Patients Undergoing Reverse Total Shoulder Arthroplasty Have Less Pain and Require Fewer Opioid Pain Medications Compared to Anatomic Total Shoulder Arthroplasty in the Early Postoperative Period: A Retrospective Review.

BACKGROUND: Recovery after anatomic total shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA) has many similarities; however, recently surgeons have suggested patients undergoing rTSA have a less difficult postoperative course with less pain compared with aTSA patients. Given the heightened awareness to postoperative pain control and opioid consumption, as well as the expanding indications for rTSA, we sought to determine the differences in pain and opioid consumption between aTSA and rTSA patients in a 12-week postoperative period. METHODS: A retrospective chart review was performed to identify all patients who underwent a primary aTSA or rTSA from January 2013 to April 2018 at a single institution. Patients with recorded visual analog scale (VAS) and American Shoulder and Elbow Surgeons (ASES) scores were included for analysis. Revision arthroplasties were excluded. VAS scores were recorded preoperatively and at standard 2-week, 6-week, and 12-week postoperative time points. P-values < 0.05 were considered statistically significant, except where Bonferroni corrections were applied. RESULTS: A total of 690 patients underwent TSA (278 aTSA, 412 rTSA). Preoperatively, aTSA and rTSA patient groups had similar VAS scores (6 vs 6, P = 0.38). Postoperatively, the aTSA group had a higher VAS at the 6-week visit, compared with rTSA patients (2.8 vs 2.2, P = 0.003). aTSA patients remained on opioids at a higher rate at the 2-week (62.4% vs 45.6%, P = < 0.001) time period. aTSA patients needed more opioid prescription refills before the 2-week (61.7% vs 45.5%, P = <0.001) and 6-week (40.4% vs 30.7%, P = 0.01) follow-up visits. CONCLUSIONS: Despite similar preoperative VAS and rates of preoperative opioid use, aTSA patients required more opioid medication refills and remained on opioids for a longer duration in the early postoperative period to achieve similar postoperative pain control as indicated by similar VAS. This study suggests that the recovery from rTSA is less difficult compared with aTSA as indicated by VAS and opioid consumption.

Hip Arthroplasty Femoral Stem Designs and Their Association With Early Postoperative Periprosthetic Femoral Fractures.

BACKGROUND: Periprosthetic femoral fractures (PFFs) in total hip arthroplasty (THA), especially those in contact with the diaphyseal stem, carry high morbidity. This study evaluated how stem design influences the risk of early Vancouver B PFF or other PFF requiring operative intervention after THA. METHODS: A multicenter, retrospective study of 3,433 primary cementless THAs performed from 2014 to 2021 included 2,302 single-taper (micro M/L [n = 1,169]; M/L [n = 1,133]) and 1,131 double-taper (fit-and-fill [n = 420]; compaction-collared [n = 711]) stems. Mean follow-up was 2.2 years (range, 0.3 to 6.5 years). Primary outcomes were Vancouver B and surgically treated postoperative PFFs among differing femoral stems. Secondary outcomes included rates of intraoperative and postoperative Vancouver A and C PFFs. RESULTS: Forty five postoperative PFFs (1.3%) occurred within 8.8 weeks (median), 25 of which were Vancouver B (0.7%) and 20 total PFFs that required operative intervention (0.6%). Compaction-collared stems had a decreased risk of Vancouver B (hazard ratio 0.18, 95% confidence interval: 0.03-0.97 P = .044) and any surgically treated PFF (hazard ratio 0.10, 95% confidence interval: 0.01-0.95; P = .037). Intraoperative PFFs were most common with fit-and-fill stems (3.6%, P < .001) and Vancouver A with compaction-collared stems (1.8%, P < .001). The cohort with PFF had a higher Charlson comorbidity index (P = .004), more women (P = .001), more Dorr A or C femora (P = .013), and more posterior or lateral surgical approaches compared to those without PFF (P ≤ .001). CONCLUSION: After controlling for confounding variables, compaction-collared stems had a significantly lower risk of postoperative Vancouver B and PFF requiring operative treatment than single-taper and double-taper stems.

Opioid-sparing pain management protocol after shoulder arthroplasty results in less opioid consumption and higher satisfaction: a prospective, randomized controlled trial.

