Proton tracking in a high-granularity Digital Tracking Calorimeter for proton CT purposes

Radiation therapy with protons as of today utilizes information from x-ray CT in order to estimate the proton stopping power of the traversed tissue in a patient. The conversion from x-ray attenuation to proton stopping power in tissue introduces range uncertainties of the order of 2-3% of the range, uncertainties that are contributing to an increase of the necessary planning margins added to the target volume in a patient. Imaging methods and modalities, such as Dual Energy CT and proton CT, have come into consideration in the pursuit of obtaining an as good as possible estimate of the proton stopping power. In this study, a Digital Tracking Calorimeter is benchmarked for proof-of-concept for proton CT purposes. The Digital Tracking Calorimeteris applied for reconstruction of the tracks and energies of individual high energy protons. The presented prototype forms the basis for a proton CT system using a single technology for tracking and calorimetry. This advantage simplifies the setup and reduces the cost of a proton CT system assembly, and it is a unique feature of the Digital Tracking Calorimeter. Data from the AGORFIRM beamline at KVI-CART in Groningen in the Netherlands and Monte Carlo simulation results are used to in order to develop a tracking algorithm for the estimation of the residual ranges of a high number of concurrent proton tracks. The range of the individual protons can at present be estimated with a resolution of 4%. The readout system for this prototype is able to handle an effective proton frequency of 1 MHz by using 500 concurrent proton tracks in each readout frame, which is at the high end range of present similar prototypes. A future further optimized prototype will enable a high-speed and more accurate determination of the ranges of individual protons in a therapeutic beam.Comment: 21 pages, 8 figure

Photodiode read-out of the ALICE photon spectrometer PbWO4PbWO_{4} crystals

Proposal of abstract for LEB99, Snowmass, Colorado, 20-24 September 1999The PHOton Spectrometer of the ALICE experiment is an electromagnetic calorimeter of high granularity consisting of 17280 lead-tungstate (PWO) crystals of dimensions 22x22x180 mm3, read out by large-area PIN-diodes with very low-noise front-end electronics. The crystal assembly is operated at -25C to increase the PWO light yield. A 16.1x17.1 mm2 photodiode, optimized for the PWO emissio spectrum at 400-500 nm, has been developed. The 20x20 mm2 preamplifier PCB is attached to the back side of the diode ceramic frame. The charge sensitive preamplifier is built in discrete logic with two input JFETs for optimum matching with the ~150pF PIN-diode. A prototype shaper has been designed and built in discrete logic. For a detector matrix of 64 units the measured ENCs are between 450-550e at -25C. Beam tests demonstrate that the required energy resolution is reached.Summary:The PHOton Spectrometer of the ALICE experiment is an electromagnetic calorimeter of high granularity consisting of 17280 lead-tungstate (PWO) crystals of dimensions 22x22x180 mm3, coupled to large-area PIN-diodes with matching low-noise preamplifiers. PHOS is optimized for measuring photons, pi0s and eta mesons in the momentum ranges 0.5-10, 1-10 and 2-10 GeV/c, respectively, and is designed for the expected large number of particles that will be produced in central Pb-Pb collisions. Lead tungstate (PWO) is a fast scintillating crystal with a rather complex emission spectrum, consisting of two components: a blue component peaking at 420 nm and a green component peaking at 480-520 nm. The light yield of PWO at room temperature is low compared with other heavy scintillating crystals, for instance BGO. However, the yield depends strongly on the temperature with a coefficient of ~-2 degree. At the selected operating temperature of -25C the yield is about a factor of 3 higher compared to room temperature. Still, in order to reach the required energy resolution for a PHOS channel, an ENC noise of less than 600e for the PIN-diode-preamplifier-shaper stage is required. This is a very low value taking into account the high capacitance of 150-200 pF of the large area PIN-diodes. In collaboration with the PHOS project, the company AME (Horten, Norway) has designed and produced a PIN-photodiode optimized for the cross-section and spectral responsivity of the PHOS PWO crystal. The photodiode has an active area of 17.1x16.1 mm2 and is fabricated on n-type silicon material of thickness 280 um. The wafer specific resistivity is between 3000 and 6000 ohm-cm, which corresponds to a depletion voltage of 70V. The photodiode response is optimized for the spectral region 400-500 nm in order to match the PWO emission spectrum. The PIN-diode is mounted on a ceramic substrate 0.65 mm thick. On this substrate the diode is surrounded by a ceramic frame. The preamplifier PCB of dimension 20x20 mm2 is attached to the back side of the frame. The PIN-diode and bondings to ground and preamplifier input are protected by an optically transparent epoxy layer. The front side of the PIN-diode is glued onto the endface of the PWO crystal with optically transparent glue (Melt-Mount Quick-Stick, Cargille Laboratories, USA). Each crystal is wrapped in White Tyvek to ensure maximum light collection efficiency and optical insulation between the crystals. The PHOS detector consists of four independent modules, each with 4320 channels. The crystal assembly with the photo detectors are operated at -25 +/- 0.3C. The power dissipation per module is ~1 kW. The charge sensitive preamplifier is an operational amplifier built in discrete logic and with two input JFETs (BF861A). Using two JFETs in parallel gives the lowest noise for detector capacitance >100 pF. A prototype shaper, comprising three amplification stages, has been designed and built in discrete logic. For a PIN-diode with capacitance ~150 pF and a leakage current <1 nA under cooling, calculations give optimum time differentiation and integration constants around 3 microsec. For a detector matrix of 64 units the measured ENCs are between 450-550 e at -25C. Beam tests of this matrix show that the required energy resolution for the PHOS is reached

