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The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

ObjectiveThe classification of clinical note sections is a critical step before doing more fine-grained natural language processing tasks such as social determinants of health extraction and temporal information extraction. Often, clinical note section classification models that achieve high accuracy for one institution experience a large drop of accuracy when transferred to another institution. The objective of this study is to develop methods that classify clinical note sections under the SOAP (“Subjective”, “Object”, “Assessment” and “Plan”) framework with improved transferability.Materials and methodsWe trained the baseline models by fine-tuning BERT-based models, and enhanced their transferability with continued pretraining, including domain adaptive pretraining (DAPT) and task adaptive pretraining (TAPT). We added out-of-domain annotated samples during fine-tuning and observed model performance over a varying number of annotated sample size. Finally, we quantified the impact of continued pretraining in equivalence of the number of in-domain annotated samples added.ResultsWe found continued pretraining improved models only when combined with in-domain annotated samples, improving the F1 score from 0.756 to 0.808, averaged across three datasets. This improvement was equivalent to adding 50.2 in-domain annotated samples.DiscussionAlthough considered a straightforward task when performing in-domain, section classification is still a considerably difficult task when performing cross-domain, even using highly sophisticated neural network-based methods.ConclusionContinued pretraining improved model transferability for cross-domain clinical note section classification in the presence of a small amount of in-domain labeled samples.

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Generative artificial intelligence (AI) is a promising direction for augmenting clinical diagnostic decision support and reducing diagnostic errors, a leading contributor to medical errors. To further the development of clinical AI systems, the Diagnostic Reasoning Benchmark (DR.BENCH) was introduced as a comprehensive generative AI framework, comprised of six tasks representing key components in clinical reasoning. We present a comparative analysis of in-domain versus out-of-domain language models as well as multi-task versus single task training with a focus on the problem summarization task in DR.BENCH (Gao et al., 2023). We demonstrate that a multi-task, clinically trained language model outperforms its general domain counterpart by a large margin, establishing a new state-of-the-art performance, with a ROUGE-L score of 28.55. This research underscores the value of domain-specific training for optimizing clinical diagnostic reasoning tasks., Comment: Accepted to the Proceedings of the 5th Clinical NLP Workshop at ACL

Radiotherapy (RT) toxicities can impair survival and quality-of-life, yet remain under-studied. Real-world evidence holds potential to improve our understanding of toxicities, but toxicity information is often only in clinical notes. We developed natural language processing (NLP) models to identify the presence and severity of esophagitis from notes of patients treated with thoracic RT. We fine-tuned statistical and pre-trained BERT-based models for three esophagitis classification tasks: Task 1) presence of esophagitis, Task 2) severe esophagitis or not, and Task 3) no esophagitis vs. grade 1 vs. grade 2-3. Transferability was tested on 345 notes from patients with esophageal cancer undergoing RT. Fine-tuning PubmedBERT yielded the best performance. The best macro-F1 was 0.92, 0.82, and 0.74 for Task 1, 2, and 3, respectively. Selecting the most informative note sections during fine-tuning improved macro-F1 by over 2% for all tasks. Silver-labeled data improved the macro-F1 by over 3% across all tasks. For the esophageal cancer notes, the best macro-F1 was 0.73, 0.74, and 0.65 for Task 1, 2, and 3, respectively, without additional fine-tuning. To our knowledge, this is the first effort to automatically extract esophagitis toxicity severity according to CTCAE guidelines from clinic notes. The promising performance provides proof-of-concept for NLP-based automated detailed toxicity monitoring in expanded domains., Comment: 17 pages, 6 tables, 1figure, submiting to JCO-CCI for review

The BioNLP Workshop 2023 initiated the launch of a shared task on Problem List Summarization (ProbSum) in January 2023. The aim of this shared task is to attract future research efforts in building NLP models for real-world diagnostic decision support applications, where a system generating relevant and accurate diagnoses will augment the healthcare providers decision-making process and improve the quality of care for patients. The goal for participants is to develop models that generated a list of diagnoses and problems using input from the daily care notes collected from the hospitalization of critically ill patients. Eight teams submitted their final systems to the shared task leaderboard. In this paper, we describe the tasks, datasets, evaluation metrics, and baseline systems. Additionally, the techniques and results of the evaluation of the different approaches tried by the participating teams are summarized., Comment: To appear in the Proceedings of the 5th BioNLP Workshop at ACL

Daily progress notes are common types in the electronic health record (EHR) where healthcare providers document the patient's daily progress and treatment plans. The EHR is designed to document all the care provided to patients, but it also enables note bloat with extraneous information that distracts from the diagnoses and treatment plans. Applications of natural language processing (NLP) in the EHR is a growing field with the majority of methods in information extraction. Few tasks use NLP methods for downstream diagnostic decision support. We introduced the 2022 National NLP Clinical Challenge (N2C2) Track 3: Progress Note Understanding - Assessment and Plan Reasoning as one step towards a new suite of tasks. The Assessment and Plan Reasoning task focuses on the most critical components of progress notes, Assessment and Plan subsections where health problems and diagnoses are contained. The goal of the task was to develop and evaluate NLP systems that automatically predict causal relations between the overall status of the patient contained in the Assessment section and its relation to each component of the Plan section which contains the diagnoses and treatment plans. The goal of the task was to identify and prioritize diagnoses as the first steps in diagnostic decision support to find the most relevant information in long documents like daily progress notes. We present the results of 2022 n2c2 Track 3 and provide a description of the data, evaluation, participation and system performance., To appear in Journal of Biomedical Informatics

