Efficacy of Topical Vancomycin- and Gentamicin-Loaded Calcium Sulfate Beads or Systemic Antibiotics in Eradicating Polymicrobial Biofilms Isolated from Diabetic Foot Infections within an In Vitro Wound Model.

Diabetic foot ulcers are notoriously difficult to heal, with ulcers often becoming chronic, in many cases leading to amputation despite weeks or months of antibiotic therapy in addition to debridement and offloading. Alternative wound biofilm management options, such as topical rather than systemic delivery of antimicrobials, have been investigated by clinicians in order to improve treatment outcomes. Here, we collected blood and tissue from six subjects with diabetic foot infections, measured the concentrations of antibiotics in the samples after treatment, and compared the microbiota within the tissue before treatment and after 7 days of antibiotic therapy. We used an in vitro model of polymicrobial biofilm infection inoculated with isolates from the tissue we collected to simulate different methods of antibiotic administration by simulated systemic therapy or topical release from calcium sulfate beads. We saw no difference in biofilm bioburden in the models after simulated systemic therapy (representative of antibiotics used in the clinic), but we did see reductions in bioburden of between 5 and 8 logs in five of the six biofilms that we tested with topical release of antibiotics via calcium sulfate beads. Yeast is insensitive to antibiotics and was a component of the sixth biofilm. These data support further studies of the topical release of antibiotics from calcium sulfate beads in diabetic foot infections to combat the aggregate issues of infectious organisms taking the biofilm mode of growth, compromised immune involvement, and poor systemic delivery of antibiotics via the bloodstream to the site of infection in patients with diabetes.

Scoping review of mode of anaesthesia in emergency surgery.

BACKGROUND: Emergency surgery encompasses more than 50 per cent of the surgical workload; however, research efforts are disproportionally low. The mode of anaesthesia used during emergency surgery may affect outcomes, but the extent of research and the impact of the different modes of anaesthesia used are unclear. METHODS: MEDLINE and Embase were searched using scoping review methodology with a rapid systematic search strategy, identifying any study comparing locoregional (local, nerve block, subarachnoid, epidural) anaesthesia with general anaesthesia. All studies describing outcomes of emergency surgery with differing modes of anaesthesia were identified. Excluded were: studies published before 2003, studies enrolling patients aged less than 18 years and studies using sedation only. RESULTS: Forty-two studies were identified, describing 11 surgical procedures. Most publications were retrospective cohort studies (32). A very broad range of clinical and patient-reported outcomes were described, with wide variation in the outcomes reported in different studies. CONCLUSION: Reporting of mode of anaesthesia is inconsistent across different procedures and is often absent. There is a need for directed research efforts to improve the reporting standards of anaesthesia interventions, to understand the role of different modes of anaesthesia in specific emergency surgical procedures, and to standardize outcome reporting using core outcome sets.

ANTECEDENTES: La cirugía de urgencias constituye > 50% de la carga de trabajo quirúrgico, aunque los esfuerzos realizados en investigación en este ámbito son desproporcionadamente bajos. La modalidad de anestesia utilizada durante la cirugía de urgencias puede afectar a los resultados, sin embargo, la investigación realizada y el impacto de los diferentes tipos de anestesia utilizados no están claros. MÉTODOS: Se realizaron búsquedas en Medline y Embase utilizando una metodología enfocada a la recuperación de revisiones, con una estrategia de búsqueda sistemática rápida, identificando cualquier estudio que comparara la anestesia locorregional (local, bloqueo nervioso, subaracnoidea, epidural) con la anestesia general. Se identificaron todos los estudios que describían los resultados de la cirugía de urgencias con diferentes tipos de anestesia. Se excluyeron los estudios publicados antes del 2003, los estudios que reclutaron pacientes < 18 años y los estudios que solo usaron sedación. RESULTADOS: Se identificaron 42 estudios que describían 11 procedimientos quirúrgicos. La mayoría de publicaciones fueron estudios de cohortes retrospectivos (n = 32). Se describió una gama muy amplia de resultados clínicos y resultados aportados por los pacientes, con una amplia variación en los resultados de los diferentes estudios. CONCLUSIÓN: Los resultados publicados respecto a la modalidad de anestesia empleada en diferentes procedimientos quirúrgicos son inconsistentes, a menudo esta información está ausente y no se pueden establecer conclusiones sobre el impacto del tipo de anestesia en los resultados. Es necesario realizar esfuerzos dirigidos a la investigación para mejorar la notificación de los estándares de los procedimientos de anestesia, comprender el papel de los diferentes tipos de anestesia en los procedimientos quirúrgicos específicos de urgencias, y estandarizar la presentación de los resultados obtenidos utilizando un conjunto de datos principales.

