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Objectives The preschool years (ages 4–6) are essential for the development of social–emotional skills, such as problem solving, emotion regulation, and conflict resolution. For children with cancer treated during this period, especially those with brain tumors, there are questions regarding the consequences of missed normative social experiences. The objective of this pilot study was to explore the social–emotional functioning of young children with brain tumors, as compared to those with non-CNS solid tumors, who have recently completed treatment. Methods Children with brain (n = 23) or solid tumors (n = 20) 4–6 years of age (5.42 ± 0.73 years; 60.5% male, 65.1% white) who were 8.21 (SD = 2.42) months post-treatment completed objective measures (Challenging Situations Task, NEPSY-II) of social functioning while a caregiver completed questionnaires (e.g., BASC-3, NIH Toolbox Emotion Measures). Results A large portion of the sample (brain tumor: 65.2%, solid tumor: 44.4%) fell in the clinical range on parent-report measures of peer interaction. There were no statistically significant differences between patient groups across measures, but effect sizes suggest youth with brain tumors potentially experienced more difficulties on some indices. All children were more likely to choose prosocial responses when presented with a challenging social situation where they were physically provoked (e.g., hit) versus socially provoked (e.g., left out). Conclusions Preschool-aged children with cancer may experience weaknesses in social functioning shortly after treatment, with youth with brain tumors potentially demonstrating greater concerns. Emphasizing social interaction is critical to ensure young children have the opportunity to develop critical social–emotional skills.

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

Nurses play an important role in educating patients on breast cancer and have a positive influence in encouraging women to participate in breast screening. This current study aimed to use a train-the-trainer model to improve the level of knowledge of nurses on breast cancer and screening in Ras Al Khaimah, United Arab Emirates. The study also focused on the nurses’ ability to train other nurses in assisting women to engage in breast screening. This interventional study used a mixed-method design. Seventeen female nurses (aged 28–60 years) were recruited from public and private health centers and participated in a breast cancer train-the-trainer workshop. They completed a survey before and after the workshop. The surveys included a series of open and closed questions to assess their knowledge of breast cancer symptoms, risk factors, diagnosis, and patient communication. The study found that nurse participants had good baseline knowledge of breast cancer topics, including breast self-examinations, clinical breast examinations, and mammography. Responses were deemed accurate if they answered open-ended questions without incorrect information and correct options were selected in the quantitative sections. However, training improved the detail and accuracy of the participant responses. Training also improved the confidence of nurse participants to teach other women and nurses how to perform breast self-examinations and provide breast cancer information. There were significant increases in nurse participants’ knowledge of risk factors (p

Rationale and Objectives Propagation-based phase-contrast CT (PB-CT) is an advanced X-ray imaging technology that exploits both refraction and absorption of the transmitted X-ray beam. This study was aimed at optimizing the experimental conditions of PB-CT for breast cancer imaging and examined its performance relative to conventional absorption-based CT (AB-CT) in terms of image quality and radiation dose. Materials and Methods Surgically excised breast mastectomy specimens (n = 12) were scanned using both PB-CT and AB-CT techniques under varying imaging conditions. To evaluate the radiological image quality, visual grading characteristics (VGC) analysis was used in which 11 breast specialist radiologists compared the overall image quality of PB-CT images with respect to the corresponding AB-CT images. The area under the VGC curve was calculated to measure the differences between PB-CT and AB-CT images. Results The highest radiological quality was obtained for PB-CT images using a 32 keV energy X-ray beam and by applying the Homogeneous Transport of Intensity Equation phase retrieval with the value of its parameter γ set to one-half of the theoretically optimal value for the given materials. Using these optimized conditions, the image quality of PB-CT images obtained at 4 mGy and 2 mGy mean glandular dose was significantly higher than AB-CT images at 4 mGy (AUCVGC = 0.901, p = 0.001 and AUCVGC = 0.819, p = 0.011, respectively). Conclusion PB-CT achieves a higher radiological image quality compared to AB-CT even at a considerably lower mean glandular dose. Successful translation of the PB-CT technique for breast cancer imaging can potentially result in improved breast cancer diagnosis.

