Miracle-dz/UniFAR-FTUs huggingface dataset:
National Trends for Primary and Revision Lumbar Disc Arthroplasty Throughout the United States

Study Design: Retrospective database study. Objectives: Analysis of economic and demographic data concerning lumbar disc arthroplasty (LDA) throughout the United States to improve value-based care and health care utilization. Methods: The National Inpatient Sample database was queried for patients who underwent primary or revision LDA between 2005 and 2013. Demographic and economic data included total surgeries, costs, length of stay, and frequency of routine discharge. The National Inpatient Sample database represents a 20% sample of discharges from US hospitals weighted to provide national estimates. Results: Primary LDA decreased 86% from 3059 to 420 from 2005 to 2013. The mean total cost of LDA increased 33% from $17 747 to $23 804. The mean length of stay decreased from 2.8 to 2.4 days. The mean routine discharge (home discharge without visiting nursing care) remained constant at 91%. Revision procedures (removal, supplemental fixation, or reoperation at the treated level) declined 30% from 194 to 135 cases over the study period. The mean revision burden, defined as the ratio of revision procedures to the sum of primary and revision procedures, was 12% (range 6% to 24%). The mean total cost of revisions ranged from $12 752 to $22 282. Conclusions: From 2005 to 2013, primary LDA significantly declined in the United States by 86% despite several studies pointing to improved efficacy and cost-efficiency. This disparity may be related to a lack of surgeon reimbursement from insurance companies. Congruently, the number of revision LDA cases has declined 30%, while revision burden has risen from 6% to 24%.
APTO-253 Is a New Addition to the Repertoire of Drugs that Can Exploit DNA BRCA1/2 Deficiency

APTO-253 is a small molecule with antiproliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]. The intracellular content of Fe(253)3 exceeded that of the native drug by approximately 18-fold, and Fe(253)3 appears to be the most active form. Treatment of cells with APTO-253 caused DNA damage, which led us to ask whether cells deficient in homologous recombination (i.e., loss of BRCA1/2 function) were hypersensitive to this drug. It was found that loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 of a magnitude similar to the effects of PARP inhibitors, olaparib. Raji cells selected for 16-fold acquired resistance had 16-fold reduced accumulation of Fe(253)3. RNA-seq analysis revealed that overexpression of the ABCG2 drug efflux pump is a key mechanism of resistance. ABCG2-overexpressed HEK-293 cells were resistant to APTO-253, and inhibition of ABCG2 reversed resistance to APTO-253 in Raji/253R. APTO-253 joins the limited repertoire of drugs that can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression. Mol Cancer Ther; 17(6); 1167–76. ©2018 AACR.
Blood Levels of Co-inhibitory-Receptors: A Biomarker of Disease Prognosis in Multiple Sclerosis