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1–3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Applying methods in natural language processing on electronic health records (EHR) data is a growing field. Existing corpus and annotation focus on modeling textual features and relation prediction. However, there is a paucity of annotated corpus built to model clinical diagnostic thinking, a process involving text understanding, domain knowledge abstraction and reasoning. This work introduces a hierarchical annotation schema with three stages to address clinical text understanding, clinical reasoning, and summarization. We created an annotated corpus based on an extensive collection of publicly available daily progress notes, a type of EHR documentation that is collected in time series in a problem-oriented format. The conventional format for a progress note follows a Subjective, Objective, Assessment and Plan heading (SOAP). We also define a new suite of tasks, Progress Note Understanding, with three tasks utilizing the three annotation stages. The novel suite of tasks was designed to train and evaluate future NLP models for clinical text understanding, clinical knowledge representation, inference, and summarization., Comment: To appear in 13th Language Resources and Evaluation Conference (LREC 2022)

The surgical plan and the anesthetic approach are vital in determining the proper treatment of lumbar disc herniation in pregnancy. The diagnostic tools available, as well as the anesthetic agents and methods of delivery, vary in pregnant patients due to factors such as radiation exposure and hemodynamics in the patient and fetus. The gestational age also plays an important role in determining treatment options. When possible, surgery should be avoided during the first trimester, especially during the period of organogenesis, as general anesthesia can interfere with this process. However, when focal neurological deficits are present, urgent surgical decompression may be necessary. In such cases, the selection of anesthesia must be guided by maternal indications and the nature of the surgery. Maternal safety and avoidance of fetal hypoxia and subsequent preterm labor are crucial when pregnant patients receive anesthesia. As a result, local anesthesia is often preferred when possible due to the decreased risk of systemic toxicity. Decompression surgery in pregnant females with lumbar disc herniation, using a multidisciplinary approach among the surgeon, obstetrician, and anesthesiologist, is an effective and safe procedure for both the mother and the fetus. We present the case of a pregnant female at four weeks of gestation who presented with lower back pain radiating down her right leg. MRI of the lumbar spine showed large L4-5 disc herniation. She underwent a successful right L4-5 microdiscectomy under local anesthesia and spinal block using bupivacaine and was completely awake throughout the procedure. Postoperatively, she experienced immediate improvement of symptoms.

Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions are known as tauopathies. We previously linked a loss-of-function mutation in the TSC1 gene to tau accumulation and frontotemporal lobar degeneration. Now, we have identified genetic variants in TSC1 that decrease TSC1/hamartin levels and predispose to tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Cellular and murine models of TSC1 haploinsufficiency, as well as human brains carrying a TSC1 risk variant, accumulated tau protein that exhibited aberrant acetylation. This acetylation hindered tau degradation via chaperone-mediated autophagy, thereby leading to its accumulation. Aberrant tau acetylation in TSC1 haploinsufficiency resulted from the dysregulation of both p300 acetyltransferase and SIRT1 deacetylase. Pharmacological modulation of either enzyme restored tau levels. This study substantiates TSC1 as a novel tauopathy risk gene and includes TSC1 haploinsufficiency as a genetic model for tauopathies. In addition, these findings promote tau acetylation as a rational target for tauopathy therapeutics and diagnostic.

BackgroundExcessive or inadequate fluid administration causes complications, but despite this, fluid administration during noncardiac surgery is highly variable. Goal-directed management helps optimize the amount and timing of fluid administration; however, implementation is difficult because algorithms are complex. The authors therefore tested the performance of the Acumen Assisted Fluid Management software (Edwards Lifesciences, USA), which is designed to guide optimal intravenous fluid administration during surgery.MethodsIn this multicenter, prospective, single-arm cohort evaluation, the authors enrolled 330 adults scheduled for moderate- to high-risk noncardiac surgery that required arterial catheter insertion and mechanical ventilation. Clinicians chose a fluid strategy based on a desired 10%, 15%, or 20% increase in stroke volume (SV) in response to a fluid bolus. Dedicated fluid management software prompted "test" or "recommended" boluses, and clinicians were free to initiate a "user" bolus of 100 to 500 ml of crystalloid or colloid. Clinicians were free to accept or decline the software prompts. The authors primarily compared the fraction of software-recommended boluses that produced suitable increases in SV to a 30% reference rate. On an exploratory basis, we compared responses to software-recommended and clinician-initiated boluses.ResultsFour hundred twenty-four of 479 (89%) software-recommended fluid boluses and 508 of 592 (86%) clinician-initiated fluid boluses were analyzed per protocol. Of those, 66% (95% CI, 62 to 70%) of delivered fluid boluses recommended by the software resulted in desired increases in SV, compared with the 30% reference rate, whereas only 41% (95% CI, 38 to 44%) of clinician-initiated boluses did (P < 0.0001). The mean ± SD increase in SV after boluses recommended by the software was 14.2 ± 13.9% versus 8.3 ± 12.1% (P < 0.0001) for those initiated by clinicians.ConclusionsFluid boluses recommended by the software resulted in desired SV increases more often, and with greater absolute SV increase, than clinician-initiated boluses. Automated assessment of fluid responsiveness may help clinicians optimize intraoperative fluid management during noncardiac surgery.Editor’s perspective