The suprascapular nerve is an ideal target for nerve blockade to alleviate shoulder pain given its widespread innervation to the shoulder girdle. Many techniques have been described. To widen the availability of this treatment we investigate whether an anatomical landmark technique can be easily learned by novice injectors to provide efficacious blockade.Five injectors were recruited with varying experience; from the novice medical student to an orthopaedic consultant. Five torsos (10 shoulders) were used. A single page of written instruction and illustration of the Dangoisse landmark technique was provided prior to injection of a Thiel embalmed cadaver bilaterally. A pre-mixed injectate with blue dye was used. Cadavers were dissected and the presence or absence of dye staining reported by 3 observers and a consensus agreement reached.Dissection demonstrated diffuse staining in the suprascapular fossa. 90% of shoulders were found to have adequate staining of the suprascapular nerve directly, or its distal branches, in a manner which would provide adequate anaesthesia. The inter-observer agreement was good (k = 0.73) for staining at the supraspinous fossa and excellent (k=0.87) for staining distally. The technique was easily performed by novice injectors with a 100% success rate.We demonstrate that this technique is reproducible by a range of clinicians to effectively provide anaesthesia of the SScN. The main risks are ineffective block (10% in this series) and of intravascular injection. Within a resource strained healthcare environment greater uptake of this technique is likely to be of benefit to a wider array of patients.

Evidence from animal models suggests that undercarboxylated osteocalcin (ucOC) is involved in muscle mass maintenance and strength. In humans, the ucOC to total (t)OC ratio may be related to muscle strength and perhaps physical function and falls risk, but data are limited. We tested the hypothesis that ucOC and ucOC/tOC ratio are associated with muscle function (muscle strength and physical function) in older women and 15-year falls-related hospitalizations. Serum tOC and ucOC were assessed in 1261 older women (mean age 75.2 ± 2.7 years) forming the Perth Longitudinal Study of Aging Women (1998 to 2013). Timed-up-and-go (TUG) and grip strength were assessed at baseline and at 5 years. Falls-related hospitalizations (14.5-year follow-up) were captured by the Hospital Morbidity Data Collection, via the Western Australian Data Linkage System. At baseline, women with higher ucOC/tOC ratio (quartile 4) had slower TUG performance compared with quartile 1 (~0.68 seconds, p .01). Grip strength and 5-year change of TUG and grip were not different (p .05) between quartiles. Fear of falling limiting house, outdoor, and combined activities was significantly different across quartiles (p .05). Higher ucOC/tOC was significantly associated with poorer TUG performance at baseline and 5-year change in performance, increased walking aid use, and fear of falling (all p .05). Higher ucOC was related to lower grip strength at baseline (p .05) but not 5-year change in strength. Those with the highest ucOC/tOC had greater falls-related hospitalizations (unadjusted log rank, p = .004) remaining significant after adjusting for key variables (hazard ratio [HR] = 1.31, 95% confidence interval [CI] 1.09-1.57, p = .004). We identified a large proportion of older women with high ucOC/tOC ratio who had reduced physical function, including its long-term decline and increased risk of falls-related hospitalizations. Early identification of women at higher risk can enable prevention and intervention strategies to occur, reducing risk for injurious falls. © 2020 American Society for Bone and Mineral Research (ASBMR)..

Up to 90% of patients with postural tachycardia syndrome (PoTS) report headaches, and comorbid migraine headaches are common. Given this, pathophysiological interaction is possible, which may reveal key aspects of disease expression and treatment opportunities. We hypothesized that PoTS subjects—both with and without migraine—would show features of central sensitization, including allodynia and photophobia. Eighty participants were evaluated, including 30 PoTS, 30 chronic migraine (CM), and 20 non-headache healthy controls (NH), using tilt table testing, psychophysical assessment of sensory sensitivity thresholds, and an online questionnaire to assess measures of headache burden and associated symptoms. Clinical characteristics and sensory thresholds were compared between disease groups and controls, as well as in a subgroup analysis within the PoTS group, based on headache phenotype. Sensory sensitivity thresholds were significantly lower and symptom scores were higher in both the PoTS and CM groups compared to controls. However, the patterns of expression differed between PoTS and CM, with pain threshold reductions in the forearm only of PoTS subjects (non-trigeminal sensory sensitization), compared to both periorbital and forearm sites in CM. Unexpectedly, light sensitivity thresholds were significantly lower in PoTS than in both CM and NH. These findings reveal an underappreciated aspect of disease burden in PoTS, and suggest network sensitization similar to, but separable from, that of migraine. The presence of both photophobia and allodynia in PoTS is reflective of exteroceptive rather than strictly interoceptive disruption, and expands our fundamental understanding of the disorder.

