Sex-biased expression of the TLR7 gene in severe COVID-19 patients: Insights from transcriptomics and epigenomics.

There is abundant epidemiological data indicating that the incidence of severe cases of coronavirus disease (COVID-19) is significantly higher in males than females worldwide. Moreover, genetic variation at the X-chromosome linked TLR7 gene has been associated with COVID-19 severity. It has been suggested that the sex-biased incidence of COVID-19 might be related to the fact that TLR7 escapes X-chromosome inactivation during early embryogenesis in females, thus encoding a doble dose of its gene product compared to males. We analyzed TLR7 expression in two acute phase cohorts of COVID-19 patients that used two different technological platforms, one of them in a multi-tissue context including saliva, nasal, and blood samples, and a third cohort that included different post-infection timepoints of long-COVID-19 patients. We additionally explored methylation patterns of TLR7 using epigenomic data from an independent cohort of COVID-19 patients stratified by severity and sex. In line with genome-wide association studies, we provide supportive evidence indicating that TLR7 has altered CpG methylation patterns and it is consistently downregulated in males compared to females in the most severe cases of COVID-19.

Salivary epidermal growth factor correlates with hospitalization length in rotavirus infection.

BACKGROUND: The IFI27 interferon gene expression has been found to be largely increased in rotavirus (RV)-infected patients. IFI27 gene encodes for a protein of unknown function, very recently linked to epidermal proliferation and related to the epidermal growth factor (EGF) protein. The EGF is a low-molecular-weight polypeptide that is mainly produced by submandibular and parotid glands, and it plays an important physiological role in the maintenance of oro-esophageal and gastric tissue integrity. Our aim was to determine salivary EGF levels in RV-infected patients in order to establish its potential relationship with IFI27 increased expression and EGF-mediated mucosal protection in RV infection. METHODS: We conducted a prospective comparative study using saliva samples from 27 infants infected with RV (sampled at recruitment during hospital admission and at convalescence, i.e. at least 3 months after recovery) and from 36 healthy control children. RESULTS: Median (SD) EGF salivary concentration was 777 (529) pg/ml in RV-infected group at acute phase and 356 (242) pg/m at convalescence, while it was 337 (119) pg/ml in the healthy control group. A significant association was found between EGF levels and hospitalization length of stay (P-value = 0.022; r2 = -0.63). CONCLUSIONS: The salivary levels of EGF are significantly increased during the acute phase of natural RV infection, and relate to length of hospitalization. Further assessment of this non-invasive biomarker in RV disease is warranted.

Incidence and risk factor prevalence of community-acquired pneumonia in adults in primary care in Spain (NEUMO-ES-RISK project).

BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality in adults even in developed countries. Several lifestyle factors and comorbidities have been linked to an increased risk, although their prevalence has not been well documented in the primary care setting. The aim of this study is to assess the incidence, risk factor and comorbid conditions distribution of CAP in adults in primary care in Spain. METHODS: Retrospective observational study in adults (>18 years-old) with CAP diagnosed and attended at primary care in Spain between 2009 and 2013, using the Computerized Database for Pharmacoepidemiological Studies in Primary Care (BIFAP). RESULTS: Twenty-eight thousand four hundred thirteen patient records were retrieved and analyzed. Mean age (standard deviation): 60.5 (20.3) years, 51.7 % males. Global incidence of CAP in adults was estimated at 4.63 per 1000 persons/year. CAP incidence increased progressively with age, ranging from a 1.98 at 18-20 years of age to 23.74 in patients over 90 years of age. According to sex, global CAP incidence was slightly higher in males (5.04) than females (4.26); CAP incidence from 18 to 65 year-olds up was comparable between males (range: 2.18-5.75) and females (range: 1.47-5.21), whereas from 65 years of age, CAP incidence was noticeable higher in males (range: 7.06-36.93) than in females (range: 5.43-19.62). Average prevalence of risk factors was 71.3 %, which increased with age, doubling the risk in males by the age of 75 (females 20 % vs males 40 %). From 55 years of age, at least one risk factor was identified in 85.7 % of cases: one risk factor (23.8 %), two risk factors (23.4 %), three or more risk factors (38.5 %). Major risk factors were: metabolic disease (27.4 %), cardiovascular disease (17.8 %) and diabetes (15.5 %). CONCLUSIONS: The annual incidence of CAP in primary care adults in Spain is high, comparable between males and females up to 65 years of age, but clearly increasing in males from that age. CAP risk increases with age and doubles in males older than 75 years. The majority of CAP cases in patients over 55 years of age is associated to at least one risk factor. The main risk factors associated were metabolic disease, cardiovascular disease, and diabetes.

