FLASH radiotherapy is a rapidly developing field which promises improved normal tissue protection compared to conventional irradiation and no compromise on tumour control. The transient hypoxic state ...induced by the depletion of oxygen at high dose rates provides one possible explanation. However, studies have mostly focused on uniform fields of dose and there is a lack of investigation into the spatial and temporal variation of dose from proton pencil-beam scanning (PBS). A model of oxygen reaction and diffusion in tissue has been extended to simulate proton PBS delivery and its impact on oxygen levels. This provides a tool to predict oxygen effects from various PBS treatments, and explore potential delivery strategies. Here we present a number of case applications to demonstrate the use of this tool for FLASH-related investigations. We show that levels of oxygen depletion could vary significantly across a large parameter space for PBS treatments, and highlight the need for in silico models such as this to aid in the development and optimisation of FLASH radiotherapy.
Objectives: The otic capsule, when compared with other bones in the body, is unique in that it undergoes no significant remodeling of bone after development. We previously demonstrated that ...osteoprotegerin (OPG), which inhibits formation and function of osteoclasts, is produced at high levels in the inner ear of normal mice and secreted into the perilymph from where it diffuses into the surrounding otic capsule bone through a lacunocanalicular system. To test our hypothesis that the high level of OPG may be important in the inhibition of otic capsule remodeling, we studied the light microscopic histology of the otic capsule in OPG knockout mice for evidence of abnormal remodeling of bone. We also tested the hearing in OPG knockout mice to determine whether OPG and its influence on surrounding bone is important for auditory function.
Methods: Temporal bone histopathology and pathophysiology were compared in homozygous OPG knockout mice and C57BL/6 (B6) mice, the background strain for the knockouts. Auditory function in age‐matched animals from each group was evaluated at approximately 4‐week intervals from 8 to 21 weeks using frequency‐specific auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). After each of the last three evaluations, the cochleae from one mouse of each group were harvested, processed, and examined by light microscopy.
Results: Osteoprotegerin knockout mice demonstrated abnormal remodeling of bone within the otic capsule with multiple foci showing osteoclastic bone resorption and formation of new bone. Such changes were not seen in the age‐matched B6 controls. The active bone remodeling process in the knockout animals showed many similarities to otosclerosis seen in human temporal bones. Over the time period that we monitored, auditory function was significantly and progressively compromised in the knockout animals relative to B6 controls. At the earliest age of test (8 wk), the loss was apparent as a mild, high‐frequency reduction in sensitivity by ABR. In contrast, DPOAE losses in the knockouts were substantial even at 8 weeks, and by 21 weeks, these losses exceeded our equipment limits. Results of ABR testing showed hearing sensitivity changes in the animals of the background strain were confined largely to the high frequencies, whereas OPG knockouts demonstrated substantial low‐frequency shifts in addition to those at high frequencies.
Conclusions: The histopathological and pathophysiological findings in OPG knockout mice support the hypothesis that OPG is important in the inhibition of bone remodeling within the otic capsule and the maintenance of normal auditory function. This mouse may provide a valuable animal model of human otosclerosis.
For patients with back pain from osteoporotic vertebral compression fractures (VCFs), vertebral augmentation remains the most utilized surgical intervention. Previous studies report 30-day ...readmission and mortality rates of up to 10% and 2%, respectively. These studies, however, have included patients with pathologic fractures and combined patients in different admission settings. We undertook the current study to address such shortcomings, which make risk stratification and appropriate counseling difficult.
Four consecutive years of the National Surgical Quality Improvement Program database were queried. Patients who underwent vertebral augmentation for osteoporotic VCFs were divided into 3 groups: (1) outpatient group (defined as patients with same-day discharge), (2) inpatient group (defined as those who were admitted postoperatively), and (3) preprocedure hospitalized group (defined as those who were already inpatient or were at acute/intermediate care facilities and transferred). Postoperative 30-day complications and readmission rates were compared between different groups and examined using multivariate analyses.
A total of 1023 patients underwent outpatient surgery; 503 were admitted on the day of surgery; and 149 patients were already in-hospital or were transferred from other facility. Mortality rates were 0.68%, 0.60%, and 2.68%, and readmission rates were 6.26%, 6.76%, and 12.8%, for outpatient, inpatient, and preprocedure hospitalization cohorts, respectively. Multivariate analyses identified preprocedure hospitalization as an independent risk factor for urinary tract infection (UTI; OR = 3.98, 95% CI = 1.41-11.20,
= 0.028), pneumonia (OR = 19.69, 95% CI = 3.81-101.65,
< 0.001), readmission (OR = 1.86, 95% CI = 1.06-3.26,
= 0.032), and mortality (OR = 4.49, 95% CI = 1.22-16.53,
= 0.024).
