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Introduction/Aims: Analysis of biofluids, especially cerebrospinal fluid (CSF), is critically important for amyotrophic lateral sclerosis (ALS) research. Collection of CSF is typically performed by lumbar puncture (LP). Previous studies have demonstrated the safety of LPs in patients with other neurodegenerative diseases, such as Alzheimer's disease, although there are no published studies of the safety of LPs in patients with ALS. We performed a retrospective analysis of complications resulting from LPs. Methods: This is a retrospective study of LPs performed between 2015 and 2021 on a total of 233 participants (healthy controls [n = 63], ALS [n = 154], and disease controls [n = 16]) as part of clinical research studies at the Washington University ALS Center. We used bivariate logistical analyses looking for associations between participant characteristics and adverse events (AEs), and likelihood ratio tests were used for significance testing. Results: We found an overall AE rate of 21.03%. AEs included headache, back pain, vasovagal syncope, and severe headache requiring epidural blood patch. Participants with ALS were not more likely to experience post‐LP AEs compared to controls (odds ratio [OR] 0.61 [0.32–1.18]). Post‐LP headaches were significantly less likely in participants with ALS (OR 0.36 [0.15–0.83]). Discussion: Our findings demonstrate that LP is a safe procedure for participants with ALS, with a similar or lower rate of AEs than in participants without ALS. [ABSTRACT FROM AUTHOR]

Objective: Accumulation of misfolded superoxide dismutase‐1 (SOD1) is a pathological hallmark of SOD1‐related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. Methods: We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. Results: In participants with heterozygous SOD1A5V mutations, known to cause rapidly progressive ALS, mutant SOD1 protein exhibited ~twofold faster turnover and ~ 16‐fold lower concentration compared to wild‐type SOD1 protein. SDGPVKV levels were increased in SOD1A5V carriers relative to controls. Thus, SOD1 mutations impact protein kinetics and stability. We applied this approach to sporadic ALS participants and found that SOD1 turnover, concentration, and SDGPVKV levels are not significantly different compared to controls. Interpretation: These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. Trial Registration: Clinicaltrials.gov: NCT03449212. [ABSTRACT FROM AUTHOR]

Even though enlarged lymph nodes and tonsils are commonly identified in patients diagnosed with monkeypox,[[1]] descriptions of lymph node pathology in human monkeypox infection are lacking. Keywords: lymph node; lymphadenitis; lymphadenopathy; Monkeypox; pathology EN lymph node lymphadenitis lymphadenopathy Monkeypox pathology 953 956 4 04/05/23 20230501 NES 230501 To the Editor: In July 2022, an outbreak of human monkeypox was reported in several nonendemic countries. [Extracted from the article]

Objective: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. Methods: We constructed a large, population‐based case‐control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. Results: We observed previously established medical associations for MND and an inverse dose–response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. Interpretation: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881–892 [ABSTRACT FROM AUTHOR]

Introduction/Aims: We investigated the age‐ and sex‐specific incidence and survival of Medicare beneficiaries with amyotrophic lateral sclerosis (ALS) in patients 66 to 90 years of age. Methods: We identified all incident ALS cases within a population‐based sample of Medicare beneficiaries in 2009 (total: 22 000 177 person‐years at risk for ALS). We calculated age‐ and sex‐specific incidence in 2009 according to multiple, progressively more stringent case definitions. Our most inclusive definition required one ALS code, whereas the most restrictive definition required at least one additional ALS code more than 6 months after the first code, including one from a neurologist. We identified associated imaging studies and electrodiagnostic testing and followed all cases through the end of 2014 to determine survival. Results: The overall incidence for our most inclusive definition was 22.84 per 100 000 person‐years for men and 16.05 per 100 000 person‐years for women. The overall incidence was 5.72 per 100 000 person‐years for men and 3.99 per 100 000 person‐years for women for our most restrictive definition. For our most inclusive definition, fewer than 39.7% of cases ever had an ALS diagnosis from a neurologist, more than 50% had an electrodiagnostic test or imaging study, and 40.1% survived less than 1 year after diagnosis, with 25.5% of these cases surviving no more than 6 months. Cases not meeting the most restrictive definition were more likely than those who did meet the restrictive definition to be older, black, or Asian. Discussion: The oldest and marginalized Medicare beneficiaries diagnosed with ALS are less likely to be included in epidemiological studies with restrictive definitions, but future studies will need to assess the accuracy of diagnosis. [ABSTRACT FROM AUTHOR]

Inert solid rocket propellant samples were subjected to dynamic inflation experiments, to characterize the viscoelastic response at high strain rates. An oxyacetylene‐driven shock tube created the shock wave, which was used to dynamically pressurize the surface of the samples during the inflation experiments. Two high‐speed cameras captured the deforming samples, which were speckled to measure the full‐field surface displacements using the digital image correlation (DIC) algorithm. An inverse finite element analysis (iFEA) was used to calibrate parameters of a generalized Maxwell model (i. e. Prony series), which was used to characterize the propellants' viscoelastic response to shock wave exposure. The viscoelastic parameters calibrated using a Prony series with one Maxwell branch provided a better fit with the out‐of‐plane displacement data from DIC. At least 50 % of the energy dissipated, within the inert solid rocket propellant, occurred within 5 ms following shock wave exposure. The softening phenomenon, due to debonding of the particles embedded in the inert solid rocket propellant, occurred since there was a decrease in instantaneous elastic modulus with increased strain rate. The results of this study will add to the limited knowledge of the linear viscoelastic behavior of inert HTPB propellant at high strain rates and may improve the predictive capabilities of health‐monitoring sensors that assess the solid rocket propellant's structural integrity. [ABSTRACT FROM AUTHOR]

