Skeletal Muscle Changes, Function, and Health-Related Quality of Life in Survivors of Pediatric Critical Illness.

OBJECTIVES: To describe functional and skeletal muscle changes observed during pediatric critical illness and recovery and their association with health-related quality of life. DESIGN: Prospective cohort study. SETTING: Single multidisciplinary PICU. PATIENTS: Children with greater than or equal to 1 organ dysfunction, expected PICU stay greater than or equal to 48 hours, expected survival to discharge, and without progressive neuromuscular disease or malignancies were followed from admission to approximately 6.7 months postdischarge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional status was measured using the Functional Status Scale score and Pediatric Evaluation of Disability Inventory-Computer Adaptive Test. Patient and parental health-related quality of life were measured using the Pediatric Quality of Life Inventory and Short Form-36 questionnaires, respectively. Quadriceps muscle size, echogenicity, and fat thickness were measured using ultrasonography during PICU stay, at hospital discharge, and follow-up. Factors affecting change in muscle were explored. Associations between functional, muscle, and health-related quality of life changes were compared using regression analysis. Seventy-three survivors were recruited, of which 44 completed follow-ups. Functional impairment persisted in four of 44 (9.1%) at 6.7 months (interquartile range, 6-7.7 mo) after discharge. Muscle size decreased during PICU stay and was associated with inadequate energy intake (adjusted ß, 0.15; 95% CI, 0.02-0.28; p = 0.030). No change in echogenicity or fat thickness was observed. Muscle growth postdischarge correlated with mobility function scores (adjusted ß, 0.05; 95% CI, 0.01-0.09; p = 0.046). Improvements in mobility scores were associated with improved physical health-related quality of life at follow-up (adjusted ß, 1.02; 95% CI, 0.23-1.81; p = 0.013). Child physical health-related quality of life at hospital discharge was associated with parental physical health-related quality of life (adjusted ß, 0.09; 95% CI, 0.01-0.17; p = 0.027). CONCLUSIONS: Muscle decreased in critically ill children, which was associated with energy inadequacy and impaired muscle growth postdischarge. Muscle changes correlated with change in mobility, which was associated with child health-related quality of life. Mobility, child health-related quality of life, and parental health-related quality of life appeared to be interlinked.

Branched-Chain Amino Acid Supplementation Does Not Preserve Lean Mass or Affect Metabolic Profile in Adults with Overweight or Obesity in a Randomized Controlled Weight Loss Intervention.

BACKGROUND: Branched-chain amino acid (BCAA) supplementation has been shown to increase muscle mass or prevent muscle loss during weight loss. OBJECTIVE: We aimed to investigate the effects of a BCAA-supplemented hypocaloric diet on lean mass preservation and insulin sensitivity. METHODS: A total of 132 Chinese adults (63 men and 69 women aged 21-45 y, BMI 25-36 kg/m2) were block randomly assigned by gender and BMI into 3 hypocaloric diet (deficit of 500 kcal/d) groups: standard-protein (14%) with placebo (control, CT) or BCAA supplements at 0.1 g · kg-1 body weight · d-1 (BCAA) or high-protein (27%) with placebo (HP). The subjects underwent 16 wk of dietary intervention with provision of meals and supplements, followed by 8 wk of weight maintenance with provision of supplements only. One-way ANOVA analysis was conducted to analyze the primary (lean mass and insulin sensitivity) and secondary outcomes (anthropometric and metabolic parameters) among the 3 groups. Paired t-test was used to analyze the change in each group. RESULTS: The 3 groups demonstrated similar significant reductions in body weight (7.97%), fat mass (13.8%), and waist circumference (7.27%) after 16 wk of energy deficit. Lean mass loss in BCAA (4.39%) tended to be lower than in CT (5.39%) and higher compared with HP (3.67%) (P = 0.06). Calf muscle volume increased 3.4% in BCAA and intramyocellular lipids (IMCLs) decreased in BCAA (17%) and HP (18%) (P < 0.05) over 16 wk. During the 8 wk weight maintenance period, lean mass gain in BCAA (1.03%) tended to be lower compared with CT (1.58%) and higher than in HP (-0.002%) (P = 0.04). Lean mass gain differed significantly between CT and HP (P = 0.03). Insulin sensitivity and metabolic profiles did not differ among the groups throughout the study period. CONCLUSIONS: BCAA supplementation does not preserve lean mass or affect insulin sensitivity in overweight and obese adults during weight loss. A higher protein diet may be more advantageous for lean mass preservation.

