactures and distributors. All teams reported improvements in their overall quality of life after three weeks of CBD therapy. The individuals who received CBD treatment for nervousness or melancholy reportedly skilled enhancements in their capability to carry out every day capabilities and reduce ache and nervousness or despair symptoms. Our CBD cream for ache sends reduction to the exact location of your ache and makes it simple to get focused ache aid precisely the place you want it. makes use of solely the very best-high quality CBD so you can get the pain relief you want without worrying about unwanted effects or getting excessive. Hire An Influencer To Market Your Product But our commitment to ache reduction goes past simply using high-quality CBD. If you’ve a headache because your neck is tight however you apply the cream to your decrease back, you’re not going to get the reduction you’re on the lookout for.
This pain relief cream expertly combines broad spectrum CBD extract and other useful elements to promote joint support and cut back inflammation. This topical cream incorporates menthol to create a soothing, cooling sensation that lasts for hours, among different pores and skin-benefiting elements like sunflower seed oil and aloe vera leaf juice.
The Way Forward For Smokable Cbd Merchandise Isn’t Great
As a result, it’s highly unlikely that there’s a single CBD-containing product that works for all individuals with all forms of arthritis. Medterra goes above and past in terms of quality requirements and transparency.
This brand offers a number of CBD topical choices, but this cream is particularly formulated to assist in ache aid with the assistance of excessive-power CBD isolate, menthol, and arnica. Every Medterra product has an in depth third-party lab report out there that breaks down cannabinoid and terpene content material, in addition to pesticide and heavy-metallic testing. FAB is dedicated to providing folks with the very best cbd gummies 500mg jar quality CBD it could possibly. All of FAB’s CBD merchandise are produced from hemp organically grown in Colorado. FAB is group-oriented and often collaborates with charity companions. We really like the addition of blood orange essential oil on this topical, which makes it smell nice. It’s a strong product at a good value point, and t applies smoothly with the addition of vitamin E and cocoa butter.
Dont Anticipate Full Relief On A Regular Basis
You should know the fact that, CBD-infused topical mainly include lotions, lotions, transdermal patches and creams which could be utilized on the body skin to eliminate numerous pores and skin issues. Most of the skincare lotions are made up of various chemical components, but this cbd cream is made up of pure components. Therefore you can also make use of this product to do away with skin associated points completely. Depending on the kind of arthritis you could have, it could be quite important to continue your conventional, prescribed medicines even if you pursue extra aid with CBD merchandise. As it turns out, topical CBD merchandise may provide some anti-inflammatory properties to help alleviate pain via cannabinoid receptors inside the pores and skin.
And in 2018, the CDC launched a report that found that greater than 50 individuals in Utah were poisoned by CBD merchandise that truly contained artificial marijuana generally often known as Spice and K2. The Food and Drug Administration do not regulate CBD for treating anxiousness or different psychological well being circumstances. People ought to use their best judgment when purchasing CBD products.
Find the supply of your ache and the CBD cream will do a significantly better job of alleviating the symptoms cbd oil dogs. The consultants at Honest Marijuana will answer all these questions and more.
Author Biography: Elena Ognivtseva
Elena is an avid blogger who enjoys writing articles on fashion, beauty, lifestyle, fitness and recently, CBD niches. Elena has been described as a "delightfully eccentric with a creative take on things" (New York Times) with an ability to "bring you new facts that will make you go WOW!" (Vanity Fair). Elena has been writing since her uni days where she was a regular contributor to the student magazine. After pursuing a career in finance in the heart of London's financial hub, Elena has decided to start blogging in her spare time as an outlet for her creativity and ideas. During her spare time, Elena enjoy horse riding, camping and hiking, interior design and keeping abreast with the latest trends. Elena is in the process of starting up her own beauty cosmetics line in the near future. Elena is also a contributing author to fashion and lifestyle magazines and has been featured in Vice, Country Living, Harrods magazine, Daily Telegraph, Grazia and Women's Health.