Effect of azithromycin on incidence of acute respiratory exacerbations in children with HIV taking antiretroviral therapy and co-morbid chronic lung disease: a secondary analysis of the BREATHE trial

Background - In the BREATHE trial weekly azithromycin decreased the rate of acute respiratory exacerbations (AREs) compared to placebo among children and adolescents with HIV-associated chronic lung disease (CLD) taking antiretroviral therapy (ART). The aim of this analysis was to identify risk factors associated with AREs and mediators of the effect of azithromycin on AREs. Methods - The primary outcome of this analysis was the rate of AREs by study arm up to 49 weeks. We analysed rates using Poisson regression with random intercepts. Interaction terms were fitted for potential effect modifiers. Participants were recruited from Zimbabwe and Malawi between15 June 2016 and 4 September 2018. Findings - We analysed data from 345 participants (171 allocated to azithromycin and 174 allocated to placebo). Rates of AREs were higher among those with an abnormally high respiratory rate at baseline (adjusted rate ratio (aRR) 2.08 95% CI 1.10-3.95 p-value 0.02) and among those with a CD4 cell count -2 and participants without baseline resistance to azithromycin. However, there was no statistical evidence for interaction due to low statistical power. Interpretation - These may represent subgroups who may benefit the most from treatment with weekly azithromycin, which could help guide targeted treatment. Funding - There was no funding source for this post hoc analysis

Racial Variation in Echocardiographic Reference Ranges for Left Chamber Dimensions in Children and Adolescents: A Systematic Review.

Echocardiography plays a critical role in the assessment of cardiac disease. Important differences in echocardiographically derived cardiac chamber dimensions have been previously highlighted in different population groups in adult studies, but this has not been systematically studied in children, whose body size changes throughout childhood. The aim of this study was to review the distribution of available reference ranges for the left cardiac chamber dimensions in older children and adolescents. The following electronic data bases were searched: Medline, Embase and Web of Science were searched to identify studies which have established echocardiographic reference ranges of left heart parameters in children and adolescents from 1975 to December 2017. There was no geographical limitation. All results were imported into Endnote. Retrieved articles were screened and data extracted by two independent reviewers. A total of 4398 studies were retrieved, with 36 studies finally included in this review. 29 (81%) references were from North America and European (Caucasians) populations, with only one study each from Africa and South America. Two-dimensional and M-mode techniques were the most commonly used echocardiography techniques. There were methodological variations in techniques and normalisation of references. Comparison of selected cardiac measures showed significant differences for interventricular septal thickness among Black African, Indian, German and US American children. Available echocardiographic references cannot be generalised to all settings and therefore, there is need for locally relevant reference ranges. Africa and South America are particularly under-represented. Future studies should focus on developing comprehensive echocardiographic reference ranges for children from different racial backgrounds and should use standardised techniques

Echocardiographic reference ranges in older children and adolescents in sub-Saharan Africa.