Kidney transplant recipients who develop symptoms consistent with COVID-19 are bringing unique challenges to health care professionals. Telemedicine has surged dramatically since the pandemic in efforts to maintain patient care and reduce the risk of COVID-19 exposure to patients, healthcare workers, and the public. Herein we present reports of three kidney transplant recipients with COVID-19 that were managed using telemedicine via synchronous video visits integrated with an electronic medical records system, from home to inpatient settings. We demonstrate how telemedicine helped assess, diagnose, triage, and treat patients with COVID-19 while avoiding an emergency room or outpatient clinic visit. While there is limited information about the duration of viral shedding for immunosuppressed patients, our findings underscore the importance of using telemedicine in the follow-up care for kidney transplant recipients with COVID-19 who have recovered from symptoms but might have persistently positive NAT tests. Our experience emphasizes the opportunities of telemedicine in the management of kidney transplant recipients with COVID-19 and in the maintenance of uninterrupted follow-up care for such immunosuppressed patients with prolonged viral shedding. Telemedicine may help increase access to care for kidney transplant recipients during and beyond the pandemic as it offers a prompt, safe, and convenient platform in the delivery of care for these patients. Yet in order to advance the practice of telemedicine in the field of kidney transplantation, barriers to increasing the widespread implementation of telemedicine should be removed, and research studies to assess the effectiveness of telemedicine in the care kidney transplant recipients are needed., Highlights • Telemedicine helped diagnose, triage, and manage transplant patients with COVID-19 • Practical workflow process for COVID-19 test and surveillance • Telemedicine aid from home to inpatient settings, while avoiding ER or clinic visit • Telemedicine provides prompt, safe, and convenient approach to COVID-19 patients • Care delivery for immunosuppressed patients with prolonged COVID-19 shedding • Uninterrupted follow-up care for kidney transplant recipients with COVID-19

Background Breast cancer is the most common occurring cancer in women worldwide. To guide current breast cancer screening program, the level of knowledge about breast cancer should be evaluated. This study aims to ascertain the level of breast cancer knowledge including risk factors, signs and symptoms, and early detection methods, especially mammography screening. Methods The study was conducted among 1353 Jordanian women from the public using a self-administered questionnaire. Responses to the knowledge test were summed for an overall knowledge score. Comparisons between socio-demographics and knowledge, attitude and practice were also measured using a Chi-square test. Results About 76% of participants were aware that breast cancer is the most common cancer among women in Jordan. About 53.7% of our participants were rated as having an intermediate level of knowledge regarding risk factors, and 44% were rated as having a good to an excellent level of knowledge about breast cancer signs and symptoms. The participants' level of education was the main factor identified as influencing the participants' knowledge of the risk factors, signs and symptoms, and knowledge of early detection methods of breast cancer. The study sample was rated as having an intermediate level of knowledge regarding mammography screening; however, their participation in this screening method was low. Conclusion Although Jordanian women had an acceptable level of knowledge of breast cancer, the screening rates for mammography were low. These findings suggest that there is a need to provide extra awareness programs for Jordanian women to improve their breast cancer knowledge and practice.

Clinical decision-making in kidney transplant (KT) during the coronavirus disease 2019 (COVID-19) pandemic is understandably a conundrum: both candidates and recipients may face increased acquisition risks and case fatality rates (CFRs). Given our poor understanding of these risks, many centers have paused or reduced KT activity, yet data to inform such decisions are lacking. To quantify the benefit/harm of KT in this context, we conducted a simulation study of immediate-KT vs delay-until-after-pandemic for different patient phenotypes under a variety of potential COVID-19 scenarios. A calculator was implemented (http://www.transplantmodels.com/covid_sim), and machine learning approaches were used to evaluate the important aspects of our modeling. Characteristics of the pandemic (acquisition risk, CFR) and length of delay (length of pandemic, waitlist priority when modeling deceased donor KT) had greatest influence on benefit/harm. In most scenarios of COVID-19 dynamics and patient characteristics, immediate KT provided survival benefit; KT only began showing evidence of harm in scenarios where CFRs were substantially higher for KT recipients (eg, ≥50% fatality) than for waitlist registrants. Our simulations suggest that KT could be beneficial in many centers if local resources allow, and our calculator can help identify patients who would benefit most. Furthermore, as the pandemic evolves, our calculator can update these predictions.

