The late effects of haematopoietic stem cell transplants in paediatric patients: a 25 year review.

CONTEXT: A rare, large single centre study covering all long-term health outcomes of paediatric allogeneic HSCT survivors, to provide comprehensive local data, and identify gaps and future directions for improved care. OBJECTIVE: To document endocrine sequelae and other late effects of all HSCT recipients. DESIGN: Retrospective review. SETTING: Royal Children's Hospital Melbourne. PATIENTS: 384 children and adolescents received HSCT. 228 formed the study cohort; 212 were alive at commencement of data accrual. INTERVENTION: None. MAIN OUTCOME MEASURES: Incidence of endocrinopathies; fertility, growth, bone and metabolic status; subsequent malignant neoplasms (SMNs). RESULTS: Gonadotoxicity was more common in females (p<0.001). Total body irradiation (TBI) conditioning was more toxic than chemotherapy alone. All females receiving TBI or higher cyclophosphamide equivalent doses (CED) developed premature ovarian insufficiency (POI) . In males, impaired spermatogenesis +/- testicular endocrine dysfunction was associated with increasing testicular radiation exposure. Preservation of gonadal function was associated with younger age at HSCT. Of sexually active females, 22% reported spontaneous pregnancies. Short stature was common, with growth hormone axis disruption in 30% of these. Of patients exposed to thyroid radiation 51% developed nodules, 30% malignant. Metabolic disturbances included hypertension, dyslipidemias, with both excess and underweight reported. Fragility fractures occurred in 6%; avascular necrosis in 6%. 13% developed SMNs, risk continuing to rise throughout follow-up. CONCLUSIONS: We confirm gonadal dysfunction, multiple endocrine and metabolic abnormalities, thyroid cancer and SMNs, as common sequelae of HSCT, and identify gaps in management - particularly the need for informed fertility counselling and pretreatment fertility preservation, evaluation and management of bone health, and underline need for early lifestyle modification, long-term surveillance, and prospective planned studies aimed at reducing complication risk.

Towards multimodal cellular imaging: optical and X-ray fluorescence.

Imaging techniques permit the study of the molecular interactions that underlie health and disease. Each imaging technique collects unique chemical information about the cellular environment. Multimodal imaging, using a single probe that can be detected by multiple imaging modalities, can maximise the information extracted from a single cellular sample by combining the results of different imaging techniques. Of particular interest in biological imaging is the combination of the specificity and sensitivity of optical fluorescence microscopy (OFM) with the quantitative and element-specific nature of X-ray fluorescence microscopy (XFM). Together, these techniques give a greater understanding of how native elements or therapeutics affect the cellular environment. This review focuses on recent studies where both techniques were used in conjunction to study cellular systems, demonstrating the breadth of biological models to which this combination of techniques can be applied and the potential for these techniques to unlock untapped knowledge of disease states.

Treatment of pathophysiologic propagation outside of the pulmonary veins in retreatment of atrial fibrillation patients: RECOVER AF study.

AIMS: RECOVER AF evaluated the performance of whole-chamber non-contact charge-density mapping to guide the ablation of non-pulmonary vein (PV) targets in persistent atrial fibrillation (AF) patients following either a first or second failed procedure. METHODS AND RESULTS: RECOVER AF was a prospective, non-randomized trial that enrolled patients scheduled for a first or second ablation retreatment for recurrent AF. The PVs were assessed and re-isolated if necessary. The AF maps were used to guide the ablation of non-PV targets through elimination of pathologic conduction patterns (PCPs). Primary endpoint was freedom from AF on or off antiarrhythmic drugs (AADs) at 12 months. Patients undergoing retreatment with the AcQMap System (n = 103) were 76% AF-free at 12 months [67% after single procedure (SP)] on or off AADs (80% free from AF on AADs). Patients who had only received a pulmonary vein isolation (PVI) prior to study treatment of non-PV targets with the AcQMap System were 91% AF-free at 12 months (83% SP). No major adverse events were reported. CONCLUSION: Non-contact mapping can be used to target and guide the ablation of PCPs beyond the PVs in persistent AF patients returning for a first or second retreatment with 76% freedom from AF at 12 months. The AF freedom was particularly high, 91% (43/47), for patients enrolled having only a prior de novo PVI, and freedom from all atrial arrhythmias for this cohort was 74% (35/47). These early results are encouraging and suggest that guiding individualized targeted ablation of PCPs may therefore be advantageous to target at the earliest opportunity in patients with persistent AF.