This study uses data from US Food and Drug Administration (FDA) databases to quantify approval of high-risk cardiovascular devices for use in pediatric populations and assess the clinical evidence supporting the approvals.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

This article considers the creation of an exhibition at the National Library of New Zealand. Specifically, this project was a collaborative endeavour between the School of Design at Victoria University of Wellington and the National Library, aimed at utilising new technologies and traditional archival research to bring forgotten and rarely accessed data back to life in a public exhibition. From the outset this project sought to combine the best of both new educational technologies (augmented reality) with tactile, physical materials (created using laser cutting and 3D printing) that the public could handle and use in a way that would break down the barriers between exhibition objects and resurrected archival data. The result was an interactive exhibition focused upon the emergence of Wellington as a city and the growth of its waterfront over the last century and a half. The design research project took place between November 2016 and February 2017 and resulted in a project exhibition open to the public running from May 2017 to February 2018. The principle supervisors were Leon Gurevitch and Tim Miller with a research team of three research assistants (Stefan Peacock, Alasdair Tarry and Louis ElwoodLeach).

Automatic phenotyping is a task of identifying cohorts of patients that match a predefined set of criteria. Phenotyping typically involves classifying long clinical documents that contain thousands of tokens. At the same time, recent state-of-art transformer-based pre-trained language models limit the input to a few hundred tokens (e.g. 512 tokens for BERT). We evaluate several strategies for incorporating pre-trained sentence encoders into document-level representations of clinical text, and find that hierarchical transformers without pre-training are competitive with task pre-trained models.

In this paper, we present our work participating in the BioCreative VII Track 3 - automatic extraction of medication names in tweets, where we implemented a multi-task learning model that is jointly trained on text classification and sequence labelling. Our best system run achieved a strict F1 of 80.4, ranking first and more than 10 points higher than the average score of all participants. Our analyses show that the ensemble technique, multi-task learning, and data augmentation are all beneficial for medication detection in tweets., Comment: Proceedings of the seventh BioCreative challenge evaluation workshop (https://biocreative.bioinformatics.udel.edu/resources/publications/bc-vii-workshop-proceedings/)

Postoperative delirium is a geriatric syndrome that manifests as changes in cognition, attention, and levels of consciousness after surgery. It occurs in up to 50% of patients after major surgery and is associated with adverse outcomes, including increased hospital length of stay, higher cost of care, higher rates of institutionalization after discharge, and higher rates of readmission. Furthermore, it is associated with functional decline and cognitive impairments after surgery. As the age and medical complexity of our surgical population increases, practitioners need the skills to identify and prevent delirium in this high-risk population. Because delirium is a common and consequential postoperative complication, there has been an abundance of recent research focused on delirium, conducted by clinicians from a variety of specialties. There have also been several reviews and recommendation statements; however, these have not been based on robust evidence. The Sixth Perioperative Quality Initiative (POQI-6) consensus conference brought together a team of multidisciplinary experts to formally survey and evaluate the literature on postoperative delirium prevention and provide evidence-based recommendations using an iterative Delphi process and Grading of Recommendations Assessment, Development and Evaluation (GRADE) Criteria for evaluating biomedical literature.

Additional file 1: Supplemental Table. Major Exclusions. Figure S1. Funnel plot of comparison: 30-day mortality. Figure S2. Funnel plot of comparison: 1 year mortality. Figure S3. Funnel plot of comparison: Stroke. Figure S4. Funnel plot of comparison: Major bleeding. Figure S5. Funnel plot of comparison: Access related vascular complications. Figure S6. Funnel plot of comparison: Need for a pacemaker. Figure S7. Funnel plot of comparison: Left ventricular ejection fraction. Figure S8. Funnel plot of comparison: Mean aortic valve gradient. Figure S9. Funnel plot of comparison: Post-procedural worsening of congestive heart failure.