Insufficient knowledge about COVID-19 and the potential risks of COVID-19 are limiting organ transplantation in wait-listed candidates and deferring essential health care in solid organ transplant recipients. In this review, we expand the understanding and present an overview of the optimized management of COVID-19 in solid organ transplant recipients. Transplant recipients are at an increased risk of severe COVID-19. The unique characteristics of transplant recipients can make it more difficult to identify COVID-19. Based on the COVID-19 data to date and our experience, we present testing, management, and prevention methods for COVID-19. Comprehensive diagnostic tests should be performed to determine disease severity, phase of illness, and identify other comorbidities in transplant recipients diagnosed with COVID-19. Outpatients should receive education for preventative measures and optimal health care delivery minimizing potential infectious exposures. Multidisciplinary interventions should be provided to hospitalized transplant recipients for COVID-19 because of the complexity of caring for transplant recipients. Transplant recipients should strictly adhere to infection prevention measures. Understanding of the transplant specific pathophysiology and development of effective treatment strategies for COVID-19 should be prioritized.

Background Kidney transplant recipients have higher risk of infectious diseases due to their reliance on immunosuppression. During the current COVID-19 pandemic, some clinicians might have opted for less potent immunosuppressive agents to counterbalance the novel infectious risk. We conducted a nationwide study to characterize immunosuppression use and subsequent clinical outcomes during the first 5 months of COVID-19 pandemic in the United States. Methods Using data from the Scientific Registry of Transplant Recipients, we studied all kidney-only recipients in the United States from January 1, 2017, to March 12, 2020 ("prepandemic" era; n = 64 849) and from March 13, 2020, to July 31, 2020 ("pandemic" era; n = 5035). We compared the use of lymphocyte-depleting agents (versus basiliximab or no induction) and maintenance steroids (versus steroid avoidance/withdrawal) in the pandemic era compared with the prepandemic era. Then, we compared early posttransplant outcomes by immunosuppression regimen during the pandemic era. Results Recipients in the pandemic era were substantially less likely to receive lymphocyte-depleting induction agents compared with their prepandemic counterparts (aOR = 0.400.530.69); similar trends were found across subgroups of state-level COVID-19 incidence, donor type, and recipient age. However, lymphocyte-depleting induction agents were associated with decreased rejection during admission (aOR = 0.110.230.47) but not with increased mortality in the pandemic era (aHR = 0.130.471.66). On the other hand, the use of maintenance steroids versus early steroid withdrawal remained similar (aOR = 0.711.071.62). Conclusions The use of lymphocyte-depleting induction agents has decreased in favor of basiliximab and no induction during the COVID-19 pandemic. However, this shift might have resulted in increases in rejection with no clear reductions in posttransplant mortality.

A 3-year-old, male neutered, domestic short-haired cat presented for evaluation of respiratory distress. Transthoracic echocardiography revealed a left-to-right shunting ventricular septal defect, a left-to-right shunting patent ductus arteriosus, and a vegetative growth on the aortic valve leaflet consistent with aortic valve endocarditis. Because of poor response to therapy, the owner elected euthanasia, and a necropsy was performed. Gross necropsy examination confirmed the congenital cardiac defects, and aortic valve endocarditis was noted on the echocardiogram. Histopathological examination revealed diffuse interstitial pneumonia and evidence for systemic septic embolism including renal infarcts and brain microabscesses. To the authors' knowledge, this is the first case report of aortic valve endocarditis in a cat in association with congenital cardiac malformations.

Objective To design a device that can support the breast during phase-contrast tomography, and characterise its fit parameterisation and comfort rating. Methods 27 participants were recruited to trial a system for breast support during simulated phase contrast imaging, including being positioned on a prone imaging table while wearing the device. Participants underwent a photogrammetry analysis to establish the geometric parameterisations. All participants trialled a single-cup design while 14 participants also trialled a double-cup with suction holder and all completed a series of questionnaires to understand subjective comfort. Results Photogrammetry revealed significant positive correlations between bra cup volume and measured prone volume (p < 0.001), and between “best fit” single-cup holder volume and measured prone volume (p < 0.005). Both holders were suitable devices in terms of subjective comfort and immobilisation while stationary. However, some re-engineering to allow for quick, easy fitting in future trials where rotation through the radiation beam will occur is necessary. Light suction was well-tolerated when required. Conclusion All participants indicated the table and breast support devices were comfortable, and they would continue in the trial. Advances in knowledge Phase contrast tomography is an emerging breast imaging modality and clinical trials are commencing internationally. This paper describes the biomedical engineering designs, in parallel with optimal imaging, that are necessary to measure breast volume so that adequate breast support can be achieved. Breast support devices have implications for comfort, motion correction and maximising breast tissue visualisation.