Background: The clinical course of multiple sclerosis ranges from benign with little disease progression and minimal disability, to severe disease requiring intensive medical treatment. There are no reliable circulating biomarkers for predicting disease outcome. Co-inhibitory receptors regulate the termination of effective immune responses to infections while limiting autoimmunity and/or immunopathology. Based on this, we studied the potential of circulating co-inhibitory receptor levels as predictive biomarkers of multiple sclerosis outcome. Methods: Co-inhibitory receptor [TIGIT (T cell immunoreceptor with Ig and ITIM domains), TIM-3 (T-cell immunoglobulin and mucin domain–containing 3), LAG-3 (lymphocyte activation gene 3), PD-1 (programmed cell death 1), CTLA-4 (cytotoxic T-lymphocyte–associated protein 4)] expression levels in peripheral blood mononuclear cells (PBMCs) were measured using reverse transcription–PCR in 19 healthy controls and 57 patients with untreated multiple sclerosis. All patients were evaluated for disease outcome and paraclinical measures during the following 9–10 years [progression index, Expanded Disability Status Scale (EDSS) score, number of relapses, number of disease modifying therapies (DMTs), baseline brain magnetic resonance imaging T2 lesion volume, and oligoclonal bands (OCBs)]. Results: Patients had significantly lower TIGIT and LAG-3 levels than the controls (P < 0.02 and P < 0.04, respectively). TIM-3 levels were significantly lower in patients with high vs. low disability index and in patients with SPMS diagnosis compared to patients who remained in the relapsing stage of the disease at final visit (both, P < 0.02). LAG-3 levels were significantly higher in patients with low disability index vs. non-low disability index multiple sclerosis (P < 0.05). TIM-3 and LAG-3 expression levels correlated significantly with 1-year progression index (r2 = 0.076, P < 0.05; 0.087, P < 0.04, respectively) and EDSS score at final visit (r2 = 0.31, P < 0.04; 0.320.088, P < 0.04, respectively). Lower LAG-3 levels were associated with higher DMT switching (r2 = 0.67, P < 0.05). Compared to the paraclinical and clinical parameters alone, the combined data of the baseline co-inhibitory receptor expression levels and the paraclinical and clinical parameters were superior for predicting the patients that would progress to secondary progressive multiple sclerosis (SPMS). Interpretation: This is an initial exploration of the utility of CTLA-4, PD-1, TIM-3, LAG-3, and TIGIT expression levels as prognostic indicators in untreated, recently diagnosed multiple sclerosis. Our results support the value of decreased PBMC expression levels of TIM-3 and LAG-3 at diagnosis as an unfavorable prognostic factor, which is to be confirmed in further studies.
Uncovering the nonequilibrium phase structure of an open quantum spin system

We experimentally and theoretically investigate the non-equilibrium phase structure of a well-controlled driven-disspative quantum spin system governed by the interplay of coherent driving, spontaneous decay and long-range spin-spin interactions. We discover that the rate of population loss provides a convenient macroscopic observable that exhibits power-law scaling with the driving strength over several orders of magnitude. The measured scaling exponents reflect the underlying non-equilibrium phase structure of the many-body system, which includes dissipation-dominated, paramagnetic and critical regimes as well as an instability which drives the system towards states with high excitation density. This opens up a new means to study and classify quantum systems out of equilibrium and extends the domain where scale-invariant behavior may be found in nature.
mGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in Rats

G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment discontinuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, which processes have translational relevance for central activity and target engagement. Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of LY354740 (1–10 mg/kg) and JNJ-42153605 (3–30 mg/kg). JNJ-42153605 showed high affinity, potency and selectivity at mGluR2. Binding site analyses and knowledge-based docking confirmed the specificity of JNJ-42153605 at the mGluR2 allosteric binding site. Acute LY354740 and JNJ-42153605 dose-dependently decreased rapid eye movement (REM) sleep time and prolonged its onset latency. Sub chronic effects of LY354740 on REM sleep measures disappeared from day 3 onwards, whereas those of JNJ-42153605 were maintained after repeated exposure. LY354740 attenuated REM sleep homeostatic recovery, while this was preserved after JNJ-42153605 administration. JNJ-42153605 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for impaired sleep quality during early stages of treatment. Abrupt cessation of JNJ-42153605 did not induce withdrawal phenomena and sleep disturbances, while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with JNJ-42153605 did not induce tolerance phenomena to its primary functional effects on sleep measures, nor adverse effects at withdrawal, while it promoted homeostatic recovery sleep. From the translational perspective, the present rodent findings suggest that mGluR2 positive allosteric modulation has therapeutic potential based on its superior long term efficacy over agonists in psychiatric disorders, particularly of those commonly occurring with REM sleep overdrive.
PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulates G-protein–coupled receptor kinase 5 (GRK5)-induced cardiac hypertrophy in vitro

