Response to dietary phosphorus deficiency is affected by genetic background in growing pigs

Concern over the environmental effect of P excretion from pig production has led to reduced dietary P supplementation. To examine how genetics influence P utilization, 94 gilts sired by 2 genetic lines (PIC337 and PIC280) were housed individually and fed either a P-adequate diet (PA) or a 20% P-deficient diet (PD) for 14 wk. Initially and monthly, blood samples were collected and BW recorded after an overnight fast. Growth performance and plasma indicators of P status were determined monthly. At the end of the trial, carcass traits, meat quality, bone strength, and ash percentage were determined. Pigs fed the PD diet had decreased (P \u3c 0.05) plasma P concentrations and poorer G:F (P \u3c 0.05) over the length of the trial. After 4 wk on trial, pigs fed the PD diet had increased (P \u3c 0.05) plasma 1,25(OH)2D3 and decreased (P \u3c 0.05) plasma parathyroid hormone compared with those fed the PA diet. At the end of the trial, pigs fed the PD diet had decreased (P \u3c 0.05) BW, HCW, and percentage fat-free lean and tended to have decreased LM area (P = 0.06) and marbling (P= 0.09) and greater (P = 0.12) 10th-rib backfat than pigs fed the PA diet. Additionally, animals fed the PD diet had weaker bones and also decreased (P \u3c 0.05) ash percentage and increased (P \u3c 0.05) concentrations of 1α-hydroxylase and parathyroid hormone receptor mRNA in kidney tissue. Regardless of dietary treatment, PIC337-sired pigs consumed more feed and gained more BW than their PIC280-sired counterparts (P \u3c 0.05) during the study. The PIC337-sired pigs also had greater (P \u3c 0.05) HCW, larger (P \u3c 0.01) LM area, and tended to have (P = 0.07) greater dressing percentage. Meat from the PIC337-sired pigs also tended to have greater (P = 0.12) concentrations of lactate but decreased (P = 0.07) concentrations of total glucose units 24 h postslaughter. Although plasma 1,25(OH)2D3 concentrations were elevated (P \u3c 0.05) in all the animals fed the PD diet, this elevation due to P deficiency tended (P = 0.09) to be greater in the PIC337-sired pigs after 12 wk on the treatment. The PIC337-sired pigs had stronger (P \u3c 0.01) bones with greater ash percentage than the PIC280-sired pigs. The difference in the strength of the radii between the PIC337-sired pigs fed the PA and PD diets was greater than their PIC280-sired counterparts, which resulted in sire line × treatment interactions (P \u3c 0.05). These data indicate differing mechanisms of P utilization between these genetic lines. Elucidating these mechanisms may lead to strategies to increase efficiency of growth in a more environmentally friendly manner

Pharmacological Blockade of Serotonin 5-HT7 Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission

The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission

The role of recombination in the emergence of a complex and dynamic HIV epidemic

<p>Abstract</p> <p>Background</p> <p>Inter-subtype recombinants dominate the HIV epidemics in three geographical regions. To better understand the role of HIV recombinants in shaping the current HIV epidemic, we here present the results of a large-scale subtyping analysis of 9435 HIV-1 sequences that involve subtypes A, B, C, G, F and the epidemiologically important recombinants derived from three continents.</p> <p>Results</p> <p>The circulating recombinant form CRF02_AG, common in West Central Africa, appears to result from recombination events that occurred early in the divergence between subtypes A and G, followed by additional recent recombination events that contribute to the breakpoint pattern defining the current recombinant lineage. This finding also corrects a recent claim that G is a recombinant and a descendant of CRF02, which was suggested to be a pure subtype. The BC and BF recombinants in China and South America, respectively, are derived from recent recombination between contemporary parental lineages. Shared breakpoints in South America BF recombinants indicate that the HIV-1 epidemics in Argentina and Brazil are not independent. Therefore, the contemporary HIV-1 epidemic has recombinant lineages of both ancient and more recent origins.</p> <p>Conclusions</p> <p>Taken together, we show that these recombinant lineages, which are highly prevalent in the current HIV epidemic, are a mixture of ancient and recent recombination. The HIV pandemic is moving towards having increasing complexity and higher prevalence of recombinant forms, sometimes existing as "families" of related forms. We find that the classification of some CRF designations need to be revised as a consequence of (1) an estimated > 5% error in the original subtype assignments deposited in the Los Alamos sequence database; (2) an increasing number of CRFs are defined while they do not readily fit into groupings for molecular epidemiology and vaccine design; and (3) a dynamic HIV epidemic context.</p