A Cross-Sectional Study of the Clinical Metrics of Functional Status Tools in Pediatric Critical Illness.

OBJECTIVES: To determine the clinical metrics of functional assessments in pediatric critical illness survivors. DESIGN: Cross-sectional observational study. SETTING: PICU follow-up clinic. PATIENTS: Forty-four PICU survivors 6-12 months post PICU stay, and 52 healthy controls 0-18 years old. INTERVENTIONS: Nil. MEASUREMENTS AND MAIN RESULTS: Function was assessed using the Pediatric Quality of Life Inventory 4.0 generic scales and infant scales, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test, and the Functional Status Scale. Muscle strength was assessed by hand grip strength in children greater than or equal to 6 years. Clinical metrics assessed included floor and ceiling effects, known-group, and convergent validity. Floor and ceiling effects were present if the participants achieving the worst or best scores exceeded 15%, respectively. Known-group validity was assessed by comparing scores between those with and without complex chronic conditions and abnormal versus good baseline function. Convergent validity was assessed using partial correlation between two tools. Functional Status Scale and Pediatric Quality of Life Inventory physical domain scores showed significant ceiling effects in PICU survivors (69.2% and 15.4%, respectively, achieved the highest possible score). Functional scores were not significantly different between children with or without complex chronic conditions or children with good versus abnormal baseline function. In healthy children, Pediatric Quality of Life Inventory physical correlated moderately with hand grip strength (partial r = 0.66; p < 0.001), whereas Pediatric Quality of Life Inventory psychosocial correlated moderately with Pediatric Evaluation of Disability Inventory-Computer Adaptive Test social/cognitive score (partial r = 0.53; p < 0.001). In PICU survivors, only Pediatric Quality of Life Inventory physical and Pediatric Evaluation of Disability Inventory-Computer Adaptive Test mobility scores were correlated (partial r = 0.55; p < 0.001). CONCLUSIONS: PICU functional assessment tools have varying clinical metrics. Considering ceiling effects, Pediatric Evaluation of Disability Inventory-Computer Adaptive Test may be more suitable in survivors than Functional Status Scale. Differences in scores between children with or without complex chronic conditions, and with or without baseline functional impairment, were not observed. Functional assessments likely require a combination of tools to measure the spectrum of pediatric critical illness and recovery.

Therapeutic plasma exchange for control of thyroid storm.

Therapeutic plasma exchange (TPE) for thyroid storm has recently been upgraded to a category II indication after decades though its recommendation level still remains at Grade 2C according to the American Society for Apheresis (ASFA). In the absence of prospective randomized controlled trials due to the rarity of thyroid storm, retrospective data from case series continue to elevate the clinical evidence supporting TPE as a life-saving modality for complicated thyroid storm patients. We report three cases of life-threatening thyroid storm from Graves' disease rescued by TPE via rapid reduction in circulating thyroid hormones. Each patient underwent TPE when it was judged that other thyroid storm treatment options were futile or unsafe. The first patient received 4 cycles of TPE while the second patient received 9 cycles of TPE, and the third patient received 2 cycles of TPE with satisfactory clinical improvement. Plasma FT4 and TSH receptor antibody levels of the first case declined by 41.3% and >50% respectively right after the first round of TPE; plasma FT4 of the second patient dropped by up to 31.6% during the course of TPE; plasma FT4 and TSH receptor antibody of the third patient declined by 66% and 56.2% respectively after the first cycle of TPE. This demonstrates the safety, efficacy, and feasibility of TPE in thyroid storm especially when other therapeutic interventions are contraindicated. TPE operates via the elimination of serum proteins-bound thyroid hormones, thyroid autoantibodies, cytokines, and catecholamines in addition to increasing unsaturated binding sites for thyroid hormones.

