Risk of early revision in total hip arthroplasty: the relative contribution of the surgeon versus the hospital.

BACKGROUND: Early revision for total hip arthroplasty is a serious adverse outcome. There are multiple contributing risk factors for early revision. Risk factors can exist at the level of the surgeon and the level of the institution. The primary research question of this study was to determine the relative contribution of surgeon-level and hospital-level variance to rates of early revision (overall and for infection) after primary total hip arthroplasty. METHODS: This is a registry-based study from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). Data for the most commonly used stem (Exeter V40) were used to reduce prosthesis variation from the analysis. A mixed effects Cox Model (also known as a frailty model) with crossed random effects for surgeon and hospital was used. Outcomes were early revision (within 2 years) for all causes and for infection. This model allowed for the risk of early revision to be explained by the variability at the surgeon level or hospital level. RESULTS: There were 32 031 procedures performed by 735 surgeons across 250 hospitals between 1 January 2015 and 31 December 2019. Surgeon variability significantly contributed to overall variation in revision for any cause and revision for infection (P < 0.0001). There was no significant contribution of hospital-level variation to overall revision or for infection. CONCLUSIONS: Surgeon-level factors play a more important role than institution-level factors in early revision after primary total hip arthroplasty. If surgeons are identified as having a higher risk of revision, there is potential for surgeon-level practice change to reduce the risk of early revision.

C1-C2 sublaminar taping for displaced odontoid synchondrosis fracture in an infant: A case report and novel surgical technique.

Pediatric cervical spine injuries are rare, and the diagnosis and management can be challenging. Surgical intervention has been recommended in unstable odontoid synchondrosis injuries or those that have failed nonoperative measures. However, the literature remains sparse on the operative management of severe injuries due to the low incidence. An 18-month-old female sustained an unstable odontoid synchondrosis fracture from a motor vehicle accident. Due to ongoing instability after initial immobilization in a halo, the decision was made to proceed with surgical management. With the patient positioned prone and neural monitoring throughout, a posterior approach was utilized. Subperiosteal exposure of the C1 posterior arch was performed bilaterally. A spinal fixation band was passed under the right C1 posterior arch, around the C2 spinous process, under the left C1 posterior arch, and finally back under the C2 spinous process. The C1-C2 distraction was reduced using intraoperative imaging, and the sublaminar tape construct was secured and reinforced. The halo was then reattached. Postoperative recovery was complicated by a halo pin-site infection which was treated with oral antibiotics. The halo was removed after 3 months, following a computerized tomography that demonstrated union. X-rays at 6 months revealed anatomical alignment with the union. Surgery is recommended in pediatric odontoid synchondrosis fractures refractory to nonoperative management. Sublaminar taping of C1-C2 with a spinal fixation band has been demonstrated to be an effective surgical technique in the management of an unstable odontoid synchondrosis fracture.

Trends in Pediatric Anterior Cruciate Ligament Reconstruction in Australia: An Analysis of Australian Medicare Benefits Schedule Database From 2001 to 2020.

BACKGROUND: Anterior cruciate ligament (ACL) injuries are common and increasingly prevalent in the pediatric population. However, there remain sparse epidemiological data on the surgical treatment of these injuries. The objective of this study is to assess the trends in the rate of pediatric ACL reconstruction in Australia over the past 2 decades. METHODS: The incidence of ACL reconstruction from 2001 to 2020 in patients 5 to 14 years of age was analyzed using the Australian Medicare Benefits Schedule (MBS) database. Data were stratified by sex and year. An offset term was introduced using population data from the Australian Bureau of Statistics to account for population changes over the study period. RESULTS: A total of 3719 reconstructions for the management of pediatric ACL injuries were performed in Australia under the MBS in the 20-year period from 2001 to 2020. There was a statistically significant annual increase in the total volume and per capita volume of pediatric ACL reconstructions performed across the study period ( P <0.0001). There was a significant increase in the rate of both male and female reconstructions ( P <0.0001), with a greater proportion of reconstructions performed on males (n=2073, 56%) than females (n=1646, 44%). In 2020, the rate of pediatric ACL reconstructions decreased to a level last seen in 2015, likely due to the effects of COVID-19. CONCLUSIONS: The incidence of ACL reconstruction in skeletally immature patients has increased in Australia over the 20-year study period. This increase is in keeping with evidence suggesting poor outcomes with nonoperative or delayed operative management.

