High Plasma Levels of Betaine, a Trimethylamine N-Oxide Related Metabolite, are Associated with Severity of Cirrhosis

Background and Aims: The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished because of impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered because of impaired hepatic flavin monooxygenase expression. Here, we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity. Methods: Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score. Results: Plasma betaine was on average 60% higher (p < .001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (p = .44). After liver transplantation (n = 13), betaine decreased (p = .017; p = .36 vs. PREVEND population), whereas TMAO levels tended to increase (p = .085) to higher levels than in the PREVEND population (p = .003). Betaine levels were positively associated with the CPT stage and MELD score (both p < .001). The association with the MELD score remained in the fully adjusted analysis (p < .001). The association of TMAO with the MELD score did not reach significance (p = .11). Neither betaine nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted p = .78 and p = .44, respectively). Conclusion: Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity and decrease after liver transplantation

The Genetics Journey: A Case Report of a Genetic Diagnosis Made 30 Years Later

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re‐evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family’s clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that “the patient” can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient’s daughter’s pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient’s husband’s internet search of his wife’s clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re‐evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147210/1/jgc40894.pd

Trends in Weekly Reported Net use by Children During and after Rainy Season in Central Tanzania.

The use of long-lasting insecticidal nets (LLINs) is one of the principal interventions to prevent malaria in young children, reducing episodes of malaria by 50% and child deaths by one fifth. Prioritizing young children for net use is important to achieve mortality reductions, particularly during transmission seasons. Households were followed up weekly from January through June 2009 to track net use among children under seven under as well as caretakers. Net use rates for children and caretakers in net-owning households were calculated by dividing the number of person-weeks of net use by the number of person-weeks of follow-up. Use was stratified by age of the child or caretaker status. Determinants of ownership and of use were assessed using multivariate models. Overall, 60.1% of the households reported owning a bed net at least once during the study period. Among net owners, use rates remained high during and after the rainy season. Rates of use per person-week decreased as the age of the child rose from 0 to six years old; at ages 0-23 months and 24-35 months use rates per person-week were 0.93 and 0.92 respectively during the study period, while for children ages 3 and 4 use rates per person-week were 0.86 and 0.80. For children ages 5-6 person-week ratios dropped to 0.55. This represents an incidence rate ratio of 1.67 for children ages 0-23 months compared to children aged 5-6. Caretakers had use rates similar to those of children age 0-35 months. Having fewer children under age seven in the household also appeared to positively impact net use rates for individual children. In this area of Tanzania, net use is very high among net-owning households, with no variability either at the beginning or end of the rainy season high transmission period. The youngest children are prioritized for sleeping under the net and caretakers also have high rates of use. Given the high use rates, increasing the number of nets available in the household is likely to boost use rates by older children

Trends in healthcare utilization among older Americans with colorectal cancer: A retrospective database analysis

<p>Abstract</p> <p>Background</p> <p>Analyses of utilization trends (cost drivers) allow us to understand changes in colorectal cancer (CRC) costs over time, better predict future costs, identify changes in the use of specific types of care (eg, hospice), and provide inputs for cost-effectiveness models. This retrospective cohort study evaluated healthcare resource use among US Medicare beneficiaries diagnosed with CRC between 1992 and 2002.</p> <p>Methods</p> <p>Cohorts included patients aged 66+ newly diagnosed with adenocarcinoma of the colon (n = 52,371) or rectum (n = 18,619) between 1992 and 2002 and matched patients from the general Medicare population, followed until death or December 31, 2005. Demographic and clinical characteristics were evaluated by cancer subsite. Resource use, including the percentage that used each type of resource, number of hospitalizations, and number of hospital and skilled nursing facility days, was evaluated by stage and subsite. The number of office, outpatient, and inpatient visits per person-year was calculated for each cohort, and was described by year of service, subsite, and treatment phase. Hospice use rates in the last year of life were calculated by year of service, stage, and subsite for CRC patients who died of CRC.</p> <p>Results</p> <p>CRC patients (mean age: 77.3 years; 44.9% male) used more resources than controls in every category (<it>P </it>< .001), with the largest differences seen in hospital days and home health use. Most resource use (except hospice) remained relatively steady over time. The initial phase was the most resource intense in terms of office and outpatient visits. Hospice use among patients who died of CRC increased from 20.0% in 1992 to 70.5% in 2004, and age-related differences appear to have evened out in later years.</p> <p>Conclusion</p> <p>Use of hospice care among CRC decedents increased substantially over the study period, while other resource use remained generally steady. Our findings may be useful for understanding CRC cost drivers, tracking trends, and forecasting resource needs for CRC patients in the future.</p