BACKGROUND: Echocardiographic reference ranges are important to identify abnormalities of cardiac dimensions. Reference ranges for children in sub-Saharan Africa have not been established. The aim of this study was to establish echocardiographic z-score references for Black children in sub-Saharan Africa. METHODS: 282 healthy subjects aged 6-16years (143 [51%] males) with no known history of cardiac disease were enrolled in the study in Harare, Zimbabwe between 2014 and 2016. Standard M-mode echocardiography was performed and nine cardiac chamber dimensions were obtained. Two non-linear statistical models (gamma weighted model and cubic polynomial model) were tested on the data and the best fitting model was used to calculate z-scores of these cardiac chamber measures. The reference ranges are presented on scatter plots against BSA. RESULTS: Normative data for the following cardiac measures were obtained and z-scores calculated: right ventricular diameter at end diastole (RVEDD); left ventricular diameter at end diastole (LVEDD) and systole (LVESD); interventricular septal wall thickness at end diastole (IVSd) and systole (IVSs); left ventricular posterior wall thickness at end diastole (LVPWd) and systole (LVPWs); left atrium diameter at end systole (LA) and tricuspid annular plane systolic excursion (TAPSE). Girls had higher values for BMI and heart rate than boys (p=0.048 and p=0.001, respectively). Mean interventricular septal and left ventricular posterior walls thickness was higher than published normal values in predominantly Caucasian populations. CONCLUSION: These are the first echocardiographic reference ranges for children from sub Saharan Africa and will allow accurate assessment of cardiac dimensions in clinical practice

Investigating the relationship between non-occupational pesticide exposure and metabolomic biomarkers

DATA AVAILABILITY STATEMENT : The datasets presented in this article are not readily available because NFBC data is available from the University of Oulu, Infrastructure for Population Studies. Permission to use the data can be applied for research purposes via an electronic material request portal. In the use of data, we follow the EU general data protection regulation (679/2016) and Finnish Data Protection Act. The use of personal data is based on cohort participant’s written informed consent at his/her latest follow-up study, which may cause limitations to its use. Please, contact the NFBC project center ([email protected]) and visit the cohort website (www.oulu.fi/nfbc) or Fairdata.fi (http://urn.fi/urn:nbn:fi:att:bc1e5408-980e-4a62-b899-43bec3755243) for additional information. Requests to access the datasets should be directed to NFBC project center ([email protected]).The relationship between pesticide exposures and metabolomics biomarkers is not well understood. We examined the changes in the serum metabolome (early biomarkers) and the metabolic pathways associated with various pesticide exposure scenarios (OPE: overall exposure, PEM: exposure in months, PEY: exposure in years, and PEU: reported specific pesticides use) using data from the Northern Finland Birth Cohort 1966 31-year cross-sectional examination. We utilized questionnaire data on pesticide exposures and serum samples for nuclear magnetic resonance (NMR)-based metabolomics analyses. For exposures and metabolites associations, participants size varied between 2,361 and 5,035. To investigate associations between metabolomics biomarkers and exposure to pesticide scenarios compared to those who reported no exposures multivariable regression analyses stratified by sex and adjustment with covariates (season of pesticide use, socioeconomic position (SEP), alcohol consumption, BMI, and latitude of residence) were performed. Multiple testing by Benjamini–Hochberg false discovery rate (FDR) correction applied. Pesticide exposures differed by sex, season of pesticide use, alcohol, SEP, latitude of residence. Our results showed that all pesticide exposure scenarios were negatively associated with decreased HDL concentrations across all lipoprotein subclasses in women. OPE, PEY, and PEU were associated with decreased branched-chain amino acid concentrations in men and decreased albumin concentrations in women. OPE, PEY and PEU were also associated with changes in glycolysis metabolites and ketone bodies in both sexes. Specific pesticides exposure was negatively associated with sphingolipids and inflammatory biomarkers in men. In women, OPE, PEM, and PEU were associated with decreased apolipoprotein A1 and increased apolipoprotein B/ apolipoprotein A1 ratio. Our findings suggest that identification of early biomarkers of disease risk related to pesticide exposures can inform strategies to reduce exposure and investigate causal pathways. Women may be more susceptible to non-occupational pesticide exposures when compared to men, and future sexspecific studies are warranted.The project EDCMET has received funding from the European Union’s Horizon 2020 research and innovation programme; Academy of Finland; the Medical Research Council (MRC) UK; Medical Research Council Biotechnology and Biological Sciences Research Council PREcisE [Nutrition & Epigenome, The Joint Programming Initiative a Healthy Diet for a Healthy Life] and Jenny and Antti Wihuri Foundation. Core funding for data generation and curation from University of Oulu; Oulu University Hospital; Ministry of Health and Social Affairs; National Institute for Health and Welfare, Helsinki; Regional Institute of Occupational Health, Oulu, Finland; and ERDF European Regional Development Fund.https://www.frontiersin.org/journals/public-health#am2024School of Health Systems and Public Health (SHSPH)SDG-03:Good heatlh and well-bein

Incidence and Progression of Echocardiographic Abnormalities in Older Children with Human Immunodeficiency Virus and Adolescents Taking Antiretroviral Therapy: A Prospective Cohort Study.