First Potent Macrocyclic A3 Adenosine Receptor Agonists Reveal G-Protein and ß-Arrestin2 Signaling Preferences.

(N)-Methanocarba adenosine derivatives (A3 adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at N6 and C2 positions with terminal alkenes for ring closure. The resulting macrocycles of 17-20 atoms retained affinity, indicating a spatially proximal orientation of these receptor-bound chains, consistent with molecular modeling of 12. C2-Arylethynyl-linked macrocycle 19 was more A3AR-selective than 2-ether-linked macrocycle 12 (both 5'-methylamides, human (h) A3AR affinities (Ki): 22.1 and 25.8 nM, respectively), with lower mouse A3AR affinities. Functional hA3AR comparison of two sets of open/closed analogues in ß-arrestin2 and Gi/o protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1. The potencies of 1 at all three Gαi isoforms were slightly less than its hA3AR binding affinity (Ki: 1.4 nM), while the Gαi1 and Gαi2 potencies of macrocycle 12 were roughly an order of magnitude higher than its radioligand binding affinity. Gαi2-coupling was enhanced in macrocycle 12 (EC50 2.56 nM, ∼40% greater maximal efficacy than 1). Di-O-allyl precursor 18 cyclized to form 19, increasing the Gαi1 potency by 7.5-fold. The macrocycles 12 and 19 and their open precursors 11 and 18 potently stimulated ß-arrestin2 recruitment, with EC50 values (nM) of 5.17, 4.36, 1.30, and 4.35, respectively, and with nearly 50% greater efficacy compared to 1. This example of macrocyclization altering the coupling pathways of small-molecule (nonpeptide) GPCR agonists is the first for potent and selective macrocyclic AR agonists. These initial macrocyclic derivatives can serve as a guide for the future design of macrocyclic AR agonists displaying unanticipated pharmacology.

Recruitment of a Middling Promiscuous Enzyme Drives Adaptive Metabolic Evolution in Escherichia coli.

A key step in metabolic pathway evolution is the recruitment of promiscuous enzymes to perform new functions. Despite the recognition that promiscuity is widespread in biology, factors dictating the preferential recruitment of one promiscuous enzyme over other candidates are unknown. Escherichia coli contains four sugar kinases that are candidates for recruitment when the native glucokinase machinery is deleted-allokinase (AlsK), manno(fructo)kinase (Mak), N-acetylmannosamine kinase (NanK), and N-acetylglucosamine kinase (NagK). The catalytic efficiencies of these enzymes are 103- to 105-fold lower than native glucokinases, ranging from 2,400 M-1 s-1 for the most active candidate, NagK, to 15 M-1 s-1 for the least active candidate, AlsK. To investigate the relationship between catalytic activities of promiscuous enzymes and their recruitment, we performed adaptive evolution of a glucokinase-deficient E. coli strain to restore glycolytic metabolism. We observed preferential recruitment of NanK via a trajectory involving early mutations that facilitate glucose uptake and amplify nanK transcription, followed by nonsynonymous substitutions in NanK that enhance the enzyme's promiscuous glucokinase activity. These substitutions reduced the native activity of NanK and reduced organismal fitness during growth on an N-acetylated carbon source, indicating that enzyme recruitment comes at a cost for growth on other substrates. Notably, the two most active candidates, NagK and Mak, were not recruited, suggesting that catalytic activity alone does not dictate evolutionary outcomes. The results highlight our lack of knowledge regarding biological drivers of enzyme recruitment and emphasize the need for a systems-wide approach to identify factors facilitating or constraining this important adaptive process.

Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: N6, C2 and 5'-Modified (N)-methanocarba-adenosine derivatives.

