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Children will enjoy poring over this book--and will come away with a fundamental understanding of not only the most common architectural terms, but also of how the built world has evolved over time.

More than two decades ago, a well-known study on heart attack treatments provided evidence suggesting that, when appropriately adjusted for quality, medical care prices were actually declining (Cutler, McClellan, Newhouse, and Remler (1998)). Our paper revisits this subject by leveraging estimates from more than 8000 cost-effectiveness studies across a broad range of conditions and treatments. We find large qualityadjusted price declines associated with treatment innovations. To incorporate these quality-adjusted indexes into an aggregate measure of inflation, we combine an unadjusted medical-care price index, quality-adjusted price indexes from treatment innovations, and proxies for the diffusion rate of new technologies. In contrast to official statistics that suggest medical care prices increased by 0.53 percent per year relative to economy-wide inflation from 2000 to 2017, we find that quality-adjusted medical care prices declined by 1.33 percent per year over the same period.

Microbe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe, Bifidobacterium dentium , which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike other Bifidobacterium species, B. dentium does not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of using B. dentium and similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier. Much remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer. Bifidobacterium species colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, select Bifidobacterium strains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived species Bifidobacterium dentium would increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans. In silico data revealed that B. dentium lacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating that B. dentium could not use naive mucin glycans as primary carbon sources in vitro . To examine B. dentium mucus modulation in vivo , Swiss Webster germfree mice were monoassociated with live or heat-killed B. dentium . Live B. dentium -monoassociated mice exhibited increased colonic expression of goblet cell markers Krüppel-like factor 4 ( Klf4 ), Trefoil factor 3 ( Tff3 ), Relm -β, Muc2 , and several glycosyltransferases compared to both heat-killed B. dentium and germfree counterparts. Likewise, live B. dentium -monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining. In vitro , B. dentium -secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified that B. dentium -secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates that B. dentium is capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production. IMPORTANCE Microbe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe, Bifidobacterium dentium , which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike other Bifidobacterium species, B. dentium does not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of using B. dentium and similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier.

رواية تتسم بالقوة والواقعية، وقد تشعرك بالصدمة عندما تتذكر طبيعة المجتمع في الفترة الزمنية التي تم إطلاقها فيها، فهي تتحدى الأعراف السائدة آنذاك وهي تتطرق للقمع الذي تعانيه النساء ومفهوم الخطيئة والدين بالإضافة للخيانة والتفكّك الأسري الذي ينتج عنها، كل ذلك عبر التصوير الواقعي لكفاح امرأة من أجل نيل استقلالها وحريتها من تلك الأغلال. بتقديمها لهذه الرواية في أوائل القرن التاسع عشر اكتسبت آن برونته مكانة خاصة في الأدب الإنجليزي على الرغم من قلة أعمالها حيث تنبري في دفاع شرس عن حقوق النساء في مواجهة الإساءة النفسية من أزواجهن ومجتمعهن، وعلى الرغم من الهجوم القاسي الذي تلقته هي والرواية إلا أنها أصبحت من أكثر الكتب مبيعاً بل ومنافساً لرواية جين آير لشقيقتها الكبرى شارلوت برونته، لكن بعد وفاة آن في عام 1849 وبعد سنة من إصدار الرواية، منعت شارلوت نفسها الناشرين من إعادة طبعها بعذر \"أن الرواية كانت خطأ كاملاً\" لأنه \"لا يمكن تصور شيء أقل انسجاماً مع طبيعة الكاتبة\" ؛ بعبارة أخرى كانت تقول أن آن شابة محترمة من عائلة موقرة ومن الظلم أن يحكم عليها الغرباء لكتابتها.

Background Candida auris is a globally emerging multidrug resistant fungal pathogen causing nosocomial transmission. We report an ongoing outbreak of C. auris in a London cardio-thoracic center between April 2015 and July 2016. This is the first report of C. auris in Europe and the largest outbreak so far. We describe the identification, investigation and implementation of control measures. Methods Data on C. auris case demographics, environmental screening, implementation of infection prevention/control measures, and antifungal susceptibility of patient isolates were prospectively recorded then analysed retrospectively. Speciation of C. aur is was performed by MALDI-TOF and typing of outbreak isolates performed by amplified fragment length polymorphism (AFLP). Results This report describes an ongoing outbreak of 50 C. auris cases over the first 16 month (April 2015 to July 2016) within a single Hospital Trust in London. A total of 44 % ( n  = 22/50) patients developed possible or proven C. auris infection with a candidaemia rate of 18 % ( n  = 9/50). Environmental sampling showed persistent presence of the yeast around bed space areas. Implementation of strict infection and prevention control measures included: isolation of cases and their contacts, wearing of personal protective clothing by health care workers, screening of patients on affected wards, skin decontamination with chlorhexidine, environmental cleaning with chorine based reagents and hydrogen peroxide vapour. Genotyping with AFLP demonstrated that C. auris isolates from the same geographic region clustered. Conclusion This ongoing outbreak with genotypically closely related C. auris highlights the importance of appropriate species identification and rapid detection of cases in order to contain hospital acquired transmission.

Adequate nutrition during the pre- and early-postnatal periods plays a critical role in programming early neurodevelopment. Disruption of neurodevelopment by nutritional deficiencies can result not only in lasting functional deficits, but increased risk of neuropsychiatric disease in adulthood. Historical periods of famine such as the Dutch Hunger Winter and the Chinese Famine have provided foundational evidence for the long-term effects of developmental malnutrition on neuropsychiatric outcomes. Because neurodevelopment is a complex process that consists of many nutrient- and brain-region-specific critical periods, subsequent clinical and pre-clinical studies have aimed to elucidate the specific roles of individual macro- and micronutrient deficiencies in neurodevelopment and neuropsychiatric pathologies. This review will discuss developmental iron deficiency (ID), the most common micronutrient deficiency worldwide, as a paradigm for understanding the role of early-life nutrition in neurodevelopment and risk of neuropsychiatric disease. We will review the epidemiologic data linking ID to neuropsychiatric dysfunction, as well as the underlying structural, cellular, and molecular mechanisms that are thought to underlie these lasting effects. Understanding the mechanisms driving lasting dysfunction and disease risk is critical for development and implementation of nutritional policies aimed at preventing nutritional deficiencies and their long-term sequelae.

It is widely accepted that maternal healthcare is vital for improving maternal and neonatal mortality rates. Furthermore, the continuum of care-the integrated delivery of antenatal, delivery and postnatal care-has been shown to be particularly important. Sub-Saharan Africa has the highest neonatal and maternal mortality rates in the world; significant improvements in the provision and utilisation of the continuum are urgently needed, therefore the barriers preventing access need to be better understood. This study aimed to identify key factors associated with the utilisation of maternal healthcare, in the Mchinji District of Malawi. 4,244 pregnant women from the Mchinji District of Malawi were interviewed between March and December 2013. The overall utilisation of maternal healthcare was calculated by combining the use of antenatal, delivery and postnatal care into one variable-continuum of care. Univariate and multivariate logistic regressions were performed to determine the factors associated with utilisation of maternal healthcare. Utilisation of maternal healthcare in the Mchinji District was inadequate; only 24% of women received the recommended package. Being further from a healthcare facility (OR = 0.2, 95%CI = 0.04-0.96), having at least one live child (OR = 0.87, 95%CI = 0.84-0.99), previous experience of miscarriage (OR = 0.64, 95%CI = 0.50-0.82) or abuse (OR = 0.81, 95%CI = 0.69-0.95) reduced utilisation, whereas being in the richest 20% (OR = 1.33 95%CI = 1.08-1.65), having a planned pregnancy (OR = 1.3, 95%CI = 1.11-1.51) or more control over decisions (OR = 1.09, 95%CI = 0.80-1.49) increased utilisation. Seven groups of women were identified as having an increased risk of low utilisation of maternal healthcare; women living >5km from a healthcare facility, within the poorest socio-economic group, experiencing an unplanned pregnancy, with at least one live child, experience of a previous miscarriage, no control over their healthcare decisions or experience of abuse. Policy makers should pay extra attention to these high-risk groups when designing and delivering strategies to improve maternal healthcare utilisation.

The fitness effect of a mutation can depend on both its genetic background, known as epistasis, and the prevailing external environment. Many examples of these dependencies are known, but few studies consider both aspects in combination, especially as they affect mutations that have been selected together. We examine interactions between five coevolved mutations in eight diverse environments. We find that mutations are, on average, beneficial across environments, but that there is high variation in their fitness effects, including many examples of mutations conferring a cost in some, but not other, genetic background-environment combinations. Indeed, even when global interaction trends are accounted for, specific local mutation interactions are common and differed across environments. One consequence of this dependence is that the range of trade-offs in genotype fitness across selected and alternative environments are contingent on the particular evolutionary path followed over the mutation landscape. Finally, although specific interactions were common, there was a consistent pattern of diminishing returns epistasis whereby mutation effects were less beneficial when added to genotypes of higher fitness. Our results underline that specific mutation effects are highly dependent on the combination of genetic and external environments, and support a general relationship between a genotype’s current fitness and its potential to increase in fitness.

Background Histamine is a key mediator of the anti-inflammatory activity conferred by the probiotic organism Lactobacillus reuteri ATCC PTA 6475 in animal models of colitis and colorectal cancer. In L. reuteri , histamine synthesis and secretion requires l -histidine decarboxylase and a l -histidine/histamine exchanger. Chloride channel (ClC)-family proton/chloride antiporters have been proposed to act as electrochemical shunts in conjunction with amino acid decarboxylase systems, correcting ion imbalances generated by decarboxylation through fixed ratio exchange of two chloride ions for one proton. This family is unique among transporters by facilitating ion flux in either direction. Here we examine the histidine decarboxylase system in relation to ClC antiporters in the probiotic organism Lactobacillus reuteri . Results In silico analyses reveal that L. reuteri possesses two ClC transporters, EriC and EriC2, as well as a complete histidine decarboxylase gene cluster (HDC) for the synthesis and export of histamine. When the transport activity of either proton/chloride antiporter is disrupted by genetic manipulation, bacterial histamine output is reduced. Using fluorescent reporter assays, we further show that ClC transporters affect histamine output by altering intracellular pH and membrane potential. ClC transport also alters the expression and activity of two key HDC genes: the histidine decarboxylase ( hdcA ) and the histidine/histamine exchanger ( hdcP ). Conclusions Histamine production is a potentially beneficial feature for intestinal microbes by promoting long-term colonization and suppression of inflammation and host immune responses. ClC transporters may serve as tunable modulators for histamine production by L. reuteri and other gut microbes.