BACKGROUND: A high prevalence of cardiac abnormalities has been reported in children with human immunodeficiency virus (HIV) taking antiretroviral therapy (ART) in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. METHODS: A prospective cohort study was conducted at a pediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and after 18 months. RESULTS: Of 197 participants recruited at baseline, 175 (89%; 48% female; median age 12 years, interquartile range 10-14 years) were followed up. The incidences of left and right heart abnormalities were 3.52 and 5.64 per 100 person-years, respectively. Stunting was associated with the development of any cardiac abnormality (adjusted odds ratio 2.59, 95% confidence interval 1.03-6.49; P = .043). Right ventricular (RV) dilatation persisted at follow-up in 92% of participants and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow-up period in 11 (6%). There was an overall increase in mean z scores for LV, left atrium (LA), RV, interventricular septum, and LV posterior wall diameters at 18 months (P < .001). CONCLUSIONS: Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z scores for LV, LA, RV, interventricular septum, and LV posterior wall diameters increased over a relatively short follow-up period, suggesting the potential for progression of cardiac abnormalities. Longer follow-up is required to understand the clinical implications of these abnormalities

Effect of Once-Weekly Azithromycin vs Placebo in Children With HIV-Associated Chronic Lung Disease: The BREATHE Randomized Clinical Trial

Importance - HIV-associated chronic lung disease (HCLD) in children is associated with small airways disease, is common despite antiretroviral therapy (ART), and is associated with substantial morbidity. Azithromycin has antibiotic and immunomodulatory activity and may be effective in treating HCLD through reducing respiratory tract infections and inflammation. Objective - To determine whether prophylactic azithromycin is effective in preventing worsening of lung function and in reducing acute respiratory exacerbations (AREs) in children with HCLD taking ART. Design, Setting, and Participants - This double-blind, placebo-controlled, randomized clinical trial (BREATHE) was conducted between 2016 and 2019, including 12 months of follow-up, at outpatient HIV clinics in 2 public sector hospitals in Malawi and Zimbabwe. Participants were randomized 1:1 to intervention or placebo, and participants and study personnel were blinded to treatment allocation. Participants included children aged 6 to 19 years with perinatally acquired HIV and HCLD (defined as forced expiratory volume in 1 second [FEV1] z score Intervention - Once-weekly oral azithromycin with weight-based dosing, for 48 weeks. Main Outcomes and Measures - All outcomes were prespecified. The primary outcome was the mean difference in FEV1 z score using intention-to-treat analysis for participants seen at end line. Secondary outcomes included AREs, all-cause hospitalizations, mortality, and weight-for-age z score. Results - A total of 347 individuals (median [interquartile range] age, 15.3 [12.7-17.7] years; 177 boys [51.0%]) were randomized, 174 to the azithromycin group and 173 to the placebo group; 162 participants in the azithromycin group and 146 placebo group participants had a primary outcome available and were analyzed. The mean difference in FEV1 z score was 0.06 (95% CI, −0.10 to 0.21; P = .48) higher in the azithromycin group than in the placebo group, a nonsignificant difference. The rate of AREs was 12.1 events per 100 person-years in the azithromycin group and 24.7 events per 100 person-years in the placebo groups (hazard ratio, 0.50; 95% CI, 0.27 to 0.93; P = .03). The hospitalization rate was 1.3 events per 100 person-years in the azithromycin group and 7.1 events per 100 person-years in the placebo groups, but the difference was not significant (hazard ratio, 0.24; 95% CI, 0.06 to 1.07; P = .06). Three deaths occurred, all in the placebo group. The mean weight-for-age z score was 0.03 (95% CI, −0.08 to 0.14; P = .56) higher in the azithromycin group than in the placebo group, although the difference was not significant. There were no drug-related severe adverse events. Conclusions and Relevance - In this randomized clinical trial specifically addressing childhood HCLD, once-weekly azithromycin did not improve lung function or growth but was associated with reduced AREs; the number of hospitalizations was also lower in the azithromycin group but the difference was not significant. Future research should identify patient groups who would benefit most from this intervention and optimum treatment length, to maximize benefits while reducing the risk of antimicrobial resistance