domain: medical


text:
Del D. Miller and Susan K. Schultz
The University of Iowa
Iowa City, Iowa
Schizophrenia is one of the first diagnoses that should come to mind when a clinician encounters a patient experiencing delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms (i.e., affective flattening, alogia, or avolition). However, the clinician must keep in mind that there is no one pathognomonic feature of schizophrenia. The above symptoms can, and often do, occur in other psychiatric, neurological, and medical conditions, as well as with certain medications and substance abuse ( 1). It cannot be emphasized enough that no single feature (e.g., cross-sectional symptomatology, course, family history, response to treatment, or laboratory findings) will alone determine a diagnosis of schizophrenia. In general, the reliability of differentiating schizophrenia from the other disorders is strengthened by the presence of several of these characteristic features occurring in a manner consistent with the persistent courses and social/occupational impairment as outlined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) ( 2).


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Vaieli’s wish for Mother’s day
Vaieli Manuele has one wish for Mother’s Day.
She wants a water tank.
The unemployed mother of three, from the village of Falease’ela-uta, continues to struggle daily with the inconsistent water supply.
Her daily routine each day is to fetch buckets of water from different families just so she could prepare meals for her children.
Mrs. Manuele has one concern and that is the welfare of her children. She believes having a water tank will ease her worries and provide a more healthy living for her family.
“We really need a water tank because it is really tiring having to walk everywhere to different families fetching our buckets of water,” she told the Village Voice team.
“There are times when we do not know how to cook our food because we need clean and fresh water to prepare our meals. We always need to be careful of what we are eating and everything that goes into our system.”
“If we are careless, there is a possibility my children could get typhoid or diarrhoea. This is the reason I really need a water tank,” said the 43-year-old.
Mrs. Manuele has many difficulties that she faces and one of them is not having a proper toilet.
“In our village, we usually have people go to each house and do inspections and we are not allowed to have pit toilets. So we have a water sealed toilet and we are in need of a proper toilet.”
“We cannot have a flush toilet when there is no water supply. So it is really challenging for us to try to figure everything out especially when money talks, money is what makes things start moving and progress,” she added.
No one works in their family and all her children attend school.
“We live off the land. We grow our crops and vegetables hoping that we would harvest them soon, but everything has its season.”
“During the season of waiting, our patience is usually tested. When there are so many things coming up and we need the money and the crops aren’t ready, it is so complicated.”
Despite living in a shack, Mrs. Manuele wishes for nothing more but a water tank.
“We have been living here my whole life, but we relocated to this new place that we are now living in at the moment.”
For anyone who is willing to help Mrs. Manuele and her family, contact the number 7750036.

domain: sociology


text:
Accepting new patients
Gastroenterology · Male
Phelps Health Medical Office Building1050 W 10th St Rolla, MO 65401
Make an Appointment
Dr. Hadi Bhurgri, MD is a gastroenterology specialist in Rolla, MO and has been practicing for 2 years. He graduated from The Aga Khan University and Hospital in 2008 and specializes in gastroenterology.


Hello Toyota Lovers, and welcome to realestateshub.us, Today our news is about the brand new version Harrier from Toyota. For the 2021 Model year, This Toyota Harrier powered by a hybrid engine system. When the supplier introduced that brand-new hybrid crossover gets on the roadway, we might not think that it will appear like a 2021 Toyota Harrier Hybrid. Nevertheless, it appears that precisely version similar to this might stand for a wonderful mix of the sportiness as well as environment-friendly engines as Harrier has. It is enhanced as well as somewhat revamped from the last version, however just in order to be functional as well as appealing.
Jump to Details
What New For 2021 Model Year?
After the redesign, there a lot of new stuff that we can see from this brand new Harrier. The 2021 Toyota Harrier Hybrid is a somewhat smaller sized SUV than in the past, yet primarily due to the transformed form of the mid-size SUV. It is currently even more like cars, with a broad rhomboidal mesh grille and also slims tightened front lights. The Toyota Harrier backside is crossover-like however still crumbed with brand-new contours as well as lines and also up-to-date broad backlights on the sides of the trunk door. There are likewise enhancements under the bumper and also slim looter on the back home window, both well-integrated fit of the automobile. Aiming to exterior Harrier looks similar to Lexus RX.
On the inside, as we currently stated that 2021 Toyota Harrier Hybrid is smaller sized this time around which influenced the dimension of the cabin, however, that does not indicate that the cabin is limited or reduced. As a matter of fact, the maker traded its dimension for convenience, roominess, as well as beauty. Thanks to the natural leather on the seats and also high-grade products on the control panel as well as doors it looks advanced as well as high-end. On broad control panel stands big 8-inch touchscreen with the boosted infomercial system, dual-zone environment control, a navigating system, as well as a stereo, better than in Ford Retreat. There are airbags on the doors and also seats, cruise ship control, auto parking sensing units, and also a rearview video camera, for motorist’s safety and security and also quickly managing of the automobile.
Powered with Hybrid Engine
One of the biggest changes that Toyota makes to this car is the Harrier now powered by a Hybrid engine system. Being a hybrid, 2021 Toyota Harrier Hybrid must use the best mix of petroleum engine and also an electrical motor, which both sends out power for much less gas usage. The supplier believed that they accomplished that mix with a 2.5-liter petroleum system as well as an electrical engine which both creates 197 horsepower of toughness. They likewise anticipated that the engine will make the very best power in the mix with the six-speed transmission, or an optional eight-speed automated one.
Pricing & Availability
For the Nort America customer the car ready on sale on January 2021. But if you are in-country like Thailand, Japan, Indonesia, Taiwan, and Malaysia you can buy the car now, Toyota has put The 2021 Harrier on sale for those markets. Speaking about the price, The beginning rate of this mid-size SUV is around $45,000 as well as with all tools that rate could be greater, as much as $70,000.


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Check out this list of some of the best books for 6th grade boys. I’ll take care of you! My top 25 picks for this middle-grade age group are here today! Check them out below!
In the middle grades, your tween’s maturity level changes a lot, and that’s why you should pay attention. Think about how different your child’s tastes are when they’re 10 years old in 5th grade and 13 years old in 8th grade.
During 5th grade, my son was a huge fan of the Captain Underpants series. At 13, he likes fantasy and anime more than Captain Underpants. He still likes Dav Pikey’s books, but he spends more time on other things.
Some good books for 6th graders to read are shown below, with a focus on books that boys like.
Best Books for a 6th Grade Boy
This post has affiliate links in it. If you buy something through one of these links, I get paid a small amount of money at no extra cost to you.
When it’s possible, I’ve put a preview on this page that you can look at right now. With most of these books, you can look through this list with your tween and check out a sample before you leave. A few books didn’t have this.
Harry Potter by JK Rowling
Most of the time, Harry Potter will be the first thing I put on most of my lists, and for a good reason. Most of the time, the series is to blame for inspiring two generations of middle-grade readers to read. I think that J.K. Rowling was a big help in starting the middle grade genre. A lot of people seemed to be more interested in books for young adults or books for elementary school kids before her amazing series came out.
If you haven’t heard of Harry Potter, the story is about a young boy who learns that he’s a wizard and goes on a quest to find out more. He also learns that his parents didn’t die in a car accident, as he had been told for most of his life. They were killed by the darkest wizard to ever live, and he killed them. For the next seven years, he learns magic at Hogwarts and fights against dark forces sent by Voldemort. … Okay, so that’s the long version of the story, but you can still get the idea.
The Giver by Lois Lowry
If you were the next Receiver of Memory, you would keep all of your memories from before Sameness. Jonas is a 12-year-old boy who was chosen to be that person. People in the society he thought were there to protect him aren’t what they seem. He also comes across a very dangerous thing: being unique.
It was one of the first middle grade books I read on my own when I was a tween. It was written by Lois Lowry. It’s a good book for both boys and girls, especially those who like dystopian stories, even though at first glance, it looks like it’s set in a utopia. It’s a good book for both boys and girls.
The Lightning Thief by Rick Riordan
One of the series that always makes my lists is Rick Riordan’s The Lightning Thief and the other books in the Percy Jackson series. They’re great for fantasy and mythology fans.