The Hubble Space Telescope/Cosmic Origins Spectrograph (COS) has opened a new discovery space for studying quasar absorption outflows and their contribution to AGN feedback. Specifically, COS provides high-quality far-ultraviolet (FUV) spectra covering the diagnostic-rich 500-1050 Angstrom rest frame (hereafter, EUV500) of medium redshift objects. The quality and quantity of EUV500 diagnostic troughs allow us to probe the very high-ionization phase, which carries 90% or more of the outflowing material, as well as to determine the distance of most outflows from the central source ($R$). The first objective is impossible to achieve with ground-based spectra, and $R$ can be measured in only $\sim$1% of them. Here, we summarize the main results of the first dedicated survey of such outflows, including the following: 1) Measurements of the three most energetic outflows to date, which can be the main agents for AGN feedback processes in the environments of the host galaxies. 2) All the outflows have a very high-ionization component, similar to the one found in warm absorbers, which carries most of the outflow's kinetic luminosity. This finding suggests that all the high-ionization outflows observed from the ground also have a similar undetected very high-ionization component. 3) Of the 13 studied EUV500 outflows, 9 have $100, 11 pages, 4 figures, 2 tables

We analyze absorption troughs from two outflows within PKS J0352-0711 (S1 at $-$1950 km s$^{-1}$ and S2 at $-$3150 km s$^{-1}$) from spectra taken with Hubble Space Telescope/Cosmic Origin Spectrograph, which cover the diagnostic-rich 585-900 Angstrom rest frame wavelength range. In S2, for the first time we clearly detect absorption troughs from Ca IV, Ca V, Ca V*, Ca VII*, and Ca VIII*. The column density measurement of Ca V suggests S2 has a super-solar metallicity. Both outflows require at least two ionization phases where the column density of the very high-ionization phase is roughly 15 times larger than the corresponding high-ionization phase. These high column densities and very high-ionization potential ions are similar to X-ray warm absorbers. The two phases of S2 show a unique velocity centroid shift between associated troughs. Through Monte Carlo measurements of the O V* absorption troughs, we determine the electron number density of S2 (fully corroborated by independent measurements from the Ca V* and Ca VIII* troughs), yielding a distance of 9 pc and a kinetic luminosity of 2$\times$10$^{43}$ erg s$^{-1}$. S1 is located farther away at 500 pc from the central source with a kinetic luminosity of 10$^{43}$ erg s$^{-1}$., 12 pages, 9 figures, 5 tables

Supplemental material, sj-pdf-1-ajs-10.1177_0363546520976626 for Unplanned Emergency Visits and Admissions After Orthopaedic Ambulatory Surgery in the First 2 Years of Operation of a University Ambulatory Surgery Center by Chelsea R. Brown, Sennay Ghenbot, Robert A. Magnussen, Sarah Harangody, David C. Flanigan and Timothy L. Miller in The American Journal of Sports Medicine

We present the analysis of two outflows (S1 at --5500 km s$^{-1}$ and S2 at --9700 km s$^{-1}$) seen in recent HST/COS observations of quasar SDSS J0755+2306 (z = 0.854). The outflows are detected as absorption troughs from both high-ionization species, including N III, O III, and S IV, and very high-ionization species, including Ar VIII, Ne VIII, and Na IX. The derived photoionization solutions show that each outflow requires a two ionization-phase solution. For S1, troughs from S IV* and S IV allow us to derive an electron number density, $n_{e}$ = 1.8$\times$10$^4$ cm$^{-3}$, and its distance from the central source of $R$ = 270 pc. For S2, troughs from O III* and O III yield $n_{e}$ = 1.2$\times$10$^3$ cm$^{-3}$ and $R$ = 1600 pc. The kinetic luminosity of S2 is $>$ 12% of the Eddington luminosity for the quasar and therefore can provide strong AGN feedback effects. Comparison of absorption troughs from O III and O VI in both outflow systems supports the idea that for a given element, higher ionization ions have larger covering fractions than lower ionization ones., 10 pages, 6 figures, published in ApJS

We present a study of the BAL outflows seen in quasar SDSS J1042+1646 (z = 0.978) in the rest-frame 500 -- 1050 $��$ (EUV500) region. The results are based on the analysis of recent Hubble Space Telescope/Cosmic Origins Spectrograph observations. Five outflow systems are identified, where in total they include $\sim$70 outflow troughs from ionic transitions. These include the first non-solar detections from transitions of O V*, Ne V*, Ar VI, Ca VI, Ca VII, and Ca VIII. The appearance of very high-ionization species (e.g., Ne VIII, Na IX, and Mg X) in all outflows necessitates at least two-ionization phases for the observed outflows. We develop an interactive Synthetic Spectral Simulation method to fit the multitude of observed troughs. Detections of density sensitive troughs (e.g., S IV* $��$ 657.32 $��$ and the O V* multiplet) allow us to determine the distance of the outflows ($R$) as well as their energetics. Two of the outflows are at $R$ $\simeq$ 800 pc and one is at $R$ $\simeq$ 15 pc. One of the outflows has the highest kinetic luminosity on record ($\dot{E_{k}}$ $ = 5\times 10^{46}$ erg s$^{-1}$), which is 20% of its Eddington luminosity. Such a large ratio suggests that this outflow can provide the energy needed for active galactic nucleus feedback mechanisms., 18 pages, 12 figures, published in ApJS