To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long-term patient health outcomes.This was an exploratory analysis of patients with TBI who were enrolled in the American Registry for Migraine Research (ARMR), a multicenter, prospective, longitudinal patient registry composed of patients with International Classification of Headache Disorders, 3rd edition (ICHD-3)-defined headache diagnoses. The ARMR study enrolled 2,707 patients between February 1, 2016 and May 6, 2020, 565 of whom qualified for this analysis. Those with headaches prior to their TBI were compared to those without headaches prior to their TBI for ICHD-3 diagnoses, headache frequency and intensity, headache-related disability (Migraine Disability Assessment score), symptoms of anxiety (General Anxiety Disorder [GAD-7]), depression (two items from Patient Health Questionnaire-9), post-traumatic stress disorder (PTSD), cutaneous allodynia (12-item Allodynia Symptom Checklist [ASC-12]), cognitive dysfunction (Migraine Attacks Subjective Cognitive Impairments Scale [Mig-SCog]), pain interference (Patient-Reported Outcomes Measurement Information System-Pain Interference), and work productivity (Work Productivity and Activity Impairment).Among 565 participants with TBI, 350 had headaches prior to their TBI. Those with pre-TBI headaches were less likely to receive a diagnosis of post-traumatic headache (PTH; 14/350 [4.0%] vs. 21/215 [9.8%], p = 0.006), even though 25.7% reported new or worsening headaches within 7 days of their TBI. Those with pre-TBI headaches had higher ASC-12 scores (2.4 ± 3.5 vs. 1.8 ± 3.4, p = 0.030), Mig-SCog scores (9.3 ± 4.7 vs. 8 ± 4.9, p = 0.004), and GAD-7 scores (6.9 ± 5.1 vs. 6.2 ± 5.4, p = 0.039), and were more likely to have a migraine diagnosis (335/350 [95.7%] vs. 192/215 [89.3%], p = 0.003).Those with headaches prior to TBI are less likely to receive a diagnosis of PTH. They have more severe symptoms of cutaneous allodynia, cognitive impairment, and generalized anxiety. This analysis suggests that pre-TBI headaches might impact post-TBI headache diagnoses and associated features.

COVID-19 led to drastic reductions in non-urgent medical visits and cancer care. Surgical patient backlogs mean new strategies are required to decrease wait times and administrative costs whilst improving patient outcomes. We review the impact of combined speciality Plastic Surgery and Dermatology 2 week-wait (2ww) clinics on wait times and hospital attendances and associated cost implications when compared to the single speciality clinics. Retrospective analysis comparing Plastic surgery (PS) and Dermatology (DM) 2ww clinics against combined Dermatology and Plastic surgery (DP) clinics across the same 3-month period in 2018 and 2019 at a single UK tertiary centre. 283 patients reviewed across the same 3-month period in 2018 and 2019 (PS n = 53, DM n = 158, PD n = 72). PD reviewed most patients per clinic (Averages: PD n = 18.0, PS n = 8.8, DM n = 12.1). Hospital attendance decreased from 1.84 to 1.51 visits. 42.9% of excisional biopsies were performed on the same day as initial assessment compared to 18.0% in PS/DM clinics. Referral to surgery time decreased from 67.7days to 50.4 days, and tertiary assessment to surgery from 49.5days to 36.9days. PD attracted tariffs of up to £29.78 more per patient. Combined clinics see more patients and attract higher tariffs per patient, whilst reducing outpatient attendances and wait times to surgery. This has significant cost-saving implications whilst optimising cancer care.

Objectives Mixed methods were used to evaluate a group self-management education intervention to address type 1 diabetes (T1D)-specific barriers to physical activity (PA). We evaluated the acceptability of study resources and procedures. Methods Consenting participants from a quantitative evaluation (n=70) were invited to participate in 1 of 5 focus groups. Interviews explored the acceptability of procedures across the randomized controlled trial schedule, acceptability of the intervention/control workshops and resources and the perceived effectiveness of the intervention/control on participant outcomes. The use and helpfulness of intervention take-home resources, Facebook data and fidelity coding were also examined to inform other aspects of intervention acceptability. Results Twenty-one focus group participants from control or intervention arms participated in 1 of the 5 focus groups. Participants were 46±10 years of age; about half were female and had been living with T1D for 23±16 years. Study procedures were widely accepted; however, randomization and some aspects of the questionnaire were of concern to a small number of participants. Group education was acceptable and preferred, but participants expressed ambivalence toward the private Facebook group. Control participants indicated that basic information on PA guidelines and hypoglycemia risk are not currently being provided in standard care. Fidelity assessment confirmed the intervention was delivered consistently and was facilitated using behaviours and communication skills based on Social Cognitive Theory. Conclusions Future definitive evaluation of this promising intervention should utilize a blinded randomized controlled trial study design. Alterations to the control workshop are required to better reflect standard care in Australia. Our qualitative findings suggest that group education can be an acceptable and preferred method of education in T1D management for PA.

