Risk Versus Reward: Hospitals Incentivized More Than Surgeons to Care for Riskier Arthroplasty Patients.

BACKGROUND: The purpose of this study was to assess the relationship between risk and reimbursement for both surgeons and hospitals among Medicare patients undergoing primary total joint arthroplasty (TJA). METHODS: The "2021 Medicare Physician and Other Provider" and "2021 Medicare Inpatient Hospitals" files were used. Patient comorbidity profiles were collected, including the mean patient hierarchal condition category (HCC) risk score. Surgeon data included all primary TJA procedures (inpatient and outpatient) billed to Medicare in 2021, while hospital data included all such inpatient episodes. Surgeon and hospital reimbursements were collected. All episodes were split into a "sicker cohort" with an HCC risk score of 1.5 or more and a "healthier cohort" with HCC risk scores less than 1.5. Variables were compared across cohorts. RESULTS: In 2021, 386,355 primary total hip and knee arthroplasty procedures were billed to Medicare and were included. The mean surgeon reimbursement among the sicker cohort was $1,021.91, which was less than for the healthier cohort of $1,060.13 (P < .001). Meanwhile, for the hospital analysis, 112,012 Medicare TJA patients were admitted as inpatients and included. The mean reimbursement to hospitals was significantly greater for the sicker cohort at $13,950.66, compared to the healthier cohort of $8,430.46. For both analyses, the sicker patient cohorts had a significantly higher rate of all comorbidities assessed (P < .001). CONCLUSIONS: This study demonstrates that mean surgeon reimbursement was lower for primary TJA among sicker patients in comparison to their healthier counterparts, while hospital reimbursement was higher for sicker patients. This represents a discrepancy in the incentivization of care for complex patients, as hospitals receive increased remuneration for taking on extra risk, while surgeons get paid less on average for performing TJA on sicker patients. Such data should inform future policy to assure continued access to arthroplasty care among complex patients.

Analogues of the pan-selectin antagonist rivipansel (GMI-1070).

The selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewisx (sLex, 1) binds to all selectins, albeit with very different affinities. Whereas P- and L-selectin require additional interactions contributed by sulfate groups for high binding affinity, E-selectin can functionally bind sLex-modified glycolipids and glycoproteins. Rivipansel (3) marked the first pan-selectin antagonist, which simultaneously interacted with both the sLex and the sulfate binding site. The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLex mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin.

Thermodynamics-Guided Design Reveals a Cooperative Hydrogen Bond in DC-SIGN-targeted Glycomimetics.

Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections. By exploring ligand rigidification and hydrogen bond engineering, a monovalent glycomimetic with an unprecedented affinity for DC-SIGN in the low µM range was discovered. A matched molecular pair analysis based on microcalorimetric data revealed a stereospecific hydrogen bond interaction with Glu358/Ser360 as the origin of this cooperative and enthalpically dominated interaction. This detailed insight into the binding mechanism paves the way for an improvement of monovalent glycomimetics targeting DC-SIGN.

Bacterial Chaperone Domain Insertions Convert Human FKBP12 into an Excellent Protein-Folding Catalyst-A Structural and Functional Analysis.

Many folding enzymes use separate domains for the binding of substrate proteins and for the catalysis of slow folding reactions such as prolyl isomerization. FKBP12 is a small prolyl isomerase without a chaperone domain. Its folding activity is low, but it could be increased by inserting the chaperone domain from the homolog SlyD of E. coli near the prolyl isomerase active site. We inserted two other chaperone domains into human FKBP12: the chaperone domain of SlpA from E. coli, and the chaperone domain of SlyD from Thermococcus sp. Both stabilized FKBP12 and greatly increased its folding activity. The insertion of these chaperone domains had no influence on the FKBP12 and the chaperone domain structure, as revealed by two crystal structures of the chimeric proteins. The relative domain orientations differ in the two crystal structures, presumably representing snapshots of a more open and a more closed conformation. Together with crystal structures from SlyD-like proteins, they suggest a path for how substrate proteins might be transferred from the chaperone domain to the prolyl isomerase domain.

Comparative study of oral microbiota in the experimental long-term opioid exposure, after its withdrawal and the use of complex drug correction.