We detect four very energetic outflows in the Hubble Space Telescope/Cosmic Origin Spectrograph spectra of quasar 2MASS J1051+1247 with a combined kinetic luminosity ($\dot{E_k}$) of 10$^{46}$ erg s$^{-1}$. Remarkable similarities are seen in these outflows: velocity centroids between 4900 and 5700 km s$^{-1}$, distances from the central source ($R$) of a few hundred parsecs that are all consistent within the errors, and an $\dot{E_k}$ within a factor of two for all outflows. Hence, a common origin for the outflows is probable. Most of the outflowing mass resides in a very high-ionization phase evident by troughs from Ne VIII, Na IX, Mg X, and Si XII, which connect the physical conditions of these ultraviolet outflows to the X-ray warm absorber outflows seen in nearby Seyfert galaxies. Three of the outflows have two or three independent diagnostics for the electron number density, yielding consistent values for each outflow, which increase the robustness of the $R$ determinations. Troughs from never-before-seen ionic transitions of Ar VI, O IV*, Ne VI*, and Ne V* are identified. With a combined $\dot{E_k}$ that is $7.0^{+6.5}_{-2.3}$ % of the quasar's Eddington luminosity, these outflows are prime candidates to be major agents for various active galactic nuclei feedback effects., 11 pages, 3 figures, 4 tables

We present an analysis of the broad absorption line (BAL) velocity shift that appeared in one of the outflow systems in quasar SDSS J1042+1646. Observations were taken by the Hubble Space Telescope/Cosmic Origin Spectrograph in 2011 and 2017 in the 500 -- 1050 $��$ rest frame. The outflow's velocity centroid shifted by $\sim$ --1550 km s$^{-1}$ from --19,500 km s$^{-1}$ to --21,050 km s$^{-1}$ over a rest-frame time of 3.2 yr. The velocity shift signatures are most apparent in the absorption features from the Ne VIII $����$ 770.41, 780.32 doublet and are supported by the absorption troughs from OV $��$ 629.73 and the Mg X $����$ 609.79, 624.94 doublet. This is the first time where a quasar outflow velocity shift is observed in troughs from more than one ion and in distinct troughs from a doublet transition (Ne VIII). We attribute the velocity shift to an acceleration of an existing outflow as we are able to exclude photoionization changes and motion of material into and out of the line of sight as alternate explanations. This leads to an average acceleration of 480 km s$^{-1}$ yr$^{-1}$ (1.52 cm s$^{-2}$) in the quasar rest frame. Both the acceleration and the absolute velocity shift are the largest reported for a quasar outflow to date. Based on the absorption troughs of the O V* multiplet, we derive a range for the distance of the outflow ($R$) from the central source, 0.05 pc $, 10 pages, 6 figures, published in ApJS

The HIgh-Resolution Mid-infrarEd Spectrometer (HIRMES) is the 3rd Generation Instrument for the Stratospheric Observatory For Infrared Astronomy (SOFIA), currently in development at the NASA Goddard Space Flight Center (GSFC), and due for commissioning in 2019. By combining direct-detection Transition Edge Sensor (TES) bolometer arrays, grating-dispersive spectroscopy, and a host of Fabry-Perot tunable filters, HIRMES will provide the ability for High Resolution (R~100,000), Mid-Resolution (R~10,000), and Low-Resolution (R~600) slit-spectroscopy, and 2D Spectral Imaging (R~2000 at selected wavelengths) over the 25 - 122 {\mu}m mid-far infrared waveband. The driving science application is the evolution of proto-planetary systems via measurements of water-vapor, water-ice, deuterated hydrogen (HD), and neutral oxygen lines. However, HIRMES has been designed to be as flexible as possible to cover a wide range of science cases that fall within its phase-space, all whilst reaching sensitivities and observing powers not yet seen thus far on SOFIA, providing unique observing capabilities which will remain unmatched for decades., Comment: Accepted to the Journal of Astronomical Instrumentation (SOFIA Special Edition) on 11th November 2018

As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.

In this paper the primary mechanisms for the plasma doping (PLAD) of 3D structures – direct implant, scattered implant, deposition & knock-in, and sputtering (etching) – are discussed. The TRI3DYN code was used to elucidate the roles these various doping mechanisms play. Through-fin SIMS profiles for an arsenic plasma doping process were calculated from the model and compared to experimental results. Further, by adjusting the competition and balance among these different doping mechanisms, we also demonstrate that the doping profile can be tuned on 3D fin structures for a boron plasma doping process.

Flux analysis of control, sALS and PLS fibroblasts under forced oxidative metabolism in galactose medium. Scatter plots of OCR baseline (A; Control mean: 3850.0, SD: 1936.7; sALS mean: 3307.5, SD: 1430.7; PLS mean: 2989.2, SD: 1164.7), oligomycin sensitive rate (B; Control mean: 3630.0, SD: 1772.0; sALS mean: 2835.0, SD: 1135.4; PLS mean: 2707.5, SD: 1138.9), maximal respiratory capacity (C; Control mean: 5325.8, SD: 2993.3; sALS mean: 3613.3, SD: 1662.5; PLS mean: 3741.7, SD: 2102.3), spare respiratory capacity (D; Control mean: 1478.8, SD: 1385.2; sALS mean: 306.8, SD: 589.2; PLS mean: 754.5, SD: 1120.1), ECAR baseline (E; Control mean: 1114.8, SD: 349.3; sALS mean: 1063.3, SD: 573.2; PLS mean: 1007.8, SD: 351.7), and OCR base/ECAR base (F; Control mean: 3.6, SD: 1.3; sALS mean: 3.5, SD: 1.4; PLS mean: 3.3, SD: 1.4). Values are shown comparing sALS, PLS, and control lines. Middle bars represent the average values and error bars show standard deviations. p-values are indicated where there was a significant difference between groups. n.s.: no significant difference. n = 12 sALS; n = 12 PLS, n = 12 controls. (DOCX 132 kb)

