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Background and Purpose: Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications. Bitter taste is mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets of TAS2Rs, targeting specific receptors may only suppress bitterness for certain, but not all, bitter-tasting compounds. Alternative strategies are needed to identify universal bitter blockers that will improve the acceptance of every medication. Taste cells in the mouth transmit signals to afferent gustatory nerve fibres through the release of ATP, which activates the gustatory nerve-expressed purine receptors P2X2/P2X3. We hypothesized that blocking gustatory nerve transmission with P2X2/P2X3 inhibitors (e.g. 5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine [AF-353]) would reduce bitterness for all medications and bitter compounds., Experimental Approach: Human sensory taste testing and mouse behavioural analyses were performed to determine if oral application of AF-353 blocks perception of bitter taste and other taste qualities but not non-gustatory oral sensations (e.g. tingle)., Key Results: Rinsing the mouth with AF-353 in humans or oral swabbing it in mice suppressed the bitter taste and avoidance behaviours of all compounds tested. We further showed that AF-353 suppressed other taste qualities (i.e. salt, sweet, sour and savoury) but had no effects on other oral or nasal sensations (e.g, astringency and oral tingle)., Conclusion and Implications: This is the first time a universal, reversible taste blocker in humans has been reported. Topical application of P2X2/P2X3 inhibitor to suppress bitterness may improve medical compliance., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Bifidobacterium adolescentis iVS-1 is a human-isolated strain known to possess several probiotic properties. Here, its genome was completely sequenced to examine genes associated with lactose metabolism and other potentially beneficial traits, such as the production of folate and gamma-aminobutyric acid (GABA)., Competing Interests: All authors are affiliated with Synbiotic Health, Inc. which supplied the funding for this study. T.A.A. and Z.T.L. are coinventors on a patent application (PCT/US23/61868) relating to iVS-1 and lactose digestion.

It is well established that the gastrointestinal (GI) microbiota plays a major role in human health. Dietary interventions, and consumption of fermented foods that contain live microbes, in particular, are among the approaches being investigated to modulate the GI microbiota and improve health. However, the persistence of fermented food-associated bacteria (FAB) within the GI tract is typically limited by host factors that limit colonization and competition with autochthonous microbes. In this research, we examined if the addition of prebiotics, dietary substrates that are selectively metabolized by microbes to improve health, would enhance the persistence of FAB. We evaluated the persistence of bacteria from three live microbe-containing fermented foods-kefir, sausage, and sauerkraut-in fecal microbial communities from four healthy adults. Fecal communities were propagated in vitro and were inoculated with fermented food-associated microbes from kefir, sausage, or sauerkraut at ~10 7  CFU/mL. Communities were diluted 1:100 every 24 h into fresh gut simulation medium to simulate microbial community turnover in the GI tract. We measured the persistence of Lactobacillaceae from fermented foods by quantitative PCR (qPCR) and the persistence of other FAB through 16S rRNA gene sequencing. FAB were unable to persist in vitro , reaching undetectable levels within 96 h. Addition of prebiotics, including xylooligosaccharides and a mixture of fructooligosaccharides and galactooligosaccharides enhanced the persistence of some species of FAB, but the level of persistence varied by fecal donor, fermented food, and prebiotic tested. Addition of prebiotics also increased the relative abundance of Bifidobacterium species, which most likely originated from the fecal microbiota. Collectively, our results support previous in vivo studies demonstrating the transient nature of FAB in the GI tract and indicate that consumption of prebiotics may enhance their persistence., Competing Interests: RH is a co-founder of Synbiotic Health, a manufacturer of probiotic microbes. JMA has a financial interest in Synbiotic Health. The remaining 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., (Copyright © 2022 Christensen, Kok, Auchtung and Hutkins.)

Children have difficulty swallowing capsules. Yet, when presented with liquid formulations, children often reject oral medications due to their intense bitterness. Presently, effective strategies to identify methods, reagents, and tools to block bitterness remain elusive. For a specific bitter-tasting drug, identification of the responsible bitter receptors and discovery of antagonists for those receptors can provide a method to block perceived bitterness. We have identified a compound (6-methylflavone) that can block responses to an intensely bitter-tasting anti-human immunodeficiency virus (HIV) drug, tenofovir alafenamide (TAF), using a primary human taste bud epithelial cell culture as a screening platform. Specifically, TAS2R39 and TAS2R1 are the main type 2 taste receptors responding to TAF observed via heterologously expressing specific TAS2R receptors into HEK293 cells. In this assay, 6-methylflavone blocked the responses of TAS2R39 to TAF. In human sensory testing, 8 of 16 subjects showed reduction in perceived bitterness of TAF after pretreating (or "prerinsing") with 6-methylflavone and mixing 6-methylflavone with TAF. Bitterness was completely and reliably blocked in two of these subjects. These data demonstrate that a combined approach of human taste cell culture-based screening, receptor-specific assays, and human psychophysical testing can successfully discover molecules for blocking perceived bitterness of pharmaceuticals, such as the HIV therapeutic TAF. Our hope is to use bitter taste blockers to increase medical compliance with these vital medicines. SIGNIFICANCE STATEMENT: Identification of a small molecule that inhibits bitter taste from tenofovir alafenamide may increase the compliance in treating children with human immunodeficiency virus infections., (Copyright © 2021 The Author(s).)

