Estimating the full health and economic benefits of current and future influenza vaccines.

In the dynamic landscape of respiratory virus vaccines, it is crucial to assess the value of novel mRNA and combination influenza/COVID-19 vaccines in low- and middle-income countries. Modeling studies, such as the one conducted by Waterlow et al., provide vital information about the cost-benefit potential of these products compared to currently licensed vaccines. However, this approach only accounts for directly measured medically attended influenza-associated illnesses and has two major limitations. First, this method fails to capture the full disease burden of influenza (including non-respiratory and non-medically attended influenza illnesses), which are particularly important drivers of disease burden in infants and older adults. Second, the model does not describe the ancillary benefits of influenza vaccination such as the attenuation of severe disease, prevention of severe non-respiratory outcomes (e.g., myocardial infarctions), or reduced antibiotic use. To obtain a comprehensive understanding of the benefits of influenza vaccines, we must strive to improve the inputs for future modeling-based evaluations.

Raising Backyard Poultry in Rural Bangladesh: Financial and Nutritional Benefits, but Persistent Risky Practices.

Poultry is commonly raised by households in rural Bangladesh. In 2007, the Government of Bangladesh began a mass media campaign to disseminate 10 recommended precautions to prevent transmission of H5N1 from poultry to humans. This longitudinal study explored the contribution of backyard poultry on household economy and nutrition and compared poultry-raising practices to government recommendations. From 2009 to 2012, we enrolled a nationally representative sample of 2489 primary backyard poultry raisers from 115 rural villages selected by probability proportional to population size. Researchers interviewed the raisers to collect data on poultry-raising practices. They followed the raisers for 2-12 months to collect data on household income and nutrition from poultry. Income from backyard poultry flocks accounted for 2.8% of monthly household income. Return on annual investment (ROI) per flock was 480%. Yearly, median family consumption of eggs was one-fifth of the total produced eggs and three poultry from their own flock. Respondents' reported practices conflicted with government recommendations. Sixty per cent of raisers had never heard of avian influenza or 'bird flu'. Among the respondents, 85% handled sick poultry or poultry that died due to illness, and 49% slaughtered or defeathered sick poultry. In 37% of households, children touched poultry. Fifty-eight per cent never washed their hands with soap after handling poultry, while <1% covered their nose and mouth with a cloth when handling poultry. Only 3% reported poultry illness and deaths to local authorities. These reported practices did not improve during the study period. Raising backyard poultry in rural Bangladesh provides important income and nutrition with an excellent ROI. Government recommendations to reduce the risk of avian influenza transmission did not impact the behaviour of poultry producers. Further research should prioritize developing interventions that simultaneously reduce the risk of avian influenza transmission and increase productivity of backyard poultry.

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.

We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.

Suicidal ideation in Spanish and Italian lesbian and gay young adults: The role of internalized sexual stigma / Ideación suicida de adultos jóvenes lesbianas y gays en España y Italia: el rol del estigma sexual interiorizado

BACKGROUND: The purpose of this study was to explore which of the outcomes attained by the application of the psychological program Intervención en Adolescentes con Fobia Social (Intervention in Adolescents with Social Phobia) can be attributed to the therapist's competence. METHOD: The experimental study consists of three conditions: Waiting list control, Group treated by expert psychologists, and Group treated by inexperienced psychologists, with a sample of 110 Spanish adolescents whose mean age was 15.42 years (SD = 0.97, range: 14-18). All participants met the criteria for diagnosis of Generalized Social Phobia) and most of them were female (65.45%). RESULTS: (I) The effect size attributable to the therapist was low compared to the effect size associated with the manual-based treatment program in the dependent variables measured, and (II) Expert therapists attained a much greater remission of the criteria for the diagnosis of Generalized Social Phobia among participants than did the inexperienced therapists. CONCLUSIONS: The IAFS Program was responsible for most of the change measured in participants