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT2B serotonin receptors as antagonists, predominantly containing branched N6-alkyl groups. N6-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT2Rs, while only N6-dicyclohexyl-methyl derivative 35 showed weak 5-HT2AR affinity (Ki 3.6 µM). The highest 5-HT2BR affinities were Ki 11-23 nM (N6-dicyclopropyl-methyl-2-iodo 11, 2-chloro-5'-deoxy-5'-methylthio 15 and N6-((R)-cyclobuty-cyclopropyl-methyl)-2-iodo 43), and Ki 73 nM at 5-HT2CR for 36. Direct comparison of adenine ribosides and their corresponding rigid (N)-methanocarba derivatives (cf. 51 and MRS8099 45) indicated a multifold affinity enhancement with the bicyclic ring system. Compounds 43, 45 and 48 were functional 5-HT2BR (KB 2-3 nM) and 5-HT2CR (KB 79-328 nM) antagonists in a Gq-mediated calcium flux assay, with 5-HT2BR functional selectivity ranging from 45- (48) to 113-fold (43). Substantial adenosine receptor (AR) affinity (Ki, A1AR < Ki, A3AR < Ki, A2AAR) was still present in this series, suggestive of dual acting compounds: 5-HT2B antagonist and A1AR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HT2BR binding selectivity (32-fold vs. 5-HT2CR, 4-fold vs. A1AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.

Self-reported reflective functioning and father-child interactions in a sample of fathers who have used intimate partner violence.

Reflective functioning (RF) has been found to be associated with mother-child interactions, but less is known about the association of fathers' self and child-focused RF and father-child relationships.  Fathers who have histories of intimate partner violence (IPV) are known to have poor RF, which may impact their father-child interactions.  The current study was designed to examine how types of RF are associated with father-child relationships.  Pretreatment assessments and recorded, coded father-child play interactions were used to examine associations among fathers' history of adverse childhood experiences (ACES), RF and coded father-child play interactions in a sample of 47 fathers with a history of IPV use in the last 6 months with their coparent.  Fathers' ACES and their child's mental states (CM) were associated with father-child dyadic play interactions.  Fathers with greater ACES and higher scores on CM had the most dyadic tension and constriction during play interactions.  Those with high ACES but low CM had scores similar to those with low ACES and low CM.  These results indicate that fathers who have used IPV and have a history of significant adversity may benefit from interventions to increase their child-focused RF and further improve their interactions with their children.

Se ha determinado que el Funcionamiento con Reflexión (RF) está asociado con las interacciones madre-niño, pero menos se conoce acerca de la asociación del propio RF de los papás y enfocado en el niño con las relaciones papá-niño. A los papás que cuentan con un historial de violencia con la pareja íntima (IPV) se les conoce por tener un débil RF, lo cual puede impactar sus interacciones papá-niño. El presente estudio se diseñó para examinar cómo los tipos de RF se asocian con las relaciones papá-niño. Las evaluaciones anteriores al tratamiento y el juego papá niño grabado y codificado se usaron para examinar las asociaciones entre el historial de los papás sobre experiencias adversas de niñez (ACES), RF y las codificadas interacciones papá-niño en un grupo muestra de 47 papás con un historial de uso de IPV en los últimos 6 meses con sus co-progenitores. Las ACES de los papás y ciertamente de los estados mentales de sus niños (CM) se asociaron con las interacciones de juego diádicas papá-niño. Los papás con mayor cantidad de ACES y más altos puntajes en CM presentaron la tensión y constricción más diádica durante las interacciones de juego. Aquellos con alto número de ACES, pero un bajo CM presentaron puntajes similares a aquellos con bajo número de ACES y un bajo CM. Estos resultados indican que los papás que han usado IPV y que tienen un historial de adversidad significativo pudieran beneficiarse de intervenciones para incrementar su RF con enfoque en el niño a fin de mejorar sus interacciones con sus niños.

