Structural Basis of an Asymmetric Condensin ATPase Cycle.

The condensin protein complex plays a key role in the structural organization of genomes. How the ATPase activity of its SMC subunits drives large-scale changes in chromosome topology has remained unknown. Here we reconstruct, at near-atomic resolution, the sequence of events that take place during the condensin ATPase cycle. We show that ATP binding induces a conformational switch in the Smc4 head domain that releases its hitherto undescribed interaction with the Ycs4 HEAT-repeat subunit and promotes its engagement with the Smc2 head into an asymmetric heterodimer. SMC head dimerization subsequently enables nucleotide binding at the second active site and disengages the Brn1 kleisin subunit from the Smc2 coiled coil to open the condensin ring. These large-scale transitions in the condensin architecture lay out a mechanistic path for its ability to extrude DNA helices into large loop structures.

A Direct Comparison Between Discrete Choice With Duration and Composite Time Trade-Off Methods: Do They Produce Similar Results?

OBJECTIVES: Discrete choice experiments including a duration attribute (DCEd) represent a promising candidate method for valuing health-related quality-of-life instruments. However, it has not been established that DCEd can produce similar results as composite time trade-off (cTTO) or EuroQol Valuation Technology (EQ-VT) valuations of the EQ-5D-5L instrument. This study provides a direct comparison between cTTO and EQ-VT, and DCEd valuation methods. METHODS: An EQ-VT study was conducted in Trinidad and Tobago to value the EQ-5D-5L. 1079 respondents each completed 10 cTTO tasks and 12 discrete choice experiments tasks without a duration attribute. A separate sample of 970 respondents each completed 18 split-triplet DCEd tasks. Several regression models were applied to the EQ-VT data, and the DCEd data were analyzed using mixed logit models with an exponential discount rate. The estimated values were compared using scatterplots and Bland-Altman plots. RESULTS: The ordering of dimensions was identical in level 5 for cTTO/EQ-VT and DCEd models, with pain/discomfort being the most important dimension and usual activities being least important. cTTO/EQ-VT models produced a value for state 55555 ranging between -0.52 and -0.69, whereas this was -0.543 for the nonlinear mixed logit model for the DCEd data. Scatterplots and Bland-Altman plots suggested excellent agreement between cTTO/EQ-VT and DCEd-based estimates. CONCLUSIONS: CTTO/EQ-VT and DCEd valuations produce similar results when correcting DCEd for nonlinear time preferences. The ordering of importance of the dimensions and scale are identical, suggesting that the 2 methods measure the same construct and produce similar results.

The EQ-5D-5L valuation study for Trinidad and Tobago.

PURPOSE: The 2016 EQ-5D-3L value set for Trinidad and Tobago (T&T) allows for the calculation of EQ-5D-5L values via the crosswalk algorithm. The 2016 value set was based on methods predating the EQ-VT protocol, now considered the gold standard for developing EQ-5D value sets. Furthermore, direct elicitation of EQ-5D-5L is preferred over crosswalked values. This study aimed to produce an EQ-5D-5L value set for T&T. METHODS: A representative sample (age, sex, geography) of adults each completed 10 composite Time Trade-Off (cTTO) tasks and 12 Discrete Choice Experiment (DCE) tasks in face-to-face interviews. The cTTO data were analyzed using a Tobit model that corrects for heteroskedasticity. DCE data were analyzed using a mixed logit model. The cTTO and DCE data were combined in hybrid models. RESULTS: One thousand and seventy-nine adults completed the valuation interviews. Among the modelling approaches that were explored, the hybrid heteroskedastic Tobit model produced all internally consistent, statistically significant coefficients, and performed best in terms of out-of-sample predictivity for single states. Compared to the existing EQ-5D-5L crosswalk set, the new value set had a higher number of negative values (236 or 7.6% versus 21 or 0.7%). The mean absolute difference was 0.157 and the correlation coefficient between the two sets was 0.879. CONCLUSION: This study provides a value set for the EQ-5D-5L for T&T using the EQ-VT protocol. We recommend this value set for QALY computations relating to T&T.

Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis.