Spanish adaptation of the Quality of Life Index-Spinal Cord Injury version.

STUDY DESIGN: A cross-sectional, validation study. OBJECTIVES: To (a) develop the Spanish version of the Quality of Life Index-Spinal Cord Injury version (SV-QLI/SCI) and (b) assess its psychometric characteristics among permanent wheelchair users and specifically among those with SCI. SETTING: Associations of wheelchair users in Mallorca (Spain). METHODS: Two forward and backward translations of the QLI/SCI into Spanish were carried out separately. Seventy-seven subjects were randomly selected among the members of the associations. They completed the SV-QLI/SCI and validated instruments to measure depression and spinal pain upon recruitment and 14 days later. Assessments included comprehensibility, reproducibility, floor and ceiling effects and correlations between quality of life, pain and depression (Spearman's correlation coefficient). Analyses were repeated excluding data from subjects without SCI. RESULTS: Three items of the SV-QLI/SCI required rephrasing. Reproducibility was 'almost perfect' for the entire questionnaire and its 'Health and functioning' subscale, 'substantial' for the 'Social and economic' and 'Family' subscales and 'moderate' for the 'Psychological/spiritual' subscale. Floor effect was not observed, and only for the 'Family' subscale >3% of the subjects reached the maximum possible score. The correlation between quality of life and depression was the strongest (r=-0.628). Results were virtually identical in the subsample with SCI. CONCLUSION: These results support the use of the SV-QLI/SCI among Spanish-speaking wheelchair users.

Effects of vibration therapy on hormone response and stress in severely disabled patients: a double-blind randomized placebo-controlled clinical trial.

PURPOSE: To assess the effects of vibration therapy (VT) on quality of life and hormone response in severely disabled patients compared with placebo. DESIGN: A longitudinal prospective, double-blind, randomized placebo-controlled trial, with pre and postintervention assessments. METHODS: A total of 20 severely disabled individuals were recruited from a National Reference Centre in Spain: 13 (65%) men and 7 (35%) women, 45.5 ± 9.32 years of age (range 41: 22-63). We evaluated their physical stress and state anxiety. RESULTS: No statistically significant changes were found in the socio-psychological variables studied, while in the experimental group state anxiety decreased significantly with p < 0.01 (Z = 2.38; one-tailed p = .009) and, among the biological variables, the level of cortisol fell (p = 0.03). CONCLUSION: Short periods of exposure to low-frequency and low-amplitude local vibration are a safe and effective mechanical stimulus that can have a positive effect in terms of hormone response. CLINICAL RELEVANCE: VT can be considered to have an anti-stress effect.

Interferon gene expression declines over time post-COVID infection and in long COVID patients.

BACKGROUND: Interferons (IFNs) represent a first-line defense against viruses and other pathogens. It has been shown that an impaired and uncontrolled release of these glycoproteins can result in tissue damage and explain severe progression of coronavirus disease 2019 (COVID-19). However, their potential role in Long-COVID syndrome (LC) remains debateable. OBJECTIVES: The objective of the present study is to shed further light on the possible role of IFNs (and related genes) gene expression patterns in the progression of COVID-19 and LC patients. METHODS: We carried out a multi-cohort study by analyzing the IFN gene expression patterns (using different IFN gene signatures) in five cohorts of acute COVID-19 (n = 541 samples) and LC patients (n = 188), and compared them to patterns observed in three autoimmune diseases (systemic lupus erythematous [n = 242], systemic sclerosis [n = 91], and Sjögren's syndrome [n = 282]). RESULTS: The data show that, while the interferon signatures are strongly upregulated in severe COVID-19 patients and autoimmune diseases, it decays with the time from symptoms onset and in LC patients. Differential pathway analysis of IFN-related terms indicates an over activation in autoimmune diseases (IFN-I/II) and severe COVID-19 (IFN-I/II/III), while these pathways are mostly inactivated or downregulated in LC (IFN-I/III). By analyzing six proteomic LC datasets, we did not find evidence of a role of IFNs in this condition. CONCLUSION: Our findings suggest a potential role of cytokine exhaustion mediated by IFN gene expression inactivation as a possible driver of LC.