Precision rehabilitation for aphasia by patient age, sex, aphasia severity, and time since stroke? A prespecified, systematic review based, individual participant data network subgroup meta-analysis

Background: Stroke rehabilitation interventions are routinely personalized to address individuals’ needs, goals, and challenges based on evidence from aggregated randomized controlled trials (RCT) data and meta-syntheses. Individual participant data (IPD) meta-analyses may better inform the development of precision rehabilitation approaches, quantifying treatment responses while adjusting for confounders and reducing ecological bias. Aim: We explored associations between speech and language therapy (SLT) interventions frequency (days/week), intensity (h/week), and dosage (total SLT-hours) and language outcomes for different age, sex, aphasia severity, and chronicity subgroups by undertaking prespecified subgroup network meta-analyses of the RELEASE database. Methods: MEDLINE, EMBASE, and trial registrations were systematically searched (inception-Sept2015) for RCTs, including ⩾ 10 IPD on stroke-related aphasia. We extracted demographic, stroke, aphasia, SLT, and risk of bias data. Overall-language ability, auditory comprehension, and functional communication outcomes were standardized. A one-stage, random effects, network meta-analysis approach filtered IPD into a single optimal model, examining SLT regimen and language recovery from baseline to first post-intervention follow-up, adjusting for covariates identified a-priori. Data were dichotomized by age (⩽/> 65 years), aphasia severity (mild–moderate/ moderate–severe based on language outcomes’ median value), chronicity (⩽/> 3 months), and sex subgroups. We reported estimates of means and 95% confidence intervals. Where relative variance was high (> 50%), results were reported for completeness. Results: 959 IPD (25 RCTs) were analyzed. For working-age participants, greatest language gains from baseline occurred alongside moderate to high-intensity SLT (functional communication 3-to-4 h/week; overall-language and comprehension > 9 h/week); older participants’ greatest gains occurred alongside low-intensity SLT (⩽ 2 h/week) except for auditory comprehension (> 9 h/week). For both age-groups, SLT-frequency and dosage associated with best language gains were similar. Participants ⩽ 3 months post-onset demonstrated greatest overall-language gains for SLT at low intensity/moderate dosage (⩽ 2 SLT-h/week; 20-to-50 h); for those > 3 months, post-stroke greatest gains were associated with moderate-intensity/high-dosage SLT (3–4 SLT-h/week; ⩾ 50 hours). For moderate–severe participants, 4 SLT-days/week conferred the greatest language gains across outcomes, with auditory comprehension gains only observed for ⩾ 4 SLT-days/week; mild–moderate participants’ greatest functional communication gains were associated with similar frequency (⩾ 4 SLT-days/week) and greatest overall-language gains with higher frequency SLT (⩾ 6 days/weekly). Males’ greatest gains were associated with SLT of moderate (functional communication; 3-to-4 h/weekly) or high intensity (overall-language and auditory comprehension; (> 9 h/weekly) compared to females for whom the greatest gains were associated with lower-intensity SLT ( 9 h over ⩾ 4 days/week. Conclusions: We observed a treatment response in most subgroups’ overall-language, auditory comprehension, and functional communication language gains. For some, the maximum treatment response varied in association with different SLT-frequency, intensity, and dosage. Where differences were observed, working-aged, chronic, mild–moderate, and male subgroups experienced their greatest language gains alongside high-frequency/intensity SLT. In contrast, older, moderate–severely impaired, and female subgroups within 3 months of aphasia onset made their greatest gains for lower-intensity SLT. The acceptability, clinical, and cost effectiveness of precision aphasia rehabilitation approaches based on age, sex, aphasia severity, and chronicity should be evaluated in future clinical RCTs

Complex speech-language therapy interventions for stroke-related aphasia: the RELEASE study incorporating a systematic review and individual participant data network meta-analysis

Background: People with language problems following stroke (aphasia) benefit from speech and language therapy. Optimising speech and language therapy for aphasia recovery is a research priority. Objectives: The objectives were to explore patterns and predictors of language and communication recovery, optimum speech and language therapy intervention provision, and whether or not effectiveness varies by participant subgroup or language domain. Design: This research comprised a systematic review, a meta-analysis and a network meta-analysis of individual participant data. Setting: Participant data were collected in research and clinical settings. Interventions: The intervention under investigation was speech and language therapy for aphasia after stroke. Main outcome measures: The main outcome measures were absolute changes in language scores from baseline on overall language ability, auditory comprehension, spoken language, reading comprehension, writing and functional communication. Data sources and participants: Electronic databases were systematically searched, including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Linguistic and Language Behavior Abstracts and SpeechBITE (searched from inception to 2015). The results were screened for eligibility, and published and unpublished data sets (randomised controlled trials, non-randomised controlled trials, cohort studies, case series, registries) with at least 10 individual participant data reporting aphasia duration and severity were identified. Existing collaborators and primary researchers named in identified records were invited to contribute electronic data sets. Individual participant data in the public domain were extracted. Review methods: Data on demographics, speech and language therapy interventions, outcomes and quality criteria were independently extracted by two reviewers, or available as individual participant data data sets. Meta-analysis and network meta-analysis were used to generate hypotheses. Results: We retrieved 5928 individual participant data from 174 data sets across 28 countries, comprising 75 electronic (3940 individual participant data), 47 randomised controlled trial (1778 individual participant data) and 91 speech and language therapy intervention (2746 individual participant data) data sets. The median participant age was 63 years (interquartile range 53-72 years). We identified 53 unavailable, but potentially eligible, randomised controlled trials (46 of these appeared to include speech and language therapy). Relevant individual participant data were filtered into each analysis. Statistically significant predictors of recovery included age (functional communication, individual participant data: 532, n = 14 randomised controlled trials) and sex (overall language ability, individual participant data: 482, n = 11 randomised controlled trials; functional communication, individual participant data: 532, n = 14 randomised controlled trials). Older age and being a longer time since aphasia onset predicted poorer recovery. A negative relationship between baseline severity score and change from baseline (p < 0.0001) may reflect the reduced improvement possible from high baseline scores. The frequency, duration, intensity and dosage of speech and language therapy were variously associated with auditory comprehension, naming and functional communication recovery. There were insufficient data to examine spontaneous recovery. The greatest overall gains in language ability [14.95 points (95% confidence interval 8.7 to 21.2 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.78 points (95% confidence interval 0.48 to 1.1 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with receiving speech and language therapy 4 to 5 days weekly; for auditory comprehension [5.86 points (95% confidence interval 1.6 to 10.0 points) on the Aachen Aphasia Test-Token Test], the greatest gains were associated with receiving speech and language therapy 3 to 4 days weekly. The greatest overall gains in language ability [15.9 points (95% confidence interval 8.0 to 23.6 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.77 points (95% confidence interval 0.36 to 1.2 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with speech and language therapy participation from 2 to 4 (and more than 9) hours weekly, whereas the highest auditory comprehension gains [7.3 points (95% confidence interval 4.1 to 10.5 points) on the Aachen Aphasia Test-Token Test] were associated with speech and language therapy participation in excess of 9 hours weekly (with similar gains notes for 4 hours weekly). While clinically similar gains were made alongside different speech and language therapy intensities, the greatest overall gains in language ability [18.37 points (95% confidence interval 10.58 to 26.16 points) on the Western Aphasia Battery-Aphasia Quotient] and auditory comprehension [5.23 points (95% confidence interval 1.51 to 8.95 points) on the Aachen Aphasia Test-Token Test] were associated with 20-50 hours of speech and language therapy. Network meta-analyses on naming and the duration of speech and language therapy interventions across language outcomes were unstable. Relative variance was acceptable (< 30%). Subgroups may benefit from specific interventions. Limitations: Data sets were graded as being at a low risk of bias but were predominantly based on highly selected research participants, assessments and interventions, thereby limiting generalisability. Conclusions: Frequency, intensity and dosage were associated with language gains from baseline, but varied by domain and subgroup