Current strategies for skeletal regeneration often require co-delivery of scaffold technologies, growth factors, and cellular material. However, isolation and expansion of stem cells can be time consuming, costly, and requires an additional procedure for harvest. Further, the introduction of supraphysiologic doses of growth factors may result in untoward clinical side effects, warranting pursuit of alternative methods for stimulating osteogenesis. In this work, we describe a nanoparticulate mineralized collagen glycosaminoglycan scaffold that induces healing of critical-sized rabbit cranial defects without addition of expanded stem cells or exogenous growth factors. We demonstrate that the mechanism of osteogenic induction corresponds to an increase in canonical BMP receptor signalling secondary to autogenous production of BMP-2 and -9 early and BMP-4 later during differentiation. Thus, nanoparticulate mineralized collagen glycosaminoglycan scaffolds may provide a novel growth factor-free and exvivo progenitor cell culture-free implantable method for bone regeneration.

The Northeast U.S. Shelf Ecosystem supports a wide array of living marine resources from Atlantic sea scallops, one of the most valuable, to the North Atlantic Right whale, one of the most endangered. All of these resources - fish, invertebrates, marine mammals, sea turtles, plants, habitats, and other ecosystem components - are being impacted by climate change and multidecadal climate variability. In fact, the pace of observed climate change in the Northeast U.S. is faster than in many other U.S. Large Marine Ecosystems, and future change in the Northeast U.S. Shelf ecosystem is projected to be greater than many other portions of the world’s oceans. These changes in climate are already creating significant challenges for the region. Species distributions are becoming out of sync with the spatial allocations of management. The productivity of some iconic species is decreasing, making rebuilding and recovery difficult. Some ports rely on one or two fisheries; changes in these fisheries could have dramatic consequences for the human communities connected to these ports. Changes in science and management can be slow, while changes in the physics, chemistry, and biology of the ecosystem are occurring rapidly. Despite these challenges, there are opportunities. Some species in the region are responding positively to the changes in climate: moving into the region and increasing in productivity. For many managed species, management actions can occur relatively rapidly: the New England Fisheries Management Council (NEFMC) and Mid-Atlantic Fisheries Management Council (MAFMC) have developed specification procedures and framework adjustments that can be implemented within a year of receiving new, peer-reviewed advice. The region has an excellent marine science infrastructure and advanced technologies offer new tools for observing, understanding, and adapting to change. Recognizing the opportunities and challenges resulting from climate change, NOAA Fisheries released the Climate Science Strategy in August 2015. This Strategy develops a national framework to meet the growing demand for information to better prepare for and respond to climate-related impacts on the nation’s living marine resources and resource-dependent communities.

We examine the ultrafast optical response of the crystalline and amorphous phases of the phase change material Ge$_2$Sb$_2$Te$_5$ below the phase transformation threshold. Simultaneous measurement of the transmissivity and reflectivity of thin film samples yields the time-dependent evolution of the dielectric function for both phases. We then identify how lattice motion and electronic excitation manifest in the dielectric response. The dielectric response of both phases is large but markedly different. At 800 nm, the changes in amorphous GST are well described by the Drude response of the generated photo-carriers, whereas the crystalline phase is better described by the depopulation of resonant bonds. We find that the generated coherent phonons have a greater influence in the amorphous phase than the crystalline phase. Furthermore, coherent phonons do not influence resonant bonding. For fluences up to 50% of the transformation threshold, the structure does not exhibit bond softening in either phase, enabling large changes of the optical properties without structural modification., Comment: 7 pages, 5 figures

Nanoscale phase coexistence and inhomogeneity are ubiquitous in correlated electron materials, existing in doped Mott insulators, manganites, and high-temperature superconductors. The small length scales and lack of contrast mechanisms make it extremely challenging to measure real-space images of the phase coexistence with high resolution. Yet, images aid our understanding of how phase coexistence and domain boundaries dictate the exotic material properties. Here we show that resonant soft-X-ray holography, previously employed to image magnetic domains, can be used to image phase separation on the nanoscale. We observe nucleation and growth of nanometre-sized metallic domains out of the insulating phase of the prototypical correlated material VO2, using linearly polarized coherent synchrotron radiation. By spectrally resolving the holograms, we extract differential soft X-ray absorption spectra with 50 nm spatial resolution. Furthermore, when combined with ultra-bright and ultra-short X-ray sources, X-ray holography could capture both nanoscale spatial variations and temporal fluctuations that occur close to the transition temperatures or are induced by femtosecond light pulses that cannot be observed with alternative imaging methods., Comment: 4 pages 4 figures

