RESUMEN

PURPOSE: Accurate measurement of out-of-field dose in radiotherapy directly impacts beam data modeling in treatment planning systems, verification of implanted electronic devices/lens/fetus dose, secondary cancer risk estimation, and organ-at-risk dose reporting. When performing out-of-field dosimetry, it is therefore imperative that the response of the detector has been well characterized. Due to the softening of the radiation beam out-of-field, many detectors will exhibit energy dependence. This study investigated the energy dependence of a range of clinical available detectors over typical energies experienced out-of-field. METHODS: The response of detectors to photon beams from 70 kV to 6 MV was measured. The relative change in response from 6 MV down to 70 kV highlighted the expected deviation in the response of detectors that would typically be calibrated in-field for use out-of-field. RESULTS: The Pinpoint detector displayed the most energy-independent response over the energy range investigated. The Micro-Lion detector was the only detector to show an under-response to all low-energy beams relative to 6 MV. The diode-type detectors showed the largest energy dependence. CONCLUSIONS: When considering detectors for use in out-of-field dose measurements, it is important that the energy dependence is investigated over a low-energy range as out-of-field the energy spectra comprise a larger component of photons in the 50-100-keV range. This study highlights the variation in response of a range of clinically available detectors to low-energy radiation beams relative to 6 MV for out-of-field dosimetry. The Pinpoint detector was the most energy-independent detector with a response close to unity over the entire energy range investigated.

Asunto(s)

RESUMEN

Kilovoltage radiotherapy dose calculations are generally performed with manual point dose calculations based on water dosimetry. Tissue heterogeneities, irregular surfaces, and introduction of lead cutouts for treatment are either not taken into account or crudely approximated in manual calculations. Full Monte Carlo (MC) simulations can account for these limitations but require a validated treatment unit model, accurately segmented patient tissues and a treatment planning interface (TPI) to facilitate the simulation setup and result analysis. EGSnrc was used in this work to create a model of Xstrahl kilovoltage unit extending the range of energies, applicators, and validation parameters previously published. The novel functionality of the Python-based framework developed in this work allowed beam modification using custom lead cutouts and shields, commonly present in kilovoltage treatments, as well as absolute dose normalization using the output of the unit. 3D user-friendly planning interface of the developed framework facilitated non-co-planar beam setups for CT phantom MC simulations in DOSXYZnrc. The MC models of 49 clinical beams showed good agreement with measured and reference data, to within 2% for percentage depth dose curves, 4% for beam profiles at various depths, 2% for backscatter factors, 0.5 mm of absorber material for half-value layers, and 3% for output factors. End-to-end testing of the framework using custom lead cutouts resulted in good agreement to within 3% of absolute dose distribution between simulations and EBT3 GafChromic film measurements. Gamma analysis demonstrated poor agreement at the field edges which was attributed to the limitations of simulating smooth cutout shapes. Dose simulated in a heterogeneous phantom agreed to within 7% with measured values converted using the ratio of mass energy absorption coefficients of appropriate tissues and air.

Asunto(s)

RESUMEN

Irradiation of the tumour site during treatment for cancer with external-beam ionising radiation results in a complex and dynamic series of effects in both the tumour itself and the normal tissue which surrounds it. The development of a spectral model of the effect of each exposure and interaction mode between these tissues would enable label free assessment of the effect of radiotherapeutic treatment in practice. In this study Fourier transform Infrared microspectroscopic imaging was employed to analyse an in-vitro model of radiotherapeutic treatment for prostate cancer, in which a normal cell line (PNT1A) was exposed to low-dose X-ray radiation from the scattered treatment beam, and also to irradiated cell culture medium (ICCM) from a cancer cell line exposed to a treatment relevant dose (2 Gy). Various exposure modes were studied and reference was made to previously acquired data on cellular survival and DNA double strand break damage. Spectral analysis with manifold methods, linear spectral fitting, non-linear classification and non-linear regression approaches were found to accurately segregate spectra on irradiation type and provide a comprehensive set of spectral markers which differentiate on irradiation mode and cell fate. The study demonstrates that high dose irradiation, low-dose scatter irradiation and radiation-induced bystander exposure (RIBE) signalling each produce differential effects on the cell which are observable through spectroscopic analysis.