Synchrotron-based X-ray fluorescence microscopy reveals accumulation of polymyxins in single human alveolar epithelial cells.

Intravenous administration of the last-line polymyxins results in poor drug exposure in the lungs and potential nephrotoxicity; while inhalation therapy offers better pharmacokinetics/pharmacodynamics for pulmonary infections by delivering the antibiotic to the infection site directly. However, polymyxin inhalation therapy has not been optimized and adverse effects can occur. This study aimed to quantitatively determine the intracellular accumulation and distribution of polymyxins in single human alveolar epithelial A549 cells. Cells were treated with an iodine-labeled polymyxin probe FADDI-096 (5.0 and 10.0 µM) for 1, 4, and 24 h. Concentrations of FADDI-096 in single A549 cells were determined by synchrotron-based X-ray fluorescence microscopy. Concentration- and time-dependent accumulation of FADDI-096 within A549 cells was observed. The intracellular concentrations (mean ± SEM, n ≥ 189) of FADDI-096 were 1.58 ± 0.11, 2.25 ± 0.10, and 2.46 ± 0.07 mM following 1, 4 and 24 h of treatment at 10 µM, respectively. The corresponding intracellular concentrations following the treatment at 5 µM were 0.05 ± 0.01, 0.24 ± 0.04, and 0.25 ± 0.02 mM (n ≥ 189). FADDI-096 was mainly localized throughout the cytoplasm and nuclear region over 24 h. The intracellular zinc concentration increased in a concentration- and time-dependent manner. This is the first study to quantitatively map the accumulation of polymyxins in human alveolar epithelial cells and provides crucial insights for deciphering the mechanisms of their pulmonary toxicity. Importantly, our results may shed light on the optimization of inhaled polymyxins in patients and the development of new-generation safer polymyxins.

Sarcopenia measurements and clinical outcomes in Crohn's disease surgical patients.

BACKGROUND: Patients with Crohn's disease (CD) have a high likelihood of being sarcopenic. Several studies have shown a positive correlation between sarcopenia measured as skeletal muscle index (SMI) and poor surgical outcomes in patients with CD. Our primary aim was to correlate SMI with the psoas muscle index (PMI), an easier measurement of sarcopenia. Secondary aim was to correlate SMI and PMI with clinical outcomes in a cohort of CD patients requiring surgery. METHODS: A retrospective cohort study of CD patients who underwent surgery at a public health service from January 2010 to December 2019. Using computed tomography and magnetic resonance enterography studies, skeletal muscle area was measured at the third lumbar vertebra level. SMI and PMI were calculated and correlated. Correlation between SMI and PMI with surgical outcomes was performed. RESULTS: Seventy-six patients were included. Median length of stay (LOS) was 6 days (IQR, 5 to 9). Eleven patients (14.5%) required ICU admission, nine patients (11.8%) required TPN and thirteen patients (17.1%) had complications. The prevalence of sarcopenia was 63.2% based on the SMI threshold of 52.4 and 38.5 cm2 /m2 for men and women, respectively. A positive correlation between SMI and PMI was found (r = 0.72, P < 0.0001). Sarcopenia status based on reported thresholds for SMI and for PMI showed no significant correlation with outcomes (LOS, ICU admission and complications). CONCLUSIONS: SMI and PMI show good correlation but there is insufficient evidence to suggest that sarcopenia status using either measurement has a significant impact on predicting clinical outcomes.

Sensitivity of pre-operative imaging and radiologist inter-rater reliability in detecting lesions in Crohn's disease.

BACKGROUND: Computed tomography (CT), computed tomography enterography (CTE) and magnetic resonance enterography (MRE) are commonly used pre-operatively in surgical planning in Crohn's Disease (CD). The findings on CT, CTE and MRE may not, however, correlate with operative findings. This study aims to establish the sensitivity of these imaging modalities and analyse radiologist inter-rater reliability by comparing imaging findings of strictures, fistulas and abscesses with intra-operative findings. METHODS: A retrospective review of CD patients who had either CT, CTE and/or MRE imaging and CD related surgical intervention at a public health service from 2010 to 2019 inclusive. The number and locations of strictures, fistulas and abscesses on pre-operative original radiology reports (OR) were recorded. Subsequently, all scans were re-read by two specialist abdominal radiologists and consensus recorded (SR). Lesions recorded from both OR and SR were compared to those found intra-operatively. RESULTS: Eighty-three patients were included. For strictures, sensitivity was 67%, 74% and 79% for OR and 88%, 71% and 87% for SR for CT, CTE and MRE respectively. The frequency of fistulas and abscesses were small hence a conclusion could not be drawn. The level of agreement between radiologists ranged from 44% to 82% for strictures and 64 to 100% for fistulas and abscesses across all three imaging modalities. CONCLUSIONS: CT and MRE have similarly high sensitivities for the identification of strictures pre-operatively when read by specialist radiologists. Inter-rater reliability calculations found similar agreement levels between specialist radiologists and between OR and SR for strictures, fistulas and abscesses across CT, CTE and MRE.