Skeletal deformities associated with nutritional congenital rickets in newborn lambs.

CASE HISTORY: A group of 545 pregnant rising 2-year-old Coopdale ewes on a Southland sheep farm were grazed over winter on a fodder beet (Beta vulgaris) crop. Subsequently, 45 out of approximately 750 lambs were born with a variety of skeletal deformities, including shortened limbs, varus and valgus angular limb deformities, palmar grade stance and cranial bowing of the carpus. Analysis of the crop showed the fodder beet contained a low percentage of phosphorus. In addition, 60 out of 460 rising 2-year-old ewes that had been grazed on the fodder beet crop as 1-year-olds had incisor abnormalities and malocclusion. PATHOLOGICAL FINDINGS: Two affected lambs (1-day-old and 3-days-old) with representative clinical signs examined postmortem were found to have markedly enlarged costochondral junctions, and noticeably enlarged long bone metaphyses. In addition, one lamb had a dense band of metaphyseal sclerosis beneath the physes of all long bones examined. Histopathological findings included small islands and columns of chondrocytes and eosinophilic cartilage matrix present in the metaphysis. Metaphyseal trabeculae were disorganised and often lined by accumulations of pale pink osteoid; similar pale pink osteoid was also present in the cortices. Unerupted molar teeth in the affected lambs lacked a layer of enamel, and the dentine was irregular with globular basophilia. DIAGNOSIS: The gross and histopathological lesions were consistent with a diagnosis of rickets. CLINICAL RELEVANCE: Nutritional congenital rickets has not been previously diagnosed in sheep, but is a recognised disease of human infants with vitamin D deficient mothers. The rickets in affected lambs was most likely associated with phosphorus deficiency as a result of the pregnant ewes grazing fodder beet during gestation. While vitamin D deficiency was not definitively ruled out in these cases, practitioners are alerted to the possible effects of feeding phosphorus-deficient fodder beet to ewes for long periods during gestation and to 1-year-old sheep during important growth periods.

Variance estimation for stratified propensity score estimators.

Propensity score methods are increasingly used to estimate the effect of a treatment or exposure on an outcome in non-randomised studies. We focus on one such method, stratification on the propensity score, comparing it with the method of inverse-probability weighting by the propensity score. The propensity score--the conditional probability of receiving the treatment given observed covariates--is usually an unknown probability estimated from the data. Estimators for the variance of treatment effect estimates typically used in practice, however, do not take into account that the propensity score itself has been estimated from the data. By deriving the asymptotic marginal variance of the stratified estimate of treatment effect, correctly taking into account the estimation of the propensity score, we show that routinely used variance estimators are likely to produce confidence intervals that are too conservative when the propensity score model includes variables that predict (cause) the outcome, but only weakly predict the treatment. In contrast, a comparison with the analogous marginal variance for the inverse probability weighted (IPW) estimator shows that routinely used variance estimators for the IPW estimator are likely to produce confidence intervals that are almost always too conservative. Because exact calculation of the asymptotic marginal variance is likely to be complex, particularly for the stratified estimator, we suggest that bootstrap estimates of variance should be used in practice.

Reduced membrane bound CD14 expression in the cord blood of infants with a family history of allergic disease.