Il est établi que le fonctionnement de réflexion (en anglais Reflective functioning, ici abrégé selon le français FR) est lié aux interactions mère-enfant mais on sait peu de choses sur le lien entre le FR sur soi et l'enfant des pères et les relations père-enfant. On sait que les pères ayant un passé de violence entre partenaires intimes (ici VPI) ont un FR diminué qui peut impacter leurs interactions père-enfant. Cette étude a été conçue afin d'examiner la manière dont les types de FR sont liés aux relations père-enfant. Des évaluations pré-traitement et des jeux père-enfant enregistrés et codés ont été utilisés afin d'examiner les liens entre l'histoire d'expériences négatives durant l'enfance (ACE) des pères, le FR et les interactions de jeu père-enfant codées chez un échantillon de 47 pères ayant un passé de VPI dans les six derniers mois avec leur coparent. Les ACE des pères et certainement des états mentaux de leur enfant (CM en anglais) ont été liés aux interactions de jeu dyadique père-enfant. Les pères avec plus de ACE et des scores CM plus élevés avaient le plus de tension dyadique et de constriction durant les interactions de jeu. Ceux avec des ACE élevés mais des CM bas avaient des scores similaires à ceux avec des ACE faibles et des CM faibles. Ces résultats indiquent que les pères ayant fait preuve de VPI qui ont un passé d'adversité importante peuvent bénéficier d'interventions pour accroître leur FR focalisé sur l'enfant afin d'améliorer leurs interactions avec leurs enfants.

Surgical management of clavicle fractures in Australia: an analysis of Australian Medicare Benefits Schedule database from 2001 to 2020.

BACKGROUND: There is no consensus on the optimal management of clavicle fractures, with advocates of both operative and non-operative management. The objective of this study is to assess the trends in the management of clavicle fractures in Australia over the past two decades. METHODS: The incidence of surgical fixation of clavicle fractures from 2001 to 2020 was analysed using the Australian Medicare Benefits Schedule database, reflective of operations performed on privately insured patients, thus excluding public patients and compensable cases. An offset term was utilized with data from the Australian Bureau of Statistics to account for population changes over the study period. RESULTS: A total of 17 089 procedures for the management of clavicle fractures were performed from 2001 to 2020. The incidence of operative intervention increased from 1.87 per 100 000 in 2001 to a peak of 6.63 per 100 000 in 2016. An overall increase was seen in males (310%) and females (347%) over the study period, as well as across all age groups. A greater proportion of operative interventions was performed on males (n = 14 075, 82%) than females (n = 3014, 18%, P < 0.001). The greatest increase in intervention was noted in those aged 65 or older (14% increase per year, 95% CI 11%-17%, P < 0.05). In 2020, the incidence of operative intervention decreased to a level last seen in 2013. CONCLUSIONS: The incidence of operative interventions for clavicle fractures has increased in Australia over the 20-year study period. This increase is in keeping with recent evidence suggesting several advantages when displaced mid-shaft clavicle fractures are operatively managed.

An audit of cancellation of elective surgery in paediatric patients at Chris Hani Baragwanath Academic Hospital.

Background: Cancellation of elective surgery is one of the quality indicators of theatre operation worldwide. The cancellation of elective surgery in paediatric patients is a worldwide problem with the rates ranging from 0.21% to 44%. This study aimed to determine the rates and describe the reasons for cancellation of elective surgeries in paediatric patients at Chris Hani Baragwanath Academic Hospital (CHBAH). Materials and Methods: A retrospective study was conducted using theatre records from 1st January to 31st December 2019. The numbers and reasons for elective paediatric surgeries were reviewed. Data were collected using the structured collection sheet and entered into Microsoft Excel. Statistical Package for the Social Sciences was also used to further analyse the data. Results were expressed as percentages in a graph and table forms. Results: In the year 2019, a total of 3399 elective paediatric procedures were scheduled in 14 specialities at CHBAH. Of these, 634 (19%) were cancelled due to various reasons. The highest number of cases cancelled were from paediatric surgery and neonates (n = 204, 31%), followed by ear nose and throat (n = 99, 24%), burns (n = 80, 20%) and paediatric orthopaedics (n = 79, 16%). The most common reason for cancellation of elective surgery in paediatric patients at CHBAH was found to be time constraint (34%). The reasons for cancellation in our study were mostly due to avoidable factors at 68% and non-avoidable at 32%. Conclusion: The rate of cancellation in our study was high. Majority of the causes for cancellation were avoidable.

Flail chest injury-changing management and outcomes.