BACKGROUND: The opioid epidemic has become a central focus in health care. In an effort to reduce opioid use, orthopedic surgeons use multimodal strategies to control postoperative pain. However, no clear consensus exists on ideal pain management strategies after shoulder arthroplasty, and most protocols are opioid-driven. This study sought to determine if patients undergoing shoulder arthroplasty using a postoperative opioid-sparing pain-control regimen would have equivalent pain scores and satisfaction as patients using a traditional opioid-based regimen. METHODS: Patients undergoing primary anatomic or reverse total shoulder arthroplasty were prospectively enrolled and randomized into an opioid-sparing (OS) or a traditional opioid-based (OB) postoperative pain protocol. Both groups received opioid education, periarticular injection with liposomal bupivacaine, and preoperative and postoperative multimodal management (acetaminophen, celecoxib, and gabapentin). The OB group was discharged with 40 oxycodone tablets and standard icing, whereas the OS group received ketorolac during admission, continuous cryotherapy, and discharged with 10 oxycodone tablets for rescue. Patients were queried regarding levels of pain and opioid consumption at days 1-7 and at 2, 6, and 12 weeks postoperatively. Patient satisfaction was recorded at 1, 2, 6, and 12 weeks. Range of motion (ROM), American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), and Single Assessment Numerical Evaluation (SANE) scores were assessed preoperatively and at 12 weeks postoperatively. Complications, readmissions, and reoperations were recorded. RESULTS: In 78 patients, no difference in VAS pain scores were seen at any time between groups. The OS group consumed less oral morphine equivalents (OME) from inpatient hospitalization to 12 weeks postoperatively (P < .05). Total OME consumption was reduced by 213% for the OS vs. the OB group (112 vs. 239; P < .0001). The OS group consumed fewer opioid pills at all time points (P < .05). A 395% reduction in number of opioid pills consumed in the first 12 weeks postoperatively was seen in the OS vs. the OB group (4.3 vs. 17.0; P < .0001). Significantly more patients in the OS group discontinued opioids by 2 weeks postoperatively (86.1% vs. 58.5%; P = .011), and 94.4% in the OS group discontinued opioids by 6 weeks postoperatively. The OS group was more satisfied with pain management at 1 and 6 weeks (P = .05). No difference in ROM, ASES or SANE scores, complications, readmissions, or reoperations were seen between groups. CONCLUSIONS: This study demonstrated a nearly 4-fold reduction in opioid pain pill consumption and earlier cessation of opioids with an OS pain management protocol. Patients also reported higher satisfaction with this pain management strategy.

Evaluation of spin in the abstracts of systematic reviews and meta-analyses related to the treatment of proximal humerus fractures.

BACKGROUND: Research has shown that many physicians rely solely on abstracts to make clinical decisions. However, many abstracts have been shown to be misleading. The primary objective of this study was to identify the prevalence of spin - bias towards particular results - within the abstracts of systematic reviews and meta-analyses pertaining to the treatment of proximal humerus fractures, one of the most common osteoporotic fractures among elderly patients. METHODS: We systematically searched MEDLINE and Embase databases to identify systematic reviews and meta-analyses examining the treatment of proximal humerus fractures. Screening and data extraction occurred in a masked, duplicate fashion. The nine most severe types of spin that occur within abstracts were extracted along with study characteristics, including journal recommendations to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and year in which the review was performed, to identify potential associations. We subsequently explored the association between spin and the methodological quality of a systematic review using the revised A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2) appraisal instrument. RESULTS: Our search retrieved 505 articles, of which 73 systematic reviews met inclusion criteria. We found that 34.2% (25/73) of the included systematic reviews contained spin. Spin type 3 (selective reporting of or overemphasis on efficacy outcomes or analysis favoring the beneficial effect of the experimental intervention) was the most common type identified (12/73, 16.4%). Three spin types were not identified in any of the abstracts. Spin was 3.2 (OR 3.2; 95% CI, 1.02-10.02) times more likely to be present in systematic reviews published in journals recommending adherence to PRISMA. Furthermore, the odds of an abstract containing spin was 1.25 (OR 1.25; 95% CI, 1.02-1.52) times more likely to be present in systematic reviews for each year after 2000. No other study characteristics were associated with spin. The methodological quality of 24 studies were rated as "critically low" (32.9%), 14 were "low" (19.2%), 28 were "moderate" (38.4%), and 7 were "high" (9.6%), but these findings were not associated with spin. CONCLUSION: Spin was present in systematic review abstracts regarding treatment of proximal humerus fractures. Measures such as education on the subject of spin and improved reporting standards should be implemented to increase awareness and reduce incidence of spin in abstracts. LEVEL OF EVIDENCE OF THE STUDY PERFORMED: Basic Science Study; Research Methodology.

mEDUrare: Supporting Integrated Care for Rare Diseases by Better Connecting Health and Education Through Policy.

