Clinical standards for drug-susceptible TB in children and adolescents.

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.

Administration and monitoring of clofazimine for NTM infections in children with and without cystic fibrosis.

Few studies have evaluated clofazimine (CLOF) drug monitoring and safety in children. We treated 10 children, 8 with CF, for NTM infection with multiple antimicrobials, including CLOF. All had serial blood CLOF concentrations measured and were followed for adverse events. Despite CLOF dose escalation, most children with CF did not reach a target CLOF concentration. Our data suggest that children with CF may require earlier initiation of CLOF at higher doses than is currently recommended.

Epidemiology and clinical characteristics of childhood TB identified using active and passive case finding.

BACKGROUND: Childhood TB cases can be found using passive case finding (PCF), i.e., by diagnosing children presenting with symptoms, or using active case finding (ACF), i.e., by identifying children with TB through contact tracing. Our study determined epidemiologic, clinical, and radiographic differences between these groups.DESIGN/METHODS: Retrospective cohort study of children aged 0-19 years diagnosed with TB from January 1, 2012 to December 31, 2019 at a U.S. TB clinic, comparing clinical, radiographic, microbiologic, and epidemiological characteristics of children identified using PCF and ACF.RESULTS: Of 178 eligible patients, 99 (55.6%) were diagnosed using PCF. Children identified using PCF were older (mean 8.9 vs. 6.1 years, P = 0.003), more often non-US-born (OR 2.29, 95% CI 1.12-4.67), had more extrapulmonary disease (44.4% vs. 3.8%, OR 20.27, 95% CI 5.98-68.64) and severe intrathoracic findings (39.4% vs. 10.1%, OR 5.77, 95% CI 2.50-13.29). Children identified using ACF were often asymptomatic, had isolated hilar/mediastinal adenopathy, but had more availability of drug susceptibility data from a link to a source case.CONCLUSION: Children identified using PCF had more severe manifestations, while those identified using ACF had greater availability of drug susceptibility data. Clinicians should be aware that clinical and radiographic presentations in children identified using PCF and those identified using ACF differ, and that the latter may be eligible for shorter treatment regimens.

Latitudinal effect of vegetation on erosion rates identified along western South America.

Vegetation influences erosion by stabilizing hillslopes and accelerating weathering, thereby providing a link between the biosphere and Earth's surface. Previous studies investigating vegetation effects on erosion have proved challenging owing to poorly understood interactions between vegetation and other factors, such as precipitation and surface processes. We address these complexities along 3500 kilometers of the extreme climate and vegetation gradient of the Andean Western Cordillera (6°S to 36°S latitude) using 86 cosmogenic radionuclide-derived, millennial time scale erosion rates and multivariate statistics. We identify a bidirectional response to vegetation's influence on erosion whereby correlations between vegetation cover and erosion range from negative (dry, sparsely vegetated settings) to positive (wetter, more vegetated settings). These observations result from competing interactions between precipitation and vegetation on erosion in each setting.

Plant proton pumping pyrophosphatase: the potential for its pyrophosphate synthesis activity to modulate plant growth.

Cellular pyrophosphate (PPi) homeostasis is vital for normal plant growth and development. Plant proton-pumping pyrophosphatases (H+ -PPases) are enzymes with different tissue-specific functions related to the regulation of PPi homeostasis. Enhanced expression of plant H+ -PPases increases biomass and yield in different crop species. Here, we emphasise emerging studies utilising heterologous expression in yeast and plant vacuole electrophysiology approaches, as well as phylogenetic relationships and structural analysis, to showcase that the H+ -PPases possess a PPi synthesis function. We postulate this synthase activity contributes to modulating and promoting plant growth both in H+ -PPase-engineered crops and in wild-type plants. We propose a model where the PPi synthase activity of H+ -PPases maintains the PPi pool when cells adopt PPi-dependent glycolysis during high energy demands and/or low oxygen environments. We conclude by proposing experiments to further investigate the H+ -PPase-mediated PPi synthase role in plant growth.

Inactivation of the bacterial pathogens Staphylococcus pseudintermedius and Acinetobacter baumannii by butanoic acid.