Asunto(s)

RESUMEN

The quest for the discovery and validation of radiosensitivity biomarkers is ongoing and while conventional bioassays are well established as biomarkers, molecular advances have unveiled new emerging biomarkers. Herein, we present the validation of a new 4-gene signature panel of CDKN1, FDXR, SESN1 and PCNA previously reported to be radiation-responsive genes, using the conventional G2 chromosomal radiosensitivity assay. Radiation-induced G2 chromosomal radiosensitivity at 0.05 Gy and 0.5 Gy IR is presented for a healthy control (n = 45) and a prostate cancer (n = 14) donor cohort. For the prostate cancer cohort, data from two sampling time points (baseline and Androgen Deprivation Therapy (ADT)) is provided, and a significant difference (p > 0.001) between 0.05 Gy and 0.5 Gy was evident for all donor cohorts. Selected donor samples from each cohort also exposed to 0.05 Gy and 0.5 Gy IR were analysed for relative gene expression of the 4-gene signature. In the healthy donor cohort, there was a significant difference in gene expression between IR dose for CDKN1, FXDR and SESN1 but not PCNA and no significant difference found between all prostate cancer donors, unless they were classified as radiation-induced G2 chromosomal radiosensitive. Interestingly, ADT had an effect on radiation response for some donors highlighting intra-individual heterogeneity of prostate cancer donors.

Asunto(s)

RESUMEN

Genetic and epigenetic profile changes associated with individual radiation sensitivity are well documented and have led to enhanced understanding of the mechanisms of the radiation-induced DNA damage response. However, the search continues to identify reliable biomarkers of individual radiation sensitivity. Herein, we report on a multi-biomarker approach using traditional cytogenetic biomarkers, DNA damage biomarkers and transcriptional microRNA (miR) biomarkers coupled with their potential gene targets to identify radiosensitivity in ataxia-telangiectasia mutated (ATM)-deficient lymphoblastoid cell lines (LCL); ATM-proficient cell lines were used as controls. Cells were 0.05 and 0.5 Gy irradiated, using a linear accelerator, with sham-irradiated cells as controls. At 1 h postirradiation, cells were fixed for γ-H2AX analysis as a measurement of DNA damage, and cytogenetic analysis using the G2 chromosomal sensitivity assay, G-banding and FISH techniques. RNA was also isolated for genetic profiling by microRNA (miR) and RT-PCR analysis. A panel of 752 miR were analyzed, and potential target genes, phosphatase and tensin homolog (PTEN) and cyclin D1 (CCND1), were measured. The cytogenetic assays revealed that although the control cell line had functional cell cycle checkpoints, the radiosensitivity of the control and AT cell lines were similar. Analysis of DNA damage in all cell lines, including an additional control cell line, showed elevated γ-H2AX levels for only one AT cell line. Of the 752 miR analyzed, eight miR were upregulated, and six miR were downregulated in the AT cells compared to the control. Upregulated miR-152-3p, miR-24-5p and miR-92-15p and all downregulated miR were indicated as modulators of PTEN and CCDN1. Further measurement of both genes validated their potential role as radiation-response biomarkers. The multi-biomarker approach not only revealed potential candidates for radiation response, but provided additional mechanistic insights into the response in AT-deficient cells.

Asunto(s)

