A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson's disease: a study protocol for a randomised controlled trial.

BACKGROUND: Parkinson's disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals' needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. METHODS/DESIGN: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. PRIMARY OUTCOME: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson's Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. DISCUSSION: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016.

Iron needs during pregnancy: do we need to rethink our targets?

This paper argues that current estimates of the need for absorbed iron, estimates of iron absorption, and hence estimates of iron requirements for pregnant women greatly depend on what is determined as the desirable or target hemoglobin concentration (goal). The existing goal appears to be based on the maximal hemoglobin concentration that can be achieved with iron supplementation of well-nourished women; this is a situation that can be expected to minimize iron absorption efficiency. I am unaware of attempts to define hemoglobin or anemia goals based on functional criteria (health of infant or mother). The current approach may seriously overestimate iron need and discourage food-based programs; furthermore, it may declare operational iron supplementation programs to be failures when, in fact, many programs may be successful in preventing functional effects of iron deficiency anemia. This is illustrated with data from a completed comparative study of daily and weekly iron supplementation. The final plea is to set aside existing traditions and, instead, attempt to develop functional criteria for anemia and establish functional goals of hemoglobin concentrations to be achieved during pregnancy.

Household food insecurity and hunger among families using food banks.

Over the past two decades, the demand for charitable food assistance has steadily grown, and a massive ad hoc system of food banks has become established in Canada. To assess the food insecurity and nutritional vulnerability of one subgroup of food bank users, interviews were conducted with a sample of 153 women in families using emergency food relief programs in Metropolitan Toronto. Ninety percent reported household incomes which were less than two thirds of the 'poverty line', and 94% reported some degree of food insecurity over the previous 12 months. Seventy percent reported some level of absolute food deprivation, despite using food banks. The findings highlight the limited capacity of ad hoc, charitable food assistance programs to respond to problems of household food insecurity which arise in the context of severe and chronic poverty.

Women's dietary intakes in the context of household food insecurity.

A study of food insecurity and nutritional adequacy was conducted with a sample of 153 women in families receiving emergency food assistance in Toronto, Canada. Contemporaneous data on dietary intake and household food security over the past 30 d were available for 145 of the women. Analyses of these data revealed that women who reported hunger in their households during the past 30 d also reported systematically lower intakes of energy and a number of nutrients. The effect of household-level hunger on intake persisted even when other economic, socio-cultural, and behavioral influences on reported dietary intake were considered. Estimated prevalences of inadequacy in excess of 15% were noted for Vitamin A, folate, iron, and magnesium in this sample, suggesting that the low levels of intake associated with severe household food insecurity are in a range that could put women at risk of nutrient deficiencies.

Prevention and the role of nutrition.

PIP: As the less developed countries develop economically, their populations will increasingly adopt many lifestyle traits of Western society commonly understood to be causally linked factors in non-communicable diseases. The expected increase in the incidence and prevalence of non-communicable disease has major implications for health care resource demands and the distribution of available resources; resources will be diverted away from lower income groups. Problems of excess and those associated with development need to be addressed. The author considers changes in lifestyle and nutritional factors which affect individual health and development with regard to heart disease and diabetes, and discusses research reports, including the issue of fat intake taken up in a FAO/World Health Organization report. The implications of early malnutrition and environmental factors upon human health and well-being are considered, with a reminder to address the difficult questions of preventing protein-energy malnutrition, to view child and adult problems as population problems, and to develop and implement holistic solutions.^ieng

Errors in the interpretation of dietary assessments.

Two years ago, I reviewed the analytic effect of error in the estimation of dietary intake, describing the emphasis on the "random" day-to-day variation in reported intake. Interest in this area is increasing and there are signs of progress in analytic strategies. This paper focuses on two concerns about the use of dietary data in analyses. The effect of different methods of adjusting analyses of fat and a health outcome for energy is illustrated through an exploration of the association between fat intake and high body mass index in data sets from the US Department of Agriculture and a Dutch national survey. Both a shift in the analytic question and a change in the error structure occur as analysis strategies are changed, leading to confusion in interpretation. The paper also addresses the growing concern about bias in the estimation of intake and the possibility that differential bias moves with stratification variables of analytic interest. The increasing use of doubly labeled water estimates of energy expenditure as a gold standard for checking on overall bias in reporting is commendable. There will always be error in dietary assessments. The challenge is to understand, estimate, and make use of the error structure during analysis.

Statistical approaches to establish mineral element recommendations.