PURPOSE: The purpose of this study was to assess trends in management of flail chest injuries over time and to determine impact on patient outcomes. METHODS: A retrospective review of data from a prospectively collated database of all trauma patients admitted to a level 1 trauma service in Victoria was conducted. All trauma patients admitted to the hospital between July 2008 and June 2020 with an Abbreviated Injury Scale (AIS) code for flail chest injury were included. RESULTS: Our study included 720 patients, mean age was 59.5 ± 17.3 years old, and 76.5% of patients were male. Length of ICU stay decreased on average by 9 h each year. Regional anaesthesia use increased by 15% per year (0% in 2009 to 36% in 2020) (p < 0.001). Surgical stabilisation of rib fractures increased by 16% per year (2.9% in 2009 to 22.3% in 2020) (p = 0.006). The use of invasive ventilation decreased by 14% per year (70% in 2008 to 27% in 2020) (p < 0.001), and invasive ventilation time decreased by 8 h per year (p = 0.007). CONCLUSION: Over the past decade, we have seen increasing rates of regional anaesthesia and surgical rib fixation in the management of flail chest. This has resulted in lower requirements for and duration of invasive mechanical ventilation and intensive care unit stay but has not impacted mortality in this patient cohort.

Fluorescent A2A and A3 adenosine receptor antagonists as flow cytometry probes.

Adenosine receptor (AR) ligands are being developed for metabolic, cardiovascular, neurological, and inflammatory diseases and cancer. The ease of drug discovery is contingent on the availability of pharmacological tools. Fluorescent antagonist ligands for the human A2A and A3ARs were synthesized using two validated pharmacophores, 1,3-dipropyl-8-phenylxanthine and triazolo[1,5-c]quinazolin-5-yl)amine, which were coupled to eight reporter fluorophores: AlexaFluor, JaneliaFluor (JF), cyanine, and near infrared (NIR) dyes. The conjugates were first screened using radioligand binding in HEK293 cells expressing one of the three AR subtypes. The highest affinities at A2AAR were Ki 144-316 nM for 10, 12, and 19, and at A3AR affinity of Ki 21.6 nM for 19. Specific binding of JF646 conjugate MRS7774 12 to the HEK293 cell surface A2AAR was imaged using confocal microscopy. Compound 19 MRS7535, a triazolo[1,5-c]quinazolin-5-yl)amine containing a Sulfo-Cy7 NIR dye, was suitable for A3AR characterization in whole cells by flow cytometry (Kd 11.8 nM), and its bitopic interaction mode with an A3AR homology model was predicted. Given its affinity and selectivity (11-fold vs. A2AAR, ~ 50-fold vs. A1AR and A2BAR) and a good specific-to-nonspecific binding ratio, 19 could be useful for live cell or potentially a diagnostic in vivo NIR imaging tool and/or therapy targeting the A3AR.

Troponin as a predictor of outcomes in transcatheter aortic valve implantation: systematic review and meta-analysis.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is emerging as a therapeutic gold standard in the management of aortic stenosis. However, post-procedural complications of this procedure are being increasingly recognised. We therefore performed this systematic review and meta-analysis on the prognostic value of elevated troponin prior to TAVI to predict risk of post-procedural complications. METHODS: We searched Medline (Ovid), Embase (Ovid), and the Cochrane Library from inception until May 2022, and included studies on the association between elevated pre-procedural troponin with 30-day mortality, long-term mortality, and post-procedural myocardial injury (PPMI). We generated summary odds ratios (OR) and hazards ratios (HR) using random-effects meta-analysis and performed subgroup analyses to evaluate differences in troponin threshold selection. Inter-study heterogeneity was tested using the I2 test. RESULTS: We included 10 studies involving 4200 patients. Serum troponin elevation prior to TAVI was significantly associated with long-term mortality [HR = 2.09 (95% CI 1.30-3.36)], but not with 30-day mortality [OR 1.76 (95% CI 0.96-3.22)]. Subgroup analysis showed a trend towards increased effect size and statistical significance for 30-day mortality as troponin elevation was more narrowly defined. Two studies reported on PPMI and found no statistically significant mean difference between groups. CONCLUSIONS: Raised serum troponin is associated with increased long-term mortality following TAVI. Further clarification on the optimal troponin threshold for risk identification is required. High-quality studies that utilise ROC analysis for threshold selection are warranted.