Increased body mass index (BMI) has been previously described as a risk factor for complications after total joint arthroplasty (TJA); however, its effect on patient-reported outcomes has not been thoroughly investigated. This study examines the effect of postoperative weight change on the Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) scores for total knee arthroplasty (TKA) and total hip arthroplasty (THA) patients.A retrospective review of 988 patients undergoing THA or TKA was performed. PROMIS-PF scores and BMI were recorded throughout the study duration. Patients were classified by a 5% change in BMI. A univariate analysis evaluated differences across groups. Mixed-effect models evaluated predictors of change in functional score over the postoperative follow-up time.43.1% patients had a THA and 56.9% patients had a TKA. At 0 to 3 months, 92% of patients had no change in BMI, 3 to 6 months 82% had no change, and 6 to 12 months 80% had no change. There were no significant demographic or comorbidity differences across groups for both THA and TKA. Similar improvements in PROMIS-PF scores were observed across weight change groups. In the mixed-effect models, postoperative time was found to be a significant predictor of postoperative PF score. Both THA and TKA patients saw greater improvements in PROMIS-PF scores in patients with lower preoperative BMIs.These results demonstrate most patients do not experience substantial changes in weight following TJA. However, lower BMIs at the time of surgery were associated with an increased functional improvement. Therefore, efforts to optimize BMI should be focused preoperatively to improve surgical outcomes.

To determine the safety and toxicity profile of intravitreal carboplatin as salvage treatment for retinoblastoma with vitreous disease.Single institution, interventional prospective clinical trial PARTICIPANTS: Patients with progressive or recurrent vitreous seeds following completion of primary treatment for intraocular retinoblastoma.Eligible eyes received an intravitreal injection of carboplatin every 14-21 days with simultaneous focal therapy (laser, thermotherapy, brachytherapy) provided at the discretion of the ocular oncologist. Evaluation with exam under anesthesia (EUA), ultrasound biomicroscopy and electroretinography were performed prior to each injection to assess for tumor response and drug-related toxicity. A serious adverse event resulted in dose recalculation and ultimately early closure of the study.Regression pattern of vitreous disease and incidence of dose-limiting toxicities.Four patients were enrolled at an initial dose of 0.3 mg. Complete regression of vitreous seeds was noted in all patients following 5, 2, 2 and 1 injections (respectively). Two patients developed recurrent vitreous disease at 3 months and 25 months after complete regression, and ultimately required enucleation. A serious adverse event occurred in one patient who developed acute vision loss with extinguished electroretinography response 72 hours after the second injection; ultimately this eye developed cataract and required enucleation. Following temporary suspension and dose modification, three patients were enrolled at an injection dose of 3 μg and treated with a total of 5, 2 and 1 injections respectively. Complete regression of vitreous disease was not achieved in any patient though ERG amplitudes remained stable. Following removal from protocol, all three patients had a complete response to intravitreal melphalan. Concern for dose escalation and further toxicity in the setting of an effective and safe alternative (melphalan) led to termination of the study.Intravitreal carboplatin may be effective in treating progressive vitreous seeding at higher doses, but permanent retinal toxicity was observed. Other alternative agents should be considered.

Touch and other types of patient stimulation are necessary in critical care and generally presumed to be beneficial. Recent pre-clinical studies as well as randomized trials assessing early mobilization have challenged the safety of such routine practices in patients with acute neurological injury such as stroke. We sought to determine whether patient stimulation could result in spreading depolarization (SD), a dramatic pathophysiological event that likely contributes to metabolic stress and ischemic expansion in such patients. Patients undergoing surgical intervention for severe acute neurological injuries (stroke, aneurysm rupture, or trauma) were prospectively consented and enrolled in an observational study monitoring SD with implanted subdural electrodes. Subjects also underwent simultaneous video recordings (from continuous EEG monitoring) to assess for physical touch and other forms of patient stimulation (such as suctioning and positioning). The association of patient stimulation with subsequent SD was assessed. Increased frequency of patient stimulation was associated with increased risk of SD (OR = 4.39 [95%CI = 1.71-11.24]). The overall risk of SD was also increased in the 60 min following patient stimulation compared to times with no stimulation (OR = 1.19 [95%CI = 1.13-1.26]), though not all subjects demonstrated this effect individually. Positioning of the subject was the subtype of stimulation with the strongest overall effect on SD (OR = 4.92 [95%CI = 3.74-6.47]). We conclude that in patients with some acute neurological injuries, touch and other patient stimulation can induce SD (PS-SD), potentially increasing the risk of metabolic and ischemic stress. PS-SD may represent an underlying mechanism for observed increased risk of early mobilization in such patients.