AIMS: This study was performed to evaluate the efficacy of butanoic acid against bacterial pathogens including Acinetobacter baumannii and Staphylococcus pseudintermedius. METHODS AND RESULTS: Vegetative bacteria were exposed to butanoic acid in vitro and log reduction was quantified using viable count assays. The maximum (8 and 9) log inactivation was determined by qualitatively assaying for growth/no-growth after a 48-h incubation (37°C). Membrane integrity after exposure to butanoic acid was determined by propidium iodide staining, scanning electron microscopy, membrane depolarization and inductively coupled plasma analysis. Cytosolic pH was measured by 5-(6-)carboxyfluorescein succinimidyl ester. CONCLUSIONS: Inhibitory concentrations of butanoic acid ranged between 11 and 21 mmol l-1 for Gram-positive and Gram-negative species tested. The maximum log reduction of A. baumannii was achieved with a 10-s exposure of 0·50 mol l-1 of butanoic acid. Staphylococcus pseudintermedius required 0·40 mol l-1 of butanoic acid to achieve the same level of reduction in the same time period. Inactivation was associated with membrane permeability and acidification of the cytosol. SIGNIFICANCE AND IMPACT OF THE STUDY: Antibiotic resistance among bacterial pathogens necessitates the utilization of novel therapeutics for disinfection and biological control. These results may facilitate the development of butanoic acid as an effective agent against a broad-spectrum of antibiotic-resistant bacterial pathogens.

Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group.

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Controversies in tuberculous infection among pediatric infectious disease specialists in North America.

OBJECTIVE: To evaluate the extent to which advancements in the diagnosis and treatment of latent tuberculous infection (LTBI) have been integrated into practice by pediatric infectious disease (PID) specialists. DESIGN: We conducted an online survey of the Infectious Diseases Society of America's Emerging Infections Network (EIN) membership. RESULTS: Of the 323 members, 197 (61%) responded: 7% cared for ⩾5 children with TB disease and 34% for ⩾5 children with LTBI annually. We identified substantial variations in the use of interferon-gamma release assays (IGRAs) based upon age, immune status, and TB risk factors. In addition, tuberculin skin test (TST) use was three times more common in younger children. Variations existed in managing children with discordant TST and IGRA results. Less variation existed in LTBI treatment, with 86% preferring a 9-month course of isoniazid; few other, newer regimens were used routinely. CONCLUSION: Substantial variations exist in LTBI management; uptake of newer diagnostic tools and treatment regimens has been slow. Variations in practice and the lag time to integrating new data into practice may indicate the relative infrequency with which providers encounter LTBI. Our findings reflect the need for increased visibility of existing TB guidelines and resources for expert consultation for scenarios not covered by guidelines.

Safety and completion of a 4-month course of rifampicin for latent tuberculous infection in children.

SETTING: Children's Tuberculosis Clinic, Houston, Texas. OBJECTIVE: To describe adherence to and tolerability of 4 months of rifampicin (4RMP) compared to 9 months of isoniazid (9INH) in children with latent tuberculous infection (LTBI). DESIGN: Retrospective descriptive case series of children treated for LTBI from 2010 to 2013 by self-administered therapy or directly observed preventive therapy (DOPT) administered by the local health department. RESULTS: Four hundred and four children were treated, 324 (80%) with 9INH and 80 with 4RMP: the mean age was 7.3 years, and 47% were girls. Of these, 37% were identified during contact investigations. DOPT was used in 51% and self-administered therapy in 49%; 81% completed therapy. Completion of self-administered 4RMP therapy was not significantly different from completion rates for children receiving 9INH administered as DOPT (93% vs. 88%, OR 0.6, 95%CI 0.2-1.7), but was significantly higher than in the 9INH self-administration group (OR 7.9, 95%CI 2.7-23.2). Adverse events were rare: 20 (6%) in the 9INH group and 2 (3%) in the 4RMP group, and none was serious. CONCLUSION: Completion rates for 4RMP surpassed those of 9INH for all methods of delivery, except for DOPT, where completion rates were similar. 4RMP was well tolerated. The increased cost of 4RMP over 9INH may be offset by increased effectiveness, as gauged by completion rates.

Controlling traffic jams by time modulating the safety distance.

The possibility of controlling traffic dynamics by applying high-frequency time modulation of traffic flow parameters is studied. It is shown that the region of the car density where the uniform (free) flow is unstable changes in the presence of time modulation compared with the unmodulated case. This region shrinks when the speed-up of cars does not exceed some critical value and expands in the opposite case. The flux of the time-modulated flow is an increasing function of the amplitude of the modulation for traffic flows whose density is larger than 1/h where h is the safety distance in the nonmodulated case, while it is a decreasing function in the opposite case. In other words, the safety distance time modulation facilitates car propagation in the case when the mean distance between cars in the congestive traffic is less than h and hinders it when the neighboring cars in the flow are well separated. A link between a microscopic description and the macroscopic fundamental diagram is established.

Requirements for the clinical evaluation of new anti-tuberculosis agents in children.

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

Twice-weekly therapy for children with tuberculosis infection or exposure.