RESUMEN

In advanced radiotherapy, treatment of the tumor with high-intensity modulated fields is balanced with normal tissue sparing. However, the non-target dose delivered to surrounding healthy tissue within the irradiated volume is a potential cause for concern. Whether the effects observed are caused after exposure to out-of-field radiation or bystander effects through neighboring irradiated cells is not fully understood. The goal of this study was to determine the effect of exposure to out-of-field radiation in lymphocyte cell lines and primary blood cells. The role of cellular radiosensitivity in altering bystander responses in out-of-field exposed cells was also investigated. Target cells were positioned in a phantom in the center of the radiation field (in-field dose) and exposed to 2 Gy irradiation. Lymphocyte cell lines (C1, AT3ABR, Jurkat, THP-1, AT2Bi and AT3Bi) and peripheral blood were placed 1 cm away from the radiation field edge (out-of-field dose) and received an average dose of 10.8 ± 4.2 cGy. Double-stranded DNA damage, cell growth and gene expression were measured in the out-of-field cells. Radiosensitive AT3ABR and primary blood cells demonstrated the largest increase in γ-H2AX foci after irradiation. Exposure of normal cells to bystander factors from irradiated radiosensitive cell lines also increased DNA damage. Expression of IL-1, IL-6, TNFα and TGFß after addition of bystander factors from radiosensitive cells showed differential effects in normally responding cells, with some evidence of an adaptive response observed. Exposure to out-of-field radiation induces DNA damage and reduces growth in radiosensitive cells. Bystander factors produced by directly irradiated cells in combination with out-of-field exposure may upregulate pro- and anti-inflammatory genes in responding cells of different radiosensitivities, with the potential of affecting the tumor microenvironment. A greater understanding of the radio-biological response in normal cells outside the primary treatment field would assist in radiation treatment planning and in reducing early and late toxicities.

Asunto(s)

RESUMEN

PURPOSE: Liquid biopsies are a potentially rich store of biochemical information that can be linked to an individual's response to therapeutic treatments, including radiotherapy, and which may ultimately play a role in the individualization of treatment regimens. Peripheral blood mononuclear cells (PBMCs) can be used not only for the biochemical profiling of the individual, but also, being living cells, can provide insights into the individuals response to ionizing radiation exposure. MATERIALS AND METHODS: The present study attempts to link the biochemical profile of lymphocytes within PBMCs obtained through Raman spectroscopy to in vitro measures of low-dose (<0.5Gy) DNA damage response and cytogenetic metrics of radiosensitivity in a cohort of healthy controls and prostate cancer patients (from CTRIAL-IE(ICORG) 08-17, NCT00951535). All parallel metrics to the Raman spectra of the cells were obtained ex vivo in cycling peripheral blood lymphocytes, with radiosensitivity estimated using the G2 chromosomal assay and DNA damage assessed using γH2AX fluorescence. Spectra from a total of 26 healthy volunteers and 22 prostate cancer patients were obtained. RESULTS: The links between both measures of cellular response to ionizing radiation and the Raman spectra were modeled using partial least squares regression (PLSR) and support-vector regression (SVR). It was found that neither regression approach could predict radiation-induced G2 score well, but could predict γH2AX MFI with the SVR outperforming PLSR, implying a non-linear relationship between spectral measurements and measures of DNA damage. CONCLUSIONS: Raman spectroscopy of PBMCs represents a label-free approach for prediction of DNA damage levels for either prospective or retrospective analysis.

Asunto(s)

RESUMEN

Multileaf collimators (MLCs) need to be characterized accurately in treatment planning systems to facilitate accurate intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT). The aim of this study was to examine the use of MapCHECK 2 and ArcCHECK diode arrays for optimizing MLC parameters in Monaco X-ray voxel Monte Carlo (XVMC) dose calculation algorithm. A series of radiation test beams designed to evaluate MLC model parameters were delivered to MapCHECK 2, ArcCHECK, and EBT3 Gafchromic film for comparison. Initial comparison of the calculated and ArcCHECK-measured dose distributions revealed it was unclear how to change the MLC parameters to gain agreement. This ambiguity arose due to an insufficient sampling of the test field dose distributions and unexpected discrepancies in the open parts of some test fields. Consequently, the XVMC MLC parameters were optimized based on MapCHECK 2 measurements. Gafchromic EBT3 film was used to verify the accuracy of MapCHECK 2 measured dose distributions. It was found that adjustment of the MLC parameters from their default values resulted in improved global gamma analysis pass rates for MapCHECK 2 measurements versus calculated dose. The lowest pass rate of any MLC-modulated test beam improved from 68.5% to 93.5% with 3% and 2 mm gamma criteria. Given the close agreement of the optimized model to both MapCHECK 2 and film, the optimized model was used as a benchmark to highlight the relatively large discrepancies in some of the test field dose distributions found with ArcCHECK. Comparison between the optimized model-calculated dose and ArcCHECK-measured dose resulted in global gamma pass rates which ranged from 70.0%-97.9% for gamma criteria of 3% and 2 mm. The simple square fields yielded high pass rates. The lower gamma pass rates were attributed to the ArcCHECK overestimating the dose in-field for the rectangular test fields whose long axis was parallel to the long axis of the ArcCHECK. Considering ArcCHECK measurement issues and the lower gamma pass rates for the MLC-modulated test beams, it was concluded that MapCHECK 2 was a more suitable detector than ArcCHECK for the optimization process.