Our findings suggest that published rates of complications and mortality are substantially impacted by the cohort of patients who are already hospitalized or transferred from other facilities. Such patients are at a higher risk of UTI, pneumonia, readmission, and mortality. Conversely, we show that a relatively healthy patient being offered outpatient same-day augmentation has a readmission risk 40% lower and a mortality risk 3 times lower than previously reported.
•A flexible low-cost alternative to commercial time-lapse microscopy environmental control systems.•The AMOEBA system enables concurrent irradiation and observation of cells for extended periods of ...time.•Uses 3D printing, modular design and off-the-shelf sensors to create an expandable system that can easily be reconfigured.
Vertical Microbeams (VMB) are used to irradiate individual cells with low MeV energy ions. The irradiation of cells using VMBs requires cells to be removed from an incubator; this can cause physiological changes to cells because of the lower CO2 concentration, temperature and relative humidity outside of the incubator. Consequently, for experiments where cells require irradiation and observation for extended time periods, it is important to provide a controlled environment. The highly customised nature of the microscopes used on VMB systems means that there are no commercially available environmentally controlled microscope systems for VMB systems. The Automated Microbeam Observation Environment for Biological Analysis (AMOEBA) is a highly flexible modular environmental control system used to create incubator conditions on the end of a VMB. The AMOEBA takes advantage of the recent “maker” movement to create an open source control system that can be easily configured by the user to fit their control needs even beyond VMB applications. When applied to the task of controlling cell medium temperature, CO2 concentration and relative humidity on VMBs it creates a stable environment that allows cells to multiply on the end of a VMB over a period of 36h, providing a low-cost (costing less than $2700 to build), customisable alternative to commercial time-lapse microscopy systems. AMOEBA adds the potential of VMBs to explore the long-term effects of radiation on single cells opening up new research areas for VMBs.
Intrauterine devices, including levonorgestrel-releasing and copper devices, are highly effective long-acting reversible contraceptives. The potential risks associated with intrauterine devices are ...low and include uterine perforation and device expulsion.
This study aimed to evaluate the risk of perforation and expulsion associated with levonorgestrel-releasing devices vs copper devices in clinical practice in the United States.
The Association of Perforation and Expulsion of Intrauterine Device study was a retrospective cohort study of women aged ≤50 years with an intrauterine device insertion during 2001 to 2018 and information on intrauterine device type and patient and medical characteristics. Of note, 4 research sites with access to electronic health records contributed data for the study: 3 Kaiser Permanente–integrated healthcare systems (Northern California, Southern California, and Washington) and 1 healthcare system using data from a healthcare information exchange in Indiana (Regenstrief Institute). Perforation was classified as any extension of the device into or through the myometrium. Expulsion was classified as complete (not visible in the uterus or abdomen or patient reported) or partial (any portion in the cervix or malpositioned). We estimated the crude incidence rates and crude cumulative incidence by intrauterine device type. The risks of perforation and expulsion associated with levonorgestrel-releasing intrauterine devices vs copper intrauterine devices were estimated using Cox proportional-hazards regression with propensity score overlap weighting to adjust for confounders.
Among 322,898 women included in this analysis, the incidence rates of perforation per 1000 person-years were 1.64 (95% confidence interval, 1.53–1.76) for levonorgestrel-releasing intrauterine devices and 1.27 (95% confidence interval, 1.08–1.48) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 0.22% (95% confidence interval, 0.20–0.24) and 0.63% (95% confidence interval, 0.57–0.68) for levonorgestrel-releasing intrauterine devices and 0.16% (95% confidence interval, 0.13–0.20) and 0.55% (95% confidence interval, 0.44–0.68) for copper intrauterine devices, respectively. The incidence rates of expulsion per 1000 person-years were 13.95 (95% confidence interval, 13.63–14.28) for levonorgestrel-releasing intrauterine devices and 14.08 (95% confidence interval, 13.44–14.75) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 2.30% (95% confidence interval, 2.24–2.36) and 4.52% (95% confidence interval, 4.40–4.65) for levonorgestrel-releasing intrauterine devices and 2.30% (95% confidence interval, 2.18–2.44) and 4.82 (95% confidence interval, 4.56–5.10) for copper intrauterine devices, respectively. Comparing levonorgestrel-releasing intrauterine devices with copper intrauterine devices, the adjusted hazard ratios were 1.49 (95% confidence intervals, 1.25–1.78) for perforation and 0.69 (95% confidence intervals, 0.65–0.73) for expulsion.