TDP‐43 is an RNA‐binding protein that forms ribonucleoprotein condensates via liquid‐liquid phase separation (LLPS) and regulates gene expression through specific RNA interactions. Loss of TDP‐43 protein homeostasis and dysfunction are tied to neurodegenerative disorders, mainly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Alterations of TDP‐43 LLPS properties may be linked to protein aggregation. However, the mechanisms regulating TDP‐43 LLPS are ill‐defined, particularly how TDP‐43 association with specific RNA targets regulates TDP‐43 condensation remains unclear. We show that RNA binding strongly promotes TDP‐43 LLPS through sequence‐specific interactions. RNA‐driven condensation increases with the number of adjacent TDP‐43‐binding sites and is also mediated by multivalent interactions involving the amino and carboxy‐terminal TDP‐43 domains. The physiological relevance of RNA‐driven TDP‐43 condensation is supported by similar observations in mammalian cellular lysate. Importantly, we find that TDP‐43‐RNA association maintains liquid‐like properties of the condensates, which are disrupted in the presence of ALS‐linked TDP‐43 mutations. Altogether, RNA binding plays a central role in modulating TDP‐43 condensation while maintaining protein solubility, and defects in this RNA‐mediated activity may underpin TDP‐43‐associated pathogenesis. SYNOPSIS: Liquid‐liquid phase separation of the RNA‐binding protein TDP‐43 is regulated by specific RNA sequences. In addition to modulating phase separation, RNA is crucial for maintaining the liquid state of TDP‐43 condensates. GU‐repeat RNA specifically promotes TDP‐43 liquid‐liquid phase separation and this increases with multiple binding sites.Binding of specific RNA sequences to the TDP‐43 RNA‐binding domains maintains liquidity of TDP‐43 condensates.Both the N‐ and C‐terminal TDP‐43 domains are required for RNA‐driven liquid‐liquid phase separation, constituting a multivalent network.The liquid properties of RNA‐driven TDP‐43 condensates are disrupted in a subset of ALS‐linked TDP‐43 mutations. [ABSTRACT FROM AUTHOR]

Background: The histopathological diagnosis of MF is challenging, and there is significant overlap with benign inflammatory processes. Clinical features may be relevant in the assessment of skin biopsies. Methods: We provided photomicrographs to board‐certified dermatopathologists and one hematopathologist with and without accompanying clinical photographs and assessed accuracy and confidence in diagnosing MF. Results: We found that access to clinical photographs improved diagnostic accuracy in both MF and non‐MF (distractors); the degree of improvement was significantly higher in the non‐MF/distractor category. Across all categories, diagnostic confidence level was higher when clinical images were available. Conclusion: These findings suggest that clinical images are useful in making an accurate diagnosis of MF, and may be particularly helpful in ruling it out when an inflammatory disorder is clinically suspected. [ABSTRACT FROM AUTHOR]

The Beverton–Holt and Ricker stock‐recruit functions were derived in terms of two pre‐recruit mortality parameters. Mace, & Doonan, (1988, A generalized bioeconomic simulation model for fish population dynamics) reparameterized the stock‐recruit function in terms of steepness, which combines pre‐recruit mortality with post‐recruit biological parameters defining unfished spawning biomass per recruit. Their parameterization explicitly assumes a stable age distribution at unexploited conditions, but also implicitly assumes that unexploited spawning biomass per recruit is time invariant. Temporal variation could occur in either pre‐recruit mortality rates or post‐recruit biological parameters, but different dynamics are produced. The former results in variation in both the stock‐recruit curve and the population equilibria, whereas variation in the latter only changes the points of equilibria on the curve. Thus, variation in either pre‐ or post‐recruit parameters will result in variation in steepness, maximum sustainable yield and associated management reference points. Empirical measures of components of post‐recruit productivity (maturity and mass at age, e.g.) are available for many managed fish stocks and often exhibit temporal variability. Yet use of the steepness parameterization requires an analyst to specify one set of post‐recruit biological parameters to define unexploited spawning biomass per recruit for the full time series. This misspecification leads to misperception of biological reference points and has implications for meta‐analyses of steepness, and interpretation of the dynamic B0 concept. Returning to the original parameterization allows the isolation of any temporal or inter‐population variation in pre‐ and post‐recruit productivity and reduces the potential for mechanistic bias in stock‐recruit parameters. [ABSTRACT FROM AUTHOR]

The Northeast U.S. shelf (NES) is an oceanographically dynamic marine ecosystem and supports some of the most valuable demersal fisheries in the world. A reliable prediction of NES environmental variables, particularly ocean bottom temperature, could lead to a significant improvement in demersal fisheries management. However, the current generation of climate model‐based seasonal‐to‐interannual predictions exhibits limited prediction skill in this continental shelf environment. Here, we have developed a hierarchy of statistical seasonal predictions for NES bottom temperatures using an eddy‐resolving ocean reanalysis data set. A simple, damped local persistence prediction model produces significant skill for lead times up to ∼5 months in the Mid‐Atlantic Bight and up to ∼10 months in the Gulf of Maine, although the prediction skill varies notably by season. Considering temperature from a nearby or upstream (i.e., more poleward) region as an additional predictor generally improves prediction skill, presumably as a result of advective processes. Large‐scale atmospheric and oceanic indices, such as Gulf Stream path indices (GSIs) and the North Atlantic Oscillation Index, are also tested as predictors for NES bottom temperatures. Only the GSI constructed from temperature observed at 200 m depth significantly improves the prediction skill relative to local persistence. However, the prediction skill from this GSI is not larger than that gained using models incorporating nearby or upstream shelf/slope temperatures. Based on these results, a simplified statistical model has been developed, which can be tailored to fisheries management for the NES. Plain Language Summary: Reliable prediction of bottom temperature could improve fisheries stock assessments on the Northeast U.S. shelf (NES), where some of the most commercially valuable fisheries are located. In this study, we have developed a collection of statistical models that produce seasonal predictions of NES bottom temperature with 1–12 months lead time. Variables considered in these prediction models include local persistence of bottom temperature from prior months, bottom temperature from an upstream or nearby region, and large‐scale atmospheric and oceanic indices representing the North Atlantic Oscillation or position of the Gulf Stream (GS). Only considering local persistence provides significant skill for lead times up to ∼5 months in the Mid‐Atlantic Bight and up to ∼10 months in the Gulf of Maine, although the skill varies by season. Using upstream or nearby bottom temperature and the GS index both generally improve the prediction skill. However, the GS index does not provide higher prediction skill than those upstream or nearby bottom temperatures. A simplified statistical model has been developed, which can be tailored to fisheries management on the NES. Key Points: A local persistence model for bottom temperature provides prediction skill up to ∼10 months with strong variation by region and seasonIncluding upstream or nearby bottom temperature as a predictor largely improves prediction skill, mainly attributed to ocean advectionAn index of Gulf Stream position produces skillful predictions in fall [ABSTRACT FROM AUTHOR]