PH domain leucine-rich repeat protein phosphatase (PHLPP) is a serine/threonine phosphatase that has been shown to regulate cell growth and survival through dephosphorylation of several members of the AGC family of kinases. G-protein–coupled receptor kinase 5 (GRK5) is an AGC kinase that regulates phenylephrine (PE)-induced cardiac hypertrophy through its noncanonical function of directly targeting proteins to the nucleus to regulate transcription. Here we investigated the possibility that the PHLPP2 isoform can regulate GRK5-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes (NRVMs). We show that removal of PHLPP2 by siRNA induces hypertrophic growth of NRVMs as measured by cell size changes at baseline, potentiated PE-induced cell size changes, and re-expression of fetal genes atrial natriuretic factor and brain natriuretic peptide. Endogenous GRK5 and PHLPP2 were found to interact in NRVMs, and PE-induced nuclear accumulation of GRK5 was enhanced upon down-regulation of PHLPP2. Conversely, overexpression of PHLPP2 blocked PE-induced hypertrophic growth, re-expression of fetal genes, and nuclear accumulation of GRK5, which depended on its phosphatase activity. Finally, using siRNA against GRK5, we found that GRK5 was necessary for the hypertrophic response induced by PHLPP2 knockdown. Our findings demonstrate for the first time a novel regulation of GRK5 by the phosphatase PHLPP2, which modulates hypertrophic growth. Understanding the signaling pathways affected by PHLPP2 has potential for new therapeutic targets in the treatment of cardiac hypertrophy and failure.
Callosal Influence on Visual Receptive Fields Has an Ocular, an Orientation-and Direction Bias

One leading hypothesis on the nature of visual callosal connections (CC) is that they replicate features of intrahemispheric lateral connections. However, CC act also in the central part of the binocular visual field. In agreement, early experiments in cats indicated that they provide the ipsilateral eye part of binocular receptive fields (RFs) at the vertical midline (Berlucchi and Rizzolatti, 1968), and play a key role in stereoscopic function. But until today callosal inputs to receptive fields activated by one or both eyes were never compared simultaneously, because callosal function has been often studied by cutting or lesioning either corpus callosum or optic chiasm not allowing such a comparison. To investigate the functional contribution of CC in the intact cat visual system we recorded both monocular and binocular neuronal spiking responses and receptive fields in the 17/18 transition zone during reversible deactivation of the contralateral hemisphere. Unexpectedly from many of the previous reports, we observe no change in ocular dominance during CC deactivation. Throughout the transition zone, a majority of RFs shrink, but several also increase in size. RFs are significantly more affected for ipsi- as opposed to contralateral stimulation, but changes are also observed with binocular stimulation. Noteworthy, RF shrinkages are tiny and not correlated to the profound decreases of monocular and binocular firing rates. They depend more on orientation and direction preference than on eccentricity or ocular dominance of the receiving neuron's RF. Our findings confirm that in binocularly viewing mammals, binocular RFs near the midline are constructed via the direct geniculo-cortical pathway. They also support the idea that input from the two eyes complement each other through CC: Rather than linking parts of RFs separated by the vertical meridian, CC convey a modulatory influence, reflecting the feature selectivity of lateral circuits, with a strong cardinal bias.
A protein standard that emulates homology for the characterization of protein inference algorithms

A natural way to benchmark the performance of an analytical experimental setup is to use samples of known content, and see to what degree one can correctly infer the content of such a sample from the data. For shotgun proteomics, one of the inherent problems of interpreting data is that the measured analytes are peptides and not the actual proteins themselves. As some proteins share proteolytic peptides, there might be more than one possible causative set of proteins resulting in a given set of peptides and there is a need for mechanisms that infer proteins from lists of detected peptides. A weakness of commercially available samples of known content is that they consist of proteins that are deliberately selected for producing tryptic peptides that are unique to a single protein. Unfortunately, such samples do not expose any complications in protein inference. For a realistic benchmark of protein inference procedures, there is, therefore, a need for samples of known content where the present proteins share peptides with known absent proteins. Here, we present such a standard, that is based on E. coli expressed human protein fragments. To illustrate the usage of this standard, we benchmark a set of different protein inference procedures on the data. We observe that inference procedures excluding shared peptides provide more accurate estimates of errors compared to methods that include information from shared peptides, while still giving a reasonable performance in terms of the number of identified proteins. We also demonstrate that using a sample of known protein content without proteins with shared tryptic peptides can give a false sense of accuracy for many protein inference methods.
A Longitudinal Study of the Feline Faecal Microbiome Identifies Changes into Early Adulthood Irrespective of Sexual Development