Asunto(s)

RESUMEN

Despite the knowledge that people with mental illness often seek care from multiple healing systems, there is limited collaboration between these systems. Greater collaboration with existing community resources could narrow the treatment gap and reduce fragmentation by encouraging more integrated care. This paper explores the origins, use, and outcomes of a collaborative programme between faith-based and allopathic mental health practitioners in India. We conducted 16 interviews with key stakeholders and examined demographic and clinical characteristics of the user population. Consistent with previous research, we found that collaboration is challenging and requires trust, rapport-building, and open dialogue. The collaboration reached a sizeable population, was reviewed favourably by key stakeholders-particularly on health improvement and livelihood restoration-and perhaps most importantly, views the client holistically, allowing for both belief systems to play a shared role in care and recovery. Results support the idea that, despite differing practices, collaboration between faith-based and allopathic mental health practitioners can be achieved and can benefit clients with otherwise limited access to mental health care.

Asunto(s)

RESUMEN

BACKGROUND: Increased preparedness for birth and complications is an essential part of antenatal care and has the potential to increase birth with a skilled attendant. We conducted a systematic review of studies to assess the effect of birth preparedness and complication readiness interventions on increasing birth with a skilled attendant. METHODS: PubMed, Embase, CINAHL and grey literature were searched for studies from 2000 to 2012 using a broad range of search terms. Studies were included with diverse designs and intervention strategies that contained an element of birth preparedness and complication readiness. Data extracted included population, setting, study design, outcomes, intervention description, type of intervention strategy and funding sources. Quality of the studies was assessed. The studies varied in BP/CR interventions, design, use of control groups, data collection methods, and outcome measures. We therefore deemed meta-analysis was not appropriate and conducted a narrative synthesis of the findings. RESULTS: Thirty-three references encompassing 20 different intervention programmes were included, of which one programmatic element was birth preparedness and complication readiness. Implementation strategies were diverse and included facility-, community-, or home-based services. Thirteen studies resulted in an increase in birth with a skilled attendant or facility birth. The majority of authors reported an increase in knowledge on birth preparedness and complication readiness. CONCLUSIONS: Birth Preparedness and Complication Readiness interventions can increase knowledge of preparations for birth and complications; however this does not always correspond to an increase in the use of a skilled attendant at birth.

Asunto(s)

RESUMEN

In the era of personalized and precision medicine, the approach to healthcare is quickly changing. Genetic and other molecular information are being increasingly demanded by clinicians and expected by patients for prevention, screening, diagnosis, prognosis, health promotion, and treatment of an increasing number of conditions. As a result of these developments, Canadian health leaders must understand and be prepared to lead the necessary changes associated with these disruptive technologies. This article focuses on precision therapeutics but also provides background on the concepts and terminology related to personalized and precision medicine and explores Canadian health leadership and system issues that may pose barriers to their implementation. The article is intended to inspire, educate, and mobilize Canadian health leaders to initiate dialogue around the transformative changes necessary to ready the healthcare system to realize the benefits of precision therapeutics.

RESUMEN

À l'ère de la médecine personnalisée et de la médecine de précision, l'approche envers les soins est en rapide mutation. Les cliniciens exigent de plus en plus d'information génétique et moléculaire et les patients s'attendent à la fournir pour la prévention, le dépistage, le diagnostic, le pronostic, la promotion de la santé et le traitement d'un nombre croissant de maladies. Les leaders en santé canadiens doivent comprendre les changements nécessaires liés à ces technologies perturbantes et ouvrir la voie. Le présent article s'attarde sur la thérapeutique de précision, mais contient également de l'information générale sur les concepts et la terminologie liés à la médecine personnalisée et à la médecine de précision. Il explore également le leadership en santé canadien et les problèmes liés au système qui peuvent nuire à leur mise en œuvre. L'article vise à inspirer, informer et mobiliser les leaders en santé canadiens à amorcer un dialogue sur les transformations nécessaires pour préparer le système de santé à profiter des bienfaits de la thérapeutique de précision.