The first probe of a FLASH proton beam by PET.

The recently observed FLASH effect related to high doses delivered with high rates has the potential to revolutionize radiation cancer therapy if promising results are confirmed and an underlying mechanism understood. Comprehensive measurements are essential to elucidate the phenomenon. We report the first-ever demonstration of measurements of successive in-spill and post-spill emissions of gammas arising from irradiations by a FLASH proton beam. A small positron emission tomography (PET) system was exposed in an ocular beam of the Proton Therapy Center at MD Anderson Cancer Center to view phantoms irradiated by 3.5 × 1010protons with a kinetic energy of 75.8 MeV delivered in 101.5 ms-long spills yielding a dose rate of 164 Gy s-1. Most in-spill events were due to prompt gammas. Reconstructed post-spill tomographic events, recorded for up to 20 min, yielded quantitative imaging and dosimetric information. These findings open a new and novel modality for imaging and monitoring of FLASH proton therapy exploiting in-spill prompt gamma imaging followed by post-spill PET imaging.

The first PET glimpse of a proton FLASH beam.

We demonstrate the first ever recorded positron-emission tomography (PET) imaging and dosimetry of a FLASH proton beam at the Proton Center of the MD Anderson Cancer Center. Two scintillating LYSO crystal arrays, read out by silicon photomultipliers, were configured with a partial field of view of a cylindrical poly-methyl methacrylate (PMMA) phantom irradiated by a FLASH proton beam. The proton beam had a kinetic energy of 75.8 MeV and an intensity of about 3.5 × 1010protons that were extracted over 101.5 ms-long spills. The radiation environment was characterized by cadmium-zinc-telluride and plastic scintillator counters. Preliminary results indicate that the PET technology used in our tests can efficiently record FLASH beam events. The instrument yielded informative and quantitative imaging and dosimetry of beam-activated isotopes in a PMMA phantom, as supported by Monte Carlo simulations. These studies open a new PET modality that can lead to improved imaging and monitoring of FLASH proton therapy.

Kilovoltage energy imaging with a radiotherapy linac with a continuously variable energy range.

PURPOSE: In this paper, the effect on image quality of significantly reducing the primary electron energy of a radiotherapy accelerator is investigated using a novel waveguide test piece. The waveguide contains a novel variable coupling device (rotovane), allowing for a wide continuously variable energy range of between 1.4 and 9 MeV suitable for both imaging and therapy. METHOD: Imaging at linac accelerating potentials close to 1 MV was investigated experimentally and via Monte Carlo simulations. An imaging beam line was designed, and planar and cone beam computed tomography images were obtained to enable qualitative and quantitative comparisons with kilovoltage and megavoltage imaging systems. The imaging beam had an electron energy of 1.4 MeV, which was incident on a water cooled electron window consisting of stainless steel, a 5 mm carbon electron absorber and 2.5 mm aluminium filtration. Images were acquired with an amorphous silicon detector sensitive to diagnostic x-ray energies. RESULTS: The x-ray beam had an average energy of 220 keV and half value layer of 5.9 mm of copper. Cone beam CT images with the same contrast to noise ratio as a gantry mounted kilovoltage imaging system were obtained with doses as low as 2 cGy. This dose is equivalent to a single 6 MV portal image. While 12 times higher than a 100 kVp CBCT system (Elekta XVI), this dose is 140 times lower than a 6 MV cone beam imaging system and 6 times lower than previously published LowZ imaging beams operating at higher (4-5 MeV) energies. CONCLUSIONS: The novel coupling device provides for a wide range of electron energies that are suitable for kilovoltage quality imaging and therapy. The imaging system provides high contrast images from the therapy portal at low dose, approaching that of gantry mounted kilovoltage x-ray systems. Additionally, the system provides low dose imaging directly from the therapy portal, potentially allowing for target tracking during radiotherapy treatment. There is the scope with such a tuneable system for further energy reduction and subsequent improvement in image quality.