Companion animals provide an excellent model for studies of the gut microbiome because potential confounders such as diet and environment can be more readily controlled for than in humans. Additionally, domestic cats and dogs are typically neutered early in life, enabling an investigation into the potential effect of sex hormones on the microbiome. In a longitudinal study to investigate the potential effects of neutering, neutering age and gender on the gut microbiome during growth, the faeces of kittens (16 male, 14 female) were sampled at 18, 30 and 42 weeks of age. DNA was shotgun sequenced on the Illumina platform and sequence reads were annotated for taxonomy and function by comparison to a database of protein coding genes. In a statistical analysis of diversity, taxonomy and functional potential of the microbiomes, age was identified as the only factor with significant associations. No significant effects were detected for gender, neutering, or age when neutered (19 or 31 weeks). At 18 weeks of age the microbiome was dominated by the genera Lactobacillus and Bifidobacterium (35% and 20% average abundance). Structural and functional diversity was significantly increased by week 30 but there was no further significant increase. At 42 weeks of age the most abundant genera were Bacteroides (16%), Prevotella (14%) and Megasphaera (8%). Significant differences in functional potential included an enrichment for genes in energy metabolism (carbon metabolism and oxidative phosphorylation) and depletion in cell motility (flagella and chemotaxis). We conclude that the feline faecal microbiome is predominantly determined by age when diet and environment are controlled for. We suggest this finding may also be informative for studies of the human microbiome, where control over such factors is usually limited.
Horizontal Pyramid Matching for Person Re-identification

Despite the remarkable progress in person re-identification (Re-ID), such approaches still suffer from the failure cases where the discriminative body parts are missing. To mitigate this type of failure, we propose a simple yet effective Horizontal Pyramid Matching (HPM) approach to fully exploit various partial information of a given person, so that correct person candidates can be identified even if some key parts are missing. With HPM, we make the following contributions to produce more robust feature representations for the Re-ID task: 1) we learn to classify using partial feature representations at different horizontal pyramid scales, which successfully enhance the discriminative capabilities of various person parts; 2) we exploit average and max pooling strategies to account for person-specific discriminative information in a global-local manner. To validate the effectiveness of our proposed HPM method, extensive experiments are conducted on three popular datasets including Market-1501, DukeMTMCReID and CUHK03. Respectively, we achieve mAP scores of 83.1%, 74.5% and 59.7% on these challenging benchmarks, which are the new state-of-the-arts.
Inter-generational housing inequalities: ‘Baby Boomers’ versus the ‘Millennials’

In contrast to the post-war period, the late 20th and early 21st centuries in the UK have been characterised by the advancement of neoliberal policies including privatisation of the housing system and employment casualisation. Consequently, there are growing socioeconomic inequalities between those born in the post-war period – the ‘Baby Boomers’ – and the younger generation – the ‘Millennials’. Such inequalities have led to narratives of inter-generational conflict with Baby Boomers framed as jeopardising the futures of Millennials. Drawing on Mannheim’s theory of social generations, the concept of generational habitus and qualitative data from 49 Baby Boomers and 62 Millennials, we unpack the ways in which inter-generational inequalities are intersubjectively understood and discussed. Our data indicate that while young people are aware of inter-generational inequalities, they do not feel resentful towards their parents’ generation for profiting at their expense. Instead, many blame the government for not representing their interests. Thus, narratives of inter-generational conflict misleadingly direct blame towards the agency of Baby Boomers rather than political structures.
Predictors of Nursing Facility Entry by Medicaid-Only Older Adults and Persons With Disabilities in California