Background: The prognostic value of tumor‐associated dendritic cells (DC) in colon cancer remains poorly understood. This may be in part due to the interchangeable expression of immunostimulatory and immunoinhibitory molecules on DC. Here we investigated the prognostic impact of CD11c+ DC co–expressing the immunoinhibitory molecule PD‐L1 and their spatial relationship with CD8+ T‐cells in patients treated for stage III colon cancer. Methods: Tissue microarrays containing representative cores of central tumor, leading edge, and adjacent normal tissue from 221 patients with stage III colon cancer were immunostained for CD8, CD11c, PD‐L1, and cytokeratin using immunofluorescent probes. Cells were quantified using StrataQuest digital image analysis software, with intratumoral and stromal regions analyzed separately. Kaplan‐Meier estimates and Cox regression were used to assess survival. Results: Intratumoral CD8+ cell density (HR =.52, 95% confidence interval [CI].33‐.83, P =.007), stromal CD11c+ cell density (HR =.52, 95% CI.33‐.83, P =.006), intratumoral CD11c+PD‐L1+ cell density (HR =.57, 95% CI.35‐.92, P =.021), and stromal CD11c+PD‐L1+ cell density (HR =.48, 95% CI.30‐.77, P =.003) on leading‐edge cores were all significantly associated with good survival. CD8+ cell density was positively correlated with both CD11c+ cell density and CD11c+PD‐L1+ cell density in tumor epithelium and stromal compartments. Conclusion: Here we showed that PD‐L1‐expressing DC in the tumor microenvironment are associated with improved survival in stage III colon cancer and likely reflect an immunologically "hot" tumor microenvironment. Further investigation into the expression of immunomodulatory molecules by tumor‐associated DC may help to further elucidate their prognostic value. [ABSTRACT FROM AUTHOR]

Introduction: Passive data from smartphone sensors may be useful for health‐care research. Our aim was to use the coronavirus disease‐2019 (COVID‐19) pandemic as a positive control to assess the ability to quantify behavioral changes in people with amyotrophic lateral sclerosis (ALS) from smartphone data. Methods: Eight participants used the Beiwe smartphone application, which passively measured their location during the COVID‐19 outbreak. We used an interrupted time series to quantify the effect of the US state of emergency declaration on daily home time and daily distance traveled. Results: After the state of emergency declaration, median daily home time increased from 19.4 (interquartile range [IQR], 15.4‐22.0) hours to 23.7 (IQR, 22.2‐24.0) hours and median distance traveled decreased from 42 (IQR, 13‐83) km to 3.7 (IQR, 1.5‐10.3) km. The participant with the lowest functional ability changed behavior earlier. This participant stayed at home more and traveled less than the participant with highest functional ability, both before and after the state of emergency. Discussion: We provide evidence that smartphone‐based digital phenotyping can quantify the behavior of people with ALS. Although participants spent large amounts of time at home at baseline, the COVID‐19 state of emergency declaration reduced their mobility further. Given participants' high level of daily home time, it is possible that their exposure to COVID‐19 could be less than that of the general population. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions. [ABSTRACT FROM AUTHOR]

Having a realistic representation of ecosystems in fisheries models is important in the context of ecosystem‐based fisheries management (EBFM). While different modelling approaches support EBFM, accounting for trophic interactions and uncertainty in stock dynamics is important for management advice. Multispecies models exist, but are rarely used for assessments. Most stock assessments are single species models and predation is subsumed into natural mortality, which is often an assumed known value. The use of state‐space assessment models, which account for stochasticity in unobserved processes (process errors), is increasing. However, many stocks are managed assuming deterministic processes. Little is known of how ignoring predation and process errors in stock assessment can impact the perception of the stocks and therefore fisheries management.We developed an age‐structured multispecies operating model that simulated data with errors in observations, recruitment and fish abundance. Four estimation models (EMs) that differed according to whether or not they accounted for predation or process errors were fitted to the simulated data. Relative differences between true and predicted outputs were estimated as a measure of bias. Equilibrium unfished biomass was estimated for each model as a proxy reference point.Ignoring predation had the largest impact on stock perception and resulted in large bias in parameters, derived outputs and absolute or relative reference points. Estimating unobserved processes was not sufficient in limiting the bias when natural mortality was misspecified.Ignoring process errors had limited bias but the bias increased when no contrasts existed in fishing mortality over time.Looking solely at likelihood values to choose among models is misleading and predictive ability could be used to prevent selecting models that overfit the data.Synthesis and applications. Ignoring trophic interactions that occur in marine ecosystems induces bias in stock assessment outputs and results in low model predictive ability with subsequently biased reference points. While it may be difficult to estimate natural mortality when no data exist to inform it, stock managers should remember that, if predation is large, assuming a constant mortality over time and/or age could have large consequences on stock perception and reference point estimates and affect resulting management advice. [ABSTRACT FROM AUTHOR]