When a committee develops a statement of requirements, the members first look to laboratory studies, and often to animal models, to identify the nature of the function of the nutrient and likely markers of this function. Then the committee looks for evidence from human studies. There are several types of evidence that they could, and should, draw upon; each has particular strengths and weaknesses. Given that all available evidence points to the fact that nutrient requirements differ among individuals, and given also the fact that unless explicitly controlled in study design, nutrient intakes vary among individual subjects, we must deal with distributions of requirements and of intakes. How we deal with distributions in different designs can lead to apparent differences in what we estimate. This paper illustrates some approaches that should be used in reviewing evidence pertaining to human nutrient requirements; it attempts to offer unifying concepts that can help us take advantage of these several types of evidence. The final message is that in estimating nutrient requirements, "congruence of evidence is happiness"; we can no longer be satisfied with a single line of evidence.

Biochemical and physicochemical properties of phosphorodithioate DNA.

The biochemical and physicochemical properties of DNA oligomers containing phosphorodithioate linkages in various configurations were evaluated. Duplex stability studies, which were carried out by thermal denaturation analysis with complementary unmodified DNA, indicated a highly cooperative process similar to completely unmodified duplexes. Oligomers containing phosphorodithioate linkages were found to have reduced melting temperatures relative to unmodified duplexes, with the degree of Tm depression paralleling the percent phosphorodithioate composition of the oligomer. Relative to activation of RNase H, DNA oligomers containing up to 50% phosphorodithioate linkages were able to direct RNase H degradation with the same efficiency as unmodified DNA while those containing from 50 to 100% acted with somewhat reduced efficiency. At limiting concentrations, an oligomer containing alternating phosphorodithioate and phosphate linkages was able to direct RNase H degradation of the target RNA in an extended incubation, while an unmodified oligomer did not. The nuclease resistance of phosphorodithioate-containing oligomers was evaluated in HeLa cell nuclear and cytoplasmic extracts, in human serum, and with nucleases S1 and DNase I. Oligomers containing alternating phosphorodithioate and phosphate were highly resistant to degradation in all systems. However, oligomers having more than one unmodified linkage separating phosphorodithioates were degraded rapidly by DNase I, while demonstrating stability to degradation in all other systems tested. These results indicate that phosphorodithioate-containing DNA oligomers are highly nuclease-resistant, are able to form stable duplexes with complementary nucleic acid sequences, and efficiently direct RNase H degradation of target RNA.

Schoolchildren have similar predicted prevalences of inadequate intakes as toddlers in village populations in Egypt, Kenya, and Mexico.

OBJECTIVES: To examine the probability of inadequacy of schoolchild nutrient intakes; to compare the predicted adequacy of schoolchild diets to previously published data for toddler diets and to examine the relative adequacy of the diets of sibling pairs. DESIGN: Food consumption data were measured 2 days per month across approximately one year. Mean nutrient intakes were calculated and compared to international standards using a probability approach. SETTING: Villages in Egypt, Kenya, and Mexico. SUBJECTS: 285 school-age children (7-9 years of age) and 255 toddlers (18-30 months of age) including 94 sibling pairs. RESULTS: Within a country, there was a striking similarity between the nutrients predicted to be inadequate in schoolchild and toddler diets across all nutrients except vitamin B12, which was more likely to be inadequate among schoolchildren. Nutrients of concern for both ages in one or more countries included iron, zinc, calcium, riboflavin, and vitamins B12, D, E, and A. For 94 toddler-schoolchild pairs, siblings at high risk of nutrient inadequacy could be identified from an indicator child with a sensitivity of 43-100% and a specificity of 59-100%. CONCLUSIONS: Nutrient adequacy tends to be a household characteristic for these two ages of children. Nutritional interventions that target the household have a high probability of benefitting multiple age groups of children.

PIP: The authors investigated the probability of inadequacy of schoolchild nutrient intakes in order to compare the predicted adequacy of schoolchild diets to previously published data for toddler diets, and to examine the relative adequacy of the diets of sibling pairs. Food consumption data were measured two days per month for approximately one year for 285 children aged 7-9 years and 255 infants aged 18-30 months, including 94 sibling pairs, in villages in Egypt, Kenya, and Mexico. Mean nutrient intakes were calculated and compared to international standards using a probability approach. Within a country, there was close similarity between the nutrients predicted to be inadequate in schoolchild and toddler diets across all nutrients except vitamin B(12), D, E, and A. For 94 toddler-schoolchild pairs, siblings at high risk of nutrient inadequacy could be identified from an indicator child with a sensitivity of 43-100% and a specificity of 59-100%. Nutritional interventions which target the household have a high probability of benefiting multiple age groups of children.