Leadless left ventricular endocardial pacing for CRT upgrades in previously failed and high-risk patients in comparison with coronary sinus CRT upgrades.

AIMS: Cardiac resynchronization therapy (CRT) upgrades may be less likely to improve following intervention. Leadless left ventricular (LV) endocardial pacing has been used for patients with previously failed CRT or high-risk upgrades. We compared procedural and long-term outcomes in patients undergoing coronary sinus (CS) CRT upgrades with high-risk and previously failed CRT upgrades undergoing LV endocardial upgrades. METHOD AND RESULTS: Prospective consecutive CS upgrades between 2015 and 2019 were compared with those undergoing WiSE-CRT implantation. Cardiac resynchronization therapy response at 6 months was defined as improvement in clinical composite score (CCS) and a reduction in LV end-systolic volume (LVESV) ≥15%. A total of 225 patients were analysed; 121 CS and 104 endocardial upgrades. Patients receiving WiSE-CRT tended to have more comorbidities and were more likely to have previous cardiac surgery (30.9% vs. 16.5%; P = 0.012), hypertension (59.2% vs. 34.7%; P < 0.001), chronic obstructive airways disease (19.4% vs. 9.9%; P = 0.046), and chronic kidney disease (46.4% vs. 21.5%; P < 0.01) but similar LV ejection fraction (30.0 ± 8.3% vs. 29.5 ± 8.6%; P = 0.678). WiSE-CRT upgrades were successful in 97.1% with procedure-related mortality in 1.9%. Coronary sinus upgrades were successful in 97.5% of cases with a 2.5% rate of CS dissection and 5.6% lead malfunction/displacement. At 6 months, 91 WiSE-CRT upgrades and 107 CS upgrades had similar improvements in CCS (76.3% vs. 68.5%; P = 0.210) and reduction in LVESV ≥15% (54.2% vs. 56.3%; P = 0.835). CONCLUSION: Despite prior failed upgrades and high-risk patients with more comorbidities, WiSE-CRT upgrades had high rates of procedural success and similar improvements in CCS and LV remodelling with CS upgrades.

A guide to representing variability and uncertainty in biodiversity indicators.

Biodiversity indicators are used to inform decisions and measure progress toward global targets, such as the United Nations Sustainable Development Goals. Indicators aggregate and simplify complex information, so underlying information influencing its reliability and interpretation (e.g., variability in data and uncertainty in indicator values) can be lost. Communicating uncertainty is necessary to ensure robust decisions and limit misinterpretations of trends, yet variability and uncertainty are rarely quantified in biodiversity indicators. We developed a guide to representing uncertainty and variability in biodiversity indicators. We considered the key purposes of biodiversity indicators and commonly used methods for representing uncertainty (standard error, bootstrap resampling, and jackknife resampling) and variability (quantiles, standard deviation, median absolute deviation, and mean absolute deviation) with intervals. Using 3 high-profile biodiversity indicators (Red List Index, Living Planet Index, and Ocean Health Index), we tested the use, suitability, and interpretation of each interval method based on the formulation and data types underpinning the indicators. The methods revealed vastly different information; indicator formula and data distribution affected the suitability of each interval method. Because the data underpinning each indicator were not normally distributed, methods relying on normality or symmetrical spread were unsuitable. Quantiles, bootstrapping, and jackknifing provided useful information about the underlying variability and uncertainty. We built a decision tree to inform selection of the appropriate interval method to represent uncertainty or variation in biodiversity indicators, depending on data type and objectives. Our guide supports transparent and effective communication of biodiversity indicator trends to facilitate accurate interpretation by decision makers.