Case Report: Everolimus reduced bone turnover markers but showed no clinical benefit in a patient with severe progressive osseous heteroplasia.

Background: Progressive osseous heteroplasia (POH) is an ultrarare genetic disorder characterized by an inactivating mutation in the GNAS gene that causes heterotopic ossification. Inhibition of the mammalian target of the rapamycin (mTOR) signalling pathway has been proposed as a therapy for progressive bone fibrodysplasia and non-genetic forms of bone heteroplasia. Herein, we describe the impact of using Everolimus as a rescue therapy for an identical twin girl exhibiting an aggressive clinical phenotype of POH. Methods: Clinical evaluation of the progression of the disease during Everolimus treatment was performed periodically. Cytokine markers involved in bone metabolism and protein markers related to bone activity were analyzed to explore bone turnover activity. Results: The patient received Everolimus therapy for 36 weeks. During treatment, no clinical improvement of the disease was perceived. Analysis of biochemical parameters, namely, ß-CTX (r 2 = -0.576, P-value = 0.016) and PNIP (r 2 = -0.598, P-value = 0.011), indicated that bone turnover activity was significantly reduced. Additionally, bone metabolism-related biomarkers showed only a significant positive correlation with PTH levels. Conclusions: Everolimus treatment did not modify the clinical progression of the disease in an aggressive form of POH, although an impact on the protein markers studied was observed.

A modification of flattening filter free linac for IMRT.

PURPOSE: This study investigates the benefits of a modified flattening filter free (FFF) linac over the standard (STD) linac equipped with the flattening filter. Energy and angular spread of the electron beam of the FFF linac were modified. Modification of FFF beam parameters is explored to maximize the monitor unit efficiency and to minimize the head scatter in IMRT delivery for large target volumes or targets lying away from the central axis. METHODS: The EGSnrc code is used to model FFF and STD linacs and study basic beam properties for both linac types in various beam configurations. Increasing energy of FFF linac results in similar beam attenuation properties and maximized dose rate compared to STD linac. Matching beam attenuation properties allows a more direct exploration of beam flatness of FFF linac in regard to IMRT delivery, especially away from the central axis where the effective dose rate is considerably smaller than the one at the central axis. Flatness of open beam dose profile of FFF linac is improved by increasing the angular spread of the electron beam. The resulting dose rate within the treatment field and outside of the field (peripheral dose) are characterized and compared to the unmodified FFF and STD linacs, RESULTS: In order to match beam penetration properties, the energy of FFF is adjusted from 6.5 to 8.0 MeV for small to medium field sizes and from 6.5 to 8.5 MeV for larger ones. Dose rate of FFF vs STD linac increased by a factor of 1.9 (6.5 MeV) and 3.4-4.1 (8.0-8.5 MeV). Adjusting the mean angular spread of the electron beam from 0 degrees to 5 degrees-10 degrees resulted in complete flattening of photon beam for field sizes between 10 x 10 cm2 and 15 x 15 cm2 and partial flattening for field sizes from 15 x 15 cm2 to 30 x 30 cm2. Values of angular spread > or =14 degrees are not recommended as they exceed the opening of the primary collimator, affecting the area at the edges of the field. FFF fields of sizes smaller than 6 x 6 cm2 are already flat and beam flattening is not necessary. Overall, the angular spread of 5 degrees-10 degrees is sufficient and can satisfactorily flatten open beam dose profiles even for larger field sizes. Increasing the electron beam angular spread amounts to a slight decrease of dose rate of FFF linac. However, for angular spread, 5 degrees-10 degrees dose rate factor of FFF vs STD is still about 1.6-2.6, depending on the field size (and the adjusted energy). Similarly, in case of peripheral dose, a moderate increase in dose can be observed for angular spread of 5 degrees-10 degrees and for field sizes 10 x 10 cm2 to 30 x 30 cm2. Lastly, beam flatness of not modified FFF linac can be conveniently described by an analytical function representing a ratio of STD vs FFF doses: 1 + b|r|(n). CONCLUSIONS: A modified FFF beamline with increased energy and electron beam angular spread results in satisfactory flattened beam and high dose rate within the field. Peripheral dose remaining at similar (or smaller) level than that of STD linac for the same delivered dose within the treatment field.