ICU Fluid Utilization Survey. (DOCX 308 kb)

In-plane anisotropic ground states are ubiquitous in correlated solids such as pnictides, cuprates and manganites. They can arise from doping Mott insulators and compete with phases such as superconductivity, however their origins are debated. Strong coupling between lattice, charge, orbital and spin degrees of freedom results in simultaneous ordering of multiple parameters, masking the mechanism that drives the transition. We demonstrate that the anisotropic orbital domains in a manganite can be oriented by the polarization of a pulsed THz light field. Through the application of the Hubbard model, we show that domain control can be achieved either through field assisted hopping of charges or a field-induced modification of bond angles. Both routes enhance the local Coulomb repulsions which drive domain reorientation and the dominant mechanism is dictated by the equilibrium Mn-O-Mn bond angle. Our results highlight the key role played by the Coulomb interaction in driving orbital order in manganites and demonstrate how THz can be utilized in new ways to understand and manipulate anisotropic phases in a broad range of correlated materials., Comment: 19 pages including supplementary information, 5 figures

A butterfish (Peprilus triacanthus) stock assessment was completed in January 2014. This document provides a summary of the data and results of the final model accepted by the Stock Assessment Review Committee panel. Commercial data used in the assessment consisted of US landings and discard estimates, and commercial mean weights at age, from 1989-2012. Survey data used in the assessment consisted of swept area abundances, and abundance indices (number/tow) by age from 1989-2012 Northeast Fisheries Science Center (NEFSC) fall surveys (inshore and offshore); and swept area abundances from the Northeast Area Monitoring and Assessment Program (NEAMAP) fall (2007-2012) survey. An augmented version of the age-structured assessment program (ASAP) catch at age model of Legault and Restrepo (1999) was used in the assessment. ASAP augmentations included: 1) reparameterization of catchability as the product of availability and efficiency; 2) estimation of natural mortality (M) made possible by fixing catchability, and 3) a length-based calibration of bottom trawl survey data in 2009-2012 was performed internal to the model. Catchability for the NEFSC fall offshore survey was reparameterized by using an average measure of availability based on bottom temperature, while efficiency was based on the relative efficiency of the FRV Albatross IV to the FSV Henry B. Bigelow, given the assumption that the Bigelow was 100% efficient for daytime tows. Results of the model include an estimate of M= 1.22 (CV = 0.05). The current fishing mortality (F2012= 0.02, CV = 0.33) is well below the accepted overfishing reference point (FMSY proxy = 2M/3 = 2 x 1.22/3 = 0.81). The accepted spawning stock biomass reference point SSBMSY proxy (median SSB based on a 50 year projection at the FMSY) proxy is 45,616 mt (CV = 0.25). SSB2012 is estimated to be 79,451 mt, which is well above the accepted SSBMSY proxy. The accepted maximum sustainable yield (MSY) proxy is 36,199 mt (CV = 0.20). SSBthreshold is one half the SSBMSY proxy, or 22,808 mt. Overfishing is not occurring, and the stock is not overfished.

Discovered in 1933 after having been hidden from the academic world for 271 years, the Hartlib Papers have been called the greatest 17th century research revelation of the 20th century. Yet 81 years later the author and collector of the papers remains a mystery and the content of the papers have been little appreciated. Who was this auctor prudens and what do his voluminous papers have to say about his time? This thesis argues that Hartlib is a critical link in a long chain of scholars who formed and shaped the development of science. An evolution which began with Roger Bacon, more fully developed into a new epistemology with Francis Bacon, is passed on by Hartlib to others who were founding members of the Royal Society. This new system of understanding, then known as experimentalism, is the empirical method which impacted the entire spectrum of modern academic disciplines.

ASAP (A Stock Assessment Program) is an age structure stock assessment modeling program originally developed by Chris Legault and Victor Restrepo while they were at the Southeast Fisheries Science Center (Legault and Restrepo 1998). Modifications made in subsequent iterations are described at the top of Appendix 1. ASAP is a variant of statistical catch-at-age models. This latest version can integrate annual catches and associated age compositions (by fleet), abundance indices and associated age compositions, annual maturity, fecundity, weight, and natural mortality at age, and annual environmental covariate effects on stock-recruit parameters or natural mortality (when estimated). It also can incorporate (size-based) calibration estimates that relate abundance index time series with periodic changes in gear. However, it is also flexible enough to handle data poor stocks without age data (dynamic pool models) or with only new and post-recruit age or size groups. Further information and instructions for new features and options are described in the ASAP version 4 User's Guide provided with the installation.

Ion implantation is known for its precise control and reproducibility of doping, enabling it to become one of the main approaches for high-efficiency cell manufacturing in the solar industry. Among the dopant materials, boron doping often represents the largest challenge to productivity as the efficiency of the traditional doping material, boron trifluoride (BF 3 ), is always low. This paper presents a high-efficiency and high-productivity solution for boron doping on an Applied Materials solar ion implanter by using diboron tetrafluoride (B 2 F 4 ) as a replacement gaseous boron source material for BF 3 . Both the B+ beam current and source life effects were evaluated. With optimized source parameters and beam tuning, the solar implanter with B 2 F 4 has demonstrated significant improvements for both B+ beam current performance and source lifetime.