Rare diseases affect an estimated 6-10% of the Australian population, a prevalence similar to that seen in other regions worldwide. These multi-system conditions are often severely debilitating and affect multiple domains of a person's life. A salient necessity for effective care provision thus, is holistic care, achieved by appropriate and continual multi-disciplinary and cross-sectoral collaboration. Synonymous with this priority for collaborative care, is the need for increased partnerships between the health and education sectors. This partnership has the potential to benefit people with rare disease of all educational ages, but in particular, school-aged children and young adults. More than 70% of rare diseases affect children, and this population often experiences difficulties with overall well-being and functioning, including impaired school performance and confounding mental and social comorbidities. Ensuring adequate schooling needs and experiences along with provision of adequate medical care, is crucial in ensuring overall well-being for this population. For this, effective partnerships between the health and education sectors are paramount. This article highlights fundamental elements of health and education priorities, ingrained in current strategic documents, to build a policy foundation that informs and supports increased inter-sectoral partnerships between health and education services. Shared priorities identified in both sectors' guidelines, co-developed with those with lived experience of rare diseases, build a strong policy base for future advocative initiatives to mold better integration between the sectors, a partnership which is vital to improving the overall quality of life, experiences and journeys of people living with rare disease.

Complications Associated With Placement of Chest Tubes: A Trauma System Perspective.

BACKGROUND: The insertion of a chest tube is a common procedure in trauma care, and the Advanced Trauma Life Support program teaches the insertion of chest tubes as an essential and life-saving skill. It is also recognized that the insertion of chest tubes is not without risks or complications. The purpose of this study was to evaluate complications of chest tube placement in a level 1 trauma center compared with those placed in surrounding referral hospitals. METHODS: A retrospective matched cohort study of trauma patients was performed between those who underwent chest tube placement at the level 1 trauma center and those with a chest tube placed before transfer to the level 1 center between 2004 and 2013. Conditional logistic regression was used to compare the likelihood of complications and death between chest tube placement groups. RESULTS: Four thousand two hundred and sixteen trauma patients had a chest tube placed at the level 1 center, and 364 patients had a chest tube placed at an outside hospital before transfer. Two hundred and eighty-one patients were matched. Patients with a chest tube placed outside the trauma center had an increased likelihood of malposition (OR 7.2, 95% CI 3.6-14.6), residual hemothorax (OR 6.3, 95% CI 3.4-11.6), residual pneumothorax (OR 6.7, 95% CI 3.9-11.4), and having a second chest tube placed (OR 3.77, 95% CI 2.37-6.01). However, the patients with a chest tube placed outside of the trauma center were also less likely to develop pneumonia (OR 0.32, 95% CI 0.14-0.73). There were no differences in the odds of developing an empyema, the need for video-assisted thoracoscopic surgery, thoracotomy, or death. CONCLUSIONS: There are opportunities for improving the care of patients who require chest tubes at both referring hospitals and the receiving trauma center. Improving the care of patients who require intercostal drainage requires a systems-based approach, focusing on training and quality improvement.

Selective alkyl ether cleavage by cationic bis(phosphine)iridium complexes.

Catalysts capable of heterolytic silane activation have been successfully applied to the conversion of alkyl ethers to silyl ethers via C-O bond cleavage. The previously-reported cationic pincer-supported iridium complex for this transformation suffers from poor selectivity with regard to monodealkylation of substrate ethers. We demonstrate that a simple non-pincer iridium complex offers improved selectivity and is capable of benzylic ether cleavage in the presence of reductively-labile alkyl and aryl halide functionality. Preliminary mechanistic experiments suggest a neutral tetrahydridosilyliridium resting state which is consistent with previous mechanistic hypotheses. These experiments suggest that a pincer ligand framework is not required for activity in ether cleavage reactions and that simple cationic bis(phosphine)iridium complexes may offer improved selectivity profiles for applications to more-complex substrate molecules.