ANTECEDENTES: la literatura científica puso de relieve que se encontraron individuos de minorías sexuales que tenían el doble de ideas suicidas que las personas heterosexuales. MÉTODO: el objetivo principal del presente estudio fue probar un modelo donde el estigma sexual interiorizado (ISS) midiera la relación entre algunos factores de estrés relacionados con la homosexualidad y las ideas suicidas. El estudio involucró a dos grupos de adultos jóvenes lesbianas y gays de España (N = 209) y de Italia (N = 345). La encuesta total incluyó 316 hombres gays y 228 mujeres lesbianas. Se utilizó el Path Analysis para verificar los efectos directos e indirectos (mediados) de las variables en repulsión por la vida. RESULTADOS: en ambos grupos, tanto el español como el italiano, las pasadas experiencias de victimización y el ISS tuvieron un efecto significativo en repulsión por la vida. En ambos grupos el ISS actuó como mediador significativo entre el efecto de la ocultación de la orientación sexual y la participación religiosa en relación con la repulsión por la vida. CONCLUSIONES: el presente estudio demostró que el ISS es un moderador potencial en la ocultación de la orientación sexual, la participación religiosa y las experiencias pasadas de la victimización en ideas suicidas

[Pyonephrosis due to xanthine stones in a bitch treated with allopurinol]. / Pyonephrose durch Xanthinsteine bei einer mit Allopurinol behandelten Hündin.

A 2-year-old, neutered, crossbreed bitch was presented as an emergency with painful abdomen, fever and vomiting. The cause of the acute abdomen was a pyonephrosis of the left kidney, caused by four xanthine stones, which had blocked the ureter. After surgical removal of the heavily altered left kidney, the bitch recovered rapidly. Because of a leishmaniasis the bitch had been treated with allopurinol over an extended period, the xanthine stone formation is likely to have resulted from allopurinol usage. Because there were additionally small concrements in the right kidney, the medication was stopped. Subsequently, the dog has received a low purine diet, and the leishmaniasis titer and renal function have been monitored regularly.

Learning by observation in children with autism spectrum disorder.

BACKGROUND: Observing another person performing a complex action accelerates the observer's acquisition of the same action and limits the time-consuming process of learning by trial and error. Learning by observation requires specific skills such as attending, imitating and understanding contingencies. Individuals with autism spectrum disorder (ASD) exhibit deficits in these skills. METHOD: The performance of 20 ASD children was compared with that of a group of typically developing (TD) children matched for chronological age (CA), IQ and gender on tasks of learning of a visuomotor sequence by observation or by trial and error. Acquiring the correct sequence involved three phases: a detection phase (DP), in which participants discovered the correct sequence and learned how to perform the task; an exercise phase (EP), in which they reproduced the sequence until performance was error free; and an automatization phase (AP), in which by repeating the error-free sequence they became accurate and speedy. RESULTS: In the DP, ASD children were impaired in detecting a sequence by trial and error only when the task was proposed as first, whereas they were as efficient as TD children in detecting a sequence by observation. In the EP, ASD children were as efficient as TD children. In the AP, ASD children were impaired in automatizing the sequence. Although the positive effect of learning by observation was evident, ASD children made a high number of imitative errors, indicating marked tendencies to hyperimitate. CONCLUSIONS: These findings demonstrate the imitative abilities of ASD children although the presence of imitative errors indicates an impairment in the control of imitative behaviours.

Impact of neighborhood biomass cooking patterns on episodic high indoor particulate matter concentrations in clean fuel homes in Dhaka, Bangladesh.

Exposure to particulate matter (PM2.5 ) from the burning of biomass is associated with increased risk of respiratory disease. In Dhaka, Bangladesh, households that do not burn biomass often still experience high concentrations of PM2.5 , but the sources remain unexplained. We characterized the diurnal variation in the concentrations of PM2.5 in 257 households and compared the risk of experiencing high PM2.5 concentrations in biomass and non-biomass users. Indoor PM2.5 concentrations were estimated every minute over 24 h once a month from April 2009 through April 2010. We found that households that used gas or electricity experienced PM2.5 concentrations exceeding 1000 µg/m(3) for a mean of 35 min within a 24-h period compared with 66 min in biomass-burning households. In both households that used biomass and those that had no obvious source of particulate matter, the probability of PM2.5 exceeding 1000 µg/m(3) were highest during distinct morning, afternoon, and evening periods. In such densely populated settings, indoor pollution in clean fuel households may be determined by biomass used by neighbors, with the highest risk of exposure occurring during cooking periods. Community interventions to reduce biomass use may reduce exposure to high concentrations of PM2.5 in both biomass and non-biomass using households.

Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up.

Chronic renal failure is a well-known long-term complication of methylmalonic aciduria (MMA-uria), occurring even under apparently optimal metabolic management. The onset of renal dysfunction seems to be dependent on the type of defect and vitamin B12-responsiveness. We report on a patient with a vitamin B12-responsive cobalamin A type (cblA) MMA-uria caused by a homozygous stop mutation (p.R145X) in the cobalamin A gene (MMAA). She was diagnosed with chronic kidney disease (CKD) stage III at the age of 12 years. Following re-evaluation, the patient received vitamin B12 (hydroxocobalamin) treatment, resulting in a significant decrease in the concentration of methylmalonic acid (MMA) in urine and plasma. Until age 29 years glomerular filtration rate remained stable probably due to hydroxocobalamin treatment slowing down progression to end-stage renal failure. Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation. The patient received a renal transplant at age 35 years. Under continuous treatment with hydroxocobalamin there is no evidence of kidney damage due to MMA-uria until the last follow-up 6 years after transplantation. This case report illustrates (i) a long-term follow-up of a patient with MMA-uria due to cblA deficiency, (ii) the involvement of the kidney as a target organ and (iii) the importance of early and adequate vitamin B12 substitution in responsive patients. Further investigation will be necessary to prove the protective effect of hydroxocobalamin in the kidney in vitamin B12-responsive patients.

Indoor exposure to particulate matter and the incidence of acute lower respiratory infections among children: a birth cohort study in urban Bangladesh.

Approximately half of all children under two years of age in Bangladesh suffer from an acute lower respiratory infection (ALRI) each year. Exposure to indoor biomass smoke has been consistently associated with an increased risk of ALRI in young children. Our aim was to estimate the effect of indoor exposure to particulate matter (PM2.5 ) on the incidence of ALRI among children in a low-income, urban community in Bangladesh. We followed 257 children through two years of age to determine their frequency of ALRI and measured the PM2.5 concentrations in their sleeping space. Poisson regression was used to estimate the association between ALRI and the number of hours per day that PM2.5 concentrations exceeded 100 µg/m(3) , adjusting for known confounders. Each hour that PM2.5 concentrations exceeded 100 µg/m(3) was associated with a 7% increase in incidence of ALRI among children aged 0-11 months (adjusted incidence rate ratio (IRR) 1.07, 95% CI 1.01-1.14), but not in children 12-23 months old (adjusted IRR 1.00, 95% CI 0.92-1.09). Results from this study suggest that reducing indoor PM2.5 exposure could decrease the frequency of ALRI among infants, the children at highest risk of death from these infections.

Influenza-associated excess mortality in southern Brazil, 1980-2008.

In order to estimate influenza-associated excess mortality in southern Brazil, we applied Serfling regression models to monthly mortality data from 1980 to 2008 for pneumonia/influenza- and respiratory/circulatory-coded deaths for all ages and for those aged ≥60 years. According to viral data, 73∙5% of influenza viruses were detected between April and August in southern Brazil. There was no clear influenza season for northern Brazil. In southern Brazil, influenza-associated excess mortality was 1∙4/100,000 for all ages and 9∙2/100,000 person-years for persons aged ≥60 years using underlying pneumonia/influenza-coded deaths and 10∙0/100,000 for all ages and 86∙6/100,000 person-years for persons aged ≥60 years using underlying respiratory/circulatory-coded deaths. Influenza-associated excess mortality rates for southern Brazil are similar to those published for other countries. Our data support the need for continued influenza surveillance to guide vaccination campaigns to age groups most affected by this virus in Brazil.

Expert variability provides perspective on the strengths and weaknesses of citizen-driven intertidal monitoring program.