Background and AimsDays to flowering initiation in species with large geographic distribution often correlate with latitude. Latitude reflects climatic gradients, but it is unclear if large-scale differentiation in flowering results from adaptation to local climate, and whether adaptation to local climate could constrain shifts in distribution and colonization of new environments.MethodsIn its Western range in Europe, L. bienne populations were surveyed to describe latitudinal patterns of flowering initiation and determine its correlation with the local climate of populations. This was measured under standardized greenhouse conditions, with a vernalization experiment to learn if chilling advances flowering, and with a reciprocal transplant experiment at three sites along the latitudinal gradient, recording flowering at the central site and plant survival in all sites. Also, genetic differentiation of populations along the latitudinal range was studied using microsatellite markers.Key ResultsFlowering initiation varied with latitude, with southern populations flowering earlier than northern populations. Latitude also predicted population response to vernalization, with chilling inducing a greater advance of flowering initiation in northern than southern populations. In general, plant survival in the reciprocal transplant experiment decreased with the geographic distance of populations to the experimental site and, at the central site, flowering initiation varied with latitude of origin. However, across experiments, the local climate of populations better predicted the differentiation in flowering initiation and vernalization response than latitude of origin. Finally, the microsatellite data revealed genetic differentiation of populations forming two groups that agree with a Mediterranean and Atlantic lineage.ConclusionsThe consistent result across experiments of a latitudinal cline in flowering initiation and in the vernalization response suggests that flowering is under genetic regulation and yet dependent on particular environmental and climatic cues at local scale. However, the genetic differentiation suggests that past population history might influenced the flowering initiation patterns detected.

Objectives: To examine whether radiologists’ performances are consistent throughout a reading session and whether any changes in performance over the reading task differ depending on experience of the reader. Methods: The performance of ten radiologists reading a test set of 60 mammographic cases without breaks was assessed using an ANOVA, 2 × 3 factorial design. Participants were categorized as more (≥2,000 mammogram readings per year) or less (Results: Significant linear interactions were found between experience and the fixed sequence of the series for sensitivity (F[1] =5.762, p = .04, partial η2 = .41) and lesion sensitivity. (F[1] =6.993, p = .03, partial η2 = .46). The two groups’ mean scores were similar for the first series but progressively diverged. By the end of the third series, significant differences in sensitivity and lesion sensitivity were evident, with the more experienced individuals demonstrating improving and the less experienced declining performance. Neither experience nor series sequence significantly affected the specificity or the area under the ROC curve. Conclusions: Radiologists’ performance may change considerably during a reading session, apparently as a function of experience, with less experienced radiologists declining in sensitivity and lesion sensitivity while more experienced radiologists actually improve. With the increasing demands on radiologists to undertake high-volume reporting, we suggest that junior radiologists be made aware of possible sensitivity and lesion sensitivity deterioration over time so they can schedule breaks during continuous reading sessions that are appropriate to them, rather than try to emulate their more experienced colleagues. Advances in knowledge: Less-experienced radiologists demonstrated a reduction in mammographic diagnostic accuracy in later stages of the reporting sessions. This may suggest that extending the duration of reporting sessions to compensate for increasing workloads may not represent the optimal solution for less-experienced radiologists.

Water has been stored in the Martian mantle since its formation, primarily in nominally anhydrous minerals. The short-lived early hydrosphere and intermittently flowing water on the Martian surface may have been supplied and replenished by magmatic degassing of water from the mantle. Estimating the water storage capacity of the solid Martian mantle places important constraints on its water inventory and helps elucidate the sources, sinks, and temporal variations of water on Mars. In this study, we applied a bootstrap aggregation method to investigate the effects of iron on water storage capacities in olivine, wadsleyite, and ringwoodite, based on high-pressure experimental data compiled from the literature, and we provide a quantitative estimate of the upper bound of the bulk water storage capacity in the FeO-rich solid Martian mantle. Along a series of areotherms at different mantle potential temperatures ($T_{p}$), we estimated a water storage capacity equal to $9.0_{-2.2} ^{+2.8}$ km Global Equivalent Layer (GEL) for the present-day Martian mantle at $T_{p}$ = 1600 K and $4.9_{-1.5}^{+1.7}$ km GEL for the initial Martian mantle at $T_{p}$ = 1900 K. The water storage capacity of the Martian mantle increases with secular cooling through time, but due to the lack of an efficient water recycling mechanism on Mars, its actual mantle water content may be significantly lower than its water storage capacity today., Comment: 52 pages including supplementary materials, 14 figures, 13 tables; manuscript accepted for publication in Icarus

