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.

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.

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.

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.

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.

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.

Population pharmacokinetics of ethionamide in patients with tuberculosis.

SETTING: Three US referral hospitals. OBJECTIVE: Determine the population pharmacokinetic (PK) parameters of ethionamide (ETA) following multiple oral doses. DESIGN: Fifty-five patients with tuberculosis (TB) participated. Patients received multiple oral doses of ETA as part of their treatment. They also received other anti-tuberculosis medications based upon in vitro susceptibility data. Serum samples were collected over 12 h post-dose, and concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS: ETA areas under the concentration-versus-time curve (AUCs) increased linearly with increasing oral doses from 250 to 1000 mg. Compared to the population pattern, delayed absorption was seen at least once in 15% of patients. ETA PK parameter estimates were independent of age, weight, height, gender, and creatinine clearance. TB patients appeared to have larger volumes of distribution (3.22 l/kg) and clearance values (1.88 l/h/kg) compared to previously studied healthy volunteers. This resulted in lower AUC values (3.95 mcg h/ml) in the TB patients. ETA displayed a short elimination half-life (1.94 h). The effect of different dosing strategies on calculated pharmacodynamic parameters was explored. Simulated doses of 250 mg BID to TID failed to achieve serum concentrations above the MIC. CONCLUSION: ETA PK parameters differed between TB patients and healthy volunteers, possibly due to differences in the completeness of absorption. Doses of at least 500 mg appear to be required to achieve serum concentrations above the typical ETA MIC. Additional research is needed to determine the optimal dosing of ETA.

Tuberculosis in the pediatric population of Houston, Texas.

From September 1984 to December 1987, the children's tuberculosis clinic in Houston, TX, cared for 110 children with active tuberculosis. The median age was 24 months. Approximately one half of the cases were in Hispanic children, but one third were in black children. Only 11% were foreign-born. Diagnosis resulted from case contact investigation in 50% of cases, routine tuberculin screening in 6%, and evaluation of an ill child in 44%. Intrathoracic disease alone was present in 77% of cases, and extrathoracic disease in 23%, including involvement of the cervical and supraclavicular lymph nodes, meninges, brain, liver, and skin. Gastric aspirates yielded Mycobacterium tuberculosis from 39% of the children with pulmonary disease. Of six children infected with drug-resistant tuberculosis, two became critically ill before referral because the probability of resistance was not recognized by the referring physician. Presently, 94% of patients have successfully completed therapy, which has been shortened from 12 to 18 months to 6 to 9 months. However, 39% were noncompliant with treatment and required twice-weekly supervised therapy to complete treatment. Tuberculosis remains a serious cause of morbidity in children; specific expertise in obtaining cultures, selecting drugs, and assuring compliance is crucial for adequate results.

Clinical features, diagnosis, and treatment of tuberculosis in infants.

OBJECTIVE: Despite the recent resurgence of tuberculosis among children in the United States, no series of infants < 1 year of age with tuberculosis has been reported in the last 20 years. This study was undertaken to describe the epidemiology, clinical, and radiographic manifestations, and response to therapy in infants < 1 year of age with tuberculous disease. METHODS: The medical records were reviewed for all infants age 12 months or less with a diagnosis of tuberculosis and cared for at the Children's Tuberculosis Clinic at Ben Taub General Hospital in Houston, Texas between January 1, 1985 and June 30, 1992. RESULTS: Of the 47 infants identified, 51% were female. The median age at diagnosis was 8 months (range 3.5 to 12 months). Fifty-one percent of the infants were African-American and over one-third were Hispanic. All patients were born in the United States. Diagnosis resulted from the examination of an ill infant in 79% of cases, a case contact investigation of an adult suspected of having tuberculosis in 19%, and routine tuberculin skin testing in 2%. An adult with infectious tuberculosis who had contact with the infant was identified in 68% of cases. Intrathoracic disease alone was present in 70% of cases. Fourteen (30%) infants had extrapulmonary tuberculosis (11 central nervous system disease, 2 disseminated disease, and 1 cervical adenitis). Gastric aspirate cultures yielded Mycobacterium tuberculosis from 75% of the infants with isolated intrathoracic disease. Forty-five infants successfully completed therapy and only one death was directly related to tuberculosis. Forty-eight percent of the infants with pulmonary tuberculosis were treated with a 6-month regimen consisting of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide. Eighteen infants received some twice weekly directly observed therapy mainly due to documented or suspected nonadherence. Treatment was well-tolerated; one patient (2%) developed hepatotoxicity due to isoniazid. No infant had a relapse or recurrence of disease in 6 months to 7 years follow-up for a median of 3 years (range, 6 months to 7 years). CONCLUSION: Most infants with tuberculosis are symptomatic at the time of diagnosis, and bacteriologic confirmation was obtained in 70% of cases. A contact investigation of the household should be initiated immediately when an infant is suspected of having tuberculosis because valuable information needed to establish the diagnosis and guide therapy in the infant may be obtained. Intensive 6-month and twice weekly directly observed therapy appear to be well-tolerated and effective for the treatment of pulmonary tuberculosis in infants.

Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction.

OBJECTIVE: We evaluated the usefulness of the polymerase chain reaction (PCR) using the insertion sequence IS6110 as the target for DNA to detect Mycobacterium tuberculosis in clinical specimens from children. STUDY DESIGN: This was a prospective, controlled, blinded study comparing PCR on clinical specimens, mycobacterial culture, and clinical diagnosis. PATIENTS: Sixty-five hospitalized children were evaluated, 35 with tuberculosis disease and 30 controls. Cases were defined by culture and/or specific clinical criteria. Controls included patients with tuberculosis infection but no detectable disease as well as patients free of tuberculosis infection and disease. RESULTS: Polymerase chain reaction had a sensitivity of 40% and a specificity of 80% compared with clinical diagnosis. Mycobacterial culture had a sensitivity of 37%. The combination of culture and PCR identified 19 of 35 children (54%) with clinically diagnosed tuberculosis. There were six children with false-positive PCR results: One had tuberculosis infection without disease, two had Mycobacterium avium lymphadenitis, and three had diagnoses unrelated to tuberculosis. CONCLUSIONS: The sensitivity of PCR is comparable to that of culture for detecting M tuberculosis in children, and may strengthen and hasten the clinical diagnosis in culture-negative patients. However, because of the limitations in specificity, the results of PCR alone are insufficient to diagnose tuberculosis in children. Although ongoing refinements in PCR techniques should improve the specificity of this test, epidemiologic and clinical information continue to be the most important consideration in the diagnosis of tuberculosis in culture-negative children.

Routine tuberculin screening of children during hospitalization.

Harris County, TX, which includes Houston, has one of the highest childhood tuberculosis case rates in the United States. For an 11-week period in the spring of 1988 all children admitted to the medical service of the Ben Taub General Hospital in Houston, TX, received a Mantoux skin test consisting of tuberculin purified protein derivative. The purpose was to assess the impact of routine tuberculin screening during hospitalization for acute medical care and to determine whether tuberculin screening in this setting is an effective means of identifying children with asymptomatic tuberculous infection. Of the 432 patients skin tested, 50% were younger than 1 year of age and only 304 were evaluable at 48 hours. Two new positive skin tests were discovered for a positive tuberculin rate of 0.66%. We conclude that even in a high risk region, routine tuberculin screening of all children admitted to the hospital may not be effective.

Congenital tuberculosis presenting as sepsis syndrome: case report and review of the literature.

We report an infant with congenital tuberculosis who presented with fulminant septic shock, disseminated intravascular coagulation and respiratory failure. Aggressive resuscitation and supportive care and prompt initiation of antituberculosis medications led to resolution of the shock state. We reviewed six other cases with a similar presentation. Congenital tuberculosis should be in the differential of the infant presenting acutely with sepsis syndrome.

Primary adenocarcinoma arising in an ileostomy.

Two cases are added to the world literature of patients in whom an adenocarcinoma developed at the ileostomy site after total proctocolectomy for ulcerative colitis. Fourteen additional cases have been reported in the world literature; of these, 12 cases have been in patients with ulcerative colitis, and four cases have been in patients with familial adenomatous polyposis. Adenocarcinoma of an ileostomy is not common. However, in the analysis of the reported cases, patients with long-standing ileostomies appear to be at a greater risk. With an aging ileostomy population, an increase in the number of cases may be seen. Three hypotheses are discussed as potential causative pathways to this entity. Continued analysis of these cases may yield information on the pathophysiology involved.

