24R,25-Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats

Osteoarthritis (OA) in humans is associated with low circulating 25-hydroxyvitamin D3 [25 (OH)D3]. In vitamin D replete rats, radiolabeled 24R,25-dihydroxyvitamin D3 [24R,25 (OH)2D3] accumulates in articular cartilage following injection of [3 H]-25(OH)D3. Previously, we showed that 24R,25(OH)2D3 blocks chondrocyte apoptosis via phospholipase D and p53, suggesting a role for 24R,25(OH)2D3 in maintaining cartilage health. We examined the ability of 24R,25(OH)2D3 to prevent degenerative changes in articular cartilage in an OAlike environment and the potential mechanisms involved. In vitro, rat articular chondrocytes were treated with IL-1β with and without 24R,25(OH)2D3 or 1α,25(OH)2D3. 24R,25(OH)2D3 but not 1α,25(OH)2D3 blocked the effects of IL-1β in a dose-dependent manner, and its effect was partially mediated through the TGF-β1 signaling pathway. In vivo, unilateral anterior cruciate ligament transections were performed in immunocompetent rats followed by intra-articular injections of 24R,25(OH)2D3 or vehicle (t = 0, 7, 14, 21 days). Tissues were harvested on day 28. Joints treated with vehicle had changes typical of OA whereas joints treated with 24R,25(OH)2D3 had less articular cartilage damage and levels of inflammatory mediators. These results indicate that 24R,25(OH)2D3 protects against OA, and suggest that it may be a therapeutic approach for preventing trauma-induced osteoarthritis

ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The µ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy.

Background:Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of β-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of β-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions. Methods:Adult patients with a score ≥4 on 11-point NRS for pain intensity received IV oliceridine either by bolus or PCA; multimodal analgesia was permitted. Safety was assessed using AE reports, study discontinuations, clinical laboratory and vital sign measures. Results:A total of 768 patients received oliceridine. The mean age (SD) was 54.1 (16.1) years, with 32% ≥65 years of age. Most patients were female (65%) and Caucasian (78%). Surgical patients comprised the majority of the study population (94%), most common being orthopedic (30%), colorectal (15%) or gynecologic (15%) procedures. Multimodal analgesia was administered to 84% of patients. Oliceridine provided a rapid reduction in NRS pain score by 2.2 ± 2.3 at 30 mins from a score of 6.3 ± 2.1 (at baseline) which was maintained to the end of treatment. No deaths or significant cardiorespiratory events were reported. The incidence of AEs leading to early discontinuation and serious AEs were 2% and 3%, respectively. Nausea (31%), constipation (11%), and vomiting (10%) were the most common AEs. AEs were mostly of mild (37%) or moderate (25%) severity and considered possibly or probably related to oliceridine in 33% of patients. Conclusion:Oliceridine IV for the management of moderate to severe acute pain was generally safe and well tolerated in the patients studied. ClinicalTrialsgov identifier:NCT02656875

Dependence of Microstructure and Mechanical Properties on Heat Treat Cycles of Electron Beam Melted Ti-6Al-4V

The EBM Ti-6Al-4V alloy has generally superior mechanical properties, owing to finely spaced α−β laths which give a good combination of strength and ductility. The grain structures in the as-printed structures are long columnar which can give rise to anisotropic mechanical properties. Moreover the non-uniformity in microstructure can also arise from part geometry where the thin features have propensity to form martensite phase. Heat treatment provides a viable solution to modify the microstructure and to tailor to the properties as desired. A wide range of heat treatment experiments were performed, followed by microstructure and tensile property analyses. It was observed that the microstructure and the tensile properties significantly changed depending on the heat treat cycle performed. Tensile properties of solution treated air-cool plus aged samples yielded globular equiaxed grains with fine α−β lath structure, which were found to be the best among the different heat treated samples and better than ASTM F1472 specifications.Mechanical Engineerin