Objectives: Radiation Risk In Mammography Screening (RRIMS) builds on the prototype, formerly known as Breast-iRRISC, to develop a model that aims to establish a dose and risk profile for females by calculating their lifetime mean glandular dose (MGD) for each age of screening between 40 and 75 years, using only the information from her first screening visit. This is then used to allocate her to a dose category and estimate the lifetime risk of radiation-induced breast cancer incidence and mortality for a population of females in that category. Methods: This model training was developed using a large dataset of Hologic images containing a total of 20,232 images from 5,076 visits from 4,154 females. The female’s breast characteristics and exposure parameters were extracted from the images to calculate the female’s MGD throughout a lifetime of screening from just her first screening visit, using modelling of various parameters and their change through time. Results: This development has ultimately provided a model that uses the female’s first screening visit to calculate the received MGD for all ages of potential screening. This has enabled the allocation of females to either a low-, medium-, or high-dose category, ultimately followed by the lifetime effective risk (LER) estimation for any screening attendance pattern. A female in the low-dose category undergoing biennial screening from 50 to 74 years would expect a risk of radiation-induced breast cancer incidence and mortality of 8.64 and 2.61 cases per 100,000 females, respectively. Similarly, a female in the medium- or high-dose category undergoing the same regimen would expect an incidence and mortality risk of 11.76 and 3.55, and 15.08 and 4.55 cases per 100,000 females, respectively. Conclusions: This novel approach of establishing a female’s dose profile and lifetime risk from a single visit will further assist females in their informed consent on breast screening attendance and help inform policy-makers when exploring the benefits and drawbacks of various screening patterns and frequencies. Advances in knowledge: RRIMS is a novel tool that enables the assessment of a female’s lifetime dose and risk profile using only the information from her first screening visit.

Background: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD. Methods: In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na/K pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. Results: We discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na/K ATPase elicits SD. Elevated K or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. Conclusions: Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory., This work was supported by grants from the Heart and Stroke Foundation of Canada and the National Science and Engineering Research Council of Canada to RDA, an NIH grant (NS106901) to CWS, a National Research, Development and Innovation Office of Hungary grant (K1343777) and EU Horizon 2020 research and innovation program (739953) to EF and from DFG Deutsche Forschungsgemeinschaft (German Research Council) (DFG DR 323/5-1), DFG DR 323/10-1, and BMBF Bundesministerium fuer Bildung und Forschung (EraNet Neuron EBio2, with funds from BMBF 01EW2004) to JPD.

Chickpea (Cicer arietinum L.) is one of the most ımportant food legume crops in the world. Chickpea is valued for its nutritive seed composition, which is high in protein content and used increasingly as a substitute for animal protein. Days to fırst flowerıng is an important component of the adaptation and productivity of chickpea in rainfed environments characterized by terminal drought and heat stress. This study aimed to identify the inheritance pattern and identify quantitative trait loci (QTLs) for days to first flowering and flowering color in F2:4 generation nested association mapping (NAM) populations of chickpea obtained using wide crosses between Gokce as the cultivated variety and wild accessions of C. reticulatum and C. echinospermum. A total of ten populations of 113 to 191 individuals each were grown under field conditions near Sanliurfa, Turkey. Two populations were genotyped for 46 single nucleotide polymorphism (SNP) markers, enabling QTL analysis. Flowering time differed between families, with the frequency distributions indicating quantitative inheritance controlled by both genes of major and minor effects. Three significant QTLs for the flowering time were mapped in one mapping family. For flower color, chi-square tests showed that five populations accepted single-gene action, two populations accepted two-gene action, and three populations accepted neither model. Two significant QTLs at three genomic regions were identified across the two genotyped populations. Days to first flowering was positively correlated with flower color for two of the ten populations. The diversity of QTLs identified underscored the potential of crop wild relatives of chickpea as sources of novel alleles for chickpea breeding.

Background Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies. Patients and methods Cohorts of 3–6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1–6, and intravenous irinotecan and oral temozolomide were administered on days 2–6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed. Results Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy. Conclusions The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted.