Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

Informing urban climate planning with high resolution data: the Hestia fossil fuel CO2 emissions for Baltimore, Maryland.

BACKGROUND: Cities contribute more than 70% of global anthropogenic carbon dioxide (CO2) emissions and are leading the effort to reduce greenhouse gas (GHG) emissions through sustainable planning and development. However, urban greenhouse gas mitigation often relies on self-reported emissions estimates that may be incomplete and unverifiable via atmospheric monitoring of GHGs. We present the Hestia Scope 1 fossil fuel CO2 (FFCO2) emissions for the city of Baltimore, Maryland-a gridded annual and hourly emissions data product for 2010 through 2015 (Hestia-Baltimore v1.6). We also compare the Hestia-Baltimore emissions to overlapping Scope 1 FFCO2 emissions in Baltimore's self-reported inventory for 2014. RESULTS: The Hestia-Baltimore emissions in 2014 totaled 1487.3 kt C (95% confidence interval of 1158.9-1944.9 kt C), with the largest emissions coming from onroad (34.2% of total city emissions), commercial (19.9%), residential (19.0%), and industrial (11.8%) sectors. Scope 1 electricity production and marine shipping were each generally less than 10% of the city's total emissions. Baltimore's self-reported Scope 1 FFCO2 emissions included onroad, natural gas consumption in buildings, and some electricity generating facilities within city limits. The self-reported Scope 1 FFCO2 total of 1182.6 kt C was similar to the sum of matching emission sectors and fuels in Hestia-Baltimore v1.6. However, 20.5% of Hestia-Baltimore's emissions were in sectors and fuels that were not included in the self-reported inventory. Petroleum use in buildings were omitted and all Scope 1 emissions from industrial point sources, marine shipping, nonroad vehicles, rail, and aircraft were categorically excluded. CONCLUSIONS: The omission of petroleum combustion in buildings and categorical exclusions of several sectors resulted in an underestimate of total Scope 1 FFCO2 emissions in Baltimore's self-reported inventory. Accurate Scope 1 FFCO2 emissions, along with Scope 2 and 3 emissions, are needed to inform effective urban policymaking for system-wide GHG mitigation. We emphasize the need for comprehensive Scope 1 emissions estimates for emissions verification and measuring progress towards Scope 1 GHG mitigation goals using atmospheric monitoring.

A pulsed-power implementation of "Laser Gate" for increasing laser energy coupling and fusion yield in magnetized liner inertial fusion (MagLIF).

Magnetized Liner Inertial Fusion (MagLIF) at Sandia National Laboratories involves a laser preheating stage where a few-ns laser pulse passes through a few-micron-thick plastic window to preheat gaseous fusion fuel contained within the MagLIF target. Interactions with this window reduce heating efficiency and mix window and target materials into the fuel. A recently proposed idea called "Laser Gate" involves removing the window well before the preheating laser is applied. In this article, we present experimental proof-of-principle results for a pulsed-power implementation of Laser Gate, where a thin current-carrying wire weakens the perimeter of the window, allowing the fuel pressure to push the window open and away from the preheating laser path. For this effort, transparent targets were fabricated and a test facility capable of studying this version of Laser Gate was developed. A 12-frame bright-field laser schlieren/shadowgraphy imaging system captured the window opening dynamics on microsecond timescales. The images reveal that the window remains largely intact as it opens and detaches from the target. A column of escaping pressurized gas appears to prevent the detached window from inadvertently moving into the preheating laser path.

Persistent Barriers to Smoking Cessation Among Urban, Underserved Women: A Feasibility Study of Tailored Barriers Text Messages.

OBJECTIVES: Despite health risks for themselves and their children, urban underserved women smoke at high rates postpartum. The postpartum period is a stressful transition time that presents unique barriers to sustained cessation. There is limited extant evidence of efficacious psychosocial programs to maintain postpartum smoking cessation. METHODS: Guided by the Cognitive-Social Health Information Processing model, we explored the feasibility of TxT2Commit, a text-messaging intervention designed to prevent postpartum smoking relapse. Participants (n = 43) received supportive cessation-focused text messages for one month postpartum. Using a convergent mixed method design, surveys and interviews assessed changes in psychosocial factors and smoking status through a three month follow-up. RESULTS: Participants reported satisfaction with TxT2Commit, rating text messages as helpful, understandable, supportive, and not bothersome. However, a majority of women (n = 28, 65.1%) relapsed by three months. Participants who stayed smoke free (i.e., non-relapsers) reported significantly less temptation to smoke at one and three months postpartum compared to relapsers (ps < .01). While relapsers had significantly less temptation at one month compared to baseline, temptation increased by three months (p < .01). Consistent with the quantitative results, qualitative interviews identified informational and coping needs, with continued temptation throughout the three months. Non-relapsers were able to manage temptation and reported greater support. CONCLUSIONS FOR PRACTICE: TxT2Commit demonstrates preliminary feasibility and acceptability among urban, underserved postpartum women. However, most participants relapsed by three months postpartum. Additional research is needed to identify targeted messaging to best help women avoid temptation and bolster support to stay smoke free in this uniquely stressful period.

An electronic patient-reported outcomes measurement system in paediatric orthopaedics.

PURPOSE: The purpose of the study was to evaluate the reliability, review differences and assess patient satisfaction of electronic patient-reported outcome measures (PROMs) compared with paper PROMs. METHODS: Participants between 12 and 19 years of age with a knee-related primary complaint were randomized into two groups. Group 1 completed paper PROMs followed by electronic, while Group 2 received the electronic followed by paper. PROMs included the Pediatric International Knee Documentation Committee (Pedi-IKDC), Hospital for Special Surgery (HSS) Pediatric Functional Activity Brief Scale (HSS Pedi-FABS), Tegner Activity Level Scale, Visual Analogue Scale (VAS), PedsQL Teen and a satisfaction survey. RESULTS: In all, 87 participants were enrolled with one excluded due to incomplete PROMs. Of the 86 participants, 54 were female and 32 were male with an average age of 14.3 years (12 to 18). A high degree of reliability was found when comparing the paper and electronic versions of the Pedi-IKDC (0.946; p < 0.001), HSS Pedi-FABS (0.923; p < 0.001), PedsQL Teen (0.894; p < 0.001), Tegner Activity Level Scale before injury (0.848; p < 0.001) and the Tegner Activity Level Scale after (0.930; p < 0.001). Differences were noted between the VAS scores, with paper scores being significantly higher than electronic (5.3 versus 4.6; p < 0.001). While not significant, a trend was noted in which electronic PROMs took, overall, less time than paper (10.0 mins versus 11.2 mins; p = 0.096).Of all participants, 69.8% preferred the electronic PROMs, 67.4% felt they were faster, 93.0% stated they would complete forms at home prior to appointments and 91.8% were not concerned about the safety/privacy of electronic forms. CONCLUSION: PROMs captured electronically were reliable when compared with paper. Electronic PROMs may be quicker, will not require manual scoring and are preferred by patients. LEVEL OF EVIDENCE: II.

Optimization of switch diagnostics on the MAIZE linear transformer driver.

The MAIZE Linear Transformer Driver consists of 40 capacitor-switch-capacitor "bricks" connected in parallel. When these 40 bricks are charged to ±100-kV and then discharged synchronously, the MAIZE facility generates a 1-MA current pulse with a 100-ns rise time into a matched load impedance. Discharging each of the capacitors in a brick is carried out by the breakdown of a spark-gap switch, a process that results in the emission of light. Monitoring this output light with a fiber optic coupled to a photomultiplier tube (PMT) and an oscilloscope channel provides information on switch performance and timing jitter-whether a switch fired early, late, or in phase with the other switches. However, monitoring each switch with a dedicated detector-oscilloscope channel can be problematic for facilities where the number of switches to be monitored (e.g., 40 on MAIZE) greatly exceeds the number of detector-oscilloscope channels available. The technique of using fibers to monitor light emission from switches can be optimized by treating a PMT as a binary digit or bit and using a combinatorial encoding scheme, where each switch is monitored by a unique combination of fiber-PMT-oscilloscope channels simultaneously. By observing the unique combination of fiber-PMT-oscilloscope channels that are turned on, the prefiring or late-firing of a single switch on MAIZE can be identified by as few as six PMT-oscilloscope channels. The number of PMT-oscilloscope channels, N, required to monitor X switches can be calculated by 2N = X + 1, where the number "2" is selected because the PMT-oscilloscope acts as a bit. In this paper, we demonstrate the use of this diagnostic technique on MAIZE. We also present an analysis of how this technique could be scaled to monitor the tens of thousands of switches proposed for various next generation pulsed power facilities.

Attitudinal barriers to participation in oncology clinical trials: factor analysis and correlates of barriers.

Patient participation in cancer clinical trials is low. Little is known about attitudinal barriers to participation, particularly among patients who may be offered a trial during an imminent initial oncology consult. The aims of the present study were to confirm the presence of proposed subscales of a recently developed cancer clinical trial attitudinal barriers measure, describe the most common cancer clinical trials attitudinal barriers, and evaluate socio-demographic, medical and financial factors associated with attitudinal barriers. A total of 1256 patients completed a survey assessing demographic factors, perceived financial burden, prior trial participation and attitudinal barriers to clinical trials participation. Results of a factor analysis did not confirm the presence of the proposed four attitudinal barriers subscale/factors. Rather, a single factor represented the best fit to the data. The most highly-rated barriers were fear of side-effects, worry about health insurance and efficacy concerns. Results suggested that less educated patients, patients with non-metastatic disease, patients with no previous oncology clinical trial participation, and patients reporting greater perceived financial burden from cancer care were associated with higher barriers. These patients may need extra attention in terms of decisional support. Overall, patients with fewer personal resources (education, financial issues) report more attitudinal barriers and should be targeted for additional decisional support.

Iron supplementation in premature infants using the zinc protoporphyrin to heme ratio: short- and long-term outcomes.

OBJECTIVE: The objective of this study was to determine the effect of incrementally higher doses of iron on the zinc protoporphyrin to heme ratio (ZnPP/H) and serum ferritin, and developmental outcomes in premature infants at risk for iron deficiency. STUDY DESIGN: Infants eligible for this prospective, randomized blinded trial were between 27 and 30 completed weeks of gestation, older than 1 week of age and tolerating 100 ml kg(-1) per day of enteral feedings. The control group was treated with 2.2 mg kg(-1) per day of ferrous sulfate and the treatment group was treated with 3 to 12 mg kg(-1) per day based on the ZnPP/H. Infants had follow-up with Bayley exams at 6 and 24 months corrected age. Statistical evaluation included Student's t-tests and Fisher's exact test. RESULT: Eighty-one infants were enrolled (40 control, 41 treatment). The average total iron dose for the control group was 2.2 mg kg(-1) per day and for the treatment group was 10.4 mg kg(-1) per day (P<0.05). The ZnPP/H was not different between the two groups. The ferritin at the end of the study was decreased in the control group but remained stable in the treatment group (control initial 202±109 ng ml(-1), final 168±141 ng ml(-1) (P<0.05); treatment initial 187±131 ng ml(-1), final 176±118 ng ml(-1)). At 24 months, infants with psychomotor development index <85 occurred in 25% of the subjects in the control group and in 7% of subjects in the treatment group in a post hoc analysis (odds ratio, 4.2; 95% confidence interval, 0.7 to 43, P=0.07). CONCLUSION: The ZnPP/H may not be a reliable marker of iron status when used in a short period of time during iron supplementation. Infants treated with a lower dose of ferrous sulfate had a decreasing serum ferritin and a trend toward increased motor delays at 24 months.

Conserving large carnivores: dollars and fence.

Conservationists often advocate for landscape approaches to wildlife management while others argue for physical separation between protected species and human communities, but direct empirical comparisons of these alternatives are scarce. We relate African lion population densities and population trends to contrasting management practices across 42 sites in 11 countries. Lion populations in fenced reserves are significantly closer to their estimated carrying capacities than unfenced populations. Whereas fenced reserves can maintain lions at 80% of their potential densities on annual management budgets of $500 km(-2) , unfenced populations require budgets in excess of $2000 km(-2) to attain half their potential densities. Lions in fenced reserves are primarily limited by density dependence, but lions in unfenced reserves are highly sensitive to human population densities in surrounding communities, and unfenced populations are frequently subjected to density-independent factors. Nearly half the unfenced lion populations may decline to near extinction over the next 20-40 years.

The relationships among knowledge, self-efficacy, preparedness, decisional conflict, and decisions to participate in a cancer clinical trial.

BACKGROUND: Cancer clinical trials (CCTs) are important tools in the development of improved cancer therapies; yet, participation is low. Key psychosocial barriers exist that appear to impact a patient's decision to participate. Little is known about the relationship among knowledge, self-efficacy, preparation, decisional conflict, and patient decisions to take part in CCTs. OBJECTIVE: The purpose of this study was to determine if preparation for consideration of a CCT as a treatment option mediates the relationship between knowledge, self-efficacy, and decisional conflict. We also explored whether lower levels of decisional conflict are associated with greater likelihood of CCT enrollment. METHOD: In a pre-post test intervention study, cancer patients (N = 105) were recruited before their initial consultation with a medical oncologist. A brief educational intervention was provided for all patients. Patient self-report survey responses assessed knowledge, self-efficacy, preparation for clinical trial participation, decisional conflict, and clinical trial participation. RESULTS: Preparation was found to mediate the relationship between self-efficacy and decisional conflict (p = 0.003 for a test of the indirect mediational pathway for the decisional conflict total score). Preparation had a more limited role in mediating the effect of knowledge on decisional conflict. Further, preliminary evidence indicated that reduced decisional conflict was associated with increased clinical trial enrollment (p = 0.049). CONCLUSIONS: When patients feel greater CCT self-efficacy and have more knowledge, they feel more prepared to make a CCT decision. Reduced decisional conflict, in turn, is associated with the decision to enroll in a clinical trial. Our results suggest that preparation for decision-making should be a target of future interventions to improve participation in CCTs.

Literacy assessment of family health history tools for public health prevention.

OBJECTIVES: This study aimed to systematically identify and evaluate the readability and document complexity of currently available family history tools for the general public. METHODS: Three steps were undertaken to identify family history tools for evaluation: (a) Internet searches, (b) expert consultation, and (c) literature searches. Tools identified were assessed for readability using the Simple Measure of Gobbledygook (SMOG) readability formula. The complexity of documents (i.e., forms collecting family history information) was assessed using the PMOSE/IKIRSCH document readability formula. RESULTS: A total of 78 tools were identified, 47 of which met the criteria for inclusion. SMOG reading grade levels for multimedia-based tools ranged from 10.1 to 18.3, with an average score of 13.6. For print-based tools, SMOG ranged from 8.7 to 14.1, with an average score of 12.0. Document complexity ranged from very low complexity (level 1 proficiency) to high complexity (level 4 proficiency). CONCLUSION: The majority of tools are written at a reading grade level that is beyond the 8th grade average reading level in the United States. The lack of family history tools that are easy to read or use may compromise their potential effectiveness in identifying individuals at increased risk for chronic diseases in the general population.

High-flow nasal cannula and extubation success in the premature infant: a comparison of two modalities.