OBJECTIVE: Aim: To study changes of dental biofilm microbiota composition during experimental opioid exposure, after its withdrawal and when using of complex drug correction.. PATIENTS AND METHODS: Materials and Methods: Microbiological studies (48 rats) included microscopic and bacteriological methods, as well as determination of antibiotic susceptibility of microbial isolates. Ceftriaxone and pentoxifylline were used to correction the changes. RESULTS: Results: The action of opioid for 10 weeks caused considerable changes in the microbiocenosis, which was illustrated by a significant increasing of the opportunistic pathogens quantitative indicators and the emergence of pathogenic microbiota. Changes in the microbiocenosis at 6 weeks of opioid exposure and after its withdrawal for 4 weeks were expressed in the appearance of pathogenic microbiota and the absence of significant differences in quantitative indicators of saprophytic and opportunistic microflora compared to similar indicators in animals with 10 weeks opioid exposure. This indicated a slow progression of dysbiotic changes and the inflammatory process in the oral cavity of rats. CONCLUSION: Conclusions: After 10 weeks of experiment with opioid administration for 6 weeks and the use of ceftriaxone and pentoxifylline on the background of 4-week opioid withdrawal, a significant reduction of quantitative indicators of opportunistic bacteria and elimination of pathogenic species of microorganisms was determined. The use of complex drug correction on the background of 10 weeks of opioid exposure led to a significant reduction in the quantitative indicators of opportunistic pathogens and contributed to the elimination of most pathogenic species of microbiota under the action of ceftriaxone.

Effects of a dual-task activity on gait parameters of people with and without intellectual disabilities.

BACKGROUND: The main objective of this study was to evaluate gait parameters in people with intellectual disability (ID) and without intellectual disability (WID) in two different walking conditions [single task vs. dual task (DT)]. A secondary aim was to evaluate the dual-task cost (DTC) that the DT causes in each group. METHODS: A total of 119 participants joined in this study: 56 ID (30 men) and 63 WID (30 men). The OptoGait system was used to assess gait. In addition, Witty photocells were added to assess gait under the DT condition. RESULTS: Single support time was lower for participants with ID (P < 0.01), while double support time was higher (P < 0.05). All coefficients of variation for gait parameters were higher in participants with ID. Additionally, changes in gait were observed in both groups during the DT condition compared with the single-task condition. These changes were larger for participants with ID in step length, double support time and gait speed (P < 0.001), resulting in a higher DTC in these variables in the ID group (P < 0.01). CONCLUSIONS: Both groups reduced gait performance in the DT condition. However, greater gait variability occurred in the ID group. In addition, DTC was higher for the ID group in all variables analysed. Therefore, people with ID show worse gait performance during a DT than people WID.

An artificial nickel chlorinase based on the biotin-streptavidin technology.

Herein, we report on an artificial nickel chlorinase (ANCase) resulting from anchoring a biotinylated nickel-based cofactor within streptavidin (Sav). The resulting ANCase was efficient for the chlorination of diverse C(sp3)-H bonds. Guided by the X-ray analysis of the ANCase, the activity of the artificial chlorinase could be significantly improved. This approach opens interesting perspectives for late-stage functionalization of organic intermediates as it complements biocatalytic chlorination strategies.

Germ Line/Multipotency Genes Show Differential Expression during Embryonic Development of the Annelid Enchytraeus coronatus.

Germ line development and the origin of the primordial germ cells (PGCs) are very variable and may occur across a range of developmental stages and in several developmental contexts. In establishing and maintaining germ line, a conserved set of genes is involved. On the other hand, these genes are expressed in multipotent/pluripotent cells that may give rise to both somatic and germline cells. To begin elucidating mechanisms by which the germ line is specified in Enchytraeus coronatus embryos, we identified twenty germline/multipotency genes, homologs of Vasa, PL10, Piwi, Nanos, Myc, Pumilio, Tudor, Boule, and Bruno, using transcriptome analysis and gene cloning, and characterized their expression by whole-mount in situ hybridization. To answer the question of the possible origin of PGCs in this annelid, we carried out an additional description of the early embryogenesis. Our results suggest that PGCs derive from small cells originating at the first two divisions of the mesoteloblasts. PGCs form two cell clusters, undergo limited proliferation, and migrate to the developing gonadal segments. In embryos and juvenile E. coronatus, homologs of the germline/multipotency genes are differentially expressed in both germline and somatic tissue including the presumptive germ cell precursors, posterior growth zone, developing foregut, and nervous system.