Improvements in beam's eye view fiducial tracking using a novel multilayer imager.

Purpose.Electronic portal image devices (EPIDs) have been investigated previously for beams-eye view (BEV) applications such as tumor tracking but are limited by low contrast-to-noise ratio and detective quantum efficiency. A novel multilayer imager (MLI), consisting of four stacked flat-panels was used to measure improvements in fiducial tracking during liver stereotactic body radiation therapy (SBRT) procedures compared to a single layer EPID.Methods.The prototype MLI was installed on a clinical TrueBeam linac in place of the conventional DMI single-layer EPID. The panel was extended during volumetric modulated arc therapy SBRT treatments in order to passively acquire data during therapy. Images were acquired for six patients receiving SBRT to liver metastases over two fractions each, one with the MLI using all 4 layers and one with the MLI using the top layer only, representing a standard EPID. The acquired frames were processed by a previously published tracking algorithm modified to identify implanted radiopaque fiducials. Truth data was determined using respiratory traces combined with partial manual tracking. Results for 4- and 1-layer mode were compared against truth data for tracking accuracy and efficiency. Tracking and noise improvements as a function of gantry angle were determined.Results. Tracking efficiency with 4-layers improved to 82.8% versus 58.4% for the 1-layer mode, a relative improvement of 41.7%. Fiducial tracking with 1-layer returned a root mean square error (RMSE) of 2.1 mm compared to 4-layer RMSE of 1.5 mm, a statistically significant (p < 0.001) improvement of 0.6 mm. The reduction in noise correlated with an increase in successfully tracked frames (r = 0.913) and with increased tracking accuracy (0.927).Conclusion. Increases in MV photon detection efficiency by utilization of a MLI results in improved fiducial tracking for liver SBRT treatments. Future clinical applications utilizing BEV imaging may be enhanced by including similar noise reduction strategies.

The accuracy of helium ion CT based particle therapy range prediction: an experimental study comparing different particle and x-ray CT modalities.

This work provides a quantitative assessment of helium ion CT (HeCT) for particle therapy treatment planning. For the first time, HeCT based range prediction accuracy in a heterogeneous tissue phantom is presented and compared to single-energy x-ray CT (SECT), dual-energy x-ray CT (DECT) and proton CT (pCT). HeCT and pCT scans were acquired using the US pCT collaboration prototype particle CT scanner at the Heidelberg Ion-Beam Therapy Center. SECT and DECT scans were done with a Siemens Somatom Definition Flash and converted to RSP. A Catphan CTP404 module was used to study the RSP accuracy of HeCT. A custom phantom of 20 cm diameter containing several tissue equivalent plastic cubes was used to assess the spatial resolution of HeCT and compare it to DECT. A clinically realistic heterogeneous tissue phantom was constructed using cranial slices from a pig head placed inside a cylindrical phantom (ø150 mm). A proton beam (84.67 mm range) depth-dose measurement was acquired using a stack of GafchromicTM EBT-XD films in a central dosimetry insert in the phantom. CT scans of the phantom were acquired with each modality, and proton depth-dose estimates were simulated based on the reconstructions. The RSP accuracy of HeCT for the plastic phantom was found to be 0.3 ± 0.1%. The spatial resolution for HeCT of the cube phantom was 5.9 ± 0.4 lp cm-1for central, and 7.6 ± 0.8 lp cm-1for peripheral cubes, comparable to DECT spatial resolution (7.7 ± 0.3 lp cm-1and 7.4 ± 0.2 lp cm-1, respectively). For the pig head, HeCT, SECT, DECT and pCT predicted range accuracy was 0.25%, -1.40%, -0.45% and 0.39%, respectively. In this study, HeCT acquired with a prototype system showed potential for particle therapy treatment planning, offering RSP accuracy, spatial resolution, and range prediction accuracy comparable to that achieved with a commercial DECT scanner. Still, technical improvements of HeCT are needed to enable clinical implementation.