Nearly one-third of adult Medicaid beneficiaries who receive long-term services and supports (LTSS) consist of older adults and persons with disabilities who are not eligible for Medicare. Beneficiaries, advocates, and policymakers have all sought to shift LTSS to home and community settings as an alternative to institutional care. We conducted a retrospective cohort study of Medicaid-only adults in California with new use of LTSS in 2006-2007 (N = 31 849) to identify unique predictors of entering nursing facilities versus receiving Medicaid home and community-based services (HCBS). Among new users, 18.3% entered into nursing facilities, whereas 81.7% initiated HCBS. In addition to chronic conditions, functional and cognitive limitations, substance abuse disorders (odds ratio [OR] 1.35; 95% confidence interval [CI]: 1.23, 1.48), and homelessness (OR: 4.35, 9% CI: 3.72, 5.08) were associated with higher odds of nursing facility entry. For older adults and persons with disabilities covered by Medicaid only, integration with housing and behavioral health services may be key to enabling beneficiaries to receive LTSS in noninstitutional settings.
Neuronal Redox-Imbalance in Rett Syndrome Affects Mitochondria as Well as Cytosol, and Is Accompanied by Intensified Mitochondrial O2 Consumption and ROS Release

Rett syndrome (RTT), an X chromosome-linked neurodevelopmental disorder affecting almost exclusively females, is associated with various mitochondrial alterations. Mitochondria are swollen, show altered respiratory rates, and their inner membrane is leaking protons. To advance the understanding of these disturbances and clarify their link to redox impairment and oxidative stress, we assessed mitochondrial respiration in defined brain regions and cardiac tissue of male wildtype (WT) and MeCP2-deficient (Mecp2-/y) mice. Also, we quantified for the first time neuronal redox-balance with subcellular resolution in cytosol and mitochondrial matrix. Quantitative roGFP1 redox imaging revealed more oxidized conditions in the cytosol of Mecp2-/y hippocampal neurons than in WT neurons. Furthermore, cytosol and mitochondria of Mecp2-/y neurons showed exaggerated redox-responses to hypoxia and cell-endogenous reactive oxygen species (ROS) formation. Biochemical analyzes exclude disease-related increases in mitochondrial mass in Mecp2-/y hippocampus and cortex. Protein levels of complex I core constituents were slightly lower in Mecp2-/y hippocampus and cortex than in WT; those of complex V were lower in Mecp2-/y cortex. Respiratory supercomplex-formation did not differ among genotypes. Yet, supplied with the complex II substrate succinate, mitochondria of Mecp2-/y cortex and hippocampus consumed more O2 than WT. Furthermore, mitochondria from Mecp2-/y hippocampus and cortex mediated an enhanced oxidative burden. In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in RTT. Intensified mitochondrial O2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT.
Segmentation of CT Thoracic Organs by Multi-resolution VB-nets

Accurate segmentation of organs at risk (OARs) is a key step in image guided radiation therapy. In this work, we proposed multi-resolution 3D V-Net networks to automatically segment thoracic organs at risk in computed tomography (CT) images. Specifically, we adopt two resolutions and propose a customized V-Net model called VB-Net for both resolutions. The VB-Net model in the coarse resolution can robustly localize the organs, while the VB-Net model in the fine resolution can accurately refine the boundary of each organ. In the SegTHOR 2019 challenge, 40 CT scans with 4 thoracic organs (i.e., esophagus, heart, trachea and aorta) were used for training. We experimented with both single-class and multi-class Dice losses to train the networks. Our best results were obtained by averaging multiple models trained with single-class Dice loss. At the time of submission, our results rank the 1st for segmentation of all four OARs.