Background: Select primary tauopathies exhibit MAPT (tau) mis‐splicing to produce an imbalance of 3R and 4R tau isoforms. Further, 3R and 4R tau isoforms deposit in neurons and glia in tauopathy patients, although it remains unclear whether tau isoform deposition is a cause or consequence of disease. Our group and others have identified a role for 4R tau in increased tau phosphorylation and aggregation, suggesting that 4R tau‐mediated mechanisms may influence disease. Therefore, therapeutic strategies targeted against 4R tau may be beneficial. Method: We developed antisense oligonucleotides (ASOs) that enable control of 3R and 4R tau splicing without altering total tau levels in human tau‐expressing mice, primary mouse astrocytes, and astrocytes derived from human induced pluripotent stem cells (iPSCs). We quantified gene markers of astrocyte reactivity and measures of astrocyte function, including glutamate uptake and response to oxidative stress. Finally, we performed bulk RNAseq from mouse brain tissue following tau splicing manipulation. Result: Increasing 4R tau in human tau mice and primary mouse astrocytes induced a neurotoxic gene signature, including evidence for complement pathway involvement. Astrocytes derived from iPSCs of tauopathy patients expressing the MAPT mutation IVS 10+16 (biases toward 4R tau expression) exhibited increased expression of genes associated with neurotoxicity, were vulnerable to oxidative stress, and had reduced glutamate uptake. 4R tau‐expressing astrocytes, including IVS 10+16 mutation carriers, promoted hyperexcitability characteristics in co‐cultured neurons compared to controls. Bulk RNAseq analysis supported isoform‐specific changes in gene expression. Conclusion: Astrocytes appear particularly vulnerable to increased 4R tau in vivo and in vitro, inducing dysfunction that may leave neurons prone to hyperexcitability and degeneration. Although tau isoform imbalance toward greater 4R tau likely induces both neuronal and glial changes, tau‐mediated toxicity within astrocytes may reveal unique mechanisms of disease progression and targets for therapeutics. [ABSTRACT FROM AUTHOR]

The mechanical failure properties of composite solid propellants are determined largely by the strength of the particle matrix interfaces. Under applied loading, separation of the particulate matter from the surrounding matrix takes place, a phenomenon called dewetting. Vacuole formation and growth result in volume changes in the bulk material, so that, during tensile testing, in situ measurement of volume change correlates with this type of microstructural damage. Dewetting and dilatation have long been an important consideration, but characterization has been difficult. Fluid based dilatometry has been the dominant measurement technique but has some inadequacies. In this work, an alternative approach is shown that needs no contact with the specimen, that requires no gas or liquid, and that can accommodate various specimen geometries. Damage was induced in two common solid propellant types using either formulation considerations or strain induced damage. The volume changes during tensile testing were measured using this optical dilatometry method and show the ability of the approach to detect damage in solid propellants. Various parameters derived from the dilatation curves are compared. Verification of the approach with results from a conventional dilatometer are also included. [ABSTRACT FROM AUTHOR]

Objectives: Clinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA‐targeted therapies. Methods: Transgenic animal models expressing human proteins implicated in neurodegenerative disorders – microtubule‐associated protein tau (hTau) or superoxide dismutase‐1 (hSOD1) – were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6‐leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics. Results: ASO treatment lowered hTau mRNA and protein production (measured by 13C6‐leucine‐labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment. Interpretation: Measures of newly generated protein show earlier pharmacodynamics changes for RNA‐lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA‐targeted therapeutics. [ABSTRACT FROM AUTHOR]

Summary: Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen‐presenting cells that are critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia can upregulate CD11c during inflammation, making it challenging to distinguish bone marrow‐derived DCs (BMDCs) from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells and regulate their function within the CNS during neuro‐inflammation. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non‐biased murine array. Several miRNAs, including miR‐31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR‐31 expression was specific to BMDCs. Interestingly, miR‐31‐binding sites were enriched in mRNAs downregulated in BMDCs that migrated into the CNS, and a subset was confirmed to be regulated by miR‐31. Finally, miR‐31 was elevated in DCs migrating through an in vitro blood–brain barrier. Our findings suggest miRNAs, including miR‐31, may regulate entry of DCs into the CNS during EAE, and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS. [ABSTRACT FROM AUTHOR]

Premise of the Study: Wildfire changes the demography, morphology, and behavior of plants, and may alter the pollinator community. Such trait changes may drastically alter the outcome of pollination mutualisms on plants; however, the direct role of fire on these mutualisms is poorly known. Methods: Following a pair of fires in the northern California coast range chaparral, we censused floral visitor communities of Trichostema laxum (Lamiaceae), quantified visiting bee behavior, and estimated outcrossing rates using a widespread Mendelian recessive floral polymorphism across a matrix of populations in burned and unburned sites. We also compared pre‐ and postfire floral visitation in two populations. Results: Outcrossing rates were significantly lower in burned areas; however, our data suggest that the much larger size of plants in burned areas, not burn status itself, drove this pattern. Large‐bodied bees dominated floral visitor communities after fire, likely recruiting to the abundant postfire floral resources. These bees visited more flowers per plant than did the smaller bees prevalent before fire and in unburned areas, likely increasing selfing through geitonogamy (within‐plant pollination), an effect made possible by the far larger size of plants in burned areas. Conclusions: Outcrossing rates dropped substantially after wildfires because of changes in the pollinators, plant display size, and their interactions. Reductions in outcrossing following fire may have important implications for population resilience and evolution in a changing climate with more frequent fires. [ABSTRACT FROM AUTHOR]