After adjusting for potential confounders, levonorgestrel-releasing intrauterine devices were associated with an increased risk of uterine perforation and a decreased risk of expulsion relative to copper intrauterine devices. Given that the absolute numbers of these events are low in both groups, these differences may not be clinically meaningful.
The Thematic Mapper (TM) instruments onboard Landsats 4 and 5 provide high-quality imagery appropriate for many different applications, including land cover mapping, landscape ecology, and change ...detection. Precise calibration was considered to be critical to the success of the Landsat 7 mission and, thus, issues of calibration were given high priority during the development of the Enhanced Thematic Mapper Plus (ETM+). Data sets from the Landsat 5 TM are not routinely corrected for a number of radiometric and geometric artifacts, including memory effect, gain/bias, and interfocal plane misalignment. In the current investigation, the effects of correcting vs. not correcting these factors were investigated for several applications. Gain/bias calibrations were found to have a greater impact on most applications than did memory effect calibrations. Correcting interfocal plane offsets was found to have a moderate effect on applications. On June 2, 1999, Landsats 5 and 7 data were acquired nearly simultaneously over a study site in the Niobrara, NE area. Field radiometer data acquired at that site were used to facilitate crosscalibrations of Landsats 5 and 7 data. Current findings and results from previous investigations indicate that the internal calibrator of Landsat 5 TM tracked instrument gain well until 1988. After this, the internal calibrator diverged from the data derived from vicarious calibrations. Results from this study also indicate very good agreement between prelaunch measurements and vicarious calibration data for all Landsat 7 reflective bands except Band 4. Values are within about 3.5% of each other, except for Band 4, which differs by 10%. Coefficient of variation (CV) values derived from selected targets in the imagery were also analyzed. The Niobrara Landsat 7 imagery was found to have lower CV values than Landsat 5 data, implying that lower levels of noise characterize Landsat 7 data than current Landsat 5 data. It was also found that following radiometric normalization, the Normalized Difference Vegetation Index (NDVI) imagery and classification products of Landsats 5 and 7 were very similar. This implies that data from the two sensors can be used to measure and monitor the same landscape phenomena and that Landsats 5 and 7 data can be used interchangeably with proper caution. In addition, it was found that difference imagery produced using Landsat 7 ETM+ data are of excellent quality.
Intrauterine devices are effective instruments for contraception, and 1 levonorgestrel-releasing device is also indicated for the treatment of heavy menstrual bleeding (menorrhagia).
To compare the ...incidence of intrauterine device expulsion and uterine perforation in women with and without a diagnosis of menorrhagia within the first 12 months before device insertion
This was a retrospective cohort study conducted in 3 integrated healthcare systems (Kaiser Permanente Northern California, Southern California, and Washington) and a healthcare information exchange (Regenstrief Institute) in the United States using electronic health records. Nonpostpartum women aged ≤50 years with intrauterine device (eg, levonorgestrel or copper) insertions from 2001 to 2018 and without a delivery in the previous 12 months were studied in this analysis. Recent menorrhagia diagnosis (ie, recorded ≤12 months before insertion) was ascertained from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. The study outcomes, viz, device expulsion and device-related uterine perforation (complete or partial), were ascertained from electronic medical records and validated in the data sources. The cumulative incidence and crude incidence rates with 95% confidence intervals were estimated. Cox proportional hazards models estimated the crude and adjusted hazard ratios using propensity score overlap weighting (13–16 variables) and 95% confidence intervals.