OBJECTIVE: To compare the effectiveness of Fisher and Paykel (FP) and Vapotherm (VT) high-flow nasal cannula (HFNC) in preventing reintubation either within 72 h or <7 days after extubation of premature infants. The primary outcome was the rate of extubation failure defined as reintubation within 72 h. Secondary outcomes included reintubation after ≤7 days. STUDY DESIGN: This was a prospective, randomized pilot study comparing the extubation success of 40 infants born between 26 and 29 weeks of gestation. RESULT: The rate of extubation failure at 72 h was 18% for FP and 9% for VT. The failure rate ≤7 days after extubation was 30% for FP and 27% for VT. None of these differences were statistically significant. CONCLUSION: There was no difference between FP and VT in the extubation success of infants born between 26 and 29 weeks.

Seizures are associated with brain injury severity in a neonatal model of hypoxia-ischemia.

Hypoxia-ischemia is a significant cause of brain damage in the human newborn and can result in long-term neurodevelopmental disability. The loss of oxygen and glucose supply to the developing brain leads to excitotoxic neuronal cell damage and death; such over-excitation of nerve cells can also manifest as seizures. The newborn brain is highly susceptible to seizures although it is unclear what role they have in hypoxic-ischemic (H/I) injury. The aim of this study was to determine an association between seizures and severity of brain injury in a piglet model of perinatal H/I and, whether injury severity was related to type of seizure, i.e. sub-clinical (electrographic seizures only) or clinical (electrographic seizures+physical signs). Hypoxia (4% O(2)) was induced in anaesthetised newborn piglets for 30 min with a final 10 min period of hypotension; animals were recovered and survived to 72 h. Animals were monitored daily for seizures both visually and with electroencephalogram (EEG) recordings. Brain injury was assessed with magnetic resonance imaging (MRI), (1)H-MR spectroscopy ((1)H-MRS), EEG and by histology (haematoxylin and eosin). EEG seizures were observed in 75% of all H/I animals, 46% displayed clinical seizures and 29% sub-clinical seizures. Seizure animals showed significantly lower background amplitude EEG across all post-insult days. Presence of seizures was associated with lower cortical apparent diffusion coefficient (ADC) scores and changes in (1)H-MRS metabolite ratios at both 24 and 72 h post-insult. On post-mortem examination animals with seizures showed the greatest degree of neuropathological injury compared to animals without seizures. Furthermore, clinical seizure animals had significantly greater histological injury compared with sub-clinical seizure animals; this difference was not apparent on MRI or (1)H-MRS measures. In conclusion we report that both sub-clinical and clinical seizures are associated with increased severity of H/I injury in a term model of neonatal H/I.

Dopaminergic projections to the medial preoptic area of postpartum rats.

Dopamine receptor activity in the rodent medial preoptic area (mPOA) is crucial for the display of maternal behaviors, as well as numerous other physiological and behavioral functions. However, the origin of dopaminergic input to the mPOA has not been identified through neuroanatomical tracing. To accomplish this, the retrograde tracer Fluorogold was iontophoretically applied to the mPOA of postpartum laboratory rats, and dual-label immunocytochemistry for Fluorogold and tyrosine hydroxylase later performed to identify dopaminergic cells of the forebrain and midbrain projecting to the mPOA. Results indicate that the number of dopaminergic cells projecting to the mPOA is moderate ( approximately 90 cells to one hemisphere), and that these cells have an unexpectedly wide distribution. Even so, more than half of the dual-labeled cells were found in either what has been considered extensions of the A10 dopamine group (particularly the ventrocaudal posterior hypothalamus and adjacent medial supramammillary nucleus), or in the A10 group of the ventral tegmental area. The rostral hypothalamus and surrounding region also contained numerous dual-labeled cells, with the greatest number found within the mPOA itself (including in the anteroventral preoptic area and preoptic periventricular nucleus). Notably, dual-labeled cells were rare in the zona incerta (A13), a site previously suggested to provide dopaminergic input to the mPOA. This study is the first to use anatomical tracing to detail the dopaminergic projections to the mPOA in the laboratory rat, and indicates that much of this projection originates more caudally than previously suggested.

Apoptotic cell death of human interstitial cells of Cajal.