Background: Advance care planning (ACP) supports individuals to define, discuss, and record goals and preferences for future medical treatment and care. Despite being internationally recommended, randomised clinical trials of ACP in patients with advanced cancer are scarce., Methods and Findings: To test the implementation of ACP in patients with advanced cancer, we conducted a cluster-randomised trial in 23 hospitals across Belgium, Denmark, Italy, Netherlands, Slovenia, and United Kingdom in 2015-2018. Patients with advanced lung (stage III/IV) or colorectal (stage IV) cancer, WHO performance status 0-3, and at least 3 months life expectancy were eligible. The ACTION Respecting Choices ACP intervention as offered to patients in the intervention arm included scripted ACP conversations between patients, family members, and certified facilitators; standardised leaflets; and standardised advance directives. Control patients received care as usual. Main outcome measures were quality of life (operationalised as European Organisation for Research and Treatment of Cancer [EORTC] emotional functioning) and symptoms. Secondary outcomes were coping, patient satisfaction, shared decision-making, patient involvement in decision-making, inclusion of advance directives (ADs) in hospital files, and use of hospital care. In all, 1,117 patients were included (442 intervention; 675 control), and 809 (72%) completed the 12-week questionnaire. Patients' age ranged from 18 to 91 years, with a mean of 66; 39% were female. The mean number of ACP conversations per patient was 1.3. Fidelity was 86%. Sixteen percent of patients found ACP conversations distressing. Mean change in patients' quality of life did not differ between intervention and control groups (T-score -1.8 versus -0.8, p = 0.59), nor did changes in symptoms, coping, patient satisfaction, and shared decision-making. Specialist palliative care (37% versus 27%, p = 0.002) and AD inclusion in hospital files (10% versus 3%, p < 0.001) were more likely in the intervention group. A key limitation of the study is that recruitment rates were lower in intervention than in control hospitals., Conclusions: Our results show that quality of life effects were not different between patients who had ACP conversations and those who received usual care. The increased use of specialist palliative care and AD inclusion in hospital files of intervention patients is meaningful and requires further study. Our findings suggest that alternative approaches to support patient-centred end-of-life care in this population are needed., Trial Registration: ISRCTN registry ISRCTN63110516., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: BH and LB are developers of Respecting Choices and report personal fees from Gundersen Health, outside the submitted work.

Divalent and trivalent salts exhibit a complex taste profile. They are perceived as being astringent/drying, sour, bitter, and metallic. We hypothesized that human bitter-taste receptors may mediate some taste attributes of these salts. Using a cell-based functional assay, we found that TAS2R7 responds to a broad range of divalent and trivalent salts, including zinc, calcium, magnesium, copper, manganese, and aluminum, but not to potassium, suggesting TAS2R7 may act as a metal cation receptor mediating bitterness of divalent and trivalent salts. Molecular modeling and mutagenesis analysis identified 2 residues, H943.37 and E2647.32, in TAS2R7 that appear to be responsible for the interaction of TAS2R7 with metallic ions. Taste receptors are found in both oral and extraoral tissues. The responsiveness of TAS2R7 to various mineral salts suggests it may act as a broad sensor, similar to the calcium-sensing receptor, for biologically relevant metal cations in both oral and extraoral tissues., (© The Author(s) 2019. Published by Oxford University Press.)

Neonatal bacterial infections leading to sepsis occur frequently in the first few days or weeks of life. NPs must be able to recognize the early signs of sepsis and understand the need for rapid evaluation and treatment. This article discusses antibiotic treatments for various types and locations of bacterial infections and sepsis in the neonate.

Background: While complementary and alternative medicine (CAM) is commonly used in the United States and elsewhere, and hazardous interactions with prescription drugs can occur, patients do not regularly communicate with physicians about their CAM use. The objective of this study was to discover patient information needs and preferences for herb-drug-disease interaction alerts., Methods: We recruited 50 people from several locations within the University of Utah Hospital to participate in this structured interview study. They were asked to provide their preferences for the herb-drug-disease interaction alerts. Qualitative methods were used to reveal the themes that emerged from the interviews., Results: Most participants reported they had previously used, or they were currently using, CAM therapies. The majority had made the effort to inform their healthcare provider(s) about their CAM usage, although some had not. We found that most respondents were interested in receiving alerts and information about potential interactions. Many preferred to receive the alerts in a variety of ways, both in person and electronically., Conclusions: In addition to conventional medicine, many patients regularly use complementary and alternative therapies. And yet, communication between patients and providers about CAM use is not consistent. There is a demand for interventions in health care that provide timely, integrative communication support. Delivering the herb-drug-disease alerts through multiple channels could help meet critical patient information needs.

Trimethoprim-sulfamethoxazole (TMP/SMX) is used as prophylaxis against Pneumocystis jiroveci during chemotherapy. Many groups recommend withholding TMP/SMX during high-dose methotrexate (HDMTX) for concerns that it will delay methotrexate clearance. We compared methotrexate exposure following HDMTX (NCT00549848) in 424 patients including 783 courses that were given concurrently and 602 courses that were not given concurrently with TMP/SMX. Among 176 patients (555 courses) on the low-risk arm (HDMTX=2.5 g/m/24 h), there was no difference in clearance (110.7 [1.8%] vs. 108.2 [0.9%] mL/min/m, P=0.3) nor in 42 hour methotrexate concentration (0.37 [5.1%] vs. 0.40 (5.0%) μM, P=0.23). Among 248 patients (830 courses) on the standard/high-risk arm (HDMTX ~5 g/m/24 h), there was slightly higher clearance (95.5 [1.4%] vs. 91.2 [0.8%] mL/min/m, P=0.005) in those receiving TMP/SMX, with no difference in the 42 hour methotrexate concentration (0.59 [4.1%] vs. 0.66 [4.2%] μM, P=0.06). There was no difference in neutrophil counts based on TMP/SMX during HDMTX (P=0.83). TMP/SMX also did not have a significant impact on myelosuppression of low-dose methotrexate (40 mg/m) given during continuation therapy among 230 patients enrolled on a prior study (NCT00137111). Thus, we found no evidence for an interaction between methotrexate and TMP/SMX given prophylactically.

Objective: To assess the accuracy of a multitarget stool DNA test (MT-sDNA) compared with fecal immunochemical testing for hemoglobin (FIT) for detection of screening-relevant colorectal neoplasia (SRN) in Alaska Native people, who have among the world's highest rates of colorectal cancer (CRC) and limited access to conventional screening approaches., Patients and Methods: We performed a prospective, cross-sectional study of asymptomatic Alaska Native adults aged 40-85 years and older undergoing screening or surveillance colonoscopy between February 6, 2012, and August 7, 2014., Results: Among 868 enrolled participants, 661 completed the study (403 [61%] women). Overall, SRN detection by MT-sDNA (49%) was superior to that by FIT (28%; P<.001); in the screening group, SRN detection rates were 50% and 31%, respectively (P=.01). Multitarget stool DNA testing detected 62% of adenomas 2 cm or larger vs 29% by FIT (P=.05). Sensitivity by MT-sDNA increased with adenoma size (to 80% for lesions ≥3 cm; P=.01 for trend) and substantially exceeded FIT sensitivity at all adenoma sizes. For sessile serrated polyps larger than 1 cm (n=9), detection was 67% by MT-sDNA vs 11% by FIT (P=.07). For CRC (n=10), detection was 100% by MT-sDNA vs 80% by FIT (P=.48). Specificities were 93% and 96%, respectively (P=.03)., Conclusion: The sensitivity of MT-sDNA for cancer and larger polyps was high and significantly greater than that of FIT for polyps of any size, while specificity was slightly higher with FIT. These findings could translate into high cumulative neoplasm detection rates on serial testing within a screening program. The MT-sDNA represents a potential strategy to expand CRC screening and reduce CRC incidence and mortality, especially where access to endoscopy is limited., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Recent reports of cadmium in electronic waste and jewelry have increased public awareness regarding this toxic metal. Human exposure to cadmium is associated with the development of osteoporosis. We previously reported cadmium induces apoptosis in human tumor-derived Saos-2 osteoblasts. In this study, we examine the extracellular signal-regulated protein kinase (ERK) and protein kinase C (PKC) pathways in cadmium-induced apoptosis and altered osteoblast gene expression. Saos-2 osteoblasts were cultured in the presence or absence of 10μM CdCl(2) for 2-72h. We detected significant ERK activation in response to CdCl(2) and pretreatment with the ERK inhibitor PD98059 attenuated cadmium-induced apoptosis. However, PKCα activation was not observed after exposure to CdCl(2) and pretreatment with the PKC inhibitor, Calphostin C, was unable to rescue cells from cadmium-induced apoptosis. Gene expression studies were conducted using qPCR. Cells exposed to CdCl(2) exhibited a significant decrease in the bone-forming genes osteopontin (OPN) and alkaline phosphatase (ALP) mRNA. In contrast, SOST, whose protein product inhibits bone formation, significantly increased in response to CdCl(2). Pretreatment with PD98059 had a recovery effect on cadmium-induced changes in gene expression. This research demonstrates cadmium can directly inhibit osteoblasts via ERK signaling pathway and identifies SOST as a target for cadmium-induced osteotoxicity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

"How do I find innovative people for my organization? And how can I become more innovative myself?" These are questions that stump most senior executives, who know that the ability to innovate is the "secret sauce" of business success. Perhaps for this reason most of us stand in awe of the work of visionary entrepreneurs such as Apple's Steve Jobs, Amazon's Jeff Bezos, eBay's Pierre Omidyar, and P&G's A.G. Lafley. How do these individuals come up with groundbreaking new ideas? In this article, Dyer, of Brigham Young University; Gregersen, of Insead; and Christensen, of Harvard Business School, reveal how innovative entrepreneurs differ from typical executives. Their study demonstrates that five "discovery skills" distinguish the most creative executives: Associating helps them discover new directions by making connections among seemingly unrelated questions, problems, or ideas. Questioning allows innovators to break out of the status quo and consider new ideas. Through observing, innovators carefully and consistently look out for small behavioral details--in the activities of customers, suppliers, and other companies -to gain insights about new ways of doing things. In experimenting, they relentlessly try on new experiences and explore the world. And through networking with diverse individuals from an array of backgrounds, they gain radically different perspectives.

Perturbed physics experiments are among the most comprehensive ways to address uncertainty in climate change forecasts. In these experiments, parameters and parametrizations in atmosphere-ocean general circulation models are perturbed across ranges of uncertainty, and results are compared with observations. In this paper, we describe the largest perturbed physics climate experiment conducted to date, the British Broadcasting Corporation (BBC) climate change experiment, in which the physics of the atmosphere and ocean are changed, and run in conjunction with a forcing ensemble designed to represent uncertainty in past and future forcings, under the A1B Special Report on Emissions Scenarios (SRES) climate change scenario.

Disruptive innovation has brought affordability and convenience to customers in a variety of industries. However, health care remains expensive and inaccessible to many because of the lack of business-model innovation. This paper explains the theory of disruptive innovation and describes how disruptive technologies must be matched with innovative business models. The authors present a framework for categorizing and developing business models in health care, followed by a discussion of some of the reasons why disruptive innovation in health care delivery has been slow.

Purpose: Patient satisfaction, safety and efficacy outcomes, and cost savings with insulin pens versus conventional insulin delivery via vials and syringes in hospitalized patients with diabetes were compared., Methods: Patients were recruited from two general medical-surgical units from July 2005 to May 2006. Patients completed a survey regarding satisfaction with the method in which insulin was administered before discharge. Patients completed a telephone survey approximately four weeks after discharge to determine home insulin use. Cost savings were determined using the average wholesale price of insulin vials and syringes, pens, and pen needles., Results: A total of 94 patients were randomized to receive insulin administered via pen devices (n = 49) or using conventional vials and syringes (n = 45). Significantly more subjects in the pen group prepared or self-injected at least one dose of insulin during hospitalization, wanted to continue taking insulin at home using the method used during hospitalization, and would recommend their method of insulin administration used during hospitalization to other patients with diabetes compared with the vial and syringe group (p < 0.05). A cost saving of $36 per patient was projected if only insulin pens were dispensed during the entire hospital stay compared to insulin vials and syringes (p < 0.05)., Conclusion: Increased patient satisfaction and continuation of the method of insulin administration used in the hospital at home were reported by patients who received insulin pens compared with patients who received conventional vials and syringes during hospitalization. A substantial cost saving was projected for patients in the insulin pen group if insulin pens had been dispensed during their entire hospital stay.

Most companies aren't half as innovative as their senior executives want them to be (or as their marketing claims suggest they are). What's stifling innovation? There are plenty of usual suspects, but the authors finger three financial tools as key accomplices. Discounted cash flow and net present value, as commonly used, underestimate the real returns and benefits of proceeding with an investment. Most executives compare the cash flows from innovation against the default scenario of doing nothing, assuming--incorrectly--that the present health of the company will persist indefinitely if the investment is not made. In most situations, however, competitors' sustaining and disruptive investments over time result in deterioration of financial performance. Fixed- and sunk-cost conventional wisdom confers an unfair advantage on challengers and shackles incumbent firms that attempt to respond to an attack. Executives in established companies, bemoaning the expense of building new brands and developing new sales and distribution channels, seek instead to leverage their existing brands and structures. Entrants, in contrast, simply create new ones. The problem for the incumbent isn't that the challenger can spend more; it's that the challenger is spared the dilemma of having to choose between full-cost and marginal-cost options. The emphasis on short-term earnings per share as the primary driver of share price, and hence shareholder value creation, acts to restrict investments in innovative long-term growth opportunities. These are not bad tools and concepts in and of themselves, but the way they are used to evaluate investments creates a systematic bias against successful innovation. The authors recommend alternative methods that can help managers innovate with a much more astute eye for future value.

Countries, organizations, and individuals around the globe spend aggressively to solve social problems, but these efforts often fail to deliver. Misdirected investment is the primary reason for that failure. Most of the money earmarked for social initiatives goes to organizations that are structured to support specific groups of recipients, often with sophisticated solutions. Such organizations rarely reach the broader populations that could be served by simpler alternatives. There is, however, an effective way to get to those underserved populations. The authors call it "catalytic innovation." Based on Clayton Christensen's disruptive-innovation model, catalytic innovations challenge organizational incumbents by offering simpler, good-enough solutions aimed at underserved groups. Unlike disruptive innovations, though, catalytic innovations are focused on creating social change. Catalytic innovators are defined by five distinct qualities. First, they create social change through scaling and replication. Second, they meet a need that is either overserved (that is, the existing solution is more complex than necessary for many people) or not served at all. Third, the products and services they offer are simpler and cheaper than alternatives, but recipients view them as good enough. Fourth, they bring in resources in ways that initially seem unattractive to incumbents. And fifth, they are often ignored, put down, or even encouraged by existing organizations, which don't see the catalytic innovators' solutions as viable. As the authors show through examples in health care, education, and economic development, both nonprofit and for-profit groups are finding ways to create catalytic innovation that drives social change.

Employers can choose from lots of tools when they want to encourage employees to work together toward a new corporate goal. One of the rarest managerial skills is the ability to understand which tools will work in a given situation and which will misfire. Cooperation tools fall into four major categories: power, management, leadership, and culture. Choosing the right tool, say the authors, requires assessing the organization along two critical dimensions: the extent to which people agree on what they want and the extent to which they agree on cause and effect, or how to get what they want. The authors plot on a matrix where various organizations fall along these two dimensions. Employees represented in the lower-left quadrant of the model, for example, disagree strongly both about what they want and on what actions will produce which results. Those in the upper-right quadrant agree on both dimensions. Different quadrants call for different tools. When employees share little consensus on either dimension, for instance, the only methods that will elicit cooperation are "power tools" such as fiat, force, and threats. Yugoslavia's Josip Broz Tito wielded such devices effectively. So did Jamie Dimon, current CEO of J.P. Morgan Chase, during the bank's integration with Bank One. For employees who agree on what they want but not on how to get it--think of Microsoft in 1995--leadership tools, such as vision statements, are more appropriate. Some leaders are blessed with an instinct for choosing the right tools--Continental Airlines' Gordon Bethune, General Electric's Jack Welch, and IBM's Lou Gerstner are all examples. Others can use this framework to help select the most appropriate tools for their circumstances.

Purpose: Following radical retropubic prostatectomy for prostate cancer, if the serum prostate specific antigen fails to become undetectable, occult micrometastatic disease is suspected. We assessed the natural history of disease progression, and predictors of recurrence and survival in this group of patients., Materials and Methods: We identified 303 men treated with radical retropubic prostatectomy for prostate cancer between 1990 and 1999, who had a detectable prostate specific antigen between 60 and 120 days postoperatively. Systemic recurrence-free and cancer specific survival were estimated using the Kaplan-Meier method, and analyzed using Cox proportional hazards models., Results: Clinical and pathological features were more adverse among men whose postoperative prostate specific antigen was detectable. These men had poorer systemic recurrence-free survival and cancer specific survival compared to men with an undetectable postoperative prostate specific antigen, and even men whose prostate specific antigen subsequently became detectable. These differences persisted after multivariate adjustment for preoperative prostate specific antigen, specimen Gleason score, seminal vesicle and margin status. With a median followup of 8.5 years, 50 systemic recurrences and 26 deaths from cancer were observed. Gleason score and the prostate specific antigen doubling time were multivariate predictors of systemic recurrence, while Gleason score, margin status and seminal vesicle invasion were predictors of death from cancer., Conclusions: A detectable prostate specific antigen immediately following radical retropubic prostatectomy confers an increased risk of progression and death, but only in a subset of patients, who may be identified on the basis of pathological features and prostate specific antigen doubling time. In future such patients may be suitable for trials of systemic therapy.

Ted Levitt used to tell his Harvard Business School students, "People don't want a quarter-inch drill--they want a quarter-inch hole." But 35 years later, marketers are still thinking in terms of products and ever-finer demographic segments. The structure of a market, as seen from customers' point of view, is very simple. When people need to get a job done, they hire a product or service to do it for them. The marketer's task is to understand what jobs periodically arise in customers' lives for which they might hire products the company could make. One job, the "I-need-to-send-this-from-here-to-there-with-perfect-certainty-as-fast-as-possible"job, has existed practically forever. Federal Express designed a service to do precisely that--and do it wonderfully again and again. The FedEx brand began popping into people's minds whenever they needed to get that job done. Most of today's great brands--Crest, Starbucks, Kleenex, eBay, and Kodak, to name a few-started out as just this kind of purpose brand. When a purpose brand is extended to products that target different jobs, it becomes an endorser brand. But, over time, the power of an endorser brand will surely erode unless the company creates a new purpose brand for each new job, even as it leverages the endorser brand as an overall marker of quality. Different jobs demand different purpose brands. New growth markets are created when an innovating company designs a product and then positions its brand on a job for which no optimal product yet exists. In fact, companies that historically have segmented and measured markets by product categories generally find that when they instead segment by job, their market is much larger (and their current share much smaller) than they had thought. This is great news for smart companies hungry for growth.

Selective cyclooxygenase-2 (COX-2) inhibitors are used for the treatment of inflammation and pain while having the reported advantage of fewer upper gastrointestinal adverse effects compared to traditional nonsteroidal anti-inflammatory drugs. Although fewer adverse effects occur, there is still a risk for developing upper gastrointestinal adverse effects. Clinical practitioners have increased concern regarding this risk. The belief that COX-2 inhibitors are safe for the gastrointestinal tract has been questioned. This has encouraged the proposal of several explanations on the mechanism of gastromucosal injury and healing relative to COX isoenzymes. These mechanisms are delineated in the following review, along with the gastrointestinal safety, risk factors, clinical and case studies, and cost effectiveness of the COX-2 inhibitors.

Theory often gets a bum rap among managers because it's associated with the word "theoretical," which connotes "impractical." But it shouldn't. Because experience is solely about the past, solid theories are the only way managers can plan future actions with any degree of confidence. The key word here is "solid." Gravity is a solid theory. As such, it lets us predict that if we step off a cliff we will fall, without actually having to do so. But business literature is replete with theories that don't seem to work in practice or actually contradict each other. How can a manager tell a good business theory from a bad one? The first step is understanding how good theories are built. They develop in three stages: gathering data, organizing it into categories highlighting significant differences, then making generalizations explaining what causes what, under which circumstances. For instance, professor Ananth Raman and his colleagues collected data showing that bar code-scanning systems generated notoriously inaccurate inventory records. These observations led them to classify the types of errors the scanning systems produced and the types of shops in which those errors most often occurred. Recently, some of Raman's doctoral students have worked as clerks to see exactly what kinds of behavior cause the errors. From this foundation, a solid theory predicting under which circumstances bar code systems work, and don't work, is beginning to emerge. Once we forgo one-size-fits-all explanations and insist that a theory describes the circumstances under which it does and doesn't work, we can bring predictable success to the world of management.

Financial difficulties are threatening many healthcare organizations. To survive and target new markets of growth, strategic decision makers need to adapt existing business frameworks using the principle of disruptive innovation, which involves framing financial problems in a manner that incorporates changes in the marketplace and redefines solutions. Rather than emphasizing technological advances to capture shrinking, highly competitive markets, healthcare providers should consider the possibility of reaching largely untapped sources of revenue through a service line that is more convenient and less costly to consumers with less intensive needs.

The purpose of this study was to develop brief methods for classifying individuals by genetic taste sensitivity to 6-n-propylthiouracil (PROP). Two methods are described, which are modifications of a commonly used, suprathreshold procedure. Eighty-nine adult subjects rated the perceived intensity of solutions of 0.032, 0.32 and 3.2 mmol/l PROP and 0.01, 0.1, 1.0 mol/l sodium chloride (NaCl) (three-solution test), as well as solutions of 0.32 mmol/l PROP and 0.1 mol/l NaCl (one-solution test) using the Labeled Magnitude Scale (LMS). Subjects were classified as PROP nontasters (n=22), medium tasters (n=51) or supertasters (n=16) by the three-solution test. Taster status was independently determined by the one-solution test using numerical cutoff scores, which were determined by calculating the +/-95% confidence interval around the group means for PROP taste intensity. Supertasters gave PROP a rating of > or =51 ("very strong" on the LMS) and nontasters gave PROP a rating of < or =15.5 (approximately "moderate" on the LMS). Medium tasters fell between these two limits. Ninety-one percent of nontasters, 82% of medium tasters and 89% of supertasters were classified in a similar way by the two methods. Agreement between methods was high [coefficient of association (P)=0.74; P < or =.001]. These data suggest that three- and one-solution methods can reliably classify subjects by taste sensitivity to PROP and could provide valuable tools in population-based studies.

It's no secret that health care delivery is convoluted, expensive, and often deeply dissatisfying to consumers. But what is less obvious is that a way out of this crisis exists. Simpler alternatives to expensive care are already here--everything from $5 eyeglasses that people can use to correct their own vision to angioplasty instead of open-heart surgery. Just as the PC replaced the mainframe and the telephone replaced the telegraph operator, disruptive innovations are changing the landscape of health care. Nurse practitioners, general practitioners, and even patients can do things in less-expensive, decentralized settings that could once be performed only by expensive specialists in centralized, inconvenient locations. But established institutions--teaching hospitals, medical schools, insurance companies, and managed care facilities--are fighting these innovations tooth and nail. Instead of embracing change, they're turning the thumbscrews on their old processes--laying off workers, delaying payments, merging, and adding layers of overhead workers. Not only is this at the root of consumer dissatisfaction with the present system, it sows the seeds of its own destruction. The history of disruptive innovations tells us that incumbent institutions will be replaced with ones whose business models are appropriate to the new technologies and markets. Instead of working to preserve the existing systems, regulators, physicians, and pharmaceutical companies need to ask how they can enable more disruptive innovations to emerge. If the natural process of disruption is allowed to proceed, the result will be higher quality, lower cost, more convenient health care for everyone.

In light of the lack of molecular data on the sexual differentiation, maturation and interaction of parasitic nematodes of livestock, the present study investigated sex-specific gene expression in the nodule worm, Oesophagostomum dentatum (Strongylida). Using the technique of RNA arbitrarily-primed polymerase chain reaction (RAP-PCR), 31 expressed sequence tags (ESTs) differentially-displayed between the sexes were cloned. Northern blot analysis proved ten ESTs to be expressed exclusively in males (adults and fourth-stage larvae), while two were expressed solely in female stages. None of the ESTs were expressed in infective third-stage larvae. Sequence analysis and subsequent database searches revealed two male-specific ESTs to have significant similarity to Caenorhabditis elegans (predicted) proteins, a protein containing an EGF-like cysteine motif and a serine/threonine phosphatase. Another two male-specific ESTs had similarity to non-nematode sequences. The two female-specific ESTs had similarity to vitellogenin-5 and endonuclease III (predicted) from C. elegans. The remaining ESTs had no similarity to any nucleic acid or protein sequences contained in the databases. The isolation and characterisation of sex-specific ESTs from O. dentatum provides a unique opportunity for studying the reproductive biology of parasitic nematodes at the molecular level, with a view toward novel approaches for parasite control.

The aim of this study was to examine interactions between Ascaris suum and Oesophagostomum dentatum infections in pigs with regard to population dynamics of the worms such as recovery, location and length; and host reactions such as weight gain, pathological changes in the liver and immune response. Seventy-two helminth-naïve pigs were allocated into four groups. Group A was inoculated twice weekly with 10000 O. dentatum larvae for 8 weeks and subsequently challenge-infected with 1000 A. suum eggs, while Group B was infected with only 1000 A. suum eggs; Group C was inoculated twice weekly with 500 A. suum eggs for 8 weeks and subsequently challenge-infected with 5000 O. dentatum larvae, whereas Group D was given only 5000 O. dentatum larvae. All trickle infections continued until slaughter. Twelve pigs from Group A and B were slaughtered 10 days post challenge infection (p.c.i.) and the remaining 12 pigs from the each of the four groups were slaughtered 28 days p.c.i.. No clinical signs of parasitism were observed. The total worm burdens and the distributions of the challenge infection species were not influenced by previous primary trickle-infections with the heterologous species. Until day 10 p.c.i. the ELISA response between A. suum antigen and sera from the O. dentatum trickle infected pigs (Group A) pigs were significantly higher compared to the uninfected Group B. This was correlated with a significantly higher number of white spots on the liver surface both on Day 10 and 28 p.c.i. in Group A compared to Group B. The mean length of the adult O. dentatum worms was significantly reduced in the A. suum trickle infected group compared to the control group. These results indicate low level of interaction between the two parasite species investigated.

In the search for a serology tool for the diagnosis of nonpatent as well as patent infections with Oesophagostomum dentatum in pigs a water-soluble, unglycosilated antigen of about 30 kDa specific for the third-stage larvae of the parasite was purified by ion-exchange chromatography. In Western blots, the antigen was first detected by antibodies at day 7 postinfection. Cross-reactivity with O. quadrispinulatum, Ascaris suum, or Trichuris suis was not detected. It is suggested that this protein is a suitable tool for the species-specific serodiagnosis of O. dentatum infection in pigs.

We examined the impact of different Oesophagostomum dentatum dose levels and durations of infection on the development and infectivity of the following generation. Pigs were trickle-infected with 200, 2,000 or 20,000 L3/week over 20 weeks. Egg hatch assays were performed at monthly intervals; however, no consistent differences were found between any of the dose groups in the development of eggs into first-stage larvae. To compare larval infectivity, larvae were derived from faecal cultures set up from the low- and the high-dose groups in the early and the late part of the experiment, and were inoculated into helminth-free pigs (5,000 L3/pig). Worm establishments were significantly higher (P<0.05) in the group of pigs receiving larvae derived early in the experiment from the low-dose group compared with the two groups receiving larvae from high-dose groups, thus indicating an adverse effect of high doses of trickle infection on the later infectivity of L3 larvae derived from excreted eggs.

We examined the possibility of establishment of patent infections after percutaneous exposure of parasite-naive pigs to 10,000 Oesophagostomum dentatum infective larvae (L3). At 5 weeks after percutaneous exposure the pigs were slaughtered and low numbers of adult O. dentatum were recovered from the large intestine. In addition, exsheathed L3 were intravenously injected into pigs, which resulted in the recovery of fourth-stage larvae (L4) from nodules in the lungs as well as of L4 and adult worms from the large intestine. This study demonstrates the ability of porcine nodular worms to establish in the large intestine when pigs have been exposed percutaneously to infective larvae. It is possible that the larvae reach the large intestine by invading blood veins or the lymphatic system at the site of penetration.

For a study on the occurrence of resistance to reinfection with porcine nodular worm species, pigs were infected twice weekly with 1,000 infective larvae (L3) of Oesophagostomum quadrispinulatum for 8 weeks. All pigs, including noninfected controls, were then treated with fenbendazole. At 10 days after treatment, all pigs received a single challenge inoculation of 5,000 L3 of either O. dentatum or O. quadrispinulatum, respectively. Pigs were slaughtered at 6 weeks after the challenge infection for determination of their worm burdens. The pigs trickle- and challenge-infected with O. quadrispinulatum had significantly lower egg excretion levels (P < 0.01) and worm burdens (P < 0.05) than challenge control pigs, thus indicating some degree of host immunity against the homologous challenge infection. No resistance to reinfection was evident for the heterologous challenge infection. This study elucidates further aspects of the interaction between nodular worm species in the pig.

The genetic diversity in eight strains of Oesophagostomum dentatum and O. quadrispinulatum was investigated by the electrophoresis study of ten enzyme systems. The loci Idh-2, Fbp, Sdh, and Pgm were found to be diagnostic between the species examined. Both the proportion of fixed allelic differences (26.3%) and the genetic distance coefficient (D = 0.54) are well above the range for differentiation of valid species. Isoenzyme patterns of susceptible and resistant lines of O. dentatum showed at polymorphic loci a reduced genetic heterogeneity in the latter group. No qualitative difference in terms of the presence/absence of alleles was observed among susceptible and resistant isolates with the enzymes studied. The detection of one possible hybrid indicates that introgression in O. dentatum and O. quadrispinuatum may occur.

To investigate eventual hybridization between two nodular worm species of pigs, Oesophagostomum dentatum and O. quadrispinulatum, we used either mature, adult worms or 10-day-old fourth-stage larvae (L4) as starting material, employing a nonsurgical transplantation technique. Following the transfer of adult worms the ensuing first generation of larvae gave rise to adult worms that were found by morphological examination to be purely O. dentatum. Therefore, we decided to use the immature L4 as starting material. After the transfer of L4 to recipient pigs, fecal cultures were established and the L3 derived from the O. dentatum male O. quadrispinulatum female cross gave rise to adult but infertile worms, which morphologically had the sexual characters of their parent generation, whereas other characteristics were intermediate between the two species. Attempts to reproduce the hybrid worms or the reciprocal cross were unsuccessful, indicating that hybridization between the two species is a rarely occurring phenomenon.

The agar-gel migration technique has previously been described, however, aspects regarding the effect of timing on worm migration needed further scrutiny. In the first experiment, pigs inoculated with Oesophagostomum dentatum were slaughtered simultaneously and their intestines stored at 21-23 degrees C until processed pairwise 2, 4, 6, 8, 12 and 18 h after slaughter. More than 95% of the worms migrated out of the agar if processed within 6 h. In the second experiment, intestines were treated immediately after slaughter and the migratory speed of adult worms or 4th-stage larvae of O. dentatum or O. quadrispinulatum, or adult Hyostrongylus rubidus were studied. For both Oesophagostomum species, more than 90% of the worms were recovered within 1 h. H. rubidus was significantly slower; however, approximately 98% of the worms had migrated out of the agar-gel by 20 h. This information is essential in planning experiments where recovery of live worms is of value.

A trickle infection experiment was undertaken to study in detail the population dynamics of Oesophagostomum dentatum in pigs. Three groups of 32 pigs were inoculated via the feed twice weekly with 100 (Group A), 1000 (Group B) or 10,000 (Group C) O. dentatum infective larvae (L3). Five pigs from each group were killed 2, 4, 8, 12, 16, and 20 weeks after the first inoculation (p.i.) to determine their worm burdens. Weekly faecal egg counts were determined. At slaughter, worms were counted, differentiated according to sex and developmental stage, and their length measured. Faecal egg counts ranked with dose rate until week 15, but later were more variable. The proportion of the total number of L3 administered which were recovered at slaughter inversely ranked with dose rate. In group C it decreased over time, whereas in groups A and B there was no consistent pattern. Worm fecundities (epg/female) in groups A and B were higher than in group C. The lengths of the female worms increased over time, whereas the lengths of the male worms remained approximately constant from week 8. The study suggests reduced establishment of incoming larvae and lower fecundity of the female worms at high dose levels.

Companies find it difficult to change strategy for many reasons, but one stands out: strategic thinking is not a core managerial competence at most companies. Executives hone their capabilities by tackling problems over and over again. Changing strategy, however, is not usually a task that they face repeatedly. Once companies have found a strategy that works, they want to use it, not change it. Consequently, most managers do not develop a competence in strategic thinking. This Manager's Tool Kit presents a three-stage method executives can use to conceive and implement a creative and coherent strategy themselves. The first stage is to identify and map the driving forces that the company needs to address. The process of mapping provides strategy-making teams with visual representations of team members' assumptions, those pictures, in turn, enable managers to achieve consensus in determining the driving forces. Once a senior management team has formulated a new strategy, it must align the strategy with the company's resource-allocation process to make implementation possible. Senior management teams can translate their strategy into action by using aggregate project planning. And management teams that link strategy and innovation through that planning process will develop a competence in implementing strategic change. The author guides the reader through the three stages of strategy making by examining the case of a manufacturing company that was losing ground to competitors. After mapping the driving forces, the company's senior managers were able to devise a new strategy that allowed the business to maintain a competitive advantage in its industry.

The present work was undertaken to examine the effects of 3 different population densities of Oesophagostomum dentatum upon the development of worm induced mucosal changes in the colon following single infections. Groups of pigs were infected with single doses of 2000 (low dose), 20,000 (medium dose) or 200,000 (high dose) infective larvae, respectively. A total of 18 infected pigs (6 from each group) were examined for histopathological changes together with 3 helminth-free control pigs. There was a dose related difference in the intensity of colonic lesions; and using morphometry it was observed that the mucosal crypts of pigs in the high dose group were significantly longer than those in the 2 other groups. These differences disappeared by day 25 after infection despite the presence of larvae in the mucosa of the high dose group. This phenomenon may be related to inflammatory reactions in the colon, possibly in connection with the initiation of an immunological response in sites distant from the parasite larvae.

Helminth-free donor pigs were inoculated with infective larvae of Oesophagostomum dentatum. Five weeks later, the donor pigs were killed to recover the adult worms. By nonsurgical rectal transplantation, 6 groups of helminth-free recipient pigs were then given different female-to-male ratios (FMR) of O. dentatum worms (10% females [F], 50% F, 90% F) at either high (300 worms) or low (30 worms) doses. Fecal egg excretions were measured once weekly following transplantation until the pigs were killed 4 wk posttransplantation to assess the worm burdens and their location. There was a strong and significant correlation between numbers of male and female worms located in the different sections of the large intestine, suggesting that the worm sex as well as physiological factors in the pig intestine may govern the location of the worms. There were no significant differences in fecal egg counts or female worm fecundity between any of the groups. However at the low dose level, the female worm fecundity was markedly lower in the L10% F group than in the 2 other groups, thus suggesting for low worm densities an upper threshold for the FMR above which O. dentatum females produce fewer eggs.

Oesophagostomum dentatum antigen preparations of third (L3) or fourth (L4) stage larvae were characterised by Western blotting. Panels of sera obtained from pigs infected with O dentatum and Ascaris suum, respectively, reacted with the same bands of L3 antigen. In contrast high specificity against a characteristic band, was observed when L4 extract was employed as antigen. To establish an enzyme-linked immunosorbent assay (ELISA), a panel of homologous and heterologous sera was tested against O dentatum L4 extract. The best combined specificity and sensitivity was obtained when horseradish peroxidase (HRP) goat anti swine IgG conjugate was used rather than HRP rabbit anti swine Ig conjugate. Testing series of sera from pigs infected with single doses of either 2000, 20,000 or 200,000 infective larvae by the ELISA, a significant dose dependency in the antibody response was observed between the low and high dosage groups. This assay may be useful in future studies of the immune-mechanisms against nodular worm infections in pigs.