Modification of the Physicochemical Properties of Active Pharmaceutical Ingredients via Lyophilization.

Bioavailability is an important biopharmaceutical characteristic of active pharmaceutical ingredients (APIs) that is often correlated with their solubility in water. One of the methods of increasing solubility is freeze drying (lyophilization). The article provides a systematic review of studies published from 2012 to 2022 aimed at optimizing the properties of active pharmaceutical ingredients by freeze drying. This review was carried out in accordance with the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). In general, 141 modifications of 36 APIs attributed to 12 pharmacological groups were reported in selected publications. To characterize the products of phase modification after lyophilization, a complex of analytical methods was used, including microscopic, thermal, X-ray, and spectral approaches. Solubility and pharmacokinetic parameters were assessed. There is a tendency to increase solubility due to the amorphization of APIs during lyophilization. Thus, the alcohol lyophilizate of dihydroquercetin is "soluble" in water compared to the initial substance belonging to the category "very poorly soluble". Based on the analysis of the literature, it can be argued that lyophilization is a promising method for optimizing the properties of APIs.

Summarizing the effects of different exercise types in chronic neck pain - a systematic review and meta-analysis of systematic reviews.

BACKGROUND: To date, no consensus exists as to whether one exercise type is more effective than another in chronic neck pain. This systematic review and meta-analysis of systematic reviews aimed to summarize the literature on the effect of various exercise types used in chronic neck pain and to assess the certainty of the evidence. METHODS: We searched the databases Ovid MEDLINE, Embase, Cochrane Library, SportDiscus, and Web of Science (Core Collection) for systematic reviews and meta-analyses on adults between 18 and 70 years with chronic neck pain lasting ≥ 12 weeks which investigated the effects of exercises on pain and disability. The included reviews were grouped into motor control exercise (MCE), Pilates exercises, resistance training, traditional Chinese exercise (TCE), and yoga. Study quality was assessed with AMSTAR-2 and the level of certainty for the effects of the exercise through GRADE. A narrative analysis of the results was performed and in addition, meta-analyses when feasible. RESULTS: Our database search resulted in 1,794 systematic reviews. We included 25 systematic reviews and meta-analyses including 17,321 participants (overlap not accounted for). The quality of the included reviews ranged from critically low to low (n = 13) to moderate to high (n = 12). We found low to high certainty of evidence that MCE, Pilates exercises, resistance training, TCE, and yoga have short-term positive effects on pain and that all exercise types except resistance training, show positive effects on disability compared to non-exercise controls. We found low to moderate certainty of evidence for conflicting results on pain and disability when the exercise types were compared to other exercise interventions in the short-term as well as in intermediate/long-term apart for yoga, as no long-term results were available. CONCLUSION: Overall, our findings show low to high certainty of evidence for positive effects on pain and disability of the various exercise types used in chronic neck pain compared to non-exercise interventions, at least in the short-term. Based on our results, no optimal exercise intervention for patients with chronic neck pain can be recommended, since no large differences between the exercise types were shown here. Because the quality of the included systematic reviews varied greatly, future systematic reviews need to increase their methodological quality. TRIAL REGISTRATION: Prospero CRD42022336014.

Vasa, Piwi, and Pl10 Expression during Sexual Maturation and Asexual Reproduction in the Annelid Pristina longiseta.