In this paper, we introduce the Solion ion source for high-throughput solar cell doping. As the source power is increased to enable higher throughput, negative effects degrade the lifetime of the plasma chamber and the extraction electrodes. In order to improve efficiency, we have explored a wide range of electron energies and determined the conditions which best suit production. To extend the lifetime of the source we have developed an in situ cleaning method using only existing hardware. With these combinations, source life-times of >200 h for phosphorous and >100 h for boron ion beams have been achieved while maintaining 1100 cell-per-hour production.

We present deep continuum observations using the GISMO camera at a wavelength of 2 mm centered on the Hubble Deep Field (HDF) in the GOODS-N field. These are the first deep field observations ever obtained at this wavelength. The 1 sigma sensitivity in the innermost approx. 4 arcminutes of the 7 utes map is approx. 135 uJy/beam, a factor of three higher in flux/beam sensitivity than the deepest available SCUBA 850 um observations, and almost a factor of four higher in flux / beam sensitivity than the combined MAMBO/AzTEC 1.2 mm observations of this region. Our source extraction algorithm identifies 12 sources directly, and another 3 through correlation with known sources at 1.2 mm and 850 um. Five of the directly detected GISMO sources have counterparts in the MAMBO/AzTEC catalog, and four of those also have SCUBA counterparts. HDF850.1, one of the first blank-field detected submillimeter galaxies, is now detected at 2 mm. The median redshift of all sources with counterparts of known redshifts is med(z) = 2.91 +/- 0.94. Statistically, the detections are most likely real for 5 of the seven 2 mm sources without shorter wavelength counterparts, while the probability for none of them being real is negligible., Comment: Accepted for publication in ApJ

As the semiconductor industry continues to scale devices of smaller dimensions and improved performance, many ion implantation processes require lower energy and higher doses. Achieving these high doses (in some cases ∼1×1016 ions/cm2) at low energies (

A transition in a Third World society from a system of familial support for the elderly to a system of individual responsibility through saving and investment would have effects in some respects similar to a transition from a Pay As You Go public pension system to a funded system. Such a transition might lead to "super-saving" as individuals find themselves behind the normal life cycle trajectory of asset accumulation, and as the elderly continue to be supported by their adult children (or the public pension) so that their dissaving does not offset that of the working age population. But there are other factors at work as well, and the net effect is difficult to intuit. This paper uses a demographically realistic model which incorporates life cycle saving motives in the presence of changing familial or public transfers. We use it to simulate the effects of the change from transfer-based old-age support to a funded system, for Taiwan and for the US, and examine changes in aggregate saving and capital accumulation. We consider a variety of possibilities regarding the degree of foresight and the degree to which pre-existing transfer obligations are honored. Under pure life cycle saving, the demographic transition leads to a large surge in aggregate saving during the later phase of fertility decline, followed by a decline in saving as the population ages. Capital per worker, however, increases substantially and permanently over the transition. Population aging contributes to growth in output per worker, because old hold large capital stocks. This is evident in simulations for both Taiwan and the US. With a transfer system in place to provide for old age support at least partially, these effects on saving rates and capital per worker are muted, and both saving rates and capital follow a substantially lower path. Population aging causes a much smaller increase in capital under transfer systems. Population aging dramatically increases the implicit debt in a transfer system, making a change of system more costly and difficult. An early change to a funded system, while still costly, harnesses the power of population aging to drive capital accumulation, despite falling saving rates. Transfer systems for old age support generate large transfer wealth and corresponding implicit debts in the US Social Security system and in the family transfer system of Taiwan. In our simulations, there are between 1 and 4 times annual GDP. If obligations are honored, these implicit debts must be repaid during a transition toward individual responsibility for old age support through saving, prolonging the effects of the transfer system past the system's dissolution. The working age population at the start of the transition and for some time after bears the cost of the transition, and has reduced consumption, at least under the relatively low interest rates we have assumed.

DESI (Dark Energy Spectroscopic Instrument) is a Stage IV ground-based dark energy experiment that will study baryon acoustic oscillations (BAO) and the growth of structure through redshift-space distortions with a wide-area galaxy and quasar redshift survey. To trace the underlying dark matter distribution, spectroscopic targets will be selected in four classes from imaging data. We will measure luminous red galaxies up to $z=1.0$. To probe the Universe out to even higher redshift, DESI will target bright [O II] emission line galaxies up to $z=1.7$. Quasars will be targeted both as direct tracers of the underlying dark matter distribution and, at higher redshifts ($ 2.1 < z < 3.5$), for the Ly-$��$ forest absorption features in their spectra, which will be used to trace the distribution of neutral hydrogen. When moonlight prevents efficient observations of the faint targets of the baseline survey, DESI will conduct a magnitude-limited Bright Galaxy Survey comprising approximately 10 million galaxies with a median $z\approx 0.2$. In total, more than 30 million galaxy and quasar redshifts will be obtained to measure the BAO feature and determine the matter power spectrum, including redshift space distortions.