Evaluation of the Design, Development, and Performance of a Mass-Flow Based, Open-Source Buffer Manufacturing System.

Buffer solutions are a critical component of the manufacturing process for therapeutic proteins and other biomolecules. The traditional way to make and use buffers is space and resource intensive, creating operational bottlenecks that impact efficiencies and costs. Here we describe a full-scale, current Good Manufacturing Practices (cGMP) capable buffer stock blending system that has an open-source, configurable design and that overcomes the challenges of traditional buffer preparation. The system comprises simplified control and operation using mass flow to provide on-demand supply of buffer solutions. The system also has self-cleaning capability and is amenable to be operated as a closed system. The data will demonstrate the excellent performance and capabilities of the system as well as illustrate its potential transformative impact on biomanufacturing.

Management of glenoid bone loss in primary reverse shoulder arthroplasty : a systematic review and meta-analysis.

AIMS: Rates of reverse total shoulder arthroplasty (rTSA) continue to grow. Glenoid bone loss and deformity remains a technical challenge to the surgeon and may reduce improvements in patients' outcomes. However, there is no consensus as to the optimal surgical technique to best reconstruct these patients' anatomy. This review aims to compare the outcomes of glenoid bone grafting versus augmented glenoid prostheses in the management of glenoid bone loss in primary reverse total shoulder arthroplasty. METHODS: This systematic review and meta-analysis evaluated study-level data in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We performed searches of Medline (Ovid), Embase (Ovid), and PubMed from their dates of inception to January 2022. From included studies, we analyzed data for preoperative and postoperative range of motion (ROM), patient-reported functional outcomes, and complication rates. RESULTS: A total of 13 studies (919 shoulders) were included in the analysis. The mean age of patients at initial evaluation was 72.2 years (42 to 87), with a mean follow-up time of 40.7 months (24 to 120). Nine studies with 292 rTSAs evaluated the use of bone graft and five studies with 627 rTSAs evaluated the use of augmented glenoid baseplates. One study was analyzed in both groups. Both techniques demonstrated improvement in patient-reported outcome measures and ROM assessment, with augmented prostheses outperforming bone grafting on improvements in the American Shoulder and Elbow Surgeons Score. There was a higher complication rate (8.9% vs 3.5%; p < 0.001) and revision rate among the bone grafting group compared with the patients who were treated with augmented prostheses (2.4% vs 0.6%; p = 0.022). CONCLUSION: This review provides strong evidence that both bone graft and augmented glenoid baseplate techniques to address glenoid bone loss give excellent ROM and functional outcomes in primary rTSA. The use of augmented base plates may confer fewer complications and revisions.Cite this article: Bone Joint J 2022;104-B(12):1334-1342.

Effects of Purinergic Receptor Deletion or Pharmacologic Modulation on Pulmonary Inflammation in Mice.

COVID-19 disease is associated with progressive accumulation of SARS-CoV-2-specific mRNA, which is recognized by innate immune receptors, such as TLR3. This in turn leads to dysregulated production of multiple cytokines, including IL-6, IFN-γ, CXCL1, and TNF-α. Excessive production of these cytokines leads to acute lung injury (ALI), which consequently compromises alveolar exchange of O2 and CO2. It is therefore of considerable interest to develop novel therapies that reduce pulmonary inflammation and stem production of pro-inflammatory cytokines, potentially for COVID-19 patients that are at high risk of developing severe disease. Purinergic signaling has a central role in fine-tuning the innate immune system, with P2 (nucleotide) receptor antagonists and adenosine receptor agonists having anti-inflammatory effects. Accordingly, we focused here on the potential role of purinergic receptors in driving neutrophilic inflammation and cytokine production in a mouse model of pulmonary inflammation. To mimic the effects of SARS-CoV-2-specific RNA accumulation in mice, we administered progressively increasing daily doses of a viral mimetic, polyinosinic:polycytidylic acid [poly(I:C)] into the airways of mice over the course of 1 week. Some mice also received increasing daily doses of ovalbumin to mimic virus-encoded protein accumulation. Animals receiving both poly(I:C) and ovalbumin displayed particularly high cytokine levels and neutrophilia, suggestive of both innate and antigen-specific, adaptive immune responses. The extent of these responses was diminished by genetic deletion (P2Y14R, P2X7R) or pharmacologic modulation (P2Y14R antagonists, A3AR agonists) of purinergic receptors. These results suggest that pharmacologic modulation of select purinergic receptors might be therapeutically useful in treating COVID-19 and other pulmonary infections.