BACKGROUND: Infants at increased risk of allergic disease have altered immune function at birth, but the specific immune changes described differ between studies and their precise nature is not well defined. Changes affecting innate immune responses may be particularly important in allergic disease pathogenesis. OBJECTIVE: We investigated whether inherited risk of allergic disease is associated with altered markers of innate immunity, T cell regulation or dendritic cell (DC) percentage in human newborns. METHODS: Cord blood was collected from infants at low risk (no parent affected by allergic disease, n=14), intermediate risk (one affected parent, n=54) or high risk (two affected parents, n=25) of developing allergic disease. Cord blood mononuclear cells were cultured with ovalbumin (OVA), lipopolysaccharide, lipoteichoic acid (LTA), heat-killed lactobacillus, alpha-CD3 or medium alone. Cells were analysed by flow cytometry for expression of CD14, FoxP3 and DC percentage, and by real-time RT-PCR for TLR2 and TLR4 expression in infants at intermediate or high risk of allergic disease. RESULTS: Infants at high risk of allergic disease had reduced percentage of CD14(+) monocytes (P=0.01) and reduced CD14 mean fluorescence intensity (P=0.01) in uncultured mononuclear cells. They also had decreased DC percentage in mononuclear cells cultured with OVA (P=0.04), lipopolysaccharide (P=0.01), LTA (P=0.02) and alpha-CD3 (P=0.03) as compared with infants at intermediate or low risk of allergic disease. No relationship was seen between risk of allergic disease and TLR2 or TLR4 expression, or FoxP3 expression in cultured cells. CONCLUSIONS: Infants with a biparental history of allergic disease have altered markers of innate immunity at birth, with reduced expression of membrane bound CD14 and consequently reduced in vitro development of DCs. Further work is needed to understand the role that these alterations play in the pathogenesis of allergic disease, and whether interventions to up-regulate fetal CD14 expression can prevent allergic disease.

Adapting the James Lind Alliance priority setting process to better support patient participation: an example from cystic fibrosis.

PLAIN ENGLISH SUMMARY: Cystic fibrosis (CF) is the commonest life-limiting inherited disorder in the UK. It affects many parts of the body including the lungs and gut leading to increased infection and problems digesting food. People with CF need to undergo many treatments each day throughout their whole lives. These include tablets, inhalers and breathing exercises, which are a huge burden, taking up several hours every dayIt is therefore, really important that the treatments we give are supported by good evidence, usually gathered from clinical trials. Unfortunately, we do not have good evidence for many of the CF treatments. We recently ran an exercise known as a James Lind Alliance Priority Setting Partnership (JLA PSP) to find out which the CF community feel are the top priority research questions. People with CF and those who look after them suggested questions to be answered by clinical trials. Through a series of online surveys and workshops these were then shortlisted to give a final top ten.Due to infection risk people with CF are advised not to mix, this meant we had to do things differently to the usual way JLA PSPs are carried out. We used videoconferencing to enable multiple people with CF to participate. Surveys were accessible online and promoted through social media. ABSTRACT: Background The James Lind Alliance (JLA) method is well recognised for setting research priorities. The JLA approach involves a combination of surveys and workshop interactions between patients, carers and health care professionals to identify and agree on a "top ten" list of research questions. Respiratory infection is one of the hallmarks of cystic fibrosis (CF). To avoid cross infection, patients are advised not to meet face to face, preventing us following standard JLA methodology. Here we describe adaptations made during our recent JLA Priority Setting Partnership (PSP) in CF. Methods We elicited and prioritised research questions, using sequential online surveys, promoted through social media. People with CF participated in steering committee meetings and the final workshop, using videoconferencing. Alterations to workshop methodology enabled participants attending in person and those joining remotely, to contribute equally. We also altered the JLA methodology to include "lone" questions, asked by only one survey respondent. We are now working with the CF community to co-produce research projects that answer these top ten. Results There were 482 respondents, from 23 countries, who submitted 1080 questions. Increases in the number of responses occurred just after promotion on social media. Use of videoconferencing enabled participation of multiple people with CF and ensured participation from anywhere in the world, including hospital inpatients. Inclusion of lone questions resulted in one being included in our top ten. Conclusions There is no "one-size-fits-all" for patient involvement methodologies. Through altering the JLA methods to fit our patient group we achieved wide participation. We believe that methods used in our project may also be applied to future partnerships to increase participation, especially where people may be hospitalised or be unable to travel. The methodology we are developing through the JLA PSP CF2 project may be useful for other PSPs to follow.

Top research priorities in healthcare-associated infection in the UK.