Assessment of step accuracy using the Consumer Technology Association standard.

The purpose of this study was to compare the accuracy of commercially-available physical activity devices when walking and running at various treadmill speeds using CTA 2056: Physical Activity Monitoring for Fitness Wearables: Step Counting, standard by the Consumer Technology Association (CTA). Twenty participants (10 males and 10 females) completed self-paced walking and running protocols on the treadmill for five minutes each. Eight devices (Apple iWatch series 1, Fitbit Surge, Garmin 235, Moto 360, Polar A360, Suunto Spartan Sport, Suunto Spartan Trainer, and TomTom Spark 3) were tested two at a time, one per wrist. Manual step counts were obtained from video to serve as the benchmark. The mean absolute percent error (MAPE) was calculated during walking and running. During walking, three devices: Fitbit Surge (11.20%), Suunto Sport (22.93%), and TomTom (10.11%) and during running, one device, Polar (10.66%), exceeded the CTA suggestion of a MAPE < 10%. The Moto 360 had the lowest MAPE of all devices for both walking and running. The devices tested had higher step accuracy with running than walking, except for the Polar. Overall, the Apple iWatch series 1, Moto 360, Garmin, and Suunto Spartan Trainer met the CTA standard for both walking and running.

Preoperative Assessment of the Peroneal Tendons in Lateral Ankle Instability: Examining Clinical Factors, Magnetic Resonance Imaging Sensitivity, and Their Relationship.

The purpose of our study was to examine the preoperative clinical factors and magnetic resonance imaging (MRI) findings associated with peroneal pathology in chronic lateral ankle instability patients, as well as the clinical factors associated with peroneal lesions being detected on MRI. Peroneal pathology was determined from intraoperative findings. Patients with/without peroneal pathology were compared regarding their preoperative clinical findings. MRI reports were examined to determine the sensitivity of detecting peroneal pathologies. Clinical factors were compared between patients (N = 238) with undetected and detected peroneal lesions on MRI. Conservative treatment, preoperative physical therapy, and lack of a traumatic inciting event were associated with peroneal pathology. MRI had a sensitivity of 61.11% for detecting peroneal pathology. No clinical factors were significantly different between "detected" and "undetected" cases. Certain historical factors were associated with peroneal pathology in patients with chronic lateral ankle instability, and MRI had a high false-negative rate. Surgeons should exercise caution when ruling out peroneal pathology based on preoperative physical examination or MRI.

Outcomes of Locking-Plate Fixation for Hindfoot Fusion Procedures in 15 Patients.

Tibiotalocalcaneal arthrodesis is a salvage procedure for various end-stage foot and ankle pathologic entities. Several factors are known to influence the union rate after these procedures, including construct rigidity. The data on locked plates as a fixation technique have been inconclusive, with variable union rates reported. One recent study suggested that locking plates can lead to high nonunion rates owing to excessive rigidity. The purpose of the present study was to retrospectively examine the outcomes of locking plate fixation. We retrospectively reviewed the cases of 15 patients (7 [46.7%] male, 8 [53.3%] female) who underwent tibiotalocalcaneal, tibiocalcaneal, or tibiotalar arthrodesis fixed with a locking plate from January 2013 to January 2014. The average age was 52.19 ± 5.8 years. The mean follow-up period was 17 ± 5.3 months. We examined the overall union rates and the effects of smoking, diabetes, and rheumatologic status on the union rate. Of the 15 cases, 11 (73.3%) did not achieve union. The mean time to failure was 10 ± 5.3 months. Age, gender, smoking, diabetes, use of augmentation screws outside the plate, and operating surgeon did not have an effect on the failure rate (p > .50). In addition, gender, smoking, and diabetes did not predict for nonunion. The high failure rate of rigid locking plate fixation reported might be attributable to the high incidence of smoking and diabetic comorbidities in our study. However, excessive construct rigidity might play an important role. Larger studies are needed to establish more reliable union rates with the use of locking plates in foot and ankle fusion.

Tibiotalocalcaneal Arthrodesis With Intramedullary Fibular Strut Graft With Adjuvant Hardware Fixation.