Precision rehabilitation for aphasia by patient age, sex, aphasia severity, and time since stroke? A prespecified, systematic review-based, individual participant data, network, subgroup meta-analysis

Background: Stroke rehabilitation interventions are routinely personalized to address individuals’ needs, goals, and challenges based on evidence from aggregated randomized controlled trials (RCT) data and meta-syntheses. Individual participant data (IPD) meta-analyses may better inform the development of precision rehabilitation approaches, quantifying treatment responses while adjusting for confounders and reducing ecological bias. Aim: We explored associations between speech and language therapy (SLT) interventions frequency (days/week), intensity (h/week), and dosage (total SLT-hours) and language outcomes for different age, sex, aphasia severity, and chronicity subgroups by undertaking prespecified subgroup network meta-analyses of the RELEASE database. Methods: MEDLINE, EMBASE, and trial registrations were systematically searched (inception-Sept2015) for RCTs, including ⩾ 10 IPD on stroke-related aphasia. We extracted demographic, stroke, aphasia, SLT, and risk of bias data. Overall-language ability, auditory comprehension, and functional communication outcomes were standardized. A one-stage, random effects, network meta-analysis approach filtered IPD into a single optimal model, examining SLT regimen and language recovery from baseline to first post-intervention follow-up, adjusting for covariates identified a-priori. Data were dichotomized by age (⩽/> 65 years), aphasia severity (mild–moderate/ moderate–severe based on language outcomes’ median value), chronicity (⩽/> 3 months), and sex subgroups. We reported estimates of means and 95% confidence intervals. Where relative variance was high (> 50%), results were reported for completeness. Results: 959 IPD (25 RCTs) were analyzed. For working-age participants, greatest language gains from baseline occurred alongside moderate to high-intensity SLT (functional communication 3-to-4 h/week; overall-language and comprehension > 9 h/week); older participants’ greatest gains occurred alongside low-intensity SLT (⩽ 2 h/week) except for auditory comprehension (> 9 h/week). For both age-groups, SLT-frequency and dosage associated with best language gains were similar. Participants ⩽ 3 months post-onset demonstrated greatest overall-language gains for SLT at low intensity/moderate dosage (⩽ 2 SLT-h/week; 20-to-50 h); for those > 3 months, post-stroke greatest gains were associated with moderate-intensity/high-dosage SLT (3–4 SLT-h/week; ⩾ 50 hours). For moderate–severe participants, 4 SLT-days/week conferred the greatest language gains across outcomes, with auditory comprehension gains only observed for ⩾ 4 SLT-days/week; mild–moderate participants’ greatest functional communication gains were associated with similar frequency (⩾ 4 SLT-days/week) and greatest overall-language gains with higher frequency SLT (⩾ 6 days/weekly). Males’ greatest gains were associated with SLT of moderate (functional communication; 3-to-4 h/weekly) or high intensity (overall-language and auditory comprehension; (> 9 h/weekly) compared to females for whom the greatest gains were associated with lower-intensity SLT ( 9 h over ⩾ 4 days/week. Conclusions: We observed a treatment response in most subgroups’ overall-language, auditory comprehension, and functional communication language gains. For some, the maximum treatment response varied in association with different SLT-frequency, intensity, and dosage. Where differences were observed, working-aged, chronic, mild–moderate, and male subgroups experienced their greatest language gains alongside high-frequency/intensity SLT. In contrast, older, moderate–severely impaired, and female subgroups within 3 months of aphasia onset made their greatest gains for lower-intensity SLT. The acceptability, clinical, and cost effectiveness of precision aphasia rehabilitation approaches based on age, sex, aphasia severity, and chronicity should be evaluated in future clinical RCTs

Communicating simply, but not too simply: Reporting of participants and speech and language interventions for aphasia after stroke