BACKGROUND: There is a mismatch between research questions which are considered to be important by patients, carers and healthcare professionals and the research performed in many fields of medicine. No relevant studies which have assessed research priorities in healthcare-associated infection (HCAI) that have involved patients' and carers' opinions were identified in the literature. AIM: The Healthcare-Associated Infections Priority Setting Partnership was established to identify the top research priorities in the prevention, diagnosis and treatment of HCAI in the UK, considering the opinions of all these groups. METHODS: The methods broadly followed the principles of the James Lind Alliance (JLA) priority setting activity. FINDINGS: In total, 259 unique valid research questions were identified from 221 valid responses to a consultation of patients, carers and healthcare professionals after seeking their opinions for research priorities. The steering committee of the priority setting partnership rationalized these to 50 unique questions. A literature review established that for these questions there were no recent high-quality systematic reviews, high-quality systematic reviews which concluded that further studies were necessary, or the steering committee considered that further research was required despite the conclusions of recent systematic reviews. An interim survey ranked the 50 questions, and the 10 main research priorities were identified from the top 32 questions by consensus at a final priority setting workshop of patients, carers and healthcare professionals using group discussions. CONCLUSIONS: A priority setting process using JLA methods and principles involving patients, carers and healthcare professionals was used to identify the top 10 priority areas for research related to HCAI. Basic, translational, clinical and public health research would be required to address these uncertainties.

Specific tumour-associated methylation in normal human term placenta and first-trimester cytotrophoblasts.

Human placentation displays many similarities with tumourigenesis, including rapid cell division, migration and invasion, overlapping gene expression profiles and escape from immune detection. Recent data have identified promoter methylation in the Ras association factor and adenomatous polyposis coli tumour suppressor genes as part of this process. However, the extent of tumour-associated methylation in the placenta remains unclear. Using whole genome methylation data as a starting point, we have examined this phenomenon in placental tissue. We found no evidence for methylation of the majority of common tumour suppressor genes in term placentas, but identified methylation in several genes previously described in some human tumours. Notably, promoter methylation of four independent negative regulators of Wnt signalling has now been identified in human placental tissue and purified trophoblasts. Methylation is present in baboon, but not in mouse placentas. This supports a role for elevated Wnt signalling in primate trophoblast invasiveness and placentation. Examination of invasive choriocarcinoma cell lines revealed altered methylation patterns consistent with a role of methylation change in gestational trophoblastic disease. This distinct pattern of tumour-associated methylation implicates a coordinated series of epigenetic silencing events, similar to those associated with some tumours, in the distinct features of normal human placental invasion and function.

Methylation of the adenomatous polyposis coli (APC) gene in human placenta and hypermethylation in choriocarcinoma cells.

Methylation of the human APC gene promoter is associated with several different types of cancers and has also been documented in some pre-cancerous tissues. We have examined the methylation of APC gene promoters in human placenta and choriocarcinoma cells. This revealed a general hypomethylation of the APC-1b promoter and a pattern with monoallelic methylation of the APC-1a promoter in full term placental tissue. However, there was no evidence of a parent-of-origin effect, suggesting random post zygotic origin of methylation. Increased methylation of this promoter was observed in all choriocarcinoma-derived trophoblast cell lines, suggesting a trophoblastic origin of placental APC methylation and implicating APC hypermethylation in the development of this group of gestational tumours. Our demonstration of placental methylation of the APC-1a promoter represents the first observation of monoallelic methylation of this gene in early development, and provides further support for a role of canonical Wnt signalling in placental trophoblast invasiveness. This also implicates tumour suppressor gene silencing as an integral part of normal human placental development.

Higher maternal dietary protein intake in late pregnancy is associated with a lower infant ponderal index at birth.

AIM: A high ponderal index at birth has been associated with later obesity and it has been suggested that intervention to prevent obesity and its sequela should consider the antenatal period. In this context, we investigated the association between maternal nutrition and birth anthropometry. DESIGN: We analyzed data on 1040 mother-infant pairs collected during the Tasmanian Infant Health Survey (TIHS), Tasmania, 1988-1989. Maternal dietary intake during pregnancy was measured by food frequency questionnaire (FFQ) applied soon after birth. Outcomes of interest were birth weight, birth length, head circumference, ponderal index, head circumference -to-ponderal index ratio, placenta-to-birth weight ratio and head circumference-to-birth length index. RESULTS: In multiple regression model, an increase of 10 g of absolute protein intake/day was associated with a reduction in birth weight of 17.8 g (95% CI: -32.7, -3.0; P=0.02). Protein intake was also associated negatively with ponderal index (beta=-0.01; 95% CI: -0.02, -0.00; P=0.01). A 1 % increase in carbohydrate intake resulted in a 1% decline in placental weight relative to birth weight. Higher protein intake in the third trimester was associated with a reduced ponderal index among large birth weight infants but not low birth weight infants. CONCLUSIONS: This raises the possibility that any effect of high protein in altering infant anthropometry at birth may involve changes in body composition and future work to examine how a high-protein diet influences body composition at birth is warranted.

