Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study.

The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts

Child and parent predictors of picky eating from preschool to school age

Background: Picky eating is prevalent in childhood. Because pickiness concerns parents and is associated with nutrient deficiency and psychological problems, the antecedents of pickiness need to be identified. We propose an etiological model of picky eating involving child temperament, sensory sensitivity and parent-child interaction. Methods: Two cohorts of 4-year olds (born 2003 or 2004) in Trondheim, Norway were invited to participate (97.2% attendance; 82.0% consent rate, n = 2475) and a screen-stratified subsample of 1250 children was recruited. We interviewed 997 parents about their child’s pickiness and sensory sensitivity using the Preschool Age Psychiatric Assessment (PAPA). Two years later, 795 of the parents completed the interview. The Children’s Behavior Questionnaire (CBQ) was used to assess children’s temperament. Parent- child interactions were videotaped and parental sensitivity (i.e., parental awareness and appropriate responsiveness to children’s verbal and nonverbal cues) and structuring were rated using the Emotional Availability Scales (EAS). Results: At both measurement times, 26% of the children were categorized as picky eaters. Pickiness was moderately stable from preschool to school age (OR = 5.92, CI = 3.95, 8.86), and about half of those who displayed pickiness at age 4 were also picky eaters two years later. While accounting for pickiness at age 4, sensory sensitivity at age 4 predicted pickiness at age 6 (OR = 1.25, CI = 1.08, 2.23), whereas temperamental surgency (OR = 0.88, CI = 0.64, 1.22) and negative affectivity (OR = 1.17, CI = 0.75, 1.84) did not. Parental structuring was found to reduce the risk of children’s picky eating two years later (OR = 0.90, CI = 0.82, 0.99), whereas parental sensitivity increased the odds for pickiness (OR = 1.10, CI = 1.00, 1.21). Conclusions: Although pickiness is stable from preschool to school age, children who are more sensory sensitive are at higher risk for pickiness two years later, as are children whose parents display relatively higher levels of sensitivity and lower levels of structuring. Our findings suggest that interventions targeting children’s sensory sensitivity, as well as parental sensitivity and structuring, might reduce the risk of childhood pickiness. Health care providers should support parents of picky eaters in repeatedly offering unfamiliar and rejected foods to their children without pressure and acknowledging child autonomy

Preventing childhood obesity: what works?

Rates of overweight in North American children and adolescents have increased dramatically since the 1970s. Childhood obesity has reached epidemic proportions and calls for prevention and treatment programs to reverse this trend have been made. However, the evidence base needed for effective action is still incomplete, especially for childhood obesity prevention programs. This paper focuses on primary prevention of childhood obesity and has three aims: (1) to briefly describe current primary prevention approaches for childhood obesity and the evidence for their impact; (2) to elucidate promising, but untested intervention strategies using an ecological framework and evidence from experimental and epidemiological research on factors influencing children\u27s eating and weight status; and (3) to introduce a multiphase strategy for screening intervention components and building and evaluating potent interventions for childhood obesity. Most childhood obesity prevention programs have focused on school-aged children and have had little success. We suggest that, given these findings, prevention efforts should be expanded to explore other contexts in which children live as possible settings for intervention efforts, including the family and childcare settings. Given that 25% of preschool children are already overweight, intervening with children before school entry should be a priority. A review of experimental research on the developing controls of food intake in infancy and childhood suggests possible intervention strategies, focusing on parenting and aspects of the feeding environment. Epidemiological findings point to even earlier modifiable risk factors, including gestational weight gain, maternal prepregnancy weight, and formula feeding. However, the potential impact of altering these risk factors remains to be evaluated. In response to this problem, we suggest a new, multiphase method for accomplishing this, including screening intervention components, refining intervention designs and confirming component efficacy to build and evaluate potent, optimized interventions