Purpose: Speech and language pathology (SLP) for aphasia is a complex intervention delivered to a heterogeneous population within diverse settings. Simplistic descriptions of participants and interventions in research hinder replication, interpretation of results, guideline and research developments through secondary data analyses. This study aimed to describe the availability of participant and intervention descriptors in existing aphasia research datasets. Method: We systematically identified aphasia research datasets containing ≥10 participants with information on time since stroke and language ability. We extracted participant and SLP intervention descriptions and considered the availability of data compared to historical and current reporting standards. We developed an extension to the Template for Intervention Description and Replication checklist to support meaningful classification and synthesis of the SLP interventions to support secondary data analysis. Result: Of 11, 314 identified records we screened 1131 full texts and received 75 dataset contributions. We extracted data from 99 additional public domain datasets. Participant age (97.1%) and sex (90.8%) were commonly available. Prior stroke (25.8%), living context (12.1%) and socio-economic status (2.3%) were rarely available. Therapy impairment target, frequency and duration were most commonly available but predominately described at group level. Home practice (46.3%) and tailoring (functional relevance 46.3%) were inconsistently available. Conclusion : Gaps in the availability of participant and intervention details were significant, hampering clinical implementation of evidence into practice and development of our field of research. Improvements in the quality and consistency of participant and intervention data reported in aphasia research are required to maximise clinical implementation, replication in research and the generation of insights from secondary data analysis. Systematic review registration: PROSPERO CRD4201811094

The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance

The James Webb Space Telescope (JWST) is a large, infrared space telescope that has recently started its science program which will enable breakthroughs in astrophysics and planetary science. Notably, JWST will provide the very first observations of the earliest luminous objects in the Universe and start a new era of exoplanet atmospheric characterization. This transformative science is enabled by a 6.6 m telescope that is passively cooled with a 5-layer sunshield. The primary mirror is comprised of 18 controllable, low areal density hexagonal segments, that were aligned and phased relative to each other in orbit using innovative image-based wavefront sensing and control algorithms. This revolutionary telescope took more than two decades to develop with a widely distributed team across engineering disciplines. We present an overview of the telescope requirements, architecture, development, superb on-orbit performance, and lessons learned. JWST successfully demonstrates a segmented aperture space telescope and establishes a path to building even larger space telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25 figure

The Gravity Collective: A Search for the Electromagnetic Counterpart to the Neutron Star-Black Hole Merger GW190814

We present optical follow-up imaging obtained with the Katzman Automatic Imaging Telescope, Las Cumbres Observatory Global Telescope Network, Nickel Telescope, Swope Telescope, and Thacher Telescope of the LIGO/Virgo gravitational wave (GW) signal from the neutron star-black hole (NSBH) merger GW190814. We searched the GW190814 localization region (19 deg$^{2}$ for the 90th percentile best localization), covering a total of 51 deg$^{2}$ and 94.6% of the two-dimensional localization region. Analyzing the properties of 189 transients that we consider as candidate counterparts to the NSBH merger, including their localizations, discovery times from merger, optical spectra, likely host-galaxy redshifts, and photometric evolution, we conclude that none of these objects are likely to be associated with GW190814. Based on this finding, we consider the likely optical properties of an electromagnetic counterpart to GW190814, including possible kilonovae and short gamma-ray burst afterglows. Using the joint limits from our follow-up imaging, we conclude that a counterpart with an $r$-band decline rate of 0.68 mag day$^{-1}$, similar to the kilonova AT 2017gfo, could peak at an absolute magnitude of at most $-17.8$ mag (50% confidence). Our data are not constraining for ''red'' kilonovae and rule out ''blue'' kilonovae with $M>0.5 M_{\odot}$ (30% confidence). We strongly rule out all known types of short gamma-ray burst afterglows with viewing angles $<$17$^{\circ}$ assuming an initial jet opening angle of $\sim$$5.2^{\circ}$ and explosion energies and circumburst densities similar to afterglows explored in the literature. Finally, we explore the possibility that GW190814 merged in the disk of an active galactic nucleus, of which we find four in the localization region, but we do not find any candidate counterparts among these sources.Comment: 86 pages, 9 figure