The story is about Percy Jackson, a young boy who learns that the strange creatures he’s seen most of his life are real.
And that he’s a demigod, too! This is the son of Poseidon, for sure! They know that Poseidon is one of the “original” gods that came from Titans, and he played a big role in taking them down. As for the Titans, they’re tired of being locked in Tartaros and are planning how to get out. It’s only Percy and his other friends at Camp Half-Blood who can stop them!
Wonder by RJ Palaci
Wonder is now a big movie starring Julia Roberts and Owen Wilson. It’s one of the best books for 6th graders. The book even led to a whole movement called Choose Kind.
The story is about Auggie, a boy who has a big “facial difference.” He just wants to be treated like any other child. They can’t get past his looks, which makes it hard for them to like him Wonder could have been just another book about what it’s like to be bullied. Instead, the author goes even further and makes it into a beautiful lesson in kindness and compassion. Anyone who has ever felt different should read this book (which is pretty much all of them).
Diary of a Wimpy Kid by Jeff Kinney
The best books for sixth-graders to read are those in this series. My son would say this is the best one! He’s read all of the books many times. Diary of a Wimpy Kid is about Greg Heffley, a “undersized weakling” who is just trying to make it through middle school, where the bullies are bigger, badder, and already shaving! During Greg’s diary writing, he tells the stories through the eyes of the person who is writing them down.
If your tween likes this series, I think you should get The Wimpy Kid Do-It-Yourself Book, too. A lot of fun things are done to get tweens to write and use their imaginations.
Paperboy by Vince Vawter
Fans of To Kill a Mockingbird will love this coming of age story about a boy who talks too much. It takes place in the South during the time when people were divided into different groups of people. He takes over his best friend’s paper route after he gets hurt while playing baseball. This is what Little Man does. Because he can’t even remember his own name, he doesn’t plan on talking to a lot of people at the store. Even though he’s afraid, Little Man has to speak up because the bully and the thief are in his neighborhood.
The story itself is based on some of the author’s own memories as a child, but not very much of them. It has won a lot of awards, including the Newberry Honor Award, which is given to the best children’s books.
Holes by Lewis Sinclair
Holes is a mix of dark humor and mystery for 6th graders. It’s a lot of fun! Newberry Medal winner Holes is a smart book that your tween will read quickly and keep reading until the last page.
This is the story of Stanley Yelnats, a “cursed” boy who has been sent to Camp Green Lake, a boys’ detention center. Holes tells his story. The boys have to dig holes every day to “build character.” Stanley quickly realizes that digging these 5×5 holes isn’t just for “character building.” There’s more to it than that. Warden: The warden wants to find something in the dried lake bed.
Smile by Raina Telgemeier
Smile looks like a book for girls, but my son really liked this one. A sixth-grade girl named Raina is the subject of the story. She just wants to be a normal girl. However, one night, she falls and hurts her two front teeth. After that, she has to deal with braces, surgery, and even fake teeth. She also has to deal with an earthquake, friends who don’t want to help her, and boys. If you’re in 6th grade, you’ll love this great story about growing up. Most 6th graders can connect to it.
Sounder by William Armstrong
This is a great book for kids who are in middle school. It’s one of the best classics to read. They live in the 1800s, during one of the worst times in Southern history. They have a coon dog and an African-American boy who owns him. Sounder is the only character in the book who has a name. In the movie, the family was called “The Morgans.” Dad takes Sounder out to look for food every night. One morning, there is food on the table. Despite the fact that that sounds like a good thing, it’s not so good when the sheriff shows up and charges the father with theft.
Sounder has been likened to Where the Red Fern Grows and Old Yeller. If you have a tween who is very sensitive to stories where the dog dies, you might not want to read this one. Both of those books, as well as Sounder, made me very sad as a child.
Stick Dog by Tom Watson
Another series that caught my son’s attention when he was in 6th grade is Stick Dog. It’s great for fans of Wimpy Kid and Captain Underpants. The dog, on the other hand, doesn’t die. The dog is, in fact, a stick figure. Laugh along with him through text and drawings as he goes on an epic quest to find the best burger! As long as you have Amazon Prime, you can read this book for free.