SETTING: Children's tuberculosis clinic, Houston, TX, United States. OBJECTIVE: To determine the safety, adherence and efficacy of intermittent directly observed preventive therapy (DOPT). DESIGN: Retrospective cohort of children receiving intermittent DOPT for exposure to tuberculosis (TB) or latent TB infection (LTBI) seen from 1989 to 2011 at one clinic. RESULTS: A total of 1383 children were treated for either TB exposure for 2-3 months (n = 935, 68%) or LTBI for 9 months (n = 448, 32%) with isoniazid 20-30 mg/kg/dose or rifampin 10-15 mg/kg/dose biweekly. All children with exposure and 411 (92%) with LTBI were identified via contact investigations. Twelve (1.3%) children with exposure experienced adverse effects (5 abdominal pain, 4 vomiting, 3 rash); 8 had transaminases evaluated and only 1 had elevated levels. Thirty (6.7%) children with LTBI experienced adverse effects (16 abdominal pain, 6 rash, 3 vomiting, 3 headache and 2 abdominal pain/vomiting); 19 had transaminases obtained and 2 had elevated transaminases. All transaminases normalized after the discontinuation of medication. Over 99% of exposed and 95.8% of infected children completed treatment. One child, who had sickle cell anemia, was treated for LTBI and later developed TB disease. When compared to rates of disease progression by age, the efficacy of intermittent DOPT was 98%. CONCLUSION: Intermittent DOPT in childhood TB is safe, effective and offers high adherence rates.

Human 6-sulfo LacNAc (slan) dendritic cells are a major population of dermal dendritic cells in steady state and inflammation.

BACKGROUND: The immune system of the skin has a network of resident dendritic cells (DCs) consisting of epidermal Langerhans cells and various subsets of dermal DCs. We recently reported on a new population of dermal DCs, called slan (6-sulfoLacNAc+) DCs, which have a potent capacity to stimulate Th17/Th1 T-cell responses. AIM: To understand the characteristics of slanDCs as a new population of dermal DCs in the context of other DC populations in healthy and psoriatic skin. METHODS: We immunofluorescently stained skin samples from healthy controls and from patients with psoriasis. RESULTS: Staining healthy skin for DCs showed that slanDCs (CD1a- CD1c- CD11c- CD14- CD163-) were present at a similar frequency to that of CD1c+ CD11c+ CD1a+ CD14- CD163- dermal DCs, which have previously been regarded as the major population of resident DCs. In psoriatic skin, the frequency of slanDCs and CD1c+ DCs was doubled, and the slanDCs expressed CD11c. In-depth analysis of DCs in psoriatic skin by four-colour immunofluorescence analysis showed that the pool of CD11c+ cells could be further subdivided into CD11c+ CD14+ CD163- DCs and CD11c+ CD163+ CD14+ macrophages. CONCLUSION: SlanDCs, initially described as large population of proinflammatory DCs in blood, are a novel and major part of the resident dermal myeloid DC system in both healthy and inflamed skin.

Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems.

Signaling downstream of receptor tyrosine kinases controls cell differentiation and survival. How signals from different receptors are integrated is, however, still poorly understood. In this work, we have identified Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin repeat-rich membrane spanning) as a main player in the modulation of neurotrophin and vascular endothelial growth factor (VEGF) signaling in vivo, and a primary determinant for neuronal and cardiovascular development. Kidins220(-/-) embryos die at late stages of gestation, and show extensive cell death in the central and peripheral nervous systems. Primary neurons from Kidins220(-/-) mice exhibit reduced responsiveness to brain-derived neurotrophic factor, in terms of activation of mitogen-activated protein kinase signaling, neurite outgrowth and potentiation of excitatory postsynaptic currents. In addition, mice lacking Kidins220 display striking cardiovascular abnormalities, possibly due to impaired VEGF signaling. In support of this hypothesis, we demonstrate that Kidins220 constitutively interacts with VEGFR2. These findings, together with the data presented in the accompanying paper, indicate that Kidins220 mediates the integration of several growth factor receptor pathways during development, and mediates the activation of distinct downstream cascades according to the location and timing of stimulation.

The influence of PEEP and tidal volume on central blood volume.