Biosynthesis of glycogen, the essential glucose (and hence energy) storage molecule in humans, animals and fungi1, is initiated by the glycosyltransferase enzyme, glycogenin (GYG). Deficiencies in glycogen formation cause neurodegenerative and metabolic disease2-4, and mouse knockout5 and inherited human mutations6 of GYG impair glycogen synthesis. GYG acts as a 'seed core' for the formation of the glycogen particle by catalysing its own stepwise autoglucosylation to form a covalently bound gluco-oligosaccharide chain at initiation site Tyr 195. Precise mechanistic studies have so far been prevented by an inability to access homogeneous glycoforms of this protein, which unusually acts as both catalyst and substrate. Here we show that unprecedented direct access to different, homogeneously glucosylated states of GYG can be accomplished through a palladium-mediated enzyme activation 'shunt' process using on-protein C-C bond formation. Careful mimicry of GYG intermediates recapitulates catalytic activity at distinct stages, which in turn allows discovery of triphasic kinetics and substrate plasticity in GYG's use of sugar substrates. This reveals a tolerant but 'proof-read' mechanism that underlies the precision of this metabolic process. The present demonstration of direct, chemically controlled access to intermediate states of active enzymes suggests that such ligation-dependent activation could be a powerful tool in the study of mechanism.

EQ-5D self-reported health in Barbados and Jamaica with EQ-5D-5L population norms for the English-speaking Caribbean.

BACKGROUND: The EQ-5D instrument is increasingly used in clinical and resource allocation decision making in developed and developing countries. EQ-5D valuation and population norms studies have been undertaken for Trinidad and Tobago, however no population norms or value sets have been generated for the other Caribbean countries. The aims of this study were to provide population norms for Barbados and Jamaica, and to develop a set of population norms that could be used by the other English-speaking Caribbean countries. METHODS: The EQ-5D-5L self-reported health questionnaire was included in surveys of representative samples of adults in Barbados and adults in Jamaica in 2013. EQ-5D health states, mean EQ VAS scores and mean EQ-5D-5L index values (using the Trinidad and Tobago value set) were calculated for demographic groups in both countries based on 2347 respondents from Barbados and 1423 from Jamaica. A set of 'Caribbean' norms were developed by combining the Barbados and Jamaica data with norms recently published for Trinidad and Tobago. RESULTS: Data were obtained for 2347 and 1423 respondents in Barbados and Jamaica respectively. The mean index and EQ VAS values were 0.943 and 81.9 for Barbados, and 0.948 and 87.8 for Jamaica. The health states most commonly observed in the two countries were similar. Generally the demographic patterns of self-reported health were consistent with those found in other studies. Some differences between the countries were observed in the patterns of rates of reporting problems on the EQ-5D dimensions among age-gender groups specifically for anxiety/depression and pain/discomfort CONCLUSION: This study has produced a set of EQ-5D population norms that can be used as base-line values in clinical and clinico-economic analyses for Barbados and Jamaica and for the English-Speaking Caribbean region.

Structural insight into the human mitochondrial tRNA purine N1-methyltransferase and ribonuclease P complexes.

Mitochondrial tRNAs are transcribed as long polycistronic transcripts of precursor tRNAs and undergo posttranscriptional modifications such as endonucleolytic processing and methylation required for their correct structure and function. Among them, 5'-end processing and purine 9 N1-methylation of mitochondrial tRNA are catalyzed by two proteinaceous complexes with overlapping subunit composition. The Mg2+-dependent RNase P complex for 5'-end cleavage comprises the methyltransferase domain-containing protein tRNA methyltransferase 10C, mitochondrial RNase P subunit (TRMT10C/MRPP1), short-chain oxidoreductase hydroxysteroid 17ß-dehydrogenase 10 (HSD17B10/MRPP2), and metallonuclease KIAA0391/MRPP3. An MRPP1-MRPP2 subcomplex also catalyzes the formation of 1-methyladenosine/1-methylguanosine at position 9 using S-adenosyl-l-methionine as methyl donor. However, a lack of structural information has precluded insights into how these complexes methylate and process mitochondrial tRNA. Here, we used a combination of X-ray crystallography, interaction and activity assays, and small angle X-ray scattering (SAXS) to gain structural insight into the two tRNA modification complexes and their components. The MRPP1 N terminus is involved in tRNA binding and monomer-monomer self-interaction, whereas the C-terminal SPOUT fold contains key residues for S-adenosyl-l-methionine binding and N1-methylation. The entirety of MRPP1 interacts with MRPP2 to form the N1-methylation complex, whereas the MRPP1-MRPP2-MRPP3 RNase P complex only assembles in the presence of precursor tRNA. This study proposes low-resolution models of the MRPP1-MRPP2 and MRPP1-MRPP2-MRPP3 complexes that suggest the overall architecture, stoichiometry, and orientation of subunits and tRNA substrates.

MANAGEMENT OF THYROTOXICOSIS AMONG GENERAL PRACTITIONERS IN TRINIDAD COMPARED WITH 2016 AMERICAN THYROID ASSOCIATION GUIDELINES FOR HYPERTHYROIDISM.

Objective: A previous Trinidadian survey highlighted the investigative and therapeutic approaches selected by general practitioners (GPs) in managing thyrotoxicosis. The main objective of this study was to compare practice with existing guidelines. Methods: In this cross-sectional study a pretested de novo questionnaire was self-administered to GPs throughout Trinidad. The survey evaluated GPs' choices in management of thyrotoxicosis cases and compared their responses to the 2016 American Thyroid Association guidelines as well as with those previously reported locally. Results: A total of 159 completed questionnaires were analyzed (59% response rate). Thyroid stimulating hormone was the preferred (94%) biochemical test to confirm thyrotoxicosis etiology. A combination of ultra-sound and thyroid scintigraphy, thyroid ultrasound alone, and scintigraphy only were the testing options selected by 41%, 38%, and 12%, respectively. Generally medical therapy with antithyroid drugs was the preferred treatment option with 86% of respondents selecting this option for the index case of newly diagnosed female Graves disease. The greatest proportion of respondents that selected radioactive iodine (RAI) was 35% for both the index case as well as the male equivalent. Surgery was the most popular option at 25% for patients with a toxic multinodular goiter. Having access to RAI and scintigraphy was reported by 32% and 28%, respectively. Conclusion: GPs appear to be constrained to making rational choices based upon availability rather than what the guidelines recommend. In the absence of formal continuing medical education for GPs on thyrotoxicosis, dissemination of guidelines at the primary care level may reduce this gap. Abbreviations: ATA = American Thyroid Association; ATD = antithyroid drugs; CME = continued medical education; GP = general practitioner; RAI = radioactive iodine; SURG = surgery; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Quality-Adjusted Life-Years without Constant Proportionality.

BACKGROUND: A quality-adjusted life-year is a common unit of measurement in health valuation. Under its constant proportionality assumption, the value of a quality-adjusted life span is defined as the product of preference weight and life span. OBJECTIVES: To empirically identify an alternative functional relationship between life span and value by relaxing the constant proportionality assumption. METHODS: Using an online survey, 5367 respondents completed 30 to 40 paired comparisons where each involved a choice between two health outcomes: one with a longer life span and health problems (five-level EuroQol five-dimensional questionnaire) and the other with a shorter life span and no problems (time trade-off pair). Using 2670 pairs, a saturated model with indicator variables for 27 life spans and 90 health problems of varying duration and severity was estimated by maximum likelihood. Its coefficients empirically illustrate the relationship between life span and value on a quality-adjusted life-year scale. RESULTS: The results reject constant proportionality (P < 0.01) and support the use of a power function to describe the relationship between life span and value, namely, value = preference weight × life spanß. The estimate of power (ß = 0.415; 95% confidence interval 0.41-0.42) appears to depend on whether life span was expressed in a temporal unit of days (0.403), weeks (0.509), months (0.541), or years (0.654). CONCLUSIONS: Raising life span to a power less than 1 implies decreasing marginal value of life span and greatly improved model fit, and confirms previous violations of proportionality. This power function may replace conventional assumptions in health valuation studies. Nevertheless, governmental agencies may favor a longer time horizon than that of the general population.

Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein.

MRPP2 (also known as HSD10/SDR5C1) is a multifunctional protein that harbours both catalytic and non-catalytic functions. The protein belongs to the short-chain dehydrogenase/reductases (SDR) family and is involved in the catabolism of isoleucine in vivo and steroid metabolism in vitro. MRPP2 also moonlights in a complex with the MRPP1 (also known as TRMT10C) protein for N1-methylation of purines at position 9 of mitochondrial tRNA, and in a complex with MRPP1 and MRPP3 (also known as PRORP) proteins for 5'-end processing of mitochondrial precursor tRNA. Inherited mutations in the HSD17B10 gene encoding MRPP2 protein lead to a childhood disorder characterised by progressive neurodegeneration, cardiomyopathy or both. Here we report two patients with novel missense mutations in the HSD17B10 gene (c.34G>C and c.526G>A), resulting in the p.V12L and p.V176M substitutions. Val12 and Val176 are highly conserved residues located at different regions of the MRPP2 structure. Recombinant mutant proteins were expressed and characterised biochemically to investigate their effects towards the functions of MRPP2 and associated complexes in vitro. Both mutant proteins showed significant reduction in the dehydrogenase, methyltransferase and tRNA processing activities compared to wildtype, associated with reduced stability for protein with p.V12L, whereas the protein carrying p.V176M showed impaired kinetics and complex formation. This study therefore identified two distinctive molecular mechanisms to explain the biochemical defects for the novel missense patient mutations.

The EQ-5D-3L valuation study for Bermuda: using an on-line EQ-VT protocol.

BACKGROUND: In many countries, methods of economic evaluation and Health Technology Assessment are used to inform healthcare resource allocation decisions. These approaches often require EQ-5D health outcomes measures. This study aimed to create an EQ-5D-3L value set for Bermuda from which EQ-5D-5L Crosswalk values could be obtained. METHODS: Respondents in Bermuda were recruited locally. A team of Trinidad-based interviewers with prior EQ-5D-3L valuation experience conducted valuation interviews on-line using the EQ-VT protocol. Respondents completed composite time-trade off (cTTO) and discrete choice experiment (DCE) tasks. A hybrid model that included both the cTTO and DCE data was estimated. An EQ-5D-5L crosswalk value set was then created from the EQ-5D-3L index values. Coefficients in the resulting crosswalk model were compared with those of crosswalk and valuation studies from other countries. RESULTS: The valuation tasks were completed by a near-representative sample of 366 adult Bermuda citizens. Half of the respondents reported being in state 11111. The lowest EQ VAS and EQ-5D-3L index values were 20 and - 0.120 respectively. The hybrid model produced all logically consistent and statistically significant coefficients that in turn produced index values that were very similar to those obtained in a preliminary model (MAD of 0.027). DISCUSSION: The on-line EQ-VT valuation study was successfully conducted in Bermuda and the values therein can now be used for economic analysis in Bermuda. The Bermuda values differed considerably from those of the other countries against which they were compared. Challenges were encountered with recruitment for an on-line survey in a small population.

Architecture and regulation of filamentous human cystathionine beta-synthase.

Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life for the production of glutathione, cysteine, and hydrogen sulfide. Appended to the conserved catalytic domain of human CBS is a regulatory domain that modulates activity by S-adenosyl-L-methionine (SAM) and promotes oligomerisation. Here we show using cryo-electron microscopy that full-length human CBS in the basal and SAM-bound activated states polymerises as filaments mediated by a conserved regulatory domain loop. In the basal state, CBS regulatory domains sterically block the catalytic domain active site, resulting in a low-activity filament with three CBS dimers per turn. This steric block is removed when in the activated state, one SAM molecule binds to the regulatory domain, forming a high-activity filament with two CBS dimers per turn. These large conformational changes result in a central filament of SAM-stabilised regulatory domains at the core, decorated with highly flexible catalytic domains. Polymerisation stabilises CBS and reduces thermal denaturation. In PC-3 cells, we observed nutrient-responsive CBS filamentation that disassembles when methionine is depleted and reversed in the presence of SAM. Together our findings extend our understanding of CBS enzyme regulation, and open new avenues for investigating the pathogenic mechanism and therapeutic opportunities for CBS-associated disorders.

Quality of life of MS patients in Trinidad and Tobago: Anomaly or adaptation?

BACKGROUND AND OBJECTIVE: There has been growing interest in quality of life associated with multiple sclerosis but the research has been overwhelmingly carried out in developed countries. This study aimed to assess quality of life of multiple sclerosis patients in Trinidad and Tobago. METHODS: All multiple sclerosis patients were asked to complete demographic, EQ-5D-5L and MSQOL-54 questionnaires. EQ-5D data were compared with population norms for Trinidad and Tobago. MSQOL-54 data were compared with results from a matching cohort of non-MS respondents. Regression analyses were used to explore the association between MSQOL-54 scales and EQ-5D utility. RESULTS: The 97 patients were mainly urban, highly educated and 75% female. EQ-5D-5L data showed more frequent and more severe problems and lower index values than the population and patients of other chronic illness clinics in Trinidad and Tobago. MSQOL-54 results showed that patients were more affected by physical items, but had high scores on mental and emotional items when compared with the matching cohort and patients in other countries. CONCLUSION: The low prevalence and demographics of patients suggest the possibility of undetected cases in rural areas and/or among less educated groups. Further investigation into the high levels of mental and emotional health among patients may lead to the design of interventions to help patients of multiple sclerosis and other illnesses.

The impact of chronic disease and accompanying bio-psycho-social factors on health-related quality of life.

Background: Most chronic illnesses lead to poor health outcomes. Bio-psycho-social sequelae and accompanying depression lead to further deterioration in health-related quality of life (HRQoL). This study explored the HRQoL of patients with major chronic diseases in a public tertiary health care institution in Trinidad and Tobago. Methods: This cross-sectional study was conducted on a convenience sample of adult patients with chronic illnesses in a public health institute in Trinidad. Data were collected using face-to-face interviews and consenting patients' records. A 43-item questionnaire comprising demographic, medical, and lifestyle questions, the nine-item patient health questionnaire (PHQ-9) on depression, and the EQ-5D-5L HRQoL questionnaire were used. Psychological and social variables were divided into six groups: Group 1 (community attachment variables), Group 2 (family and friends), Group 3 (life satisfaction), Group 4 (depression symptoms), Group 5 (social support), and Group 6 (lifestyle variables). The impact of these variables on HRQoL was investigated using regression and canonical correlation analysis. Results: Patients were primarily female (70.3%), Indo-Trinidadian (63.9%), having diabetes mellitus (46.0%) or cancer (35.8%). The quality of life was lower than Trinidad and Tobago EQ-5D-5L population norms. Females and older patients had worse HRQoL than males and younger patients, respectively. Furthermore, kidney failure, all cancer patients, and middle-aged female cancer patients fared worse than other categories. Life satisfaction and exercise were significantly associated with better HRQoL. Depressive symptoms were consistently and significantly negatively associated with HRQoL. Conclusions: HRQoL was lower among participants with chronic disease than in the general population. Depressive symptoms led to worse HRQoL, whereas life satisfaction and exercise significantly improved HRQoL. The EQ-5D dimension most frequently affected was anxiety/depression.

Health-Related Quality of Life Population Norms for Belize Using EQ-5D-5L.

OBJECTIVES: There has been a growing interest in the use of EQ-5D health outcomes measures in Latin America and the Caribbean. Population norms data provide a benchmark against which clinicians, researchers, and policy makers can compare the health status of patient, treatment, or demographic groups. This study aimed to provide EQ-5D-5L population norms for Belize. METHODS: The EQ-5D-5L questionnaire was included in a national survey in Belize in 2014. The survey also captured key demographic variables. EQ-5D-5L health states, EQ-5D visual analog scale (EQ VAS) scores, and EQ-5D-5L index values (based on the Trinidad and Tobago value set) were obtained for key demographic groups in Belize. RESULTS: A representative sample of 2078 respondents completed the survey. The mean index value, EQ VAS score, and ceiling level for Belize were 0.947, 82.6, and 67.8%, respectively. Similar to other Caribbean countries, Belizeans self-reported relatively high EQ VAS scores and ceiling levels compared with non-Caribbean regions. Men reported generally higher health status than women, health status declined as age rises, and the dimensions with the highest burden were pain/discomfort and mobility. CONCLUSIONS: This study provides researchers and practitioners in Belize with tools to use EQ-5D-5L. Users can apply the EQ VAS scores and EQ-5D-5L states presented herein as reference values. Until an EQ-5D-5L value set is created for Belize, the Trinidad and Tobago index values can be applied to Belizean-reported EQ-5D-5L states, which can then be compared with the index values presented in this study.

Evaluating Health Inequality in Five Caribbean Basin Countries Using EQ-5D-5L.

BACKGROUND: EQ-5D-5L is a standardized health outcomes instrument that can be added to national surveys to measure inequality in health outcomes. The aim of this study was to produce baseline values of health inequality using EQ-5D-5L for five countries in the Caribbean Basin region based on national surveys in 2012-2014. METHODS: The EQ-5D-5L questionnaire was included in adult population surveys of Barbados, Belize, Colombia, Jamaica and Trinidad and Tobago. EQ-5D-5L measures were calculated for demographic groups using stratifiers from the World Health Organization's PROGRESS-Plus framework, and generalized linear models were used to test for association between EQ-5D-5L and the PROGRESS-Plus variables. Ordered logit models were used to obtain odds ratios for the effect of the PROGRESS-Plus variables on reporting problems on the EQ-5D-5L dimensions. The Kakwani index was calculated for each country. RESULTS: Data were obtained for representative samples in each country, giving a combined total of 11,284 respondents. Different patterns of inequality were observed among the five countries. The biggest drivers of inequality were age and gender, and the biggest EQ-5D factors were self-care in Belize and pain/discomfort in the other four countries. CONCLUSION: This study demonstrated that the EQ-5D-5L instrument can easily be added to national surveys. Inequality measures from this study can be used as baseline values for comparisons with future similar surveys in these five countries to infer changes in health inequality as measured by EQ-5D outcomes. These can be used to track the performance of policy initiatives aimed at specific demographic groups.

Quality of Life and Health Status Among Patients Receiving Renal Replacement Therapy in Trinidad and Tobago, West Indies.

PURPOSE: The determinants of quality of life for patients on renal replacement therapy vary across the world. The aim of this study is to determine the quality of life of patients on renal replacement therapy in Trinidad and Tobago and predictors thereof. PATIENTS AND METHODS: This cross-sectional study took place over a 1-year period. Data were obtained from 530 out of 1383 patients meeting inclusion criteria (100 transplants, 80 peritoneal dialyses, 350 hemodialyses) using the survey instruments. Stratified random sampling with proportional allocation was used to select patients at hemodialysis centres. The Kidney Disease Quality of Life questionnaire (KDQOL-36), EuroQol and demographic questionnaires were administered via face-to-face interviews. SPSS24, STATA14 and MINITAB18 were used for descriptive and inferential data analysis. RESULTS: Of the 530 patients, 52.5% were male, 37.5% were in the 56-65 years age group and 51.3% were of Indo-Trinbagonian descent. Hypertension (25.5%) and type 2 diabetes mellitus (62.0%) were reported as the main causes of kidney disease in the dialysis group. In the transplant category, chronic glomerulonephritis (45%) was the main aetiology of kidney disease. The KDQOL-36 domain scores and significantly associated variables included modality of renal replacement, Charlson's Comorbidity Index, ethnicity, income and employment status. Transplant patients had higher mean subcomponent Kidney Disease Quality of Life scores and performed better in the EuroQol than patients on dialysis. Patients on peritoneal dialysis had a better quality of life than hemodialysis patients. Among patients on hemodialysis, an arteriovenous fistula significantly impacted their quality of life. CONCLUSION: Renal transplant recipients enjoy the best quality of life and health state among patients on renal replacement therapy in Trinidad and Tobago. Increasing patients' access to renal transplantation or peritoneal dialysis will markedly improve health status for the number of years of renal replacement therapy.

EQ-5D-5L Population Norms and Health Inequality in Colombia.

OBJECTIVES: The EQ-5D-3L and EQ-5D-5L instruments have been used in studies of patient and demographic groups in Colombia, but to date there are no 5L population norms. This study aimed to produce a set of EQ-5D-5L population norms for Colombia and to see what insights into health inequality in Colombia can be discerned from these norms. METHODS: The EQ-5D-5L self-reported health questionnaire was included in a survey of a representative sample of 3400 adults aged 18 to 64 in Colombia. EQ-5D-5L states, mean EQ VAS, and index values were obtained by sex, age, education, income group, ethnicity, residence, employment status, health insurance status, and household size. EQ-5D-5L index values from Uruguay were used. Regression models were used to investigate inequality. RESULTS: The mean EQ VAS value was 85.3, the mean index value was 0.953, and 52.2% of the sample reported being in state 11111. Self-reported health was higher for men, declined in higher age groups, and was lower for lower-income and education groups. The EQ-5D-5L instrument was observed to be more sensitive than the EQ-5D-3L instrument in Colombia. The dimensions with the highest prevalence of reported problems were anxiety/depression and pain/discomfort. The main drivers of inequality were age, sex, income, and education. CONCLUSIONS: The population norms developed in this study can be used as baseline values for future studies of patient or treatment groups, and for investigations into the health of specific demographic groups.

Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase.

Cobalamin, commonly known as vitamin B12, is an essential micronutrient for humans because of its role as an enzyme cofactor. Cobalamin is one of over a dozen structurally related compounds - cobamides - that are found in certain foods and are produced by microorganisms in the human gut. Very little is known about how different cobamides affect B12-dependent metabolism in human cells. Here, we test in vitro how diverse cobamide cofactors affect the function of methylmalonyl-CoA mutase (MMUT), one of two cobalamin-dependent enzymes in humans. We find that, although cobalamin is the most effective cofactor for MMUT, multiple cobamides support MMUT function with differences in binding affinity (Kd), binding kinetics (kon), and concentration dependence during catalysis (KM, app). Additionally, we find that six disease-associated MMUT variants that cause cobalamin-responsive impairments in enzymatic activity also respond to other cobamides, with the extent of catalytic rescue dependent on the identity of the cobamide. Our studies challenge the exclusive focus on cobalamin in the context of human physiology, indicate that diverse cobamides can support the function of a human enzyme, and suggest future directions that will improve our understanding of the roles of different cobamides in human biology.

Preliminary findings of an investigation into the relationship between national culture and EQ-5D value sets.

BACKGROUND: Despite the growing importance of the EQ-5D descriptive system as a basis for the valuation of QALYs in cost-utility analysis, for most countries, there are no EQ-5D value sets. Researchers and policy makers wishing to use the EQ-5D descriptive system in a country for which there is no value set are advised to use one from a nearby or 'similar' population. Factors other than geographic proximity can affect the relative values of EQ-5D states. OBJECTIVE: This study explores the links between national culture and EQ-5D value sets. METHOD: Rank correlation analysis is used to explore relationships between the relative values of a set of EQ-5D states and dimensions of national culture. The latter are taken from Hofstede's framework which operationalizes national culture in five dimensions. RESULTS: For the data currently available (countries for which EQ-5D value sets and scores on dimensions of culture both exist), moderate and strong correlations were found between the culture dimension of power distance and individualism and the EQ-5D dimensions of pain/discomfort and anxiety/depression. Moderate correlations were also observed between the cultural dimension of masculinity and the EQ-5D dimensions of self care, usual activities and pain/discomfort. Uncertainty avoidance correlates with the EQ-5D dimension of anxiety/depression. DISCUSSION: The correlation patterns observed are generally consistent with a priori expectations based on the nature of the dimensions of culture and the EQ-5D model. This analysis demonstrates the potential of national culture in providing insight into the drivers of the relative values of EQ-5D dimensions for different countries and in informing decisions about which EQ-5D value sets to use in situations where one does not exist.