Approaches to analysis of dietary data: relationship between planned analyses and choice of methodology.

Dietary intake cannot be estimated without error and probably never will be. The nature and magnitude of the error depends on both the dietary data collection methodology and the subjects studied. The impact of particular types of error depends on the question being asked and the analytical methodology used to address it. Examples of these phenomena are presented in this review paper. The future lies in improved estimation and understanding of the error terms and in the development of analytical and statistical methods of coping with these error terms rather than with "improvements" in dietary methodology per se.

Estimated vitamin intakes of toddlers: predicted prevalence of inadequacy in village populations in Egypt, Kenya, and Mexico.

Vitamin intakes of 255 toddlers (aged 18-30 mo) were estimated from food consumption recorded during 1 y at sites in Egypt, Kenya, and Mexico. Mean intakes were compared with requirements standards by using a probability approach to estimate the prevalence of inadequate intakes. There were predicted inadequacies for vitamin A (32%) and riboflavin (20%) in Egypt, vitamins A (68%) and C (63%) and riboflavin (52%) in Mexico, and vitamin B-12 (44%) in Kenya. Vitamin E was inadequate in all diets, but in relation to polyunsaturated fatty acids only the intake in Mexico was low. No diet provided the recommended amount of vitamin D, but its dietary requirement is uncertain. Correlations among nutrient intakes suggest factors that may contribute to reported associations of consumption of animal products with improved growth or development among these children: provision of vitamin B-12 and available minerals, displacement of fiber and phytate-rich energy sources, and increased energy density.

PIP: Data on 255 children, 18-30 months old, in Kalama village on the Nile delta in Egypt, the Embu district in Kenya, and the Solis Valley in Mexico were analyzed over a 1-year period to study the relationships of energy and animal protein intakes with vitamins, minerals, and two factors that affect bioavailability, dietary fiber and phytate. The researchers used the probability approach to determine the prevalence of inadequate intakes. Estimated intake inadequacies were 32% for vitamin A and 20% for riboflavin in Egypt; 68% for vitamin A, 63% for vitamin C, and 52% for riboflavin in Mexico, and 44% for vitamin B12 in Kenya. All the diets were deficient in vitamin E. Yet, when researchers compared vitamin E in relation to polyunsaturated fatty acids, the vitamin E intake was low only in Mexico. None of the diets had the recommended amount of vitamin D, but actual dietary requirements were unknown. Further, the researchers had no information on solar exposure. Provision of vitamin B12 and available minerals, displacement of fiber and phytate-rich energy sources, and increased energy density were associated with improved growth or development among children ingesting animal products (p 0.05). Intakes of folacin, niacin, and thiamin were negatively related to animal protein intake (p 0.05).

Estimation of possible impact of non-caloric fat and carbohydrate substitutes on macronutrient intake in the human.

This paper addresses the expected impact of use of macronutrient substitutes by individuals without strong motivation to control macronutrient or energy intake when such modified foods serve as replacements of foods normally ingested rather than as "add-ons". A basic premise of the paper is that individuals are likely to replace a substantial part of the energy equivalent of the original substitution. It further assumes that the macronutrient composition of the additional foods consumed will reflect normal food selection behaviours. The paper derives a description of the expected selection behaviour from examination of the within subject variance in energy and macronutrient intake of 29 subjects followed for 365 consecutive days (the Beltsville One Year Dietary Intake Study). Patterns observed in these subjects were validated through examination of associations between macronutrient intake and energy intake in 600 women, each of whom contributed 6 days of dietary data (USDA CSFII-85). As presently proposed the model suggests that the use of non-caloric fat replacements, by subjects without strong motivation to control fat or energy intake, can be expected to result in a net decrease (less than original substitution) in fat intake and net increases in carbohydrate and protein intakes. Conversely, use of carbohydrate replacements in core foods can be expected to result in net increases in fat and protein intakes and a partial decrease in carbohydrate intake. The magnitude of these net changes is seen to be a function of the extent of replacement of energy.

Estimated mineral intakes of toddlers: predicted prevalence of inadequacy in village populations in Egypt, Kenya, and Mexico.