Current chemotherapy for tuberculosis in children.

Antituberculosis medications are extremely well tolerated by children and have proved to be very successful. The newer regimens of intensive short-course chemotherapy for tuberculosis have several advantages over traditional two-drug regimens, including faster sterilization and bactericidal action, shorter duration over which patient noncompliance can occur, less expenditure of resources for monitoring treatment, lower failure and relapse rates, and broader coverage for possible drug-resistant M. tuberculosis. The currently recommended regimen for pulmonary and most extrapulmonary forms of tuberculosis in children is 6 months of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide. Treatment during the first 1 to 2 months should, if possible, be daily but the last 4 to 5 months of therapy can be either daily or twice weekly under direct observation of a health-care professional. For patients in whom social or other constraints prevent reliable self-administration of daily treatment in the initial phase, medications may be given twice weekly from the beginning under close observation. For these situations, a total duration of treatment of 6 to 9 months is reasonable. Non-life-threatening forms of extrapulmonary tuberculosis can be treated in the same manner as pulmonary tuberculosis. Although tuberculous meningitis probably will respond to these regimens, the relative lack of data at present leads most experts to recommend total durations of between 6 and 12 months for this form of tuberculosis. The major limitation to controlling tuberculosis in the United States is noncompliance or nonadherence to medications by patients. The physician and other health-care providers must devote a great deal of their time and energy to ensuring adherence with medications and take whatever steps are necessary to make sure that the child with tuberculosis is adequately treated.

A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis.

SETTING: The diagnosis of tuberculosis (TB) in children is seldom confirmed, and is based mainly on clinical signs, symptoms and special investigations. Various attempts in the form of diagnostic approaches have been made to rationalise this diagnostic process. AIMS: To review and describe published diagnostic approaches aimed at diagnosing mainly intrathoracic tuberculosis in children in developing countries; to compare diagnostic approaches with each other and with bacteriologically confirmed TB; and to describe modifications to the diagnosis of TB in HIV-infected or malnourished children. METHODS: Literature review classified into 1) diagnostic approaches, 2) characteristics used in diagnostic approaches, and 3) studies done to validate diagnostic approaches. RESULTS: Sixteen systems were analysed. Comparison of systems is difficult because characteristic definitions and the ranking of characteristics are not standardised, few studies have been performed to validate these diagnostic approaches, and the gold standard of diagnosis is not practicable in most settings. The minority of systems are adapted for HIV-infected and malnourished patients. RECOMMENDATIONS: Characteristic definitions and ranking of characteristics should be standardised. Any new diagnostic approaches developed should be relevant to developing countries with limited resources, a high burden of tuberculosis, malnutrition and HIV/AIDS and a young population. Studies done to validate diagnostic approaches should be conducted scientifically.

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.

The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era.

The pre-chemotherapy literature documented the natural history of tuberculosis in childhood. These disease descriptions remain invaluable for guiding public health policy and research, as the introduction of effective chemotherapy radically changed the history of disease. Specific high-risk groups were identified. Primary infection before 2 years of age frequently progressed to serious disease within the first 12 months without significant prior symptoms. Primary infection between 2 and 10 years of age rarely progressed to serious disease, and such progression was associated with significant clinical symptoms. In children aged >3 years the presence of symptoms represented a window of opportunity in which to establish a clinical diagnosis before serious disease progression. Primary infection after 10 years of age frequently progressed to adult-type disease. Early effective intervention in this group will reduce the burden of cavitating disease and associated disease transmission in the community. Although the pre-chemotherapy literature excluded the influence of human immune deficiency virus (HIV) infection, recent disease descriptions in HIV-infected children indicate that immune-compromised children behave in a similar fashion to immune immature children (less than 2 years of age). An important concept deduced from the natural history of tuberculosis in childhood is that of relevant disease. Deciding which children to treat may be extremely difficult in high-prevalence, low-resource settings. The concept of relevant disease provides guidance for more effective public health intervention.