Tibiotalocalcaneal arthrodesis (TTCA) is a well-established operative procedure for different severe pathologic conditions of the ankle and hindfoot joints. We present our results with a modified technique of TTCA using an intramedullary fibular strut graft in a series of complex cases of patients treated for multiple etiologies shown to have improved union rates. The technique involves inserting the fibular strut graft intramedullary after joint preparation and the use of either a Taylor spatial frame or plate and screws for definitive fixation. We reviewed the records of 16 patients who had undergone TTCA with this technique at our hospital from September 2013 to April 2015. Sixteen patients (10 males [62.5%] and 6 females [37.5%]) were included in the present study. These patients had complex cases and multiple risk factors, including diabetes, smoking, poor bone stock, and a history of previous surgeries. The mean follow-up time was 9.1 (range 9 to 18) months. Thirteen patients (81.2%) subsequently achieved union. The mean visual analog scale scores at the final follow-up examination had improved from 6.9 to 1.2. We suggest that our technique of TTCA with intramedullary fibular strut graft with fixation is a reasonable option to salvage complex cases with risk factors for operative complications.

Allocation of cytoplasm to macromeres in embryos of annelids and molluscs is positively correlated with egg size.

Evolutionary transitions between feeding and nonfeeding larval development have occurred many times in marine invertebrates, but the developmental changes underlying these frequent and ecologically important transitions are poorly known, especially in spiralians. We use phylogenetic comparative methods to test the hypothesis that evolutionary changes in egg size and larval nutritional mode are associated with parallel changes in allocation of cytoplasm to macromere cell lineages in diverse annelids and molluscs. Our analyses show that embryos of species with large eggs and nonfeeding larvae tend to allocate relatively more embryonic cytoplasm to macromeres at 3rd cleavage than do embryos of species with small eggs and feeding larvae. The association between egg size and allocation to macromeres in these spiralians may be driven by constraints associated with mitotic spindle positioning and size, or may be a result of "adaptation in cleavage" to maintain rapid cell cycles in micromeres, position yolk in cell lineages where it can be most efficiently used, or adjust allocation to ectoderm to accommodate changes in embryonic surface area/volume ratio.

Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease.

OBJECTIVE: Proline-glycine-proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD). DESIGN: In intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry. Peripheral blood polymorphonuclear cell (PMN) supernatants were also analysed accordingly and incubated with collagen to assess PGP generation ex vivo. PGP levels were measured by mass spectrometry, and PGP neutralisation was achieved with a PGP antagonist and PGP antibodies. RESULTS: In the intestine of patients with IBD, MMP8 and MMP9 levels were elevated, while PE was expressed at similar levels to control tissue. PGP levels were increased in intestinal tissue of patients with IBD. Similar results were obtained in intestine from DSS-treated mice. PMN supernatants from patients with IBD were far more capable of generating PGP from collagen ex vivo than healthy controls. Furthermore, PGP neutralisation during DSS-induced colitis led to a significant reduction in neutrophil infiltration in the intestine. CONCLUSIONS: The proteolytic cascade that generates PGP from collagen, as well as the tripeptide itself, is present in the intestine of patients with IBD and mice with DSS-induced colitis. PGP neutralisation in DSS-treated mice showed the importance of PGP-guided neutrophilic infiltration in the intestine and indicates a vicious circle in neutrophilic inflammation in IBD.

Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function.

RATIONALE: Several extrapulmonary disorders have been linked to cigarette smoking. Smoking is reported to cause cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the airway, and is also associated with pancreatitis, male infertility, and cachexia, features characteristic of cystic fibrosis and suggestive of an etiological role for CFTR. OBJECTIVES: To study the effect of cigarette smoke on extrapulmonary CFTR function. METHODS: Demographics, spirometry, exercise tolerance, symptom questionnaires, CFTR genetics, and sweat chloride analysis were obtained in smokers with and without chronic obstructive pulmonary disease (COPD). CFTR activity was measured by nasal potential difference in mice and by Ussing chamber electrophysiology in vitro. Serum acrolein levels were estimated with mass spectroscopy. MEASUREMENTS AND MAIN RESULTS: Healthy smokers (29.45 ± 13.90 mEq), smokers with COPD (31.89 ± 13.9 mEq), and former smokers with COPD (25.07 ± 10.92 mEq) had elevated sweat chloride levels compared with normal control subjects (14.5 ± 7.77 mEq), indicating reduced CFTR activity in a nonrespiratory organ. Intestinal current measurements also demonstrated a 65% decrease in CFTR function in smokers compared with never smokers. CFTR activity was decreased by 68% in normal human bronchial epithelial cells exposed to plasma from smokers, suggesting that one or more circulating agents could confer CFTR dysfunction. Cigarette smoke-exposed mice had decreased CFTR activity in intestinal epithelium (84.3 and 45%, after 5 and 17 wk, respectively). Acrolein, a component of cigarette smoke, was higher in smokers, blocked CFTR by inhibiting channel gating, and was attenuated by antioxidant N-acetylcysteine, a known scavenger of acrolein. CONCLUSIONS: Smoking causes systemic CFTR dysfunction. Acrolein present in cigarette smoke mediates CFTR defects in extrapulmonary tissues in smokers.