The SSTARS (STeroids and Stents Against Re-Stenosis) Trial: Different stent alloys and the use of peri-procedural oral corticosteroids to prevent in-segment restenosis after percutaneous coronary intervention.

BACKGROUND: Stent design and technological modifications to allow for anti-proliferative drug elution influence restenosis rates following percutaneous coronary intervention (PCI). We aimed to investigate whether peri-procedural administration of corticosteroids or the use of thinner strut cobalt alloy stents would reduce rates of binary angiographic restenosis (BAR) after PCI. METHODS: This was a two centre, mixed single and double blinded, randomised controlled trial using a factorial design. We compared (a) the use of prednisolone to placebo, starting at least six hours pre-PCI and continued for 28days post-PCI, and (b) cobalt chromium (CoCr) to stainless steel (SS) alloy stents, in patients admitted for PCI. The primary end-point was BAR at six months. RESULTS: 315 patients (359 lesions) were randomly assigned to either placebo (n=145) or prednisolone (n=170) and SS (n=160) or CoCr (n=160). The majority (58%) presented with an ACS, 11% had diabetes and 287 (91%) completed angiographic follow up. BAR occurred in 26 cases in the placebo group (19.7%) versus 31 cases in the prednisolone group (20.0%) respectively, p=1.00. For the comparison between SS and CoCr stents, BAR occurred in 32 patients (21.6%) versus 25 patients (18.0%) respectively, p=0.46. CONCLUSION: Our study showed that treating patients with a moderately high dose of prednisolone for 28days following PCI with BMS did not reduce the incidence of BAR. In addition, we showed no significant reduction in 6month restenosis rates with stents composed of CoCr alloy compared to SS (http://www.isrctn.com/ISRCTN05886349).

Impact of low birth weight and cardiovascular risk factors on endothelial function in early adult life.

BACKGROUND: Low birth weight is related to increased risk of coronary heart disease in adults and recently has been associated with vascular endothelial dysfunction in children. We investigated whether the relation between birth weight and endothelial function was still present in early adult life and whether there was an interaction with emerging risk factors. METHODS AND RESULTS: In 315 adults (165 women, 150 men, aged 20 to 28 years), high-resolution ultrasound was used to determine endothelium-dependent and -independent vascular responses of the brachial artery. Vascular measures were related to classic risk factors (smoking history, lipid profile, blood pressure, fasting insulin, exercise capacity, body mass index, and combined risk score) and birth weight. Low birth weight was associated with reduced flow-mediated dilation (coefficient=0.18 kg(-1), 95% CI 0.004 to 0.35, P:=0.04) but not with endothelium-independent dilation. The difference in flow-mediated dilation between the top and bottom fifths of birth weight was the same as between smokers and nonsmokers. Increasing levels of acquired risk factors overwhelmed the association, and there was a significant interaction of risk score with the birth weight-endothelial function relation (coefficient of interaction term [birth weightxrisk score] = -0.12, 95% CI -0.22 to -0.03, P:=0.01). CONCLUSIONS: Low birth weight is associated with endothelial dysfunction in young adults. This is most marked in individuals with lower risk factor profiles and may be relevant to the pathogenesis of atherosclerosis in later life.

Brain morphometry and IQ measurements in preterm children.

Although IQ is thought to remain relatively stable in the normal population, a decline in IQ has been noted in children born preterm. It is not clear, however, to what extent the inclusion of children with clear neurological damage has influenced these findings. We examined IQ scores obtained in childhood and then again in adolescence from a group of children born at 30 weeks gestation or less who had been classified as neurologically normal at 7.5-8 years. They showed a significant decline in mean IQ scores over time. MRI scans obtained from a subset of children at adolescence were read as normal in approximately 50% of cases and, in the others, there were no consistent relationships between radiological abnormalities and IQ results. Such children can, however, have relatively subtle brain abnormalities that are not seen on conventional MRI, and we hypothesized that these would be related to declines in IQ. Voxel-based morphometry (VBM) analyses of the MRI scans revealed that absolute IQ scores were related to areas in both the parietal and temporal lobes. The analyses also showed that frontal and temporal lobe regions were associated with the decline in VIQ, while occipital and temporal lobe regions (including the hippocampi) were associated with the decline in PIQ. Hippocampal volume measurements were consistent with the VBM findings. We concluded that preterm children are at risk of declining IQ over time even if they have not suffered obvious neurological damage and that the decline is associated with specific neural regions. Whether this is true of children born at >30 weeks gestation and what other factors predispose to this decline have yet to be determined.

Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children.

BACKGROUND: Preterm children are at high risk of poor growth performance. In 2 randomized trials, preterm infants fed preterm formula grew better in the neonatal period than those fed banked donor breast milk or standard term formula. OBJECTIVE: Our objective was to test the hypothesis that for preterm infants, the neonatal period is a critical one for programming growth performance and that early diet influences long-term growth. DESIGN: A total of 926 preterm infants were recruited into 2 parallel, randomized trials of neonatal diet. In trial 1, infants were fed either banked donor breast milk or preterm formula whereas in trial 2, infants were fed either standard term formula or preterm formula. Within each trial, the allocated milk was the sole diet for some infants (study A), whereas for others it was a supplement to maternal breast milk, given when not enough expressed breast milk was available (study B). We followed up 781 of 833 survivors (94%) to age 7.5-8 y. Trained assessors obtained anthropometric measurements according to a standard protocol. RESULTS: Despite significantly better neonatal growth performance in infants fed preterm formula (compared with either banked donor breast milk or standard formula), early diet had no influence on weight, height, head circumference, or skinfold thicknesses at 9 or 18 mo postterm or at age 7.5-8 y. CONCLUSIONS: These findings suggest that the preterm period is not a critical window for nutritional programming of growth, which contrasts with evidence from these trials showing that early diet influences later neurodevelopment.

Double-blind, randomized trial of a synthetic triacylglycerol in formula-fed term infants: effects on stool biochemistry, stool characteristics, and bone mineralization.

BACKGROUND: The low sn-2 palmitate content of infant formulas results in formation of fatty acid calcium soaps in the stools and reduced calcium absorption. OBJECTIVE: Our objective was to test the hypotheses that increasing the proportion of sn-2 palmitate in formula for term infants would result in greater skeletal mineral deposition and reduced stool hardness. DESIGN: Healthy term neonates were randomly assigned to receive standard formula (n = 103) or formula containing 50% sn-2 palmitate (high-sn-2 formula; n = 100) for 12 wk. One hundred twenty breast-fed infants were also studied. The main outcome measures were 1) radial (single-photon absorptiometry) and whole-body (dual-energy X-ray absorptiometry) bone mineral content (WBBMC) at 12 wk and 2) stool frequency, volume, and consistency at 6 and 12 wk. Secondary outcome measures included stool fatty acid content. RESULTS: Infants receiving high-sn-2 formula had higher WBBMC (128.1 +/- 9.7 compared with 122.7 +/- 10.1 g, adjusted for size and sex), softer stools at 6 and 12 wk, and a lower proportion of stool soap fatty acids than did infants receiving the control formula. Breast-fed infants had adjusted WBBMC values (128.3 +/- 9.1 g) similar to those of infants fed high-sn-2 formula and significantly higher than those of infants fed the control formula. CONCLUSIONS: Changing the stereoisomeric structure of palmitate in infant formula resulted in higher WBBMC, reduced stool soap fatty acids, and softer stools more like those of breast-fed infants. The greater bone mass measured could be important if it persists beyond the trial period; this merits further investigation.

Catch-up growth in small-for-gestational-age term infants: a randomized trial.

BACKGROUND: Small-for-gestational-age (SGA) term infants are at risk of long-term growth deficits. OBJECTIVE: The objectives were to test the hypothesis that postnatal growth in SGA term infants can be altered by dietary intervention and to examine whether there is a critical window for nutritional programming of the growth trajectory during the first 9 mo postnatally. DESIGN: Healthy term (gestation > or =37 wk) infants with birth weights below the 10th centile were randomly assigned to receive standard term formula (TF; n = 147) or nutrient-enriched formula (EF; n = 152) for the first 9 mo; 175 breast-fed SGA term infants formed a reference group. The main outcome measures were weight, length, and occipitofrontal head circumference (OFC) at 9 and 18 mo. RESULTS: The infants fed the EF showed greater gains in length by 9 (1.1 cm; 95% CI: 0.38, 1.79) and 18 (1.0 cm; 0.25, 1.83) mo and in OFC by 9 (0.5 cm; 0.1, 0.9) and 18 (0.6 cm; 0.2, 1.1) mo than did infants fed the TF; the differences were larger in females. The dietary effects were independent of the pattern of growth retardation. Breast-fed infants showed greater gains in weight and OFC by 18 mo than did infants fed the TF; however, these differences disappeared after adjustment for age, parental size, and birth order. CONCLUSIONS: Linear growth and OFC gains in SGA term infants improve after nutritional intervention during the first 9 mo of life and the effects persist for > or =9 mo beyond the intervention period. Further information on whether catch-up growth is beneficial or detrimental to long-term outcomes is required before public health interventions can be recommended.

Randomized outcome trial of human milk fortification and developmental outcome in preterm infants.

Despite potential benefits, human milk may fail to meet preterm infants' nutrient requirements. We tested the hypothesis that fortified breast milk, fed alone or with preterm formula, would improve neurodevelopment and growth at 18-mo follow-up without adverse short-term clinical or biochemical consequences. Two hundred seventy-five preterm infants from two medical centers (birth weight < 1850 g; mean gestation 29.8 +/- 2.7 wk) whose mothers chose to provide breast milk were randomly assigned to receive for a mean of 39 d a multinutrient fortifier or control supplement containing phosphate and vitamins. Breast milk comprised 47.6% and 46.4% of enteral intake in fortified and control groups, respectively; preterm formula supplements were used when insufficient breast milk was available. Overall, there were no significant growth advantages with fortification; although, when breast milk exceeded 50% of intake, fortification promoted faster weight gain (an advantage of 1.6 g.kg-1.d-1; 95% CI: 0.1, 3.1; P < 0.05). Compared with control infants, the fortified group showed 1) higher plasma urea from week 2 (P = 0.04), 2) higher plasma calcium (mean 2.34 +/- 0.01 compared with 2.27 +/- 0.02 mmol/L; P = 0.003), 3) a greater rise in alkaline phosphatase by week 6 (P = 0.04), 4) more clinical infections (suspected plus proven; 43% compared with 31%, P = 0.04), 5) a nonsignificantly increased incidence of necrotizing enterocolitis (5.8% compared with 2.2%, P = 0.12), and 6) higher white cell and platelet counts. Developmental scores at 18 mo were slightly but not significantly higher in the fortified group. This study confirmed that breast milk fortifiers can improve short-term growth (when breast milk intakes are high); but beneficial effects on long-term development remained unproven. Future research is required to evaluate potential adverse consequences and explore more optimal fortification strategies.

Compliance with topical timolol treatment.

To determine if compliance with timolol treatment was better than compliance with pilocarpine treatment (as reported previously), we measured compliance with timolol treatment in a sample of 110 patients using an unobtrusive eyedrop medication monitor, which recorded electronically the date and time of each drug administration over a four- to six-week period. The patients administered a mean +/- S.D. of 82.7% +/- 19.0% of the prescribed timolol doses (range, 20% to 100%). Forty-five patients were treated concurrently with timolol and pilocarpine. These patients administered a mean +/- S.D. of 84.3% +/- 14.0% of the prescribed timolol doses and 77.7% +/- 18.7% of the prescribed pilocarpine doses (P = .012, van der Waerden test). Our results suggest that while compliance is influenced by the drug regimen, defaulting is not eliminated by prescribing a more convenient medication with fewer side effects.

Handedness in blood donors: no association with blood group or twinning.

There has been considerable interest in the contribution of inheritance to determination of handedness and in observed associations between hand laterality and twinning, gender and age. Unpublished data from a study of children born preterm suggested an association between AB0 blood group and handedness. A questionnaire filled in by 3815 blood donors, gave information on blood group, age, gender, whether they were a twin, hand used for writing and perceived handedness. There was no association between AB0 blood group or rhesus group and handedness. Significantly more females than males considered themselves right handed (82.5% versus 79.9%) and more subjects aged 50+ wrote with the right hand (90.6% versus 87.6% if younger). Twins did not differ from other subjects in this study and we hypothesise that the generally inconsistent findings relating to twins may be explained by population differences in the proportion of twins born preterm.