Among 228,834 nonpostpartum women, the mean age was 33.1 years, 44.4% of them were White, and 31,600 (13.8%) had a recent menorrhagia diagnosis. Most women had a levonorgestrel-releasing device (96.4% of those with and 78.2% of those without a menorrhagia diagnosis). Women with a menorrhagia diagnosis were likely to be older, obese, and have dysmenorrhea or fibroids. Women with a menorrhagia diagnosis had a higher intrauterine device–expulsion rate (40.01 vs 10.92 per 1000 person-years) than those without, especially evident in the first few months after insertion. Women with a menorrhagia diagnosis had a higher cumulative incidence (95% confidence interval) of expulsion (7.00% 6.70–7.32 at 1 year and 12.03% 11.52–12.55 at 5 years) vs those without (1.77% 1.70–1.84 at 1 year and 3.69% 3.56–3.83 at 5 years). The risk of expulsion was increased for women with a menorrhagia diagnosis vs for those without (adjusted hazard ratio, 2.84 95% confidence interval, 2.66–3.03). The perforation rate was low overall (<1/1000 person-years) but higher in women with a diagnosis of menorrhagia vs in those without (0.98 vs 0.63 per 1000 person-years). The cumulative incidence (95% confidence interval) of uterine perforation was slightly higher for women with a menorrhagia diagnosis (0.09% 0.06–0.14 at 1 year and 0.39% 0.29–0.53 at 5 years) than those without it (0.07% 0.06–0.08 at 1 year and 0.28% 0.24–0.33 at 5 years). The risk of perforation was slightly increased in women with a menorrhagia diagnosis vs in those without (adjusted hazard ratio, 1.53; 95% confidence interval, 1.10–2.13).
The risk of expulsion is significantly higher in women with a recent diagnosis of menorrhagia. Patient education and counseling regarding the potential expulsion risk is recommended at insertion. The absolute risk of perforation for women with a recent diagnosis of menorrhagia is very low. The increased expulsion and perforation rates observed are likely because of causal factors of menorrhagia.
Abstract Objective To develop and validate the Baby Pediatric Symptom Checklist (BPSC), a brief social/emotional screening instrument for children less than 18 months. The BPSC is modeled after the ...Pediatric Symptom Checklist (PSC) and is part of the Survey of Wellbeing of Young Children, a comprehensive, freely available screening instrument designed for use in pediatric primary care. Method BPSC items were developed by a team of experts who reviewed existing assessment instruments and relevant research literature. Scale construction and initial validation were conducted with 205 families from pediatric primary care sites and 54 families from referral clinics. A replication sample of 146 additional families were enrolled from an independent set of primary care practices. Results Exploratory factor analysis revealed 3 dimensions of the BPSC: irritability, inflexibility, and difficulty with routines. Factor structure was confirmed in the replication sample. Retest reliability and internal reliability were adequate (intraclass correlation coefficient >0.70) across subscales, with the exception of the “irritability” subscale’s internal reliability in the replication sample. Construct validity of the “irritability” and the “difficulty with routines” subscales is supported by correlations with the Parenting Stress Index and the Ages & Stages Questionnaire: Social/Emotional, but the “inflexibility” subscale seems to be distinct from performance on these instruments. Tests of differential item functioning revealed no significant effects for race/ethnicity, child gender, parent education, or family income. Age-based normative data were calculated for each subscale. Conclusion The BPSC assesses 3 domains of behavior for very young children and shows promise as a social/emotional screening instrument for pediatric primary care.
Abstract Objective This article describes the development and initial validation of the Preschool Pediatric Symptom Checklist (PPSC), a social/emotional screening instrument for children 18 to 60 ...months of age. The PPSC was created as part of a comprehensive screening instrument designed for pediatric primary care and is modeled after the Pediatric Symptom Checklist. Method Items for the PPSC were developed by a team of experts who reviewed existing assessment instruments and relevant research literature. Scale construction and initial validation (including factor analysis and tests of construct validity) were conducted with 292 families from pediatric primary care sites and 354 families from referral clinics. One hundred seventy-one additional families were recruited from primary care sites to obtain an independent replication sample. Results Exploratory factor analysis revealed 4 dimensions of the PPSC: Externalizing, Internalizing, Attention Problems, and Parenting Challenges. These dimensions were incorporated into a bifactor model that displayed a strong general factor, thus supporting the use of a total score. The PPSC total score shows strong internal and retest reliability, and it identifies children who score in the clinical range of a longer, well-validated, and more comprehensive parent-report instrument (the Child Behavior Checklist), as well as children who are reported to have a range of behavioral diagnoses. Moreover, sensitivity and specificity with respect to these criteria were comparable to those of another well-accepted but longer screener, the Ages & Stages Questionnaire: Social/Emotional. Finally, results for the PPSC total scale remained consistent when replicated in an independent sample. Conclusion The PPSC shows promise as a social/emotional screening instrument for use in pediatric primary care.
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