Determinants of intramyocellular lipid accumulation in early childhood.

BACKGROUND/OBJECTIVES: Accumulation of lipid droplets inside skeletal muscle fibers (intramyocellular lipids or IMCL) with increasing obesity has been linked to skeletal muscle insulin resistance and risk of type 2 diabetes in both adults and prepubertal children. We aimed to evaluate the associations of race, genotype, prenatal factors, and postnatal factors with IMCL in early childhood. SUBJECTS/METHODS: This study was a secondary analysis performed on the GUSTO birth cohort. Soleus muscle IMCL of 392 children at 4.5 years of age was measured by magnetic resonance spectroscopy, of which usable imaging data were obtained from 277 children (137 Chinese, 87 Malays, and 53 Indians). Metabolic assessments (fasting glucose, insulin, and HOMA-IR) were performed at age 6. RESULTS: The mean IMCL level at 4.5 years was 0.481 ± 0.279% of water resonance (mean ± sd). Corroborating with results from adults, Indian children had the highest IMCL levels compared with Malay and Chinese children. Among the prenatal factors, the rate of gestational weight gain (GWG rate) was associated with offspring IMCL (B = 0.396 (0.069, 0.724); p = 0.018). Both race and GWG rate continued to be associated with offspring IMCL even after accounting for current offspring BMI. Postnatally, IMCL was associated with shorter breastfeeding duration (B = 0.065 (0.001, 0.128); p = 0.045) and conditional relative weight gain between ages 2 and 3 (B = 0.052 (0.012, 0.093); p = 0.012). The associations with postnatal factors were attenuated after adjusting for current offspring BMI. IMCL was positively associated with offspring BMI (B = 0.028 (0.012, 0.044); p = 0.001). IMCL levels were not associated with fasting glucose, fasting insulin, and HOMA-IR at age 6. CONCLUSION: This study provides evidence that IMCL accumulation occurs in early childhood and that developmental factors and race are associated with it. We also show that early childhood IMCL accumulation is well tolerated, suggesting that the adverse associations between IMCL and insulin resistance may emerge at older ages.

The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis.

An association between impaired fetal growth and the postnatal development of obesity has been established. Here, by comparing adipocytes differentiated from mesenchymal stem cells (MSCs) taken from the umbilical cord and derived from normal and growth-restricted neonates, we identified the transcription factor SOX6 as highly expressed only in growth-restricted individuals. We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST. We further show that SOX6 interacts with ß-catenin in adipocytes, suggesting an inhibition of WNT/ß-catenin signaling, thereby promoting adipogenesis. The upstream regulatory region of the MEST gene in MSCs from growth-restricted subjects harbors hypomethylated CpGs next to SOX6 binding motifs, and we found that SOX6 binding is impaired by adjacent CpG methylation. In summary, we report that SOX6 is a novel regulator of adipogenesis synergizing with epigenetic mechanisms.

Body Composition and Acquired Functional Impairment in Survivors of Pediatric Critical Illness.