Selective A3 Adenosine Receptor Antagonist Radioligand for Human and Rodent Species.

The A3 adenosine receptor (A3AR) is a target for pain, ischemia, and inflammatory disease therapy. Among the ligand tools available are selective agonists and antagonists, including radioligands, but most high-affinity non-nucleoside antagonists are limited in selectivity to primate species. We have explored the structure-activity relationship of a previously reported A3AR antagonist DPTN 9 (N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide) for radiolabeling, including 3-halo derivatives (3-iodo, MRS7907), and characterized 9 as a high -affinity radioligand [3H]MRS7799. A3AR K d values were (nM): 0.55 (human), 3.74 (mouse), and 2.80 (rat). An extended methyl acrylate (MRS8074, 19) maintained higher affinity (18.9 nM) than a 3-((5-chlorothiophen-2-yl)ethynyl) derivative 20. Compound 9 had an excellent brain distribution in rats (brain/plasma ratio ∼1). Receptor docking predicted its orthosteric site binding by engaging residues that were previously found to be essential for AR binding. Thus the new radioligand promises to be a useful species-general antagonist tracer for receptor characterization and drug discovery.

Relationships between the hard and soft dimensions of the nose in Pan troglodytes and Homo sapiens reveal the positions of the nasal tips of Plio-Pleistocene hominids.

By identifying homogeneity in bone and soft tissue covariation patterns in living hominids, it is possible to produce facial approximation methods with interspecies compatibility. These methods may be useful for producing facial approximations of fossil hominids that are more realistic than currently possible. In this study, we conducted an interspecific comparison of the nasomaxillary region in chimpanzees and modern humans with the aim of producing a method for predicting the positions of the nasal tips of Plio-Pleistocene hominids. We addressed this aim by first collecting and performing regression analyses of linear and angular measurements of nasal cavity length and inclination in modern humans (Homo sapiens; n = 72) and chimpanzees (Pan troglodytes; n = 19), and then performing a set of out-of-group tests. The first test was performed on four subjects that belonged to the same genus as the training sample, i.e., Homo (n = 2) and Pan (n = 2), and the second test, which functioned as an interspecies compatibility test, was performed on Pan paniscus (n = 1), Gorilla gorilla (n = 3), Pongo pygmaeus (n = 1), Pongo abelli (n = 1), Symphalangus syndactylus (n = 3), and Papio hamadryas (n = 3). We identified statistically significant correlations in both humans and chimpanzees with slopes that displayed homogeneity of covariation. Prediction formulae combining these data were found to be compatible with humans and chimpanzees as well as all other African great apes, i.e., bonobos and gorillas. The main conclusion that can be drawn from this study is that our set of regression models for approximating the position of the nasal tip are homogenous among humans and African apes, and can thus be reasonably extended to ancestors leading to these clades.

Interaction of A3 adenosine receptor ligands with the human multidrug transporter ABCG2.