Introduction: Three studies evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of CK-2127107 (CK-107), a next-generation fast skeletal muscle troponin activator (FSTA), in healthy participants. We tested the hypothesis that CK-107 would amplify the force-frequency response of muscle in humans.Methods: To assess the force-frequency response, participants received single doses of CK-107 and placebo in a randomized, double-blind, 4-period, crossover study. The force-frequency response of foot dorsiflexion following stimulation of the deep fibular nerve to activate the tibialis anterior muscle was assessed.Results: CK-107 significantly increased tibialis anterior muscle response with increasing dose and plasma concentration in a frequency-dependent manner; the largest increase in peak force was ∼60% at 10 Hz.Discussion: CK-107 appears more potent and produced larger increases in force than tirasemtiv-a first-generation FSTA-in a similar pharmacodynamic study, thereby supporting its development for improvement of muscle function of patients. Muscle Nerve 57: 729-734, 2018. [ABSTRACT FROM AUTHOR]

The justification for incorporating environmental effects into fisheries stock assessment models has been investigated and debated for a long time. Recently, a state-space age-structured assessment model which includes the stochastic change in the environmental covariate over time and its effect on recruitment was developed for Southern New England-Mid Atlantic yellowtail flounder ( Limanda ferruginea). In this paper, we first investigated the correlations of environmental covariates with Southern New England-Mid Atlantic yellowtail flounder recruitment deviations. The covariate that was most strongly correlated with the recruitment deviations was then incorporated into the state-space model and alternative effects on the stock-recruit relationship were estimated and compared. For the model that performed best as measured by Akaike information criterion, we also compared the estimates and predictions of various population attributes and biological reference points with those from an otherwise identical model without the environmental covariate in the stock-recruit function. We found that the estimates of population parameters are similar for the two models but the predictions differed substantially. To evaluate which model provided more reliable predictions, we quantitatively compared the prediction skill of the two models by generating two series of retrospective predictions. Comparison of the retrospective prediction pattern suggested that from an average point of view, the environmentally explicit model can provide more accurate near-term recruitment predictions especially the one year ahead recruitment prediction. However, the accuracy of the near-term recruitment prediction from the environmentally explicit model was largely determined by the accuracy of the corresponding environment prediction the model provides. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Surveys of bumble bees and the plants they visit, carried out in 1974 near the Rocky Mountain Biological Laboratory in Colorado, were repeated in 2007, thus permitting the testing of hypotheses arising from observed climate change over the intervening 33‐yr period. As expected, given an increase in average air temperature with climate warming and a declining temperature with increasing elevation, there have been significant shifts toward higher elevation for queens or workers or both, for most bumble bee species, for bumble bee queens when species are combined, and for two focal plant species, with no significant downward shifts. However, contrary to our hypotheses, we failed to observe significant altitudinal changes for some bumble bee species and most plant species, and observed changes in elevation were often less than the upward shift of 317 m required to maintain average temperature. As expected, community flowering phenology shifted toward earlier in the season throughout our study area, but bumble bee phenology generally did not change, resulting in decreased synchrony between bees and plants. However, we were unable to confirm the narrower expectation that phenologies of bumble bee workers and community flowering coincided in 1974 but not in 2007. As expected, because of reduced synchrony between bumble bees and community flowering, bumble bee abundance was reduced in 2007 compared with 1974. Hence, climate change in our study area has apparently resulted primarily in reduced abundance and upward shift in distribution for bumble bees and shift toward earlier seasonality for plant flowering. Quantitative disagreements between climate change expectations and our observations warrant further investigation. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: The aim of this study was to determine whether a history of pre-morbid type 2 diabetes mellitus (DM2) is a prognostic factor in amyotrophic lateral sclerosis (ALS). Methods: The relationship between DM2 and survival was analyzed in a study population consisting of 1,322 participants from 6 clinical trials. Results: Survival did not differ by diabetes status (log-rank test, P = 0.98), but did differ by body mass index (BMI) (log-rank test, P = 0.008). In multivariate analysis, there was no significant association between diabetes and survival ( P = 0.18), but the risk of reaching a survival endpoint decreased by 4% for each unit increase in baseline BMI (HR 0.96, 95% CI 0.94-0.99, P = 0.001). DM2 was less prevalent among ALS clinical trial participants than predicted. Conclusions: A history of pre-morbid DM2 is not an independent prognostic factor in ALS clinical trial databases. The low DM2 prevalence rate should be examined in a large, prospective study to determine whether DM2 affects ALS risk. Muscle Nerve 52:339-343, 2015 [ABSTRACT FROM AUTHOR]

* Premise of the study: Ultraviolet (UV) floral patterns are common in angiosperms and mediate pollinator attraction, efficiency, and constancy. UV patterns may vary within species, yet are cryptic to human observers. Thus, few studies have explicitly described the distribution or ecological significance of intraspecific variation in UV floral patterning. Here, we describe the geographic distribution and pattern of inheritance of a UV polymorphism in the model plant species Mimulus guttatus (Phrymaceae). We then test whether naturally occurring UV phenotypes influence pollinator interactions within M. guttatus. * Methods: We document UV patterns in 18 annual and 19 perennial populations and test whether UV pattern is associated with life history. To examine the pattern of inheritance, we conducted crosses within and between UV phenotypes. Finally, we tested whether bee pollinators discriminate among naturally occurring UV phenotypes in two settings: wild bee communities and captive Bombus impatiens. * Key results: Within M. guttatus, perennial populations exhibit a small bulls-eye pattern, whereas a bilaterally symmetric runway pattern occurs mainly in annual populations. Inheritance of UV patterning is consistent with a single-locus Mendelian model in which the runway phenotype is dominant. Bee pollinators discriminate against unfamiliar UV patterns in both natural and controlled settings. * Conclusions: We describe a widespread UV polymorphism associated with life history divergence within Mimulus guttatus. UV pattern influences pollinator visitation and should be considered when estimating reproductive barriers between life history ecotypes. This work develops a new system to investigate the ecology and evolution of UV floral patterning in a species with extensive genomic resources. [ABSTRACT FROM AUTHOR]