Real-world outcomes of two different sensor-augmented insulin pumps with predictive low glucose suspend function in type 1 diabetes patients.

AIM: To analyse the real-life outcomes of two sensor-augmented pumps (SAP) with predictive low glucose suspend (PLGS) function, Medtronic Minimed 640G™ with SmartGuard (MM640G) and Tandem T Slim X2™ with Basal-IQ™ (TTSX2), in Type 1 Diabetes Mellitus (T1DM) patients. METHODS: Observational cross-sectional study using data obtained from computerized clinical records. All T1DM patients on TTSX2 therapy were compared (1:1) with MM640G treated patients selected through stratified sampling. Primary efficacy outcome was to describe time in rage (TIR, 70-180 mg/dL, 3.9-10 mmol/L) interstitial glucose differences according to a non-inferiority hypothesis with TTSX2 compared to MM640G. RESULTS: Forty-four patients were analyzed (female 66%). Mean age was 38.9 yrs. (range 23-59 yrs.) and mean diabetes duration was 23.4 ± 9.2 yrs. Patients treated with TTSX2 showed a numerically slightly lower, but non-statistically significantly different, TIR from the MM640G pump group (64.9 ± 16.4% vs. 72.4 ± 17.0%, P = 0.108). Similarly, we did no find differences in HbA1c between T1D patients treated with TTSX2 and MM640G (6.8 ± 1.0% vs. 7.0 ± 0.9%, 51 ± 11 mmol/mol vs. 53 ± 10 mmol/mol, P = 0.312). Moreover, rest of evaluated glycemic outcomes were similar between both treatment groups. CONCLUSIONS: Patients using two different SAP with PLGS automatic function showed similar glycaemic control in a real-world scenario. NCT04741685.

Clinical translation of a new flat-panel detector for beam's-eye-view imaging.

Electronic portal imaging devices (EPIDs) lend themselves to beams-eye view clinical applications, such as tumor tracking, but are limited by low contrast and detective quantum efficiency (DQE). We characterize a novel EPID prototype consisting of multiple layers and investigate its suitability for use under clinical conditions. A prototype multi-layer imager (MLI) was constructed utilizing four conventional EPID layers, each consisting of a copper plate, a Gd2O2S:Tb phosphor scintillator, and an amorphous silicon flat panel array detector. We measured the detector's response to a 6 MV photon beam with regards to modulation transfer function, noise power spectrum, DQE, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and the linearity of the detector's response to dose. Additionally, we compared MLI performance to the single top layer of the MLI and the standard Varian AS-1200 detector. Pre-clinical imaging was done on an anthropomorphic phantom, and the detector's CNR, SNR and spatial resolution were assessed in a clinical environment. Images obtained from spine and liver patient treatment deliveries were analyzed to verify CNR and SNR improvements. The MLI has a DQE(0) of 9.7%, about 5.7 times the reference AS-1200 detector. Improved noise performance largely drives the increase. CNR and SNR of clinical images improved three-fold compared to reference. A novel MLI was characterized and prepared for clinical translation. The MLI substantially improved DQE and CNR performance while maintaining the same resolution. Pre-clinical tests on an anthropomorphic phantom demonstrated improved performance as predicted theoretically. Preliminary patient data were analyzed, confirming improved CNR and SNR. Clinical applications are anticipated to include more accurate soft tissue tracking.

Routine infant vaccination of pneumococcal conjugate vaccines has decreased pneumonia across all age groups in Northern Spain.