BACKGROUND AND OBJECTIVE: Measurement of central blood volumes (CBV), such as global end-diastolic volume (GEDV) and right ventricular end-diastolic volume (RVEDV) are considered appropriate estimates of intravascular volume status. However, to apply those parameters for preload assessment in mechanically ventilated patients, the influence of tidal volume (TV) and positive endexpiratory airway pressure (PEEP) on those parameters must be known. METHODS: In 13 mechanically ventilated piglets, the effect of low (10 mL kg(-1)) and high (20 mL kg(-1)) TVs on CBV was investigated in absence and presence of PEEP (0 and 15 cm H(2)O). GEDV, RVEDV, right heart (RHEDV) and left heart end-diastolic volume (LHEDV) were measured by thermodilution. Blood flow on the descending thoracic aorta measured with an ultrasonic flow-probe served to determine stroke volume (SV). Measurements were performed during baseline conditions, after volume loading with previously extracted haemodilution blood (20 mL kg(-1)) and following haemorrhage (30 mL kg(-1)). RESULTS: Application of PEEP decreased GEDV and SV significantly (P < 0.05). Augmenting TV did not reduce GEDV systematically, but significantly reduced SV (P < 0.05). Changes in ventilator settings only influenced RVEDV following volume loading (P < 0.05). RHEDV and LHEDV decreased following application of PEEP, but only RHEDV decreased after augmenting TV at baseline and following volume loading. Correlation of SV with parameters of CBV was r = 0.487 (P < 0.01) for GEDV, r = 0.553 (P < 0.01) for RVEDV, r = 0.596 (P < 0.01) for RHEDV and r = 0.303 (P < 0.01) for LHEDV. CONCLUSION: Application of PEEP decreases CBV and SV. Augmenting TV reduces SV but not CBV. There is a moderate correlation between parameters of CBV and cardiac performance.

Model of calcium oscillations due to negative feedback in olfactory cilia.

We present a mathematical model for calcium oscillations in the cilia of olfactory sensory neurons. The underlying mechanism is based on direct negative regulation of cyclic nucleotide-gated channels by calcium/calmodulin and does not require any autocatalysis such as calcium-induced calcium release. The model is in quantitative agreement with available experimental data, both with respect to oscillations and to fast adaptation. We give predictions for the ranges of parameters in which oscillations should be observable. Relevance of the model to calcium oscillations in other systems is discussed.

Analysis and visualization of growth-related and treatment-induced craniofacial changes.

An analysis and visualization of craniofacial shape changes due to growth or orthodontic treatment is presented. The suggested method is based on an adapted Karhunen-Loève decomposition of time-discrete data based on landmarks in lateral X-rays of the skull. It allows for a reduction of the high-dimensional dynamic problem to a few spatial modes representing synchronous components of growth patterns with time-dependent mode coefficients. The growth-related shape changes as well as the orthodontic treatment effects are visualized by overdrawing the underlying shape changes. The results based on this technique give insight into the still controversially discussed question to which degree the craniofacial skeletal structures can be influenced by orthodontic appliances.

Modulation of plant ion channels by oxidizing and reducing agents.

Ion channels are proteins forming hydrophilic pathways through the membranes of all living organisms. They play important roles in the electrogenic transport of ions and metabolites. Because of biophysical properties such as high selectivity for the permeant ion, high turnover rate, and modulation by physico-chemical parameters (e.g., membrane potential, calcium concentration), they are involved in several physiological processes in plant cells (e.g., maintenance of the turgor pressure, stomatal movements, and nutrient absorption by the roots). As plants cannot move, plant metabolism must be flexible and dynamic, to cope with environmental changes, to compete with other living species and to prevent pathogen invasion. An example of this flexibility and dynamic behavior is represented by their handling of the so-called reactive oxygen species, inevitable by-products of aerobic metabolism. Plants cope with these species on one side avoiding their toxic effects, on the other utilizing them as signalling molecules and as a means of defence against pathogens. In this review, we present the state-of-the-art of the modulation of plant ion channels by oxidizing and reducing agents.

Pharmacokinetics of ethambutol in children and adults with tuberculosis.

SETTING: Five hospitals in the United States. OBJECTIVE: To describe ethambutol pharmacokinetics in children and adults with active tuberculosis (TB). DESIGN: Prospective, open-labeled study in 56 adults and 14 children with active tuberculosis who received ethambutol as part of their multidrug TB regimens. RESULTS: Most serum samples were collected up to 10 h post dose and assayed using a validated gas chromatography assay with mass selective detection (GC/MS). Concentration data were analyzed using non-compartmental and population pharmacokinetic methods. Drug exposure increased with dose, but less than proportionally at doses >3000 mg. Lower than expected maximum serum concentrations (Cmax <2 microg/ml) were common in adults. Very low Cmax (<1 microg/ml) were common in children, as was delayed absorption (time to Cmax >3 h). Many Cmax were at or below typical TB minimal inhibitory concentrations. Cmax values for HIV-positive patients were 20% lower than HIV-negative patients with daily doses, but were similar with larger twice-weekly doses. CONCLUSIONS: Adult TB patients often had lower than expected ethambutol serum concentrations, and most pediatric TB patients had very low ethambutol serum concentrations. Higher doses and therapeutic drug monitoring may be indicated for many of these patients.