Naidids are tiny, transparent freshwater oligochaetes, which are well known for their ability to propagate asexually. Despite the fact that sexually mature individuals and cocoons with embryos are sometimes found in nature, in long-period laboratory cultures, worms reproduce agametically only. In this paper, we showed, for the first time, the expression of Vasa, Piwi, and Pl10 homologs in mature Pristina longiseta worms with well-developed reproductive system structures and germ cells. Although the animals have been propagated asexually by paratomic fission for over 20 years in our lab, some individuals become sexualized under standard conditions for our laboratory culture and demonstrate various stages of maturation. The fully matured animals developed a complete set of sexual apparatus including spermatheca, atrium, seminal vesicles, and ovisac. They also had a clitellum and were able to form cocoons. The cues for the initiation of sexual maturation are still unknown for P. longiseta; nevertheless, our data suggest that the laboratory strain of P. longiseta maintains the ability to become fully sexually mature and to establish germline products even after a long period of agametic reproduction. On the other hand, many of the sexualized worms formed a fission zone and continued to reproduce asexually. Thus, in this species, the processes of asexual reproduction and sexual maturation do not preclude each other, and Vasa, Piwi, and Pl10 homologs are expressed in both somatic and germline tissue including the posterior growth zone, fission zone, nervous system, germline cells, and gametes.

Protective Properties of Spheroidal Taxifolin Form in Streptozotocin-Induced Diabetic Rats.

One of the key factors in the pathogenesis of diabetes and its complications is oxidative stress. To inhibit this process, antioxidants may be helpful. Herein, we focused on the protective properties of taxifolin spheroidal form (TS) in the streptozotocin rat model of diabetes mellitus. After 4 weeks of treatment with TS, the fasting blood glucose level of the diabetic animals decreased by 12% compared with the level right after the injection of streptozotocin. While the feed intake in the untreated diabetic rats increased by 5.3% compared with the healthy group, the TS-treated group showed a pronounced 15.3% decrease. Therapeutic administration of TS has a protective effect on the pancreas and the liver against the cytotoxic action of streptozotocin. The plasma antioxidant capacity of all diabetic groups appeared to be approximately 15% lower than in healthy rats with no significant difference between the TS-treated and untreated diabetic animals. Apparently, this can be attributed to taxifolin and plasma proteins binding. These data demonstrate the potential of TS in antidiabetic therapy.

[1st Clinical Case Competition 'Open your eyes in narcolepsy']. / I Concurso de casos clínicos 'Abre los ojos en narcolepsia'.

TITLE: I Concurso de casos clínicos 'Abre los ojos en narcolepsia'.

Spatial Colinear but Broken Temporal Expression of Duplicated ParaHox Genes in Asexually Reproducing Annelids, Nais communis and Pristina longiseta.

ParaHox genes are key developmental regulators involved in the patterning of the digestive tract along the anteroposterior axis and the development of the nervous system. Most studies have focused on the function of these genes in embryogenesis, while their expression patterns in postembryonic development often remain unknown. In this study, we identified for the first time all ParaHox orthologs in two naidid oligochaetes, N. communis and P. longiseta, and described their expression patterns during normal growth and fission in these animals. We showed that Gsx and Cdx are presented by two paralogs, while Xlox is a single copy gene in both species. Using whole-mount in situ hybridization, we also found that orthologs, except for the Xlox gene, have similar activity patterns with minor differences in details, while the expression patterns of paralogs can differ significantly. However, all these genes are involved in axial patterning and/or in tissue remodeling during growth and asexual reproduction in naidids. Moreover, during paratomic fission, these genes are expressed with spatial colinearity but temporal colinearity is broken. The results of this study may be evidence of the functional diversification of duplicated genes and suggest involvement of the ParaHox genes in whole-body patterning during growth and asexual reproduction in annelids.

Genetic landscape in Russian patients with familial left ventricular noncompaction.

Background: Left ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214). Methods: All index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines. Results: A total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants -8 of 54 (14.8%) -have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 -7.37; p <0.001) per variant after adjustment for sex, age, and family. Conclusion: Overall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients.

A key GPCR phosphorylation motif discovered in arrestin2⋠CCR5 phosphopeptide complexes.

The two non-visual arrestins, arrestin2 and arrestin3, bind hundreds of GPCRs with different phosphorylation patterns, leading to distinct functional outcomes. Structural information on these interactions is available only for very few GPCRs. Here, we have characterized the interactions between the phosphorylated human CC chemokine receptor 5 (CCR5) and arrestin2. We identified several new CCR5 phosphorylation sites necessary for stable arrestin2 complex formation. Structures of arrestin2 in the apo form and complexes with CCR5 C-terminal phosphopeptides, together with NMR, biochemical, and functional assays, revealed three phosphoresidues in a pXpp motif that are essential for arrestin2 binding and activation. The identified motif appears responsible for robust arrestin2 recruitment in many other GPCRs. An analysis of receptor sequences and available structural and functional information provides hints on the molecular basis of arrestin2/arrestin3 isoform specificity. Our findings demonstrate how multi-site phosphorylation controls GPCR⋅arrestin interactions and provide a framework to probe the intricate details of arrestin signaling.