Objective To define the genetic landscape of amyotrophic lateral sclerosis (ALS) and assess the contribution of possible oligogenic inheritance, we aimed to comprehensively sequence 17 known ALS genes in 391 ALS patients from the United States. Methods Targeted pooled-sample sequencing was used to identify variants in 17 ALS genes. Fragment size analysis was used to define ATXN2 and C9ORF72 expansion sizes. Genotype-phenotype correlations were made with individual variants and total burden of variants. Rare variant associations for risk of ALS were investigated at both the single variant and gene level. Results A total of 64.3% of familial and 27.8% of sporadic subjects carried potentially pathogenic novel or rare coding variants identified by sequencing or an expanded repeat in C9ORF72 or ATXN2; 3.8% of subjects had variants in >1 ALS gene, and these individuals had disease onset 10 years earlier ( p = 0.0046) than subjects with variants in a single gene. The number of potentially pathogenic coding variants did not influence disease duration or site of onset. Interpretation Rare and potentially pathogenic variants in known ALS genes are present in >25% of apparently sporadic and 64% of familial patients, significantly higher than previous reports using less comprehensive sequencing approaches. A significant number of subjects carried variants in >1 gene, which influenced the age of symptom onset and supports oligogenic inheritance as relevant to disease pathogenesis. ANN NEUROL 2015;77:100-113 [ABSTRACT FROM AUTHOR]

The life history of North American Atlantic salmon ( Salmo salar) is characterized by extensive round-trip migrations between freshwater rearing habitats and marine feeding grounds off the coasts of Canada and Greenland. Growth is rapid during the marine migration, and growth rate and condition factor may be indicators of salmon health during this period. Growth data were evaluated from a tag-recovery program conducted from 1969 to 1991 using hatchery-reared Atlantic salmon smolts released in the Penobscot River, Maine, U.S.A. Information from recaptures of 3167 salmon that were at large in the marine environment for 1 month to 3 yr was analyzed. Length-weight measurements coupled with time-at-large data were used to estimate von Bertalanffy and allometric growth parameters specific to the marine phase. Variations in growth and condition factor in relation to smolt age, release date, and temperature conditions in the northwest Atlantic were also examined. The von Bertalanffy k parameter declined with ordinal release date, indicating faster growth rates during the first year of smolts released earlier in the spring. The 2-yr-old smolts had a larger k than 1-yr-old smolts, although 1-yr-old smolts grew to a larger asymptotic size. Sea surface temperature had variable effects on growth parameters and condition factor, with temperature at the beginning of the migration and in overwintering habitat during the first year at sea having the greatest influence on length-weight relationships. Determining the mechanisms that influence growth of individuals during the marine phase will help elucidate the factors responsible for historic growth trends, establishing a baseline for current research. [ABSTRACT FROM AUTHOR]

Diagnostic delays in Pompe disease are common. The diagnostic gap (the time from the onset of symptoms to the diagnosis of Pompe disease) and factors associated with diagnostic delays were examined among Pompe Registry patients in three onset categories: Group A, onset ≤12 months of age with cardiomyopathy; Group B, onset ≤12 months without cardiomyopathy and onset >12 months to ≤12 years; and Group C, onset >12 years. Of 1,003 patients, 647 were available for analysis. In all groups, musculoskeletal signs and symptoms were among the most frequent presenting signs and symptoms, in addition to cardiomyopathy in Group A, which was part of the group's definition. Diagnostic gaps existed in all three groups. Patients presenting with respiratory and musculoskeletal signs and symptoms concurrently had the shortest diagnostic gap, while those presenting with neither respiratory nor musculoskeletal signs and symptoms had the longest. Independent factors influencing the probability of a long diagnostic gap included presenting signs and symptoms (all three groups) and year of diagnosis and age at symptom onset (Groups B and C). Group B, which represents the infantile patients without cardiomyopathy and juvenile Pompe cases, had the longest median gap (12.6 years). Diagnostic testing methods used also were reviewed. Despite the availability of blood-based assays that can be used to quickly and accurately diagnose Pompe disease, diagnostic gaps in Pompe patients across the disease spectrum continue. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

SUMMARY Technology scaling is having an increasingly detrimental effect on microprocessor reliability, with increased variability and higher susceptibility to errors. At the same time, as integration of chip multiprocessors increases, power consumption is becoming a significant bottleneck. To ensure continued performance, growth of microprocessors requires development of powerful and energy-efficient solutions to reliability challenges. This paper presents a reliable multicore architecture that provides targeted error protection by adapting to the characteristics of individual cores and workloads, with the goal of providing reliability with minimum energy. The user can specify an acceptable reliability target for each chip, core, or application. The system then adjusts a range of parameters, including replication and supply voltage, to meet that reliability goal. In this multicore architecture, each core consists of a pair of pipelines that can run independently (running separate threads) or in concert (running the same thread and verifying results). Redundancy is enabled selectively, at functional unit granularity. The architecture also employs timing speculation for mitigation of variation-induced timing errors and to reduce the power overhead of error protection. On-line control based on machine learning dynamically adjusts multiple parameters to minimize energy consumption. Evaluation shows that dynamic adaptation of voltage and redundancy can reduce the energy delay product of a chip multiprocessor by 30 − 60% compared with static dual modular redundancy. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Metacommunity theory allows predictions about the dynamics of potentially interacting species' assemblages that are linked by dispersal, but strong empirical tests of the theory are rare. We analyzed the metacommunity dynamics of Florida rosemary scrub, a patchily distributed pyrogenic community, to test predictions about turnover rates, community nestedness, and responses to patch size, arrangement, and quality. We collected occurrence data for 45 plant species from 88 rosemary scrub patches in 1989 and 2005 and used growth form, mechanism of regeneration after fire, and degree of habitat specialization to categorize species by life history. We tested whether patch size, fire history, and structural connectivity (a measure of proximity and size of surrounding patches) could be used to predict apparent extinctions and colonizations. In addition, we tested the accuracy of incidence-function models built with the patch survey data from 1989. After fire local extinction rates were higher for herbs than woody plants, higher for species that regenerated only from seed than species able to resprout, and higher for generalist than specialist species. Fewer rosemary specialists and a higher proportion of habitat generalists were extirpated on recently burned patches than on patches not burned between 1989 and 2005. Nestedness was highest for specialists among all life-history groups. Estimated model parameters from 1989 predicted the observed (1989-2005) extinction rates and the number of patches with persistent populations of individual species. These results indicate that species with different life-history strategies within the same metacommunity can have substantially different responses to patch configuration and quality. Real metacommunities may not conform to certain assumptions of simple models, but incidence-function models that consider only patch size, configuration, and quality can have significant predictive accuracy. [ABSTRACT FROM AUTHOR]

Introduction: Palliative care services that address physical pain and emotional, psychosocial, and spiritual needs may benefit individuals with Duchenne muscular dystrophy (DMD). Methods: The objective of this study was to describe the palliative care services that families of males with DMD report they receive. A questionnaire was administered to families of males with DMD born prior to January 1, 1982. Thirty-four families responded. Results: Most families (85%) had never heard the term palliative care. Only attendant care and skilled nursing services showed much usage, with 44% and 50% indicating receipt of these services, respectively. Receipt of other services was reported less frequently: pastoral care (27%); respite care (18%); pain management (12%); and hospice care (6%). Only 8 respondents (25%) reported having any type of directive document in place. Conclusion: The data suggest a need for improved awareness of palliative care and related services among families of young men with DMD. Muscle Nerve 44: 93-101, 2011 [ABSTRACT FROM AUTHOR]

Theoretical and empirical results suggest that there are externalities to childbearing, but those results usually assume that these externalities accrue uniformly within a homogeneous population. We advance this argument by developing separate estimates of the fiscal externalities associated with parents-those who devote time or material resources to minor children-and nonparents. Our analysis uses data from the US Panel Study of income Dynamics on the age profiles of taxes paid and publicly funded benefts consumed by parents and nonparents, together with a previously developed intertemporal economic-demographic accounting model. The accounting framework takes into account the net fiscal impacts of future generations as well as the present population. Our findings indicate that, with a 3 percent discount rate, parents produce a substantial net fiscal externality, about $217,000 in 2009 dollars. This is equivalent to a lifetime annuity of nearly $8,100 per year beginning at age 18. The results are sensitive to both the discount rate used and the proportion of parents within the cohort. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease affecting the cortex, brainstem and spinal cord. In familial and sporadic ALS, the levels of a complex of α2‐Na+/K+‐ATPase (encoded by the Atp1a2 gene) and α‐adducin are increased in the spinal cord. In the SOD1*G93A mouse model of ALS, upregulation of this complex is specifically observed in astrocytes and Atp1a2+/‐ SOD1*G93A mice show increased mobility and lifespan than Atp1a2+/+ littermate controls. Further, RNAi‐mediated knockdown of Atp1a2 in SOD1*G93A primary mouse astrocytes prevents cell death and dendrite degeneration in co‐cultured motor neurons. These findings suggest that Atp1a2 might represent a therapeutic target in ALS. Antisense oligonucleotides (ASOs) have emerged as a safe and effective method to modify gene expression in animal models and in the clinic. Method: Here we characterize the suitability of Atp1a2 knockdown using ASOs as a means to attenuate astrocyte‐mediated neurotoxicity in SOD1*G93A mice. Two lead ASOs targeting the 3'‐UTR of Atp1a2 and reducing Atp1a2 expression by 50‐70% were identified. These two ASOs were then tested in vivo to determine their impact on disease progression and survival in SOD1*G93A mice. Result: Atp1a2 ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. However, Atp1a2 ASO‐treated mice exhibited significantly earlier disease onset and shorter lifespan than animals receiving control ASOs. Conclusion: Together, these results demonstrate a decoupling of SOD1 aggregation and disease course, thereby, suggesting that reducing Atp1a2 expression in adulthood may not have the same beneficial effects of gene knockout at birth in SOD1*G93A mice. Additional studies are required to understand the divergence of these effects and the efficacy of Atp1a2 as a therapeutic target in ALS. [ABSTRACT FROM AUTHOR]

The FXYD family, which contains seven members, are tissue specific regulators of the Na,K-ATPase. Increased expression of FXYD5, a cancer–cell-associated membrane glycoprotein, has been associated with increased cell motility and metastatic potential. To better understand how FXYD5 may modulate cell motility, we analyzed S163, a conserved residue in all FXYD family members located in the C-terminus. Ectopic expression of human FXYD5 S163 mutants in HEK 293 cells showed that negative charge at S163 (S163D) decreased membrane localization, assessed by immunofluorescence. Coimmunoprecipitation studies revealed decreased FXYD5/Na,K-ATPase interaction for S163D compared with wild-type or S163A mutants. Interestingly, FXYD5 overexpression induced expression of vimentin, a marker of epithelial–mesenchymal transition, in murine airway epithelial cells. Because Na,K-ATPase expression is decreased in some forms of cancer and is critical for establishing cell polarity and suppressing cell motility, we analyzed S163 mutants in an epithelial cell scratch-wound model as a measure of cell migration. Wild-type FXYD5 overexpression increased reepithelialization ( p<0.0001), which was further increased in S163D mutants ( p<0.005). However, S163A mutants inhibited epithelial cell migration compared with wild-type FXYD5 overexpression ( p<0.0001). We conclude that negative charge at S163 regulates FXYD5/Na,K-ATPase interaction and that this interaction modulates cell migration across a wound in airway epithelial cells. [ABSTRACT FROM AUTHOR]