RESUMEN

INTRODUCTION: Section 5(ii) of The Hindu Marriage Act, 1955 (HMA) states that under certain circumstances, mental illness is accepted as a ground for the annulment of marriage, while Section 13(1) (iii) states that mental illness is a ground for divorce. There is little data on how this provision is used and applied in matrimonial petitions. This paper assesses judicial practices in divorce cases, exploring the extent to which gender and the diagnosis of mental illness affect the decision to grant annulment or divorce. METHODS: The paper analyses judgments related to annulment and divorce at the Family Court in Pune and at the High Courts in India. RESULTS: In the Family Court at Pune, 85% of the cases were filed by husbands, who alleged that their spouse was mentally ill. Medical evidence of mental illness was presented in only 36% of the cases and in many cases, divorce/nullity was granted even in the absence of medical evidence. In 14% of the cases, nullity/divorce was granted even when both spouses were not present. Of the Family Court cases reaching the High Court, 95% were filed by male petitioners. The High Courts reversed the lower courts' judgments in 50% of the cases. DISCUSSION: Our analysis highlights the need for standardised guidelines for lower courts on what constitutes adequate medical proof of mental illness when hearing a petition related to nullity or divorce under HMA. It also provides a critical review of Section 5(ii) of HMA.

Asunto(s)

RESUMEN

Hand preference - which is related to cerebral dominance - is thought to be associated with cognitive skills; however, findings on this association are inconsistent and there is no consensus whether left- or right-handers have an advantage in either spatial or verbal abilities. In addition, it is not clear whether an interaction between sex and hand preference exists in relation to these cognitive abilities. As these matters are relevant from a neurodevelopmental perspective we performed a meta-analysis of the available literature. We searched PubMed and Embase, and included 14 studies (359,890 subjects) in the verbal ability meta-analysis and 16 studies (218,351 subjects) in the spatial ability meta-analysis. There was no difference between the full sample of left and right-handers for verbal ability, nor was there a hand preference-by-sex interaction. Subgroup analysis of children showed a small right-hand benefit. Our results further revealed a modest but significant effect favouring right-handedness for overall spatial ability, which was more pronounced when analysis was restricted to studies applying the mental rotation test. We could not identify a specific interaction with sex. Our results indicate that there is a small but significant cognitive advantage of right-handedness on spatial ability. In the verbal domain, this advantage is only significant in children. An interaction effect with sex is not confirmed.

Asunto(s)

RESUMEN

Although psychiatric advance directives give service users control over their care, very few studies exist on the content of PADs. This paper aims to contribute to this evidence base by presenting the content of psychiatric advance directives in India. Participants were 75 clients seeking outpatient care at a mental health services organisation in Tamil Nadu, India, who agreed to draft a PAD. Most clients were comfortable with appointing a representative (usually a family member) to make decisions on their behalf during a period of decisional incapacity or relapse, were willing to accept admission to the hospital/clinic and take medication if required, wanted to have a trusted person to discuss their mental health problems. No client used the opportunity to outright refuse treatment. This study highlights an important first step in improving the quality of mental health care by documenting user preferences for care in India. More in-depth research is needed to elicit rich descriptions of experiences of care and user-centred understanding of rights.

Asunto(s)

RESUMEN

Despite advocacy and demand for psychiatric advance directives (PADs), uptake and implementation in clinical practice is low. We examine why PAD implementation has been difficult globally by reviewing barriers in existing evidence. The review includes 30 studies, and identified 13 barriers, clustered into system level barriers, health professional level barriers, and service user level barriers. The considerable barriers to uptake and implementation hamper PAD use. We propose several potential strategies for overcoming some of the barriers. In order to realise these strategies, additional research is needed, particularly more field-based and operational research to understand processes and difficulties experienced in clinical practice.