Since the early 2000s, pneumococcal conjugate vaccines (PCVs) have been shown to be effective in the prevention of pneumonia and invasive pneumococcal diseases. In 2011, the Galician region incorporated PCV in the routine infant immunization, the very first stable program in Spain. We aim to assess direct and indirect benefits of PCV vaccination on all-cause pneumonia in the region across different age groups using an ecological study design. For this, we calculated the annual hospitalization rates using a hospital-based disease registry. We identified all-cause pneumonia, pneumococcal pneumonia and pneumococcal invasive diseases within the registry. Hospitalization rates were computed and compared across three study periods: pre-vaccination (1998-2003), early-vaccination (2005-2009) and routine-vaccination (2011-2015). Across Northern Spain, we identified 114,873 all-cause pneumonia hospitalizations, of which 24,808 were further diagnosed with pneumococcal pneumonia. The majority were elderly > 64 years (67.3%). Hospitalizations from all-cause pneumonia had a net increase from 20.6 (pre-PCV) and 21.4/10,000 (early) to 28.4/10,000 (routine) (+32.7%, p < .0001), this is attributed to the huge number of cases in the elderly age group. In contrast, a net reduction of incidence of hospitalized pneumococcal pneumonia was observed from 6.3/10,000 (pre-PCV) and 5.7/10,000 (early) to 2.4/10,000 (routine) cases (-57.9%, p < .0001). Thus, routine infant vaccination may have resulted to an overall decline of pneumococcal pneumonia in infants, as well as in elderly age groups. However, a paradoxical increase on all-cause pneumonia was observed in Galicia, mostly attributed to the growing number of cases in the elderly population.

Experimental exploration of a mixed helium/carbon beam for online treatment monitoring in carbon ion beam therapy.

Recently, it has been proposed that a mixed helium/carbon beam could be used for online monitoring in carbon ion beam therapy. Fully stripped, the two ion species exhibit approximately the same mass/charge ratio and hence could potentially be accelerated simultaneously in a synchrotron to the same energy per nucleon. At the same energy per nucleon, helium ions have about three times the range of carbon ions, which could allow for simultaneous use of the carbon ion beam for treatment and the helium ion beam for imaging. In this work, measurements and simulations of PMMA phantoms as well as anthropomorphic phantoms irradiated sequentially with a helium ion and a carbon ion beam at equal energy per nucleon are presented. The range of the primary helium ion beam and the fragment tail of the carbon ion beam exiting the phantoms were detected using a novel range telescope made of thin plastic scintillator sheets read out by a flat-panel CMOS sensor. A 10:1 carbon to helium mixing ratio is used, generating a helium signal well above the carbon fragment background while adding little to the dose delivered to the patient. The range modulation of a narrow air gap of 1 mm thickness in the PMMA phantom that affects less than a quarter of the particles in a pencil beam were detected, demonstrating the achievable relative sensitivity of the presented method. Using two anthropomorphic pelvis phantoms it is shown that small rotations of the phantom as well as simulated bowel gas movements cause detectable changes in the helium/carbon beam exiting the phantom. The future prospects and limitations of the helium/carbon mixing as well as its technical feasibility are discussed.

Copper(II) succinate complexes with 1,2-di-4-pyridylethane and 1,3-di-4-pyridylpropane.

The compounds poly[di-mu(4)-succinato-mu(2)-1,2-di-4-pyridylethane-dicopper(II)], [Cu(2)(C(4)H(4)O(4))(2)(C(12)H(12)N(2))](n), (I), and poly[di-mu(4)-succinato-mu(2)-1,3-di-4-pyridylpropane-dicopper(II)], [Cu(2)(C(4)H(4)O(4))(2)(C(13)H(14)N(2))](n), (II), exhibit polymeric structures with the dicopper units doubly bridged by bis-bidentate succinate groups and crosslinked by the separator bis(pyridyl) molecules. In (I), the molecule exhibits a centre of inversion located midway between the core Cu-dimer atoms and another that relates half of the bis(pyridyl)ethane ligand to the other half. Compound (II) has a similar molecular packing but with a doubled lattice constant and noncentrosymmetric core units. An antiferromagnetic interaction due to the dinuclear copper units was deduced from magnetic subsceptibility measurements, and spin triplet signals were detected in the electron paramagnetic resonance spectra for both compounds.