OBJECTIVES: To identify whether body mass and composition is associated with acquired functional impairment in PICU survivors. DESIGN: Retrospective dual-cohort study. SETTING: Single multidisciplinary PICU. PATIENTS: Two distinct PICU survivor cohorts: 432 unselected admissions from April 2015 to March 2016, and separately 92 patients with abdominal CT imaging at admission from January 2010 to December 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Admission body mass index and Functional Status Scale scores at admission, PICU discharge, and hospital discharge were obtained for all patients. Acquired functional impairment was defined as increase greater than or equal to 3 in Functional Status Scale from baseline. Patients were classified as having: "temporary acquired impairment" (acquired impairment at PICU discharge recovering by hospital discharge), "persistent acquired impairment" (acquired impairment at PICU discharge persisting to hospital discharge), and "no acquired impairment." CT scans were analyzed for skeletal muscle and fat area using National Institute of Health ImageJ software (Bethesda, MD). Multinomial logistic regression analyses were conducted to identify associations between body mass index, muscle and fat indices, and acquired functional impairment. High baseline body mass index was consistently predictive of persistent acquired impairment in both cohorts. In the second cohort, when body mass index was replaced with radiologic anthropometric measurements, greater skeletal muscle, and visceral adipose tissue indices were independently associated with persistent acquired impairment at hospital discharge (adjusted odds ratio, 1.29; 95% CI, 1.03-1.61; p = 0.024 and adjusted odds ratio, 1.13; 95% CI, 1.01-1.28; p = 0.042, respectively). However, this relationship was no longer significant in children with PICU stay greater than 2 days. CONCLUSIONS: In PICU survivors, baseline body mass and composition may play a role in the persistence of acquired functional impairment at hospital discharge. Characterization and quantification of skeletal muscle and fat deserves further study in larger cohorts of PICU children.

Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians.

BACKGROUND: The importance of ectopic fat deposition and physical fitness in the pathogenesis of insulin resistance and beta cell dysfunction in subjects from the nonobese Asians is not known. MATERIALS AND METHODS: We conducted a cross-sectional study and measured insulin sensitivity (M value; 4-hour hyperinsulinaemic-euglycaemic clamp), insulin secretion rate (3-hour mixed meal tolerance test with oral minimal modelling), percent body fat, visceral adipose tissue, intramyocellular and intrahepatic lipid contents (magnetic resonance imaging and spectroscopy), cardiorespiratory fitness (VO2 max; graded exercise test) and habitual physical activity (short International Physical Activity Questionnaire) in 60 healthy nonobese Asian subjects (BMI = 21.9 ± 1.7 kg/m2 , age = 41.8 ± 13.4 years). RESULTS: M was inversely associated with percent body fat (r = -0.460, P < 0.001), visceral fat (r = -0.623, P < 0.001) and liver fat (r = -0.601, P < 0.001), whereas insulin secretion correlated positively with these adiposity indices (percent body fat: r = 0.303, P = 0.018; visceral fat: r = 0.409, P = 0.010; hepatic fat: r = 0.393, P = 0.002). VO2 max correlated negatively with insulin secretion rate (r = -0.420, P < 0.001) and positively with M (r = 0.658, P < 0.001). The amount of vigorous physical activity was positively associated with VO2 max (r = 0.682, P < 0.001). Multiple stepwise linear regression analyses indicated that VO2 max, age, and IHTG or VAT were independent determinants of insulin sensitivity and secretion (adjusted R2  = 69% and 33%, respectively, P < 0.001). CONCLUSIONS: Increased ectopic fat deposition is associated with reduced insulin sensitivity and increased insulin secretion in healthy nonobese Asians. Poor cardiorespiratory fitness, likely due to inadequate participation in vigorous exercise, is strongly related to suboptimal metabolic function. Interventions to encourage engagement in physical activity may thus be important for improving metabolic health in nonobese Asians.

Functional Outcomes and Physical Impairments in Pediatric Critical Care Survivors: A Scoping Review.

OBJECTIVE: Although more children are surviving critical illness, little is known about long-term physical impairment. This scoping review aims to critically appraise existing literature on functional outcome measurement tools, prevalence, and risk factors for physical impairments in pediatric critical care survivors. DATA SOURCES: PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature, using a combination of MeSH terms and keywords (critical illness, intensive care, and functional outcomes/status). STUDY SELECTION: All human studies reporting functional outcomes in children 0-18 years old admitted to the PICU. Non-English language, adult and preterm infant studies were excluded. DATA SYNTHESIS: Three global assessment tools and eight multidimensional measures were used to measure functional outcome in pediatric survivors of critical illness. Rates of acquired functional impairment in a general pediatric intensive care cohort ranged from 10% to 36% at discharge and 10% to 13% after more than 2 years. Risk factors for acquired functional impairment include illness severity, the presence of organ dysfunction, length of ICU stay, and younger age. There is some evidence that physical impairment may be more severe and persistent than psychosocial components. CONCLUSIONS: Functional impairment may be persistent in pediatric survivors of critical care. Unfortunately, studies varied largely in measurement timing and tools used. The lack of differentiation between impairment in different functional domains limited the generalizability of data. Further studies using a combination of standardized measures at various time points of the disease process can help establish more comprehensive rates of physical impairment.

Treatment of severe perinatal mood disorders on a specialized perinatal psychiatry inpatient unit.

Perinatal patients with bipolar and psychotic mood disorder exacerbations are challenging to treat and often receive suboptimal care. We sought to examine the treatment patterns and outcomes on one of the only US-based Perinatal Psychiatry Inpatient Units (PPIU). Perinatal patients admitted to the PPIU completed self-report measures at admission and before discharge. Retrospective chart reviews extracted history, diagnoses (current and past), and medication treatment. Patients who had discharge diagnoses of bipolar disorder, major depression with psychotic features, or postpartum psychosis were included. Forty-seven met the diagnostic inclusion criteria. Over an average length of stay (ALOS) of 9.96 days, there was significant improvement in depressive and anxiety symptoms and daily functioning (Work and Social Adjustment Scale). Psychiatric comorbidity was common. Polypharmacy was utilized in 87 %. The most common medications prescribed at discharge were antipsychotics, alone or in combination with mood stabilizers or antidepressants. ECT was performed in 10 % of cases. The complexity of patients with severe mood disorders or psychosis admitted to the PPIU supports individualized treatment plans that address both primary diagnosis and psychiatric comorbidities. Our results provide important information that can be disseminated to others to improve clinical outcomes for severe perinatal mood disorders.

A long-term study examining the antibacterial effectiveness of Agion silver zeolite technology on door handles within a college campus.

Laboratory studies have shown that small concentrations of silver are effective at inhibiting the growth micro-organisms through the disruption of important cell structures and processes. The additional ability to incorporate silver into surfaces has increased the usage of silver in the medical field and expanded its use into the consumer market. To understand the impact of increased silver-containing antimicrobial use, it is important to determine whether silver-based consumer goods are effective at reducing bacterial populations. Our study examined the antibacterial effectiveness of Agion silver zeolite technology applied to 25 silver- and control-coated door handles across a college campus. Door handles were sampled for 6 week periods in both the fall and spring semester, and bacteria were cultured and enumerated on tryptic soy agar (TSA), MacConkey agar (MAC) and mannitol salt agar (MSA). A significant difference was observed between the bacterial populations isolated from silver- and control-coated door handles after 3 years. However, bacteria were consistently isolated from silver-coated door handles suggesting that the silver zeolite was only effective against a portion of the bacterial populations, and further studies are necessary to determine the identities of the isolated bacteria and the prevalence of silver resistance.

Endocrine effects of heat exposure and relevance to climate change.

Climate change is increasing both seasonal temperatures and the frequency and severity of heat extremes. As the endocrine system facilitates physiological adaptations to temperature changes, diseases with an endocrinological basis have the potential to affect thermoregulation and increase the risk of heat injury. The effect of climate change and associated high temperature exposure on endocrine axis development and function, and on the prevalence and severity of diseases associated with hormone deficiency or excess, is unclear. This Perspective summarizes current knowledge relating to the hormonal effects of heat exposure in species ranging from rodents to humans. We also describe the potential effect of high temperature exposures on patients with endocrine diseases. Finally, we highlight the need for more basic science, clinical and epidemiological research into the effects of heat on endocrine function and health; this research could enable the development of interventions for people most at risk, in the context of rising environmental temperatures.

14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial.