Los indicadores de biodiversidad se usan para orientar las decisiones y medir el progreso hacia los objetivos globales, como los Objetivos de Desarrollo Sustentable de las Naciones Unidas. Los indicadores agregan y simplifican la información compleja, por lo que la información subyacente que influye sobre su confiabilidad e interpretación (p. ej.: variabilidad en los datos e incertidumbre en los valores indicadores) puede perderse. Es necesario comunicar la incertidumbre para asegurar decisiones sólidas y limitar las malas interpretaciones de las tendencias. Aun así, rara vez se cuantifican la variabilidad y la incertidumbre en los indicadores de biodiversidad. Desarrollamos una guía para representar la incertidumbre y la variabilidad en los indicadores de biodiversidad. Consideramos los propósitos importantes de los indicadores de biodiversidad y los métodos comúnmente usados para representar la incertidumbre (error estándar, remuestreo bootstrap, remuestreo jackknife) y la variabilidad (quantiles, desviación estándar, desviación mediana absoluta, desviación media absoluta) con intervalos. Usamos tres indicadores de biodiversidad de alto perfil (Red List Index, Living Planet Index, Ocean Health Index) para analizar el uso, idoneidad e interpretación de cada método de intervalo con base en la formulación y los tipos de datos fundamentales para los indicadores. Los métodos revelaron información ampliamente diferente; la fórmula del indicador y la distribución de los datos afectaron la idoneidad de cada método de intervalo. Ya que los datos fundamentales para cada indicador no tuvieron una distribución normal, los métodos que dependen de la normalidad o el esparcimiento simétrico no fueron idóneos. Los quantiles, el bootstrap y el jackknife proporcionaron información útil sobre la variabilidad y la incertidumbre subyacentes. Construimos un árbol de decisiones para guiar la selección del método de intervalo apropiado para representar la incertidumbre o la variación en los indicadores de biodiversidad, dependiendo del tipo de datos y de los objetivos. Nuestra guía respalda la comunicación efectiva y transparente de las tendencias en los indicadores de biodiversidad para facilitarle al órgano decisorio la interpretación acertada de estas tendencias.

Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans.

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

Leadless left ventricular endocardial pacing in nonresponders to conventional cardiac resynchronization therapy.

BACKGROUND: Endocardial pacing may be beneficial in patients who fail to improve following conventional epicardial cardiac resynchronization therapy (CRT). The potential to pace anywhere inside the left ventricle thus avoiding myocardial scar and targeting the latest activating segments may be particularly important. The WiSE-CRT system (EBR systems, Sunnyvale, CA) reliably produces wireless, endocardial left ventricular (LV) pacing. The purpose of this analysis was to determine whether this system improved symptoms or led to LV remodeling in patients who were nonresponders to conventional CRT. METHOD: An international, multicenter registry of patients who were nonresponders to conventional CRT and underwent implantation with the WiSE-CRT system was collected. RESULTS: Twenty-two patients were included; 20 patients underwent successful implantation with confirmation of endocardial biventricular pacing and in 2 patients, there was a failure of electrode capture. Eighteen patients proceeded to 6-month follow-up; endocardial pacing resulted in a significant reduction in QRS duration compared with intrinsic QRS duration (26.6 ± 24.4 ms; P = .002) and improvement in left ventricular ejection fraction (LVEF) (4.7 ± 7.9%; P = .021). The mean reduction in left ventricular end-diastolic volume was 8.3 ± 42.3 cm3 (P = .458) and left ventricular end-systolic volume (LVESV) was 13.1 ± 44.3 cm3 (P = .271), which were statistically nonsignificant. Overall, 55.6% of patients had improvement in their clinical composite score and 66.7% had a reduction in LVESV ≥15% and/or absolute improvement in LVEF ≥5%. CONCLUSION: Nonresponders to conventional CRT have few remaining treatment options. We have shown in this high-risk patient group that the WiSE-CRT system results in improvement in their clinical composite scores and leads to LV remodeling.

Real-world experience of leadless left ventricular endocardial cardiac resynchronization therapy: A multicenter international registry of the WiSE-CRT pacing system.