Island of the Blue Dolphins by Scott O’Dell
This is a book that my brother thinks every middle school boy should read. He bought my son a copy for his birthday in 6th grade. This is a story about a Native American who was stranded on an island off the coast of California for 18 years. It is based on the true story. The movie is called Island of the Blue Dolphins (although she is 12 in the novel). It tells how she ended up alone on the island, how she lived, and how she was found.
All middle schoolers will enjoy Island of the Blue Dolphins, even though the main character is a girl. People who like survival stories or stories where the main character has a strong connection to animals will enjoy it the most, though. If you have Kindle FreeTime Unlimited, this one is also there.
Diary of a 6th Grade Ninja by Marcus Emerson
This book is great for 6th grade boys because it has the word “boys” right in it. Diary of a 6th Grade Ninja is the story of Chase Cooper, a small boy who gets a job with a group of ninjas. Chase writes about all of his fun and exciting adventures in a diary.
Epic Zero by R.L. Ullman
In a family of superheroes, life is hard when you’re not one of them! This is what Elliott Harkness wants to be, just like his parents did. As well as his younger sister And his dog, too! Elliott, on the other hand, is a “zero,” which means “powerless.” So while his family is having fun, he’s stuck in middle school. Elliott, on the other hand, may be the only person who can save the world when things go wrong. Can he find the hero inside of him?
The Wednesday Wars by Gary D. Schmidt
The Wednesday Wars is a book about a teen boy’s adventures during the 1967-89 school year. It won a Newberry Honor for best picture book. The story takes place on Long Island, which is in New York. It’s very funny and interesting. It seems like Holling Hoodhood has a bad teacher on Wednesday afternoons. He gets religious advice from her. It’s hard for the country as a whole to deal with Vietnam, and Holling’s father wants him to be on the best behavior possible because his business is at stake. Isn’t that hard? Not for Holling, who has bullies, angry rats, and more to deal with!
The Secret Sheriff of Sixth Grade
During the book The Secret Sheriff of Sixth Grade, Maverick learns that bad things can happen to good kids, and he wants to help change this.
The badge was a gift from his father before he died. Maverick carries it with him to remind him that it’s important to stand up for other people. When you read the title, you think it’s going to be a comedy. Instead, it’s a heartwarming story that encourages kids to stand up against bullying.

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PARIS — Fragile half-ton cubes of colored confetti lay on Loewe’s white runway at Paris Fashion Week. Ushers desperately tried to guide guests including Jamie Dornan, Naomi Campbell and Catherine O’Hara around the blocks fearing the decor would disintegrate at the slightest brush. Sometimes, it partially did.
The highly creative show itself by Jonathan Anderson – that used feathers, and satins and velvet — continued the theme of reduction and ephemeral impressions.
Here are some highlights of Friday’s fall-winter 2023-2024 ready-to-wear shows in Paris.
LOEWE IS SUBLIME
For fall, the brand’s lauded Northern Irish designer continued his exploration of pared-down and reductive styles — where a single garment often comprised the entire look.
Loewe described it as “an idea of elementality: one piece, and that’s it, reduced to the bluntest shape possible.”
The touchstone of the Old Master painters, as seen in Anderson’s men’s collection, was felt here again with collapsed leather Renaissance boots and use of satin, silk duchesse, velvet, crystals and feather.
The pastel-rich collection’s feathered pieces were the most original: The plumes were unusually wide and placed across garments like a shell. They came as a downy covering on a buttery white top with some feathers jutting out haphazardly, or on thick texture blue-gray flared pants evoking an anthropomorphic bird.
One pale blue gown appeared to be simply a length of satin draped from the chest from a big gold ball. Elsewhere, the idea of fashion or life itself as ephemeral and ever-moving was conveyed through blurred prints on loose gowns, which sometimes resembled an X-ray.
They were, the house said, “about putting into focus what may seem unclear right now.” It’s clear that Loewe under Anderson’s creative eye has become one of the most anticipated collections in the industry.
In perhaps the most original take on color blocking ever seen at Paris Fashion Week, Loewe collaborated with Italian artist Lara Favaretto to create literal blocks of color. Twenty-one confetti cubes standing 90 centimeters (35 inches) high, together weighing some 10 tons, created in deep reds, blues, yellows and greens impressed guests.
O’Hara, who watched the show beside US Vogue Editor-in-Chief Anna Wintour, exclaimed “Wow look at the blue” as a guest evaded security to pose by one cube — triggering a crumble of confetti flakes.
“I was kind of hoping one would dissolve in the show, as there’s nothing really holding them together,” O’Hara told The Associated Press. “Isn’t that crazy?” O’Hara said Anderson’s designs showed “completely original ideas, fresh, without being new for new sake.”
“They were the most unusual silhouettes and shapes but still were flattering,” she added.
ISSEY MIYAKE’S SQUARE
A fusion of music, dance and theater awaited at the Japanese techno-fabric-loving house.
A live marimba percussion performance opened the show at the Chatelet Theater, one of Paris’ most prestigious stages. The show took the idea of a music score, or a canvas, or a piece of fabric being square – and explored this theme of squareness.
“The collection engages with this rational shape … to develop garments of striking forms,” the house explained. It said its aesthetic was based on “a new iteration” of the unfilled space.
Three-dimensional “canopy” gowns folded down like paper origami. Square motifs were knitted horizontally and vertically — hitting a high on a stretchy green gown with a stretch lozenge shaped front. Creative looks included gowns made with cutting edge technology to shrink woven yarn to a unique texture.
VALLI GETS ECLECTIC
A Balkan and Eastern aesthetic permeated a sparkling, and sometimes eclectic, display from Italian designer Giambattista Valli.
Tight ethnic waistcoats mixed with ruffles, gold buttons, 60s minidresses, florals, floaty tulle, thick tweed, black leather biker boots, shades, gold banded waists and even menswear looks.
The best designs were those with a simple Balkan flavor — such as one fluttery, off-white column dress with diagonal banding. It was accessorized with ethnic pear-shaped earrings.


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Shares of Tenet Healthcare Corp. fell more than 10% late Monday after the company reported a larger-than-expected quarterly loss. Tenet reported a net loss of $55 million, or 55 cents a share, in the second quarter, compared with a net loss of $46 million, or 46 cents a share, a year ago. Sales reached $4.8 billion. Analysts polled by FactSet had expected Tenet to report a GAAP loss of 17 cents a share on sales of $4.9 billion in the quarter. The company said it expects full-year 2017 revenue of $19.1 billion to $19.4 billion. The analysts surveyed by FactSet expect sales of $19.8 billion for the year.
Copyright © 2017 MarketWatch, Inc.
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As reported by Zachary Brennan of RAPS the FDA received the first NDA for a combination product consisting of a sensor embedded into a tablet. The goal being to have an effective way to track patient adherence to taking prescribed medicine.
How it works: The sensor is linked to a wearable patch and sends a time stamp when the tablet reaches the stomach. This information is forwarded to the patients smart phone or other blue tooth device and with permission may be communicated to the patient’s care giver via wireless communication. This would provide the care giver confirmation that required medicines were being taken or alternatively one would assume an application could be built to provide warnings if medications were not taken within a set window.
Interesting way to innovate patient adherence / compliance when taking medicine and the potential elimination of missed doses.
Bertolucci (2012) of Kiplinger, wrote about the use of technology to help seniors stay at home. One of the examples provided was the use of wireless technology to keep tabs on an elderly relative. In Bertolucci’s example if you wanted to know whether an elderly relative was waking up and going to sleep on time, eating properly, showering and taking medicine. New systems allow adult children to monitor the everyday habits of their ailing parents.
Monitoring services will install wireless sensors in areas of the home that a senior uses most often, including the bathroom, bedroom and kitchen. The sensors will track certain kinds of movement, such as when a refrigerator, medicine cabinet or front door opens. During setup, the service will study the senior’s normal pattern of daily activities.


With all the talk of the Cleveland Cavaliers, Philadelphia 76ers and Los Angeles Lakers this free agency period, you'd be forgiven if you you thought there was only three teams in the NBA free agent LeBron James could possibly go to this summer.
But a fourth team has enquired about signing LeBron this week, and it's a team you'd never expect.
According to Chris Mannix of Yahoo Sports, the Denver Nuggets will “aggressively” pursue a meeting with LeBron James, and have already been in contact with his agent, Rich Paul.
Even though it may be an extremely long shot by Denver, as all signs are pointing to LBJ heading to LA, you can't fault them for trying to nab the 14-time All-Star.
Denver has proven before that they're able to sign marquee free agents, grabbing All-Star Paul Millsap last offseason from Atlanta.
The cap would be a major issue for the Nuggets if they were able to sign LeBron, as after signing Nikola Jokic and Will Barton during the initial hours of the free agency period, they don't have a lot of money left to spend.
The only way to acquire James would be via sign-and-trade, requiring the Nuggets to shed $54.4 million in salaries, which would mean gutting a large portion of their roster. The likes of Wilson Chandler, Kenneth Faried, Darrell Arthur, and Mason Plumlee would all need to be moved, as well as one of Millsap or Gary Harris.
But then again, if you have a chance to sign LeBron and thrust your franchise into NBA Finals contention, you go for it 10 times out of 10.


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Hacking North by NorthEast...
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06-11-2010, 06:07 PM
Deaf on Wheels
Joined: Dec 2007
Location: Prescott, Arizona, USA
Everything is bilingual in New Brunswick; street signs; placards...menus, they even have 3 French TV stations beamed there, not so in Nova Scotia?
Saint John in the morning..
Residents of Hill Top Park
St. John's River traffic
Our ferry-'Princess of Acadia'
Made friends with 2 other HD tourers: a 69 year young from Virginia touring Nova Scotia and an Ontario couple heading to Newfounland.
Into the mouth of Jonah the Whale
Up the staircase
Gangway to the Salons
Section of the Bow lifts to allow vehicles to enter
Then the bow evens flush with the deck
Guess what I am watching via satellite the Soccer World Cup and talking soccer with my son via email on pager....
RSA vs. Mexico------1:1
Approaching Digby, Nova Scotia inlet..
Digby is famous for its Scallops ...bar none!
Ain't a good picture...google it instead...
There they are.....picture big enuff for you hungry folks? Koi farm...get your bib on before you drool on yer shirt!
Clam and Lobster roll to complement...yummm yummm
You can order from here.....via UPS to the USA..
The Town of Digby...mostly fisheries and tourism..
Beautiful signs indicating we were riding on Harvest Highway
many flowers like these in pink, purple & white everywhere along the highways & byways
R&R here for the day...
until tomorrow....au revoir (gotta practice my french)!
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Owning swimming pool gives a feel of being a bit costly chore. However, pool equipments can break or make your swimming experience. Apparently, there are some types of swimming pool equipment that help in maintaining your pool. Yet, buying the right type of pool equipment assists in contributing a beautiful pool with pure refreshing water. Similarly, understanding the role of pool equipments help in justifying the expense and in deciding the necessary pool equipment.

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Green, (blue) and grey?
The last one is some faded street art off Waterloo Bridge on the Southbank. The other two also featured in my other blog post about London, I'll admit.
I like both these sets of photos to be honest. Different views on life, and good to recall both. The last three were at the top of my Flickr photostream for quite a while as the last photos I'd uploaded, and I noticed how grey they made London seem. Which is not how I've found it - people complain about it being grey, but I find it quite a bit brighter and the light seems more expansive than Dublin. And there is beauty to be found, some of it obvious, some of it brutal, some of it gentle. A reminder to look more closely.

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East London is only 26 km away, a mere 15 minutes drive from the East London airport. This makes it an ideal stop for people doing business in the area or families traveling along the coast.
Grahamstown and Hogsback are also within easy reach, as are the spectacular Amathole Mountains. The area is rich in history, culture, shipwrecks and other fascinating stories.
A SERIOUS DOSE OF VITAMIN SEA
A STONES THROW FROM THE BEACH
This is the perfect place to escape the rat race.
Kick off your shoes and relax, then consider a leisurely stroll to the beach with its tidal pool, lagoon and long sandy beaches as far as the eye can see and end up with a dip in our safe swimming area.
Scavenge the beach and rock pools for shells especially our famous pumpkin shells. Don’t be surprised if people wave and greet as they pass you by, either, cycling, running or walking their dogs. Flip flops, costumes and wraps are the fashion of the day.
Stroll across the street to one of our local restaurants
Breeze Inn is an establishment that is based on a comfortable relaxed time and you will be welcomed and hosted by Dave and Terry Doveton, who lovingly have created a stylish yet laid-back, "home-away-from-home".
Take the R72 from East London to Port Alfred or Port Alfred to East London. Take the Kidds Beach turn off. We are Number 69 on the left of the main road close to the beach. If you get lost ask a local they will know where we are.

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Imaging in 2017: An Evolution in Value and Standards
The term “value” means different things to different people in medical imaging.
Technologists define value through the quality of the medical images acquired in diagnostic procedures. Radiologists view it as a contribution to patient care through the interpretation of images. For referring clinicians, value is in the diagnostic quality and efficiency of the radiology imaging services they receive. Patients see it in the timeliness of the imaging procedures as part of their treatments. CMIOs and executives, responsible for the efficiency, quality and overall business health of a diagnostic service, define it through clinical outcomes and productivity, reduced turnaround times and cost. IT staff is balancing these needs with accessibility, high availability and compliance with privacy and data security policies. With so many different interpretations, how does a health care enterprise define “the value of imaging?” And what will the future hold for “value” in 2017?
All of these perspectives help to define “imaging value,” but the focus is always getting the right data to the right people at the right time. Having all of the patient’s images from previous exams, as well as having the complete medical record available to the radiologist, significantly helps radiologists maximize their value when interpreting images. Likewise, sharing everything from the results of the interpretation (the diagnostic report, structured findings and key images) helps radiologists to maximize their value to the broader care team. As a result of the interpretation, the diagnostic report and associated key images must be made available to other care team members, typically in a platform outside of PACS where sharing data remains a challenge. However, the broader care team does not use the PACS system, which is where the radiologist completes his/her work, so the information needs to be distributed to others. This can only be accomplished via enhanced collaboration tools as well as interoperability between the PACS and the information systems.
Best practices for image exchange and sharing of information from medical image interpretations exist, but departments must demand technical platforms where interoperability is built-in by design rather than being an afterthought. The technical, clinical and business experts in health care organizations now understand and agree that true interoperability requires the exchange of image-related data that are relevant and contextual. As such, a solid contextual and semantic interoperability is the first and most fundamental requirement to deliver the value of imaging today.
Vendor neutral archives (VNA) is one way to create this data exchange and improve clinical productivity. Initially, it was developed to connect siloed departments and manage image storage and distribution throughout the hospital. This creates cost savings, IT efficiency and improves patient outcomes by making relevant data accessible. VNAs need to continue pioneering integration progress with other patient information systems, such as EHRs, EMRs and personal health records.
This evolution will greatly assist the development of tailored treatment plans for each patient, and thus help radiologists track toward value in the new year.
Advances in imaging and image-guided surgery open a completely new area in replacing traditional surgeries with minimally invasive procedures (such as TAVI) that drastically reduce patient risk and improve accessibility to care. This is yet another area where radiologists can provide value through precision imaging measurement. This strategy helps radiology align closer with the patient and provide better coordinated care.
Despite the ever-changing health care landscape, the future of radiology on the 2017 horizon is bright. Radiologists will continue to play an important role in the journey to value-based care from improving patient outcomes to cost-efficient techniques. Through the adoption of innovative technologies and solutions, radiology departments will not only continue to make an impact, but will drastically improve overall quality of care.
To learn more about the pillars that support enterprise imaging, download Beyond Imaging: Key Components for a Holistic Enterprise Imaging Strategy.