A robotic wheelchair trainer: design overview and a feasibility study

<p>Abstract</p> <p>Background</p> <p>Experiencing independent mobility is important for children with a severe movement disability, but learning to drive a powered wheelchair can be labor intensive, requiring hand-over-hand assistance from a skilled therapist.</p> <p>Methods</p> <p>To improve accessibility to training, we developed a robotic wheelchair trainer that steers itself along a course marked by a line on the floor using computer vision, haptically guiding the driver's hand in appropriate steering motions using a force feedback joystick, as the driver tries to catch a mobile robot in a game of "robot tag". This paper provides a detailed design description of the computer vision and control system. In addition, we present data from a pilot study in which we used the chair to teach children without motor impairment aged 4-9 (n = 22) to drive the wheelchair in a single training session, in order to verify that the wheelchair could enable learning by the non-impaired motor system, and to establish normative values of learning rates.</p> <p>Results and Discussion</p> <p>Training with haptic guidance from the robotic wheelchair trainer improved the steering ability of children without motor impairment significantly more than training without guidance. We also report the results of a case study with one 8-year-old child with a severe motor impairment due to cerebral palsy, who replicated the single-session training protocol that the non-disabled children participated in. This child also improved steering ability after training with guidance from the joystick by an amount even greater than the children without motor impairment.</p> <p>Conclusions</p> <p>The system not only provided a safe, fun context for automating driver's training, but also enhanced motor learning by the non-impaired motor system, presumably by demonstrating through intuitive movement and force of the joystick itself exemplary control to follow the course. The case study indicates that a child with a motor system impaired by CP can also gain a short-term benefit from driver's training with haptic guidance.</p

Developmental Trajectories of Body Mass Index Among Japanese Children and Impact of Maternal Factors during Pregnancy

Background The aims of this study were to 1) determine the distinct patterns of body mass index (BMI) trajectories in Japanese children, and 2) elucidate the maternal factors during pregnancy, which contribute to the determination of those patterns. Methodology/Principal Findings All of the children (1,644 individuals) born in Koshu City, Japan, between 1991 and 1998 were followed in a longitudinal study exploring the subjects’ BMI. The BMI was calculated 11 times for each child between birth and 12 years of age. Exploratory latent class growth analyses were conducted to identify trajectory patterns of the BMI z-scores. The distribution of BMI trajectories were best characterized by a five-group model for boys and a six-group model for girls. The groups were named “stable thin,” “stable average,” “stable high average,” “progressive overweight,” and “progressive obesity” in both sexes; girls were allocated to an additional group called “progressive average.” Multinomial logistic regression found that maternal weight, smoking, and skipping breakfast during pregnancy were associated with children included in the progressive obesity pattern rather than the stable average pattern. These associations were stronger for boys than for girls. Conclusions/Significance Multiple developmental patterns in Japanese boys and girls were identified, some of which have not been identified in Western countries. Maternal BMI and some unfavorable behaviors during early pregnancy may impact a child’s pattern of body mass development. Further studies to explain the gender and regional differences that were identified are warranted, as these may be important for early life prevention of weight-associated health problems

Nitrogen limitation constrains sustainability of ecosystem response to CO2

Enhanced plant biomass accumulation in response to elevated atmospheric CO2 concentration could dampen the future rate of increase in CO2 levels and associated climate warming. However, it is unknown whether CO2-induced stimulation of plant growth and biomass accumulation will be sustained or whether limited nitrogen (N) availability constrains greater plant growth in a CO2-enriched world(1-9). Here we show, after a six-year field study of perennial grassland species grown under ambient and elevated levels of CO2 and N, that low availability of N progressively suppresses the positive response of plant biomass to elevated CO2. Initially, the stimulation of total plant biomass by elevated CO2 was no greater at enriched than at ambient N supply. After four to six years, however, elevated CO2 stimulated plant biomass much less under ambient than enriched N supply. This response was consistent with the temporally divergent effects of elevated CO2 on soil and plant N dynamics at differing levels of N supply. Our results indicate that variability in availability of soil N and deposition of atmospheric N are both likely to influence the response of plant biomass accumulation to elevated atmospheric CO2. Given that limitations to productivity resulting from the insufficient availability of N are widespread in both unmanaged and managed vegetation(5,7-9), soil N supply is probably an important constraint on global terrestrial responses to elevated CO2.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62769/1/nature04486.pd

Intensive therapy for moderate established rheumatoid arthritis: the TITRATE research programme

BackgroundRheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management.ObjectivesTo (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials.DesignObservational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis.SettingObservational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions).ParticipantsPatients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs.InterventionsIntensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care.Main outcome measuresDisease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR ResultsEvaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68; p = 0.004), and reduced fatigue [mean difference –18, 95% confidence interval –24 to –11 (scale 0–100); p LimitationsThe main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’.ConclusionThe benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who were substantially overweight usually did not achieve remission.Future workFurther research should (1) identify the most effective components of the intervention, (2) consider its most cost-effective delivery and (3) identify alternative strategies for patients not responding to intensive management.Trial registrationCurrent Controlled Trials ISRCTN70160382.FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.NIH

A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli.

Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and elicits a strong immune response from humans and other animals. We developed a quantitative model of the nine enzyme-catalyzed steps of Escherichia coli lipid A biosynthesis, drawing parameters from the experimental literature. This model accounts for biosynthesis regulation, which occurs through regulated degradation of the LpxC and WaaA (also called KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide concentration, which we deduced from prior results, model results, and new LpxK overexpression results. The model agrees reasonably well with many experimental findings, including the lipid A production rate, the behaviors of mutants with defective LpxA enzymes, correlations between LpxC half-lives and cell generation times, and the effects of LpxK overexpression on LpxC concentrations. Its predictions also differ from some experimental results, which suggest modifications to the current understanding of the lipid A pathway, such as the possibility that LpxD can replace LpxA and that there may be metabolic channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) concentration is low and/or to control the number of KDO residues that get attached to lipid A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate concentrations are not in excess. Based on these results, we suggest that LpxK may be a much better drug target than LpxC, which has been pursued most often

Biologics registers in RA: methodological aspects, current role and future applications

The beginning of the 21st century saw a biopharmaceutical revolution in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis. The fast-evolving use of biologic therapies highlighted the need to develop registers at national and international levels with the aim of collecting long-term data on patient outcomes. Over the past 15 years, many biologics registers have contributed a wealth of data and provided robust and reliable evidence on the use, effectiveness and safety of these therapies. The unavoidable challenges posed by the continuous introduction of new therapies, particularly with regard to understanding their long-term safety, highlights the importance of learning from experience with established biologic therapies. In this Perspectives article, the role of biologics registers in bridging the evidence gap between efficacy in clinical trials and real-world effectiveness is discussed, with a focus on methodological aspects of registers, their unique features and challenges and their role going forward

Distinct Merkel Cell Polyomavirus Molecular Features in Tumour and Non Tumour Specimens from Patients with Merkel Cell Carcinoma

Merkel Cell Polyomavirus (MCPyV) is associated with Merkel Cell carcinoma (MCC), a rare, aggressive skin cancer with neuroendocrine features. The causal role of MCPyV is highly suggested by monoclonal integration of its genome and expression of the viral large T (LT) antigen in MCC cells. We investigated and characterized MCPyV molecular features in MCC, respiratory, urine and blood samples from 33 patients by quantitative PCR, sequencing and detection of integrated viral DNA. We examined associations between either MCPyV viral load in primary MCC or MCPyV DNAemia and survival. Results were interpreted with respect to the viral molecular signature in each compartment. Patients with MCC containing more than 1 viral genome copy per cell had a longer period in complete remission than patients with less than 1 copy per cell (34 vs 10 months, P = 0.037). Peripheral blood mononuclear cells (PBMC) contained MCPyV more frequently in patients sampled with disease than in patients in complete remission (60% vs 11%, P = 0.00083). Moreover, the detection of MCPyV in at least one PBMC sample during follow-up was associated with a shorter overall survival (P = 0.003). Sequencing of viral DNA from MCC and non MCC samples characterized common single nucleotide polymorphisms defining 8 patient specific strains. However, specific molecular signatures truncating MCPyV LT were observed in 8/12 MCC cases but not in respiratory and urinary samples from 15 patients. New integration sites were identified in 4 MCC cases. Finally, mutated-integrated forms of MCPyV were detected in PBMC of two patients with disseminated MCC disease, indicating circulation of metastatic cells. We conclude that MCPyV molecular features in primary MCC tumour and PBMC may help to predict the course of the disease