BACKGROUND: Biventricular endocardial pacing (BiV ENDO) is a therapy for heart failure patients who cannot receive transvenous epicardial cardiac resynchronization therapy (CRT) or have not responded adequately to CRT. BiV ENDO CRT can be delivered by a new wireless LV ENDO pacing system (WiSE-CRT system; EBR Systems, Sunnyvale, CA), without the requirement for lifelong anticoagulation. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of the WiSE-CRT system during real-world clinical use in an international registry. METHODS: Data were prospectively collected from 14 centers implanting the WiSE-CRT system as part of the WiCS-LV Post Market Surveillance Registry. (ClinicalTrials.gov Identifier: NCT02610673). RESULTS: Ninety patients from 14 European centers underwent implantation with the WiSE-CRT system. Patients were predominantly male, age 68.2 ± 10.5 years, left ventricular ejection fraction 30.6% ± 8.9%, mean QRS duration 180.7 ± 27.0 ms, and 40% with ischemic etiology. Successful implantation and delivery of BiV ENDO pacing was achieved in 94.4% of patients. Acute (<24 hours), 1- to 30-day, and 1- to 6-month complications rates were 4.4%, 18.8%, and 6.7%, respectively. Five deaths (5.6%) occurred within 6 months (3 procedure related). Seventy percent of patients had improvement in heart failure symptoms. CONCLUSION: BiV ENDO pacing with the WiSE-CRT system seems to be technically feasible, with a high success rate. Three procedural deaths occurred during the study. Procedural complications mandate adequate operator training and implantation at centers with immediately available cardiothoracic and vascular surgical support.

Outcomes of Zoledronic Acid Use in Paediatric Conditions.

INTRODUCTION: Limited evidence is available concerning experience with use of zoledronic acid (ZA) and treatment for conditions other than primary bone fragility. MATERIALS AND METHODS: A retrospective review of all Royal Children Hospital patients who had been administered at least 1 dose of intravenous ZA from 2002 to 2015 was undertaken. RESULTS: The audit included 309 children with 228 being treated for bone fragility conditions. Of the 228, 68 had height-adjusted lumbar spine bone mineral density Z-scores available over up to a 5-year period, and median increases were +2.0 SD (median absolute deviation = 0.9) (N = 36, p value for median increase of at least 0.5 in Z-score <0.001), for patients with osteogenesis imperfecta or other primary bone fragility disorders, +1.0 SD (0.9) (N = 14, p = 0.029), for immobility conditions, +0.5 SD (0.7) (N = 10, p = 0.399), and for glucocorticoid-induced secondary osteoporosis, +0.7 SD (0.6) (N = 8, p = 0.015). 81/309 children were treated for bone abnormality indications (e.g., avascular necrosis [AVN], fibrous dysplasia, and bone cysts). Of 39 with AVN, outcome data were available for 33, with joint integrity maintained for 24/33 from 6 to 24 months after last ZA, subjective reports (22/28) of reduced pain. Reduction in bone lesion size was seen in 2/4 patients with bone cysts within 12 months of ZA commencement. DISCUSSION/CONCLUSION: This is the largest cohort of reported outcomes of ZA use in a paediatric population. Results demonstrate a good efficacy profile and associated improved bone density for osteoporotic conditions and stabilization of non-traumatic AVN with a low rate of joint collapse.

CuII(atsm) Attenuates Neuroinflammation.

Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer's disease (AD). Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation. Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex CuII(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro. Results: By using a sophisticated in vivo magnetic resonance imaging (MRI) approach, we report the efficacy of CuII(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). CuII(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes. Conclusion: The beneficial effects of CuII(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.

Guidance for Optimal Site Selection of a Leadless Left Ventricular Endocardial Electrode Improves Acute Hemodynamic Response and Chronic Remodeling.

OBJECTIVES: This study hypothesized that guided implants, in which the optimal left ventricular endocardial (LVENDO) pacing location was identified and targeted, would improve acute markers of contractility and chronic markers of cardiac resynchronization (CRT) response. BACKGROUND: Biventricular endocardial (BiVENDO) pacing may offer a potential benefit over standard CRT; however, the optimal LVENDO pacing site is highly variable. Indiscriminately delivered BiVENDO pacing is associated with a reverse remodeling response rate of between 40% and 60%. METHODS: Registry of centers implanting a wireless, LVENDO pacing system (WiSE-CRT System, EBR Systems, Sunnyvale, California); John Radcliffe Hospital (Oxford, United Kingdom), Guy's and St. Thomas' Hospital (London, United Kingdom), and The James Cook University Hospital (Middlesbrough, United Kingdom). Centers used a combination of preprocedural imaging and electroanatomical mapping the identify the optimal LVENDO site. RESULTS: A total of 26 patients across the 3 centers underwent a guided implant. Patients were predominantly male with a mean age of 68.8 ± 8.4 years, the mean LV ejection fraction was 34.2 ± 7.8%. The mean QRS duration was 163.8 ± 26.7 ms, and 30.8% of patients had an ischemic etiology. It proved technically feasible to selectively target and deploy the pacing electrode in a chosen endocardial segment in almost all cases, with a similar complication rate to that observed during indiscriminate BiVENDO. Ninety percent of patients met the definition of echocardiographic responder. Reverse remodeling was observed in 71%. CONCLUSIONS: Guided endocardial implants were associated with a higher degree of chronic LV remodeling compared with historical nonguided approaches.

Bone mineral density is related to lung function outcomes in young people with cystic fibrosis-A retrospective study.

INTRODUCTION: Improvements in the medical management of cystic fibrosis (CF) in recent years have resulted in increased prevalence of long-term sequelae of the condition, such as low bone mineral density (BMD) and hence an increased risk of fractures in later life. Aim To explore the interaction between BMD and lung function, nutrition, and genotype. METHODS: This study was a retrospective audit of 202 children with CF from August 2000 to January 2016 to investigate associations between BMD Z-scores with clinical status, nutrition, and genetics using dual-energy absorptiometry X-ray data from the Royal Children's Hospital Melbourne, Australia. RESULTS: Severity of both lung disease (P < 0.0001) and nutritional status (P < 0.05) was found to be strongly associated with BMD Z-scores. CONCLUSIONS: This is the biggest study to date to provide further evidence that the severity of pulmonary disease is related to BMD in CF patients and therefore screening guidelines for bone health in children with CF should target individuals with the poorest clinical status.

Radiation Dose Limits for Bioanalytical X-ray Fluorescence Microscopy.

Analytical approaches that preserve the endogenous state of the examined system are essential for the in vivo study of bioinorganics. X-ray fluorescence microscopy of biological samples can map elements in vivo at subcellular resolutions in tissue samples and multicellular organisms. However, X-ray irradiation induces modifications that accumulate with dose. Consequently, the utility of X-ray fluorescence microscopy is intrinsically limited by the radiation damage it causes and the degree to which it alters the target features of interest. Identification of the dose threshold, below which the integrity of the specimen and its elemental distribution is preserved, is required to ensure valid interpretation of concentrations. Here we use the nematode, Caenorhabditis elegans, to explore these issues using three chemical-free specimen preparations: lyophilization, cryofixation, and live. We develop quantitative methods for investigating damage and present dose limits for each preparation pertaining to the micrometer-scale spatial distribution of specific analytes (potassium, calcium, manganese, iron, and zinc), and discuss dose-appropriate guidelines for X-ray fluorescence microscopy of microscale biological samples.

Nanoscale Imaging Reveals Big Role for Iron in Alzheimer's Disease.

In this issue of Cell Chemical Biology, Telling et al. (2017) apply advanced X-ray microscopy techniques to reveal magnetite iron species in plaques from a mouse model of Alzheimer's disease. The characterization of abnormal iron chemistry in the disease model highlights the potential for iron to combine with the ß-amyloid peptide and accelerate the disease process.

Asthma, bones and corticosteroids: Are inhaled corticosteroids associated with fractures in children with asthma?

AIM: The prevalence of asthma worldwide among older children varies between 10 and 20%. One of the most effective therapies to treat asthma and prevent exacerbations is inhaled corticosteroids (ICSs). Systemic corticosteroids are known to decrease bone mineral density and increase the risk of fractures among children, but little is known about the effect of ICSs on fracture risk in children with asthma. The aim of this study was to investigate the fracture rates in children with asthma using ICSs. METHODS: A survey on fracture history and risk, bone health and asthma was administered by a researcher to children aged 6-18 years attending a tertiary care children's hospital in Melbourne, Australia over a 6-month period. Fracture risks were compared in children on low or high dose ICS with those not on any ICS and non-asthmatics. RESULTS: A total of 216 healthy control participants were compared with 211 children with asthma - 22% (n = 46) on low dose ICS therapy, 44% (n = 94) on high dose ICS and 34% (n = 71) not on any ICS. There was no difference in the incidence of fractures between children with asthma (24.6% n = 53) and healthy controls (24% n = 51) (χ2 = 0.132; P = 0.717). There were no differences in fracture incidence in the sub-groups of children with asthma (P = 0.695). CONCLUSION: ICS use was not associated with fracture risk in children with asthma.