Interstitial cells of Cajal (ICC) are specialized mesenchyme-derived cells that regulate contractility and excitability of many smooth muscles with loss of ICC seen in a variety of gut motility disorders. Maintenance of ICC numbers is tightly regulated, with several factors known to regulate proliferation. In contrast, the fate of ICC is not established. The aim of this study was to investigate whether apoptosis plays a role in the regulation of ICC numbers in the normal colon. ICC were identified by immunolabelling for the c-Kit receptor tyrosine kinase and by electron microscopy. Apoptosis was detected in colon tissue by immunolabelling for activated caspase-3, terminal dUTP nucleotide end labelling and by ultrastructural changes in the cells. Apoptotic ICC were identified and counted in double-labelled tissue sections. They were identified in all layers of the colonic muscle. In the muscularis propria 1.5 +/- 0.2% of ICC were positive for activated caspase-3 and in the circular muscle layer 2.1 +/- 0.9% of ICC were positive for TUNEL. Apoptotic ICC were identified by electron microscopy. Apoptotic cell death is a continuing process in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks.

Predictors of life satisfaction in individuals with intellectual disabilities.

BACKGROUND: The purpose of this study was to examine factors that predict life satisfaction in individuals with intellectual disabilities (ID). Two groups of variables were studied: life skills (interpersonal, instrumental and leisure) and higher-order predictors (social support, self-determination and productivity). METHOD: Fifty-six participants with ID were recruited from two community agencies in Wisconsin. Data were collected using both a self-report inventory, which was administered to each individual in an interview format, and a behaviour rating scale, which was completed by a knowledgeable staff member. Hierarchical regression was used to analyse the data. RESULTS: Both sets of variables were found to explain a significant amount of the variance in life satisfaction. Within the sets, social support and interpersonal skills were individually significantly associated with life satisfaction. CONCLUSION: It is hoped that the results of this study will help support providers organise services in such a way that maximises the life satisfaction of the consumers that they serve.

Distribution of interstitial cells of Cajal and nitrergic neurons in normal and diabetic human appendix.

The objective of this study was to determine the distribution of enteric nerves and interstitial cells of Cajal (ICC) in the normal human appendix and in type 1 diabetes. Appendixes were collected from patients with type 1 diabetes and from non-diabetic controls. Volumes of nerves and ICC were determined using 3-D reconstruction and neuronal nitric oxide synthase (nNOS) expressing neurons were counted. Enteric ganglia were found in the myenteric plexus region and within the longitudinal muscle. ICC were found throughout the muscle layers. In diabetes, c-Kit positive ICC volumes were significantly reduced as were nNOS expressing neurons. In conclusion, we describe the distribution of ICC and enteric nerves in health and in diabetes. The data also suggest that the human appendix, a readily available source of human tissue, may be useful model for the study of motility disorders.

Regulation of interstitial cells of Cajal in the mouse gastric body by neuronal nitric oxide.

The factors underlying the survival and maintenance of interstitial cells of Cajal (ICC) are not well understood. Loss of ICC is often associated with loss of neuronal nitric oxide synthase (nNOS) in humans, suggesting a possible link. The aim of this study was to determine the effect of neuronal NO on ICC in the mouse gastric body. The volumes of ICC were determined in nNOS(-/-) and control mice in the gastric body and in organotypic cultures using immunohistochemistry, laser scanning confocal microscopy and three-dimensional reconstruction. ICC numbers were determined in primary cell cultures after treatment with an NO donor or an NOS inhibitor. The volumes of myenteric c-Kit-immunoreactive networks of ICC from nNOS(-/-) mice were significantly reduced compared with control mice. No significant differences in the volumes of c-Kit-positive ICC were observed in the longitudinal muscle layers. ICC volumes were either decreased or unaltered in the circular muscle layer after normalization for the volume of circular smooth muscle. The number of ICC was increased after incubation with S-nitroso-N-acetylpenicillamine and decreased by N(G)-nitro-l-arginine. Neuronally derived NO modulates ICC numbers and network volume in the mouse gastric body. NO appears to be a survival factor for ICC.