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1

Outdoor host seeking behaviour of Anopheles gambiae mosquitoes following initiation of malaria vector control on Bioko Island, Equatorial Guinea

<p>Abstract</p> <p>Background</p> <p>Indoor-based anti-vector interventions remain the preferred means of reducing risk of malaria transmission in malaria endemic areas around the world. Despite demonstrated success in reducing human-mosquito interactions, these methods are effective solely against endophilic vectors. It may be that outdoor locations serve as an important venue of host seeking by <it>Anopheles gambiae </it>sensu lato (s.l.) mosquitoes where indoor vector suppression measures are employed. This paper describes the host seeking activity of anopheline mosquito vectors in the Punta Europa region of Bioko Island, Equatorial Guinea. In this area, <it>An. gambiae </it>sensu stricto (s.s.) is the primary malaria vector. The goal of the paper is to evaluate the importance of <it>An gambiae </it>s.l. outdoor host seeking behaviour and discuss its implications for anti-vector interventions.</p> <p>Methods</p> <p>The venue and temporal characteristics of host seeking by anopheline vectors in a hyperendemic setting was evaluated using human landing collections conducted inside and outside homes in three villages during both the wet and dry seasons in 2007 and 2008. Additionally, five bi-monthly human landing collections were conducted throughout 2009. Collections were segregated hourly to provide a time distribution of host-seeking behaviour.</p> <p>Results</p> <p>Surprisingly high levels of outdoor biting by <it>An. gambiae </it>senso stricto and <it>An. melas </it>vectors were observed throughout the night, including during the early evening and morning hours when human hosts are often outdoors. As reported previously, <it>An. gambiae </it>s.s. is the primary malaria vector in the Punta Europa region, where it seeks hosts outdoors at least as much as it does indoors. Further, approximately 40% of <it>An. gambiae </it>s.l. are feeding at times when people are often outdoors, where they are not protected by IRS or LLINs. Repeated sampling over two consecutive dry-wet season cycles indicates that this result is independent of seasonality.</p> <p>Conclusions</p> <p><it>An. gambiae </it>s.l. mosquitoes currently seek hosts in outdoor venues as much as indoors in the Punta Europa region of Bioko Island. This contrasts with an earlier pre-intervention observation of exclusive endophagy of <it>An. gambiae </it>in this region. In light of this finding, it is proposed that the long term indoor application of insecticides may have resulted in an adaptive shift toward outdoor host seeking in <it>An. gambiae </it>s.s. on Bioko Island.</p

Malaria eradication: the economic, financial and institutional challenge

Malaria eradication raises many economic, financial and institutional challenges. This paper reviews these challenges, drawing on evidence from previous efforts to eradicate malaria, with a special focus on resource-poor settings; summarizes more recent evidence on the challenges, drawing on the literature on the difficulties of scaling-up malaria control and strengthening health systems more broadly; and explores the implications of these bodies of evidence for the current call for elimination and intensified control

The influence of mosquito resting behaviour and associated microclimate for malaria risk

<p>Abstract</p> <p>Background</p> <p>The majority of the mosquito and parasite life-history traits that combine to determine malaria transmission intensity are temperature sensitive. In most cases, the process-based models used to estimate malaria risk and inform control and prevention strategies utilize measures of mean outdoor temperature. Evidence suggests, however, that certain malaria vectors can spend large parts of their adult life resting indoors.</p> <p>Presentation of hypothesis</p> <p>If significant proportions of mosquitoes are resting indoors and indoor conditions differ markedly from ambient conditions, simple use of outdoor temperatures will not provide reliable estimates of malaria transmission intensity. To date, few studies have quantified the differential effects of indoor <it>vs </it>outdoor temperatures explicitly, reflecting a lack of proper understanding of mosquito resting behaviour and associated microclimate.</p> <p>Testing the hypothesis</p> <p>Published records from 8 village sites in East Africa revealed temperatures to be warmer indoors than outdoors and to generally show less daily variation. Exploring the effects of these temperatures on malaria parasite development rate suggested indoor-resting mosquitoes could transmit malaria between 0.3 and 22.5 days earlier than outdoor-resting mosquitoes. These differences translate to increases in transmission risk ranging from 5 to approaching 3,000%, relative to predictions based on outdoor temperatures. The pattern appears robust for low- and highland areas, with differences increasing with altitude.</p> <p>Implications of the hypothesis</p> <p>Differences in indoor <it>vs </it>outdoor environments lead to large differences in the limits and the intensity of malaria transmission. This finding highlights a need to better understand mosquito resting behaviour and the associated microclimate, and to broaden assessments of transmission ecology and risk to consider the potentially important role of endophily.</p

Malaria control under the Taliban regime: insecticide-treated net purchasing, coverage, and usage among men and women in eastern Afghanistan

BACKGROUND: Scaling up insecticide-treated mosquito net (ITN) coverage is a key malaria control strategy even in conflict-affected countries 12. Socio-economic factors influence access to ITNs whether subsidized or provided free to users. This study examines reported ITN purchasing, coverage, and usage in eastern Afghanistan and explores women's access to health information during the Taliban regime (1996-2001). This strengthens the knowledge base on household-level health choices in complex-emergency settings. METHODS: Fifteen focus group discussions (FGDs) and thirty in-depth interviews were conducted with men and women from ITN-owning and non-owning households. FGDs included rank ordering, pile sorting and focused discussion of malaria knowledge and ITN purchasing. Interviews explored general health issues, prevention and treatment practices, and women's malaria knowledge and concerns. Seven key informant interviews with health-related workers and a concurrent survey of 200 ITN-owning and 214 non-owning households were used to clarify or quantify findings. RESULTS: Malaria knowledge was similar among men and women and ITN owners and non-owners. Women reported obtaining health information through a variety of sources including clinic staff, their husbands who had easier access to information, and particularly female peers. Most participants considered ITNs very desirable, though not usually household necessities. ITN owners reported more household assets than non-owners. Male ITN owners and non-owners ranked rugs and ITNs as most desired, while women ranked personal assets such as jewellery highest. While men were primarily responsible for household decision-making and purchasing, older women exerted considerable influence. Widow-led and landless households reported most difficulties purchasing ITNs. Most participants wanted to buy ITNs only if they could cover all household members. When not possible, preferential usage was given to women and children. CONCLUSIONS: Despite restricted access to health facilities and formal education, Afghan women were surprisingly knowledgeable about the causes of malaria and the value of ITNs in prevention. Inequities in ITN usage were noted between rather than within households, with some unable to afford even one ITN and others not wanting ITNs unless all household members could be protected. Malaria knowledge thus appears a lesser barrier to ITN purchasing and coverage in eastern Afghanistan than are pricing and distribution strategies

The politics of heroes through the prism of popular heroism

This is the author accepted manuscript. The final version is available from Palgrave Macmillan via the DOI in this record.In modern day Britain, the discourse of national heroification is routinely utilised by politicians, educationalists and cultural industry professionals, whilst also being a popular concept to describe deserving ‘do-gooders’ who contribute to British society in a myriad of ways. We argue that although this heroification discourse is enacted as a discursive device of encouraging politically and morally desirable behaviour, it is dissociated from the largely under-explored facets of contemporary popular heroism. To compensate for this gap, this paper explores public preferences for heroes using survey data representative of British adults. This analysis demonstrates a conceptual stretching in the understanding of heroism, and allows identifying age- and gender-linked dynamics which effect public choices of heroes. In particular, we demonstrate that age above all determines the preference for having a hero, but does not explain preferences for specific hero-types. The focus on gender illustrates that the landscape of popular heroism reproduces a male-dominated bias which exists in the wider political and cultural heroification discourse. Simultaneously, our study shows that if national heroification discourse in Britain remains male-centric, the landscape of popular heroism is characterised by a gendered trend towards privatisation of heroes being particularly prominent amongst women. In the conclusion, this paper argues for a conceptual revision and re-gendering of the national heroification discourse as a step towards both empirically grounded, and age- and gender-sensitive politics of heroes and heroines.AHR