Clinical Characterization and the Caregiver Burden of Dementia in China

AbstractObjectivesThe prevalence of dementia in China is among the highest in the world, but systematic estimates of the rate of dementia subtypes and characterization of associated deficits are lacking. The primary aim of this study was to determine the clinical presentation of dementia and describe the caregiver burden in mainland China.MethodsA 3-month, open-enrollment, multicenter, cross-sectional study was conducted at 48 tier-3 hospitals. Caregivers who qualified for study entry (provided amount and duration of care information), had intimate knowledge of patient status, and accompanied enrolled patients to study sites were asked to participate in an interview about patient care and caregiver burden. Caregiver burden was assessed via the Chinese version of the validated Zarit Burden Interview.ResultsA total of 1425 caregivers completed the survey. Patients had mild to moderate dementia (mean Clinical Dementia Rating score of 1.67±0.79), and the most common dementia subtypes were Alzheimer disease (46.7%) and vascular dementia (28.7%). Among caregivers, 57% were females, 52% were patients’ spouses, and 67.3% had been caring for patients for 1 year or more. Most patients required family help and lived at home or with a family member. Caregiver awareness of dementia was limited. The mean total caregiver Zarit Burden Interview score was 26.6. Observations were similar across age, gender, education, dementia type, Clinical Dementia Rating score, and duration of care.ConclusionsChina faces multiple obstacles in preparing to care for its fast-growing dementia population. Better understanding of patients and caregivers may mitigate these challenges by improving awareness and education

Primary Alcohol-Activated Human and Mouse Hepatic Stellate Cells Share Similarities in Gene-Expression Profiles.

Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins and formation of a fibrous scar. Hepatic stellate cells (HSCs) are the major source of collagen type 1 producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol-induced activation of human and mouse HSCs is not fully understood. We compared the gene-expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n = 3) or without underlying liver disease (n = 4) using RNA-sequencing analysis. Furthermore, the gene-expression profile of ALD hHSCs was compared with that of alcohol-activated mHSCs (isolated from intragastric alcohol-fed mice) or CCl4-activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, in addition to alcohol-activated and CCl4-activated mHSCs, share the expression of common HSC activation (Col1a1 [collagen type I alpha 1 chain], Acta1 [actin alpha 1, skeletal muscle], PAI1 [plasminogen activator inhibitor-1], TIMP1 [tissue inhibitor of metalloproteinase 1], and LOXL2 [lysyl oxidase homolog 2]), indicating that a common mechanism underlies the activation of human and mouse HSCs. Furthermore, alcohol-activated mHSCs most closely recapitulate the gene-expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely up-regulated in primary cultured alcohol-activated hHSCs and freshly isolated mHSCs, which include CSF1R (macrophage colony-stimulating factor 1 receptor), PLEK (pleckstrin), LAPTM5 (lysosmal-associated transmembrane protein 5), CD74 (class I transactivator, the invariant chain), CD53, MMP9 (matrix metallopeptidase 9), CD14, CTSS (cathepsin S), TYROBP (TYRO protein tyrosine kinase-binding protein), and ITGB2 (integrin beta-2), and other genes (compared with CCl4-activated mHSCs). Conclusion: We identified genes in alcohol-activated mHSCs from intragastric alcohol-fed mice that are largely consistent with the gene-expression profile of primary cultured hHSCs from patients with ALD. These genes are unique to alcohol-induced HSC activation in two species, and therefore may become targets or readout for antifibrotic therapy in experimental models of ALD

Forming Giant Planets Around Late-M Dwarfs: Pebble Accretion and Planet-Planet Collision

We propose a pebble-driven core accretion scenario to explain the formation of giant planets around the late-M dwarfs of $M_{\star}{=}0.1{-}0.2 \ M_{\odot}$. In order to explore the optimal disk conditions for giant planet, we perform N-body simulations to investigate the growth and dynamical evolution of both single and multiple protoplanets in the disks with both inner viscously heated and outer stellar irradiated regions. The initial masses of the protoplanets are either assumed to be equal to$0.01 \ M_{\oplus}$or calculated based on the formula derived from streaming instability simulations. Our findings indicate that massive planets are more likely to form in disks with longer lifetimes, higher solid masses, moderate to high levels of disk turbulence, and larger initial masses of protoplanets. In the single protoplanet growth cases, the highest planet core mass that can be reached is generally lower than the threshold necessary to trigger rapid gas accretion, which impedes the formation of giant planets. Nonetheless, in multi-protoplanet cases, the cores can exceed the pebble isolation mass barrier aided by frequent planet-planet collisions. This consequently speeds up their gas accretion and promotes giant planet formation, making the optimal parameter space to grow giant planets substantially wider. Taken together, our results suggest that even around very low-mass stellar hosts, the giant planets with orbital periods of${\lesssim}100$days are still likely to form when lunar-mass protoplanets first emerge from planetesimal accretion and then grow rapidly by a combination of pebble accretion and planet-planet collisions in disks with a high supply of pebble reservoir${>}50 \ M_{\oplus}$and turbulent level of$\alpha_{\rm t} {\sim} 10^{-3}{-}10^{-2}$.Comment: 22 pages, 13 figures, 3 tables, Accepted for publication in A&