Intakes of minerals and factors that might affect their bioavailability were estimated for 255 toddlers aged 18-30 mo living in villages in Egypt, Kenya, and Mexico. Mean intakes over 1 y were compared with international-requirement estimates by using a probability approach. The prevalence of iron intakes likely to be inadequate to prevent anemia was estimated as 35% in Egypt, 13% in Kenya, and 43% in Mexico. The prevalence of zinc intakes likely to be inadequate to meet basal requirements was estimated as 57% and 25% in Kenya and Mexico, respectively, but only 10% in Egypt, where the use of yeast-leavened breads was judged to have improved zinc availability. There was no suggestion that estimated copper or magnesium intakes were inadequate, but calcium intakes in Kenya and Egypt were well below recommended amounts. Studies of factors affecting mineral bioavailability in the diets of these countries' populations could suggest dietary changes that might improve effective mineral intake with minimal cost.

Inhibition of human immunodeficiency virus activity by phosphorodithioate oligodeoxycytidine.

Phosphorothioate oligodeoxynucleotides exert a sequence-independent cytoprotective effect against human immunodeficiency virus type 1 (HIV-1). We now report that phosphorodithioate-containing oligodeoxycytidines are very potent inhibitors of HIV-1 reverse transcriptase in vitro, as they exhibit an increasing inhibitory effect with length and number of phosphorodithioate internucleotide linkages. This inhibitory effect can be at least 30-fold greater with phosphorodithioate oligodeoxycytidine than for the corresponding phosphorothioate analog of similar length. In cell culture, phosphorodithioate oligodeoxycytidines are active inhibitors of syncytia formation and effectively inhibit de novo infection of target cells by HIV-1. Moreover, comparative experiments show that a deoxycytidine phosphorodithioate 14-mer is as effective an inhibitor of de novo infection as a phosphorothioate-containing 28-mer. Such potent inhibition by oligomers of relatively short length makes dithioate analogs an additional class of potential therapeutic agents against acquired immunodeficiency syndrome.

Estimated protein intakes of toddlers: predicted prevalence of inadequate intakes in village populations in Egypt, Kenya, and Mexico.

This paper presents a probability assessment of the adequacy of protein intakes of toddlers (aged 18-30 mo) in study communities in Egypt, Kenya, and Mexico judged in relation to FAO/WHO/UNU estimates of requirements. Effects of supplementing amino acid intakes, or of assuming lower bioavailability for lysine are also considered. In Egypt and Mexico existing protein intakes of toddlers were adequate. In Kenya existing intakes were marginal. Total protein intake was low and often lysine or tryptophan concentration was low. If Kenyan intakes met estimated energy requirements, protein intakes would be adequate. We conclude that protein intake is unlikely to be a primary limiting factor for toddler growth and development, and the benefit to be expected from increasing the intake of limiting amino acids is marginal. Reported associations of animal-source protein and energy with growth, size, and psychologic function of these toddlers are unlikely to be causally attributable to inadequacy of protein intakes.

Day-to-day variation in energy and nutrient intake: evidence of individuality in eating behaviour?

A study of within-subject variation in the reported food intakes and food selections of 29 adults participating in the Beltsville One-Year Dietary Intake Study suggests that individuals possess characteristics levels of day-to-day variation in intake. Application of Bartlett's test of homogeneity of variance indicated heterogeneity of within-subject variance in energy intake and in selected nutrients controlled for energy. Comparisons of estimates of within-subject variation derived from a split sample of days revealed the relative stability of individuals' magnitudes of day-to-day variation in energy and nutrient intake over time. For some nutrient variables, a large proportion of the observed heterogeneity in within-subject variation could be explained by a linear relationship between subjects' standard deviations and their mean intake levels. However, heterogeneity persisted when subjects' coefficients of variation were compared, suggesting that mean intake differences are insufficient to explain the observed differences in subjects' levels of day-to-day variation. The magnitude of observed variation in an individual's food intake and food selection from one day to the next appears to be a meaningful descriptor of that individual's intake behaviour.

Statistical estimation of dietary parameters: implications of patterns in within-subject variation--a case study of sampling strategies.

Patterns within intraindividual variation in energy intake were described previously. Using case studies based on the same Beltsville One-Year Dietary Intake Study data set, we examined the interaction between random and nonrandom variation and the choice of sampling strategy in estimation of individuals' usual intakes over 1 y. Mean intake estimates derived from adjacent-day samples were less reliable and more likely to be biased than were those based on randomly selected days. A finite adjacent-day sample fails to encompass longer-term trends. Because adjacent-day samples underestimate true within-subject variation, by customary tests they appear more reliable. This may present an interpretational problem. Comparisons of random weekend and week-day samples confirm that failure to proportionately sample both will bias the estimation of the usual (1-y mean) intake and the within-subject variance.