Citizen scientist programs are a means to efficiently conduct large-scale surveys of ecosystems or managed species, provided that concerns over the quality and use of data generated by nonexperts can be addressed. This study presents actions taken in a citizen science program to assure data quality and demonstrates the validity of citizen-generated data. In this case the accuracy of data collected by secondary school students as citizens in a program that quantitatively sampled benthic rocky intertidal communities at 13 sites on Maui, Molokai, Oahu, and Hawai'i island during the years 2004-2007 was evaluated. In 2007, two independent research teams collected data simultaneously with students at five sites on eight sampling dates. Comparisons of Shannon diversity and Bray-Curtis similarity values computed and simulated from student and researcher collected data revealed that nonexpert students accurately collect community-level data within the range of the variation that occurs between researchers. Students were, however, likely to misidentify cryptic and rare species. These findings have direct implications for the conservation goals of the monitoring program as the assessment reveals that students are likely to misidentify early alien introductions but are able to monitor the abundances of native and introduced species once they become established. The validity assessment designed for this investigation is unique in that it directly compares consistent errors made by citizens in data collection to expert variability to identify usage limitations and can be a guide for future studies that involve the efforts of trained volunteers.

Prevalent high-risk respiratory hygiene practices in urban and rural Bangladesh.

OBJECTIVES: To identify existing respiratory hygiene risk practices, and guide the development of interventions for improving respiratory hygiene. METHODS: We selected a convenience sample of 80 households and 20 schools in two densely populated communities in Bangladesh, one urban and one rural. We observed and recorded respiratory hygiene events with potential to spread viruses such as coughing, sneezing, spitting and nasal cleaning using a standardized assessment tool. RESULTS: In 907 (81%) of 1122 observed events, households' participants coughed or sneezed into the air (i.e. uncovered), 119 (11%) into their hands and 83 (7%) into their clothing. Twenty-two per cent of women covered their coughs and sneezes compared to 13% of men (OR 2.6, 95% CI 1.6-4.3). Twenty-seven per cent of persons living in households with a reported monthly income of >72.6 US$ covered their coughs or sneezes compared to 13% of persons living in households with lower income (OR 3.2, 95% CI 1.6-6.2). In 956 (85%) of 1126 events, school participants coughed or sneezed into the air and 142 (13%) into their hands. Twenty-seven per cent of coughs/sneezes in rural schools were covered compared to 10% of coughs/sneezes in urban schools (OR 2.3, 95% CI 1.5-3.6). Hand washing was never observed after participants coughed or sneezed into their hands. CONCLUSION: There is an urgent need to develop culturally appropriate, cost-effective and scalable interventions to improve respiratory hygiene practices and to assess their effectiveness in reducing respiratory pathogen transmission.

Coenzyme Q(10) is decreased in fibroblasts of patients with methylmalonic aciduria but not in mevalonic aciduria.

The content of coenzyme Q(10) (CoQ(10)) was examined in skin fibroblasts of 10 patients with mevalonic aciduria (MVA) and of 22 patients with methylmalonic aciduria (MMA). Patients with these inborn errors of metabolism are thought to be at risk for CoQ(10) depletion either by direct inhibition of the proximal pathway of CoQ(10) synthesis (MVA) or indirectly by inhibition of mitochondrial energy metabolism (MMA). We demonstrated that CoQ(10) concentrations were not significantly different from controls in MVA patients, suggesting that there may be upregulatory effects. On the other hand the CoQ(10) content in fibroblasts of patients with MMA was significantly reduced.

Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB).

Isolated methylmalonic acidurias comprise a heterogeneous group of inborn errors of metabolism caused by defects of methylmalonyl-CoA mutase (MCM) (mut0, mut-) or deficient synthesis of its cofactor 5'-deoxyadenosylcobalamin (AdoCbl) (cblA, cblB). The aim of this study was to compare the long-term outcome in patients from these four enzymatic subgroups. Eighty-three patients with isolated methylmalonic acidurias (age 7-33 y) born between 1971 and 1997 were enzymatically characterized and prospectively followed to evaluate the long-term outcome (median follow-up period, 18 y). Patients with mut0 (n = 42), mut- (n = 10), cblA (n = 20), and cblB (n = 11) defects were included into the study. Thirty patients (37%) died, and 26 patients survived with a severe or moderate neurologic handicap (31%), whereas 27 patients (32%) remained neurologically uncompromised. Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF. Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects. In addition, long-term outcome was dependent on the age cohort and cobalamin responsiveness.

Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations.

Isolated methylmalonic acidurias (MMA-urias) comprise a group of rare autosomal recessively inherited disorders characterised by accumulation of MMA in urine and other body fluids, resulting from deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM). Isolated MMA-uria results from either MCM apoenzyme defects (mut(0) and mut(-)) or defects in synthesis of its cofactor 5-deoxyadenosylcobalamin, i.e. cblA, cblB and cblD-variant 2. To date various studies have identified 171 disease-causing mutations in the MCM gene (MUT). We report mutation analysis in 32 probands with mut MMA-uria including 13 probands with a mut(-) defect. Sixty two of 64 possible mutant alleles were identified, seven of which were novel missense alleles. We found three novel mutations (c.427C>T/p.H143Y; c.862T>C/p.S288P; c.1361G>A/p.G454E) among 19 probands with a mut(0) defect and four novel mutations (c.299A>G/p.Y100C; c.1031C>T/p.S344F; c.1097A>G/p.N366S; c.2081G>T/p.R694L) among 13 probands with a mut(-) defect. Our study provides evidence that the p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut(-) phenotype.

The first case of 3-methylcrotonyl-CoA carboxylase (MCC) deficiency responsive to biotin.

3-Methylcrotonylglycinuria is an inborn error of leucine catabolism with an autosomal recessive pattern of inheritance that results from a deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). We report on a nine-year-old boy with severe psychomotor retardation who developed infantile spasms at the age of three weeks. Urine analysis at the age of two years revealed massive 3-methylcrotonylglycinuria and 3-hydroxyisovaleric aciduria suggesting MCC deficiency. Carnitine serum levels were decreased. Biotin therapy led to a dramatic decrease in the frequency of seizures, disappearance of hypsarrhythmia, and near normalisation of organic aciduria. Four months later a protein-restricted diet was introduced in addition and the boy remained clinically and metabolically stable. However, severe psychomotor delay persisted, and the seizures partially reoccurred. Biochemical findings showed partial MCC deficiency in cultured fibroblasts. Molecular genetic studies revealed a heterozygote missense mutation, MCCA-R385S, converting arginine to serine in a highly conserved region of the MCCA gene. This is the first patient with MCC deficiency caused by a heterozygote mutation and who demonstrated a substantial and sustained clinical and biochemical response to therapeutic doses of biotin. Sadly, this patient again also demonstrates that the main determinant of the outcome of even easily treatable metabolic diseases is timely diagnosis.

Severe holocarboxylase synthetase deficiency with incomplete biotin responsiveness resulting in antenatal insult in samoan neonates.

We describe 7 Polynesian babies with a unique severe form of holocarboxylase synthetase deficiency characterized by antenatal growth retardation, subependymal cysts, only partial response to biotin, and a poor outcome.

Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation.

CONTEXT: Pyruvate dehydrogenase phosphatase (PDP) deficiency has been previously reported as an enzymopathy, but the genetic basis for such a defect has never been established. OBJECTIVE: The aim of this study was to identify the cause of the defect in two patients who presented with PDP deficiency. PATIENTS: We studied two brothers of consanguineous parents who presented with neonatal hypotonia, elevated lactate, and less than 25% native pyruvate dehydrogenase complex (PDHc) activity in skin fibroblasts compared with controls. The activity of the complex could be restored to normal values by preincubation of the cells with dichloroacetate or by treating cell extracts with calcium. RESULTS: These two individuals were found to be homozygous for a 3-bp deletion in the coding sequence of the PDP isoform 1 (PDP1), which removes the amino acid residue leucine from position 213 of the protein. A recombinant version of this protein was synthesized and found to have a very reduced (<5%) ability to activate purified PDHc. Reduced steady-state levels of PDP1 in the patient's fibroblasts coupled with the low catalytic activity of the mutant PDP1 resulted in native PDHc activity being reduced, but this could be corrected by the addition of recombinant PDP1 (wild type). CONCLUSION: We have identified mutations in PDP1 in two brothers with PDP deficiency and have proven that the mutation is disease-causing. This is the first demonstration of human disease due to a mutation in PDP1.

Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy.

Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.