LRRK1 regulation of actin assembly in osteoclasts involves serine 5 phosphorylation of L-plastin

Mice with disruption of Lrrk1 and patients with nonfunctional mutant Lrrk1 exhibit severe osteopetrosis phenotypes because of osteoclast cytoskeletal dysfunction. To understand how Lrrk1 regulates osteoclast function by modulating cytoskeleton rearrangement, we examined the proteins that are differentially phosphorylated in wild-type mice and Lrrk1-deficient osteoclasts by metal affinity purification coupled liquid chromatography/mass spectrometry (LC/MS) analyses. One of the candidates that we identified by LC/MS is L-plastin, an actin bundling protein. We found that phosphorylation of L-plastin at serine (Ser) residues 5 was present in wild-type osteoclasts but not in Lrrk1-deficient cells. Western blot analyses with antibodies specific for Ser5 phosphorylated L-plastin confirmed the reduced L-plastin Ser5 phosphorylation in Lrrk1 knockout (KO) osteoclasts. micro computed tomography (Micro-CT) analyses revealed that the trabecular bone volume of the distal femur was increased by 27% in the 16 to 21-week-old L-plastin KO females as compared with the wild-type control mice. The ratio of bone volume to tissue volume and connectivity density were increased by 44% and 47% (both P \u3c 0.05), respectively, in L-plastin KO mice. Our data suggest that targeted disruption of L-plastin increases trabecular bone volume, and phosphorylation of Ser5 in L-plastin in the Lrrk1 signaling pathway may in part contribute to actin assembly in mature osteoclasts

Closing the Coverage Gaps: Reducing Health Insurance Disparities in Massachusetts

Massachusetts has been exemplary in developing health insurance coverage policies to cover its residents. By 2019, the state's uninsurance rate was 3.0 percent, the lowest rate in the nation, representing about 204,000 uninsured residents. While the state's overall uninsured rate at a given point in time is low, more than twice as many people - 503,000, or 7.3 percent of the population - experienced a gap in coverage over the previous twelve months. And importantly, not all groups benefit equally. People who are Black or Hispanic, or who have lower incomes, experience significantly higher rates of uninsurance than the state population overall. As a result, these groups are more likely to face access barriers and financial insecurity associated with being uninsured.The purpose of this report is to begin charting a course toward closing the coverage gaps in Massachusetts, with a particular focus on creating a more racially and ethnically equitable system of coverage. The report and accompanying infographics describe the people in Massachusetts without health insurance and the barriers to coverage they face, including affordability, administrative complexity, and immigration, language, and cultural barriers. It then proposes a menu of policy options that address the specific circumstances in Massachusetts. The proposed options are meant to inform a statewide conversation about the best approaches to closing the remaining coverage gaps in Massachusetts and removing structural barriers that result in racial and ethnic disparities in health insurance coverage

Biogeography and Virulence of Staphylococcus aureus

Staphylococcus aureus is commonly carried asymptomatically in the human anterior nares and occasionally enters the bloodstream to cause invasive disease. Much of the global diversity of S. aureus remains uncharacterised, and is not clear how disease propensity varies between strains, and between host populations.We compared 147 isolates recovered from five kindergartens in Chengdu, China, with 51 isolates contemporaneously recovered from cases of pediatric infection from the main hospital serving this community. The samples were characterised by MLST, the presence/absence of PVL, and antibiotic resistance profiling.Genotype frequencies within individual kindergartens differ, but the sample recovered from cases of disease shows a general enrichment of certain MLST genotypes and PVL positive isolates. Genotypes under-represented in the disease sample tend to correspond to a single sequence cluster, and this cluster is more common in China than in other parts of the world.Virulence propensity likely reflects a synergy between variation in the core genome (MLST) and accessory genome (PVL). By combining evidence form biogeography and virulence we demonstrate the existence of a "native" clade in West China which has lowered virulence, possibility due to acquired host immunity