BACKGROUND: New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. METHODS: In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. FINDINGS: The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. INTERPRETATION: PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. FUNDING: The Global Alliance for TB Drug Development (TB Alliance).

Brown fat detection by infrared thermography-An invaluable research methodology with noteworthy uncertainties confirmed by a mathematical proof.

Brown adipose tissue (BAT) represents a pivotal scientific renaissance worthy as a strategy for obesity and diabetes since its re-discovery in adults over a decade ago. Equally compelling is the adoption of infrared thermography (IRT) in recent times as a precise and viable alternative methodology over the 'gold standard' PET-CT scan, given constraints of the latter's high ionizing radiation doses and costs. Unravelling BAT metabolic physiology in live humans has been challenging until recent rigorous validation of IRT against PET. Nevertheless, IRT remains a nascent technique with pitfalls unbeknownst to many researchers. Factors impacting its accuracy merit an in-depth scientific scrutiny. This article discusses the strengths and pitfalls of IRT as an emergent BAT detection technique and provides a mathematical proof of its limitations that BAT researchers should be cognizant of. Understanding these limitations of IRT can prompt extra efforts to control these uncertainties with greater rigour. In conclusion, this warrants further investigations of improving IRT quality via advanced auto-segmentation, powerful image processing of thermograms and protocol standardization along the lines of BARCIST 1.0 to minimize errors and enhance the confidence of the global BAT research community in IRT as a robust and reliable BAT research tool.

Muscle Ultrasound Changes and Physical Function of Critically Ill Children: A Comparison of Rectus Femoris Cross-Sectional Area and Quadriceps Thickness Measurements.

Quadriceps thickness (QT) and rectus femoris cross-sectional area (RFCSA) are both used to evaluate muscle changes in critically ill children. However, their correlation and association with physical function has not been compared. OBJECTIVES: To compare QT with RFCSA changes, and their association with physical function in critically ill children. DESIGN SETTING AND PARTICIPANTS: Secondary analysis of a prospective cohort study of children 0-18 years old admitted to a tertiary mixed PICU between January 2015 and October 2018 with PICU stay greater than 48 hours and greater than or equal to one organ dysfunction. MAIN OUTCOMES AND MEASURES: Ultrasound QT and RFCSA were measured at PICU admission, PICU discharge, hospital discharge, and 6 months post-discharge. QT and RFCSA changes from baseline were compared with each other and with change in motor function, physical ability, and physical health-related quality of life (HRQOL). RESULTS: Two hundred thirty-seven images from 66 subjects were analyzed. RFCSA change was not significantly different from QT change at PICU (-8.07% [interquartile range (IQR), -17.11% to 4.80%] vs -4.55% [IQR, -14.32% to 4.35%]; p = 0.927) or hospital discharge (-5.62% [IQR, -15.00% to 9.42%] vs -8.81% [IQR, -18.67% to 2.39%]; p = 0.238) but was significantly greater than QT change at 6 months (32.7% [IQR, 5.74-109.76%] vs 9.66% [IQR, -8.17% to 25.70%]; p < 0.001). Motor function change at PICU discharge was significantly associated with RFCSA change (adjusted ß coefficient, 0.02 [95% CI, 0.01-0.03]; p = 0.013) but not QT change (adjusted ß coefficient, -0.01 [95% CI, -0.02 to 0.01]; p = 0.415). Similar results were observed for physical HRQOL changes at hospital discharge (adjusted ß coefficient for RFCSA change, 0.51 [95% CI, 0.10-0.92]; p = 0.017 and adjusted ß coefficient for QT change, -0.21 [-0.76 to 0.35]; p = 0.458). Physical ability was not significantly associated with RFCSA or QT changes at 6 months post-discharge. CONCLUSIONS AND RELEVANCE: Ultrasound derived RFCSA is associated with PICU motor function and hospital discharge physical HRQOL changes, unlike QT, and may be more useful for in-hospital muscle monitoring in critically ill children.

Phase II dose-ranging trial of the early bactericidal activity of PA-824.

PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml sputum (± standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.