Label-free high-throughput screening via acoustic ejection mass spectrometry put into practice.

Acoustic droplet ejection-open port interface-mass spectrometry (ADE-OPI-MS) is a novel label-free analytical technique, promising to become a versatile readout for high-throughput screening (HTS) applications. The recent introduction of ADE-OPI-MS devices to the laboratory equipment market, paired with their compatibility with laboratory automation platforms, should facilitate the adoption of this technology by a broader community. Towards this goal, instrument robustness in the context of HTS campaigns - where up to millions of samples in complex matrices are tested in a short time frame - represents a major challenge, which explains the absence of detailed literature reports on this subject. Here, we present the results of our first fully automated HTS campaign, based on the ADE-OPI-MS technology, aiming to identify inhibitors of a metabolic enzyme in a >1 million compound library. The report encompasses the assay development and validation steps, as well as the adaptation for HTS requirements, where refinement of the capillary cleaning concept was crucial for final success. Altogether, our study unequivocally demonstrates the applicability of the ADE-OPI-MS technology for HTS-based drug discovery.

Does fatigue affect the kinematics of endurance running? / ¿Afecta la fatiga a la cinemática de la carrera de resistencia?

The purpose of this study was to determine the foot strike pattern (FSP), inversion (INV) and spatial-temporal variables in a large sample of recreational runners during a long-distance competition, according to sex and changes in the classification race. A total of 368 men and 67 women, who participated in the XVII International Half Marathon of Cordoba (Spain) were analysed. It was recorded at km 5 and km 15, where high-speed camcorder and 2D-photogrammetric techniques were used to measure FSP, INV, contact time (CT) and flight time (FT). The group that worsened their classification at km 15 increase RFS prevalence and INV asymmetry. A Pearson analysis indicates that variation of the classification in the race between the marks km 5 and km 15 is related with CT (r=0.429, p<0.001) and FT (r=-0.360, p<0.001). RFS prevalence and spatial-temporal parameters showed different patterns depending on whether the runners improved or worsened their ranking. (AU)

El objetivo de este estudio fue determinar el patrón de pisada, inversión y variables espaciotemporales para una amplia muestra de corredores amateurs, durante una carrera de larga distancia, según sexo y posición de clasificación. Se analizaron 368 hombres y 67 mujeres, que participaron en la XVII Media Maratón Internacional de Córdoba (España). Se registró el km 5 y km 15, utilizando técnicas de fotogrametría 2D de alta velocidad para medir la pisada, la inversión, el tiempo de contacto (TC) y el tiempo de vuelo (TV). El grupo que empeoró su clasificación en el km 15 aumentó la prevalencia de FSP y la asimetría del INV. Un análisis de Pearson indica que la variación de la clasificación en la carrera está relacionada con TC (r=0,429, p<0,001) y TV (r=-0,360, p<0,001). La prevalencia de retropié y los parámetros espaciotemporales mostraron diferentes patrones dependiendo de si los corredores mejoraron o empeoraron su clasificación. (AU)

Noisy voter model: Explicit expressions for finite system size.

Urn models are classic stochastic models that have been used to describe a diverse kind of complex systems. Voter and Ehrenfest's models are very well-known urn models. An opinion model that combines these two models is presented in this work and it is used to study a noisy voter model. In particular, at each temporal step, an Ehrenfest's model step is done with probability α or a voter step is done with probability 1-α. The parameter α plays the role of noise. By performing a spectral analysis, it is possible to obtain explicit expressions for the order parameter, susceptibility, and Binder's fourth-order cumulant. Recursive expressions in terms of the dual Hahn polynomials are given for first passage and return distributions to consensus and the equal coexistence of opinions. In the cases where they follow power-law distributions, their exponents are computed. This model has a pseudocritical noise value that depends on the system size; a discussion about thermodynamic limits is given.