Asunto(s)

RESUMEN

This study is the first in-depth qualitative study of service user involvement in the development of multidisciplinary mental health guidelines in the Netherlands. The study comprised a desk study of guidelines (n = 12) and case studies of service user involvement in five guidelines using document analysis, interviews (n = 24) and observations. The desk study shows that all multidisciplinary mental health guidelines have taken service user perspectives into account to some extent. The five guideline case studies led to the identification of ten main themes. Findings will assist guideline developers in making early, informed decisions on involving service users effectively.

Asunto(s)

RESUMEN

The United Nations Convention on the Rights of Persons with Disabilities (CRPD) serves as a comprehensive and legally binding framework for the rights of persons with mental illness. The extent to which countries have adapted their mental health legislation to reflect the binding provisions outlined in the CRPD is unclear. This paper reviews the situation across the Commonwealth.

RESUMEN

BACKGROUND: Psychiatric advance directives, a tool to document preferences for care in advance of decisional incapacity, have been shown to benefit persons with mental illness in a number of countries through improving medication adherence, reducing symptoms from escalating in a crisis, accelerating recovery, and enhancing service user autonomy. While concepts such as autonomy are important in a number of high-income country settings, it remains unclear whether tools like psychiatric advance directives are suitable in a different context. The recent introduction of the psychiatric advance directive into draft legislation in India prompts the question as to how feasible psychiatric advance directives are in the Indian context. The aim of this study is to explore the feasibility and utility of PADs in India, with a focus on the need for individual control over decision making and barriers to implementation, by exploring views of its central stakeholders, service users and carers. METHODS: Qualitative semi-structured interviews (n = 51) with clients (n = 39) and carers (n = 12) seeking mental health treatment at outpatient clinics in urban and rural settings provided by a non-profit organisation in Tamil Nadu, India. RESULTS: Clients engaged in a number of forms of decision-making (passive, active, and collaborative) depending on the situation and decision at hand, and had high levels of self-efficacy. Most clients and carers were unfamiliar with PADs, and while some clients felt it is important to have a say in treatment wishes, carers expressed concerns about service user capacity to make decisions. After completing PADs, clients reported an increase in self-efficacy and an increased desire to make decisions. CONCLUSIONS: The introduction of psychiatric advance directives in India appears to be associated with positive outcomes for some service users, however, there is a need to better understand how this tool can be adapted to better suit the care context in India and hold meaning and value for service users to complete.

RESUMEN

BACKGROUND: One of the effective strategies for reducing the number of maternal deaths is delivery by a skilled birth attendant. Low utilization of skilled birth attendants has been attributed to delay in seeking care, delay in reaching a health facility and delay in receiving adequate care. Health workers could play a role in helping women prepare for birth and anticipate complications, in order to reduce delays. There is little evidence to support these birth preparedness and complication readiness (BP/CR) programs; however, BP/CR programs are frequently implemented. The objective of this review is to assess the effect of BP/CR programs on increasing skilled birth attendance in low-resource settings. METHODS: Due to the complexity of BP/CR programs and the need to understand why certain programs are more effective than others, we will combine both quantitative and qualitative studies in this systematic review. Search terms were selected with the assistance of a health information specialist. Three reviewers will independently select and assess studies for quality. Data will be extracted by one reviewer and checked for accuracy and completeness by a second reviewer. Discussion between the reviewers will resolve disagreements. If disagreements remain, a third party will be consulted. Data analysis will be carried out in accordance with the BP/CR matrix, developed by the Johns Hopkins Program for International Education in Gynecology and Obstetrics (JHPIEGO). Study data will be grouped and analyzed by quality and study design and regrouped according to type of intervention strategy. DISCUSSION: This review will provide: 1) an insight into existing BP/CR programs, 2) recommendations on effective elements of the different approaches, 3) proposals for concrete action plans for health professionals in the field of reproductive health in resource-poor settings and 4) an overview of existing knowledge gaps requiring further research. TRIAL REGISTRATION: PROSPERO registration no.: CRD42012003124.

Asunto(s)