1. Lipids have more negative δ13C values relative to other major biochemical compounds in plant and animal tissues. Although variable lipid content in biological tissues alters results and conclusions of δ13C analyses in aquatic food web and migration studies, no standard correction protocol exists. 2. We compared chemical extraction and mathematical correction methods for freshwater and marine fishes and aquatic invertebrates to better understand impacts of correction approaches on carbon (δ13C) and nitrogen (δ15N) stable isotope data. 3. Fish and aquatic invertebrate tissue δ13C values increased significantly following extraction for almost all species and tissue types relative to nonextracted samples. In contrast, δ15N was affected for muscle and whole body samples from only a few freshwater and marine species and had a limited effect for the entire data set. 4. Lipid normalization models, using C : N as a proxy for lipid content, predicted lipid-corrected δ13C for paired data sets more closely with parameters specific to the tissue type and species to which they were applied. 5. We present species- and tissue-specific models based on bulk C : N as a reliable alternative to chemical extraction corrections. By analysing a subset of samples before and after lipid extraction, models can be applied to the species and tissues of interest that will improve estimates of dietary sources using stable isotopes. [ABSTRACT FROM AUTHOR]

The presence of myotonia and paramyotonia on clinical examination and of myotonic discharges during electrodiagnostic (EDX) studies are important for the diagnosis of certain neuromuscular conditions. The increased muscle activity of myotonia produces muscle stiffness that improves with repeated activity. Paramyotonia produces a similar symptom, but the stiffness paradoxically increases with activity. Myotonic discharges are easily recognized on EDX testing because of the waxing and waning discharges. Myotonic dystrophy and myotonia congenita share both clinical and electrodiagnostic myotonia. Paramyotonia congenita and hyperkalemic periodic paralysis are associated with clinical paramyotonia and electrical myotonia. Acid maltase deficiency often produces myotonic potentials without clinical evidence of myotonia or paramyotonia. The differential diagnosis of these myotonic disorders is discussed. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

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Abstract Under the life-cycle saving model, population aging leads to an increased demand for life-cycle wealth. Changes in transfer systems create or destroy one component of life-cycle wealth—transfer wealth. The decline in the familial transfer system in Taiwan and reform of the US Social Security system are two examples of ways that transfer wealth is reduced. The combined effects of aging and changes in transfer systems are analyzed using simulation analysis. Rapid aging and radical decline in transfer systems lead to a large but transitory surge in aggregate saving. Capital per worker increases rapidly and remains at a high level. [ABSTRACT FROM AUTHOR]

Objective: To quantify uncertainty in forecasts of health expenditures.Study Design: Stochastic time series models are estimated for historical variations in fertility, mortality, and health spending per capita in the United States, and used to generate stochastic simulations of the growth of Medicare expenditures. Individual health spending is modeled to depend on the number of years until death.Data Sources/study Setting: A simple accounting model is developed for forecasting health expenditures, using the U.S. Medicare system as an example.Principal Findings: Medicare expenditures are projected to rise from 2.2 percent of GDP (gross domestic product) to about 8 percent of GDP by 2075. This increase is due in equal measure to increasing health spending per beneficiary and to population aging. The traditional projection method constructs high, medium, and low scenarios to assess uncertainty, an approach that has many problems. Using stochastic forecasting, we find a 95 percent probability that Medicare spending in 2075 will fall between 4 percent and 18 percent of GDP, indicating a wide band of uncertainty. Although there is substantial uncertainty about future mortality decline, it contributed little to uncertainty about future Medicare spending, since lower mortality both raises the number of elderly, tending to raise spending, and is associated with improved health of the elderly, tending to reduce spending. Uncertainty about fertility, by contrast, leads to great uncertainty about the future size of the labor force, and therefore adds importantly to uncertainty about the health-share of GDP. In the shorter term, the major source of uncertainty is health spending per capita.Conclusions: History is a valuable guide for quantifying our uncertainty about future health expenditures. The probabilistic model we present has several advantages over the high-low scenario approach to forecasting. It indicates great uncertainty about future Medicare expenditures relative to GDP. [ABSTRACT FROM AUTHOR]

BSTRACT: Data from long-term ecosystem monitoring and research stations in North America and results of simulations made with interpretive models indicate that changes in climate (precipitation and temperature) can have a significant effect on the quality of surface waters. Changes in water quality during storms, snowmelt, and periods of elevated air temperature or drought can cause conditions that exceed thresholds of ecosystem tolerance and, thus, lead to water-quality degradation. If warming and changes in available moisture occur, water-quality changes will likely first occur during episodes of climate-induced stress, and in ecosystems where the factors controlling water quality are sensitive to climate variability. Continued climate stress would increase the frequency with which ecosystem thresholds are exceeded and thus lead to chronic water-quality changes. Management strategies in a warmer climate will therefore be needed that are based on local ecological thresholds rather than annual median condition. Changes in land use alter biological, physical, and chemical processes in watersheds and thus significantly alter the quality of adjacent surface waters; these direct human-caused changes complicate the interpretation of water-quality changes resulting from changes in climate, and can be both mitigated and exacerbated by climate change. A rigorous strategy for integrated, long-term monitoring of the ecological and human factors that control water quality is necessary to differentiate between actual and perceived climate effects, and to track the effectiveness of our environmental policies. [ABSTRACT FROM AUTHOR]

Discusses the cost-of-quality model developed by the El Camino College in California to assist in the implementation of total quality management in the campus. Model's role of organizing an monitoring all process improvement teams; Results of a pilot test of the model made at the campus.

Summarizes the results of a study that aimed to determine the feasibility of using logistic regression procedures to detect differential item functioning (DIF) in polytomous test items. Three conditions of non-uniform DIF and one of uniform DIF; Recoding of data into multiple dichotomies in order to use logistic regression procedures.