Various adenosine receptor nucleoside-like ligands were found to modulate ATP hydrolysis by the multidrug transporter ABCG2. Both ribose-containing and rigidified (N)-methanocarba nucleosides (C2-, N6- and 5'-modified), as well as adenines (C2-, N6-, and deaza modified), were included. 57 compounds out of 63 tested either stimulated (50) or inhibited (7) basal ATPase activity. Structure-activity analysis showed a separation of adenosine receptor and ABCG2 activities. The 7-deaza modification had favorable effects in both (N)-methanocarba nucleosides and adenines. Adenine 37c (MRS7608) and (N)-methanocarba 7-deaza-5'-ethyl ester 60 (MRS7343) were found to be potent stimulators of ABCG2 ATPase activity with EC50 values of 13.2 ± 1.7 and 13.2 ± 2.2 nM, respectively. Both had affinity in the micromolar range for A3 adenosine receptor and lacked the 5'-amide agonist-enabling group (37c was reported as a weak A3 antagonist, Ki 6.82 µM). Compound 60 significantly inhibited ABCG2 substrate transport (IC50 0.44 µM). Docking simulations predicted the interaction of 60 with 21 residues in the drug-binding pocket of ABCG2.

A3 adenosine receptor agonists containing dopamine moieties for enhanced interspecies affinity.

Following our study of 4'-truncated (N)-methanocarba-adenosine derivatives that displayed unusually high mouse (m) A3AR affinity, we incorporated dopamine-related N6 substituents in the full agonist 5'-methylamide series. N6-(2-(4-Hydroxy-3-methoxy-phenyl)ethyl) derivative MRS7618 11 displayed Ki (nM) 0.563 at hA3AR (∼20,000-fold selective) and 1.54 at mA3AR. 2-Alkyl ethers maintained A3 affinity, but with less selectivity than 2-alkynes. Parallel functional assays of G protein-dependent and ß-arrestin 2 (ßarr2)-dependent pathways indicate these are full agonists but not biased. Through use of computational modeling, we hypothesized that phenyl OH/OMe groups interact with polar residues, particularly Gln261, on the mA3AR extracellular loops as the basis for the affinity enhancement. Although the pharmacokinetics indicated facile clearance of parent O-methyl catechol nucleosides 21 and 31, prolonged mA3AR activation in vivo was observed in a hypothermia model, suggested potential formation of active metabolites through demethylation. Selected analogues induced mouse hypothermia following i.p. injection, indicative of peripheral A3AR agonism in vivo.

Perioperative gabapentinoid use lowers short-term opioid consumption following lower limb arthroplasty: Systematic review and meta-analysis.

BACKGROUND: The management of post-operative pain and high levels of acute and chronic opioid use following total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain challenges to the perioperative team. We performed a system-atic review and meta-analysis to determine the opioid sparing effects, analgesic effects, and safety profile of perioperative gabapentinoid usage in lower limb arthroplasty. METHODS: We searched multiple databases from inception until May 2019 and included randomized controlled trials (RCT) on perioperative gabapentinoids in lower limb arthroplasty. The primary outcome was cumulative opioid con-sumption (oral morphine equivalents) at 24 and 48 hours, and the secondary outcomes were pain scores, time to hospi-tal discharge, and adverse events including nausea, vomiting, pruritus, and sedation. Methodological quality was as-sessed using the Cochrane tool. The grading of recommendations assessment, development, and evaluation method-ology for the certainty of evidence was also used. RESULTS: We included 19 RCT involving 2,455 patients undergoing lower limb arthroplasty. The overall methodological quality of included studies was good. Gabapentinoid use was associated with a significant reduction in opioid consump-tion at 24 hour (mean difference (MD) 22.81 mg [95 percent Confidence Interval (CI) 13.64-31.98]) and 48 hour (MD 44.03 mg [95 percent CI 16.92-71.14]). We found no meaningful difference in pain scores at rest between gabapenti-noid and placebo groups at 24 or 48 hours. Gabapentinoid use reduced the risk of post-operative nausea (risk ratio (RR) 0.69 [95 percent CI 0.57-0.82]), vomiting (RR 0.65 [95 percent CI 0.47-0.91]), and pruritus (RR 0.60 [0.37-0.98]), but not sedation (RR 1.25 [0.76-2.06]). There was no effect on time to discharge from hospital (MD-0.05 days [95 per-cent CI -0.31 to 0.20]. CONCLUSIONS: The addition of gabapentinoids to perioperative multimodal analgesia decreases opioid consumption fol-lowing lower limb arthroplasty, while also lowering rates of nausea, vomiting, and pruritus. Further study is required to evaluate the effect of gabapentinoid use on long-term opioid use and dependence.