Educational, developmental and psychological outcomes of resettled refugee children in Western Australia: a review of School of Special Educational Needs: Medical and Mental Health input.

AIM: There are limited data regarding the educational backgrounds and associated psychological and developmental outcomes of refugee children resettling in Western Australia (WA). The WA paediatric Refugee Health Service (RHS) revised its first consult questionnaire (August 2011) to increase educational and psychosocial documentation, concurrent with engagement of a School of Special Educational Needs: Medical and Mental Health (SSEN: MMH) liaison teacher. This study aims to utilise these data to increase understanding of this cohort's educational, developmental and psychological needs and to describe SSEN: MMH's role within the RHS. METHODS: Retrospective audit and analyses were performed on all initial standardised questionnaires for school-aged refugee children (4-18 years) and SSEN: MMH referrals between August 2011 and December 2012. RESULTS: Demographic data from 332 refugees are described (mean age 9.58 ± standard deviation 3.43 years). Detailed educational information was available for 205 children. Prior education was limited (median 2 years), 64.9% experienced likely schooling interruption and 55.8% received education in their primary language. Language development concerns were significantly associated with previous education in a second language (odds ratio (OR) 4.55, P < 0.05). Other severe developmental and schooling issues were uncommon at presentation, with few correlations to prior education. In contrast, several migration factors, including family separation and mandatory detention, were significantly associated with psychological comorbidities such as post-traumatic stress disorder (OR 5.60, P < 0.001 and OR 14.57, P < 0.001, respectively). SSEN: MMH reviewed 59 complex cases. Referral was significantly associated with multiple educational, developmental and psychological concerns. CONCLUSIONS: Refugee children have varied migration, trauma and educational backgrounds, impacting on health and psychological outcomes. In-depth multidisciplinary history including prior education and psychosocial issues is recommended. Partnering with education services appears to play an effective, multifaceted role in aiding resettlement; however, longitudinal studies are required.

Computer-Aided Design and Biological Evaluation of Diazaspirocyclic D4R Antagonists.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D4R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D4R antagonists. However, developing selective D4R antagonists suitable for clinical translation remains a challenge.

Songbird mesostriatal dopamine pathways are spatially segregated before the onset of vocal learning.

Diverse dopamine (DA) pathways send distinct reinforcement signals to different striatal regions. In adult songbirds, a DA pathway from the ventral tegmental area (VTA) to Area X, the striatal nucleus of the song system, carries singing-related performance error signals important for learning. Meanwhile, a parallel DA pathway to a medial striatal area (MST) arises from a distinct group of neighboring DA neurons that lack connectivity to song circuits and do not encode song error. To test if the structural and functional segregation of these two pathways depends on singing experience, we carried out anatomical studies early in development before the onset of song learning. We find that distinct VTA neurons project to either Area X or MST in juvenile birds before the onset of substantial vocal practice. Quantitative comparisons of early juveniles (30-35 days post hatch), late juveniles (60-65 dph), and adult (>90 dph) brains revealed an outsized expansion of Area X-projecting neurons relative to MST-projecting neurons in VTA over development. These results show that a mesostriatal DA system dedicated to social communication can exist and be spatially segregated before the onset of vocal practice and associated sensorimotor experience.

Micrococcal nuclease regulates biofilm formation and dispersal in methicillin-resistant Staphylococcus aureus USA300.

Biofilm formation is an important virulence factor for methicillin-resistant Staphylococcus aureus (MRSA). The extracellular matrix of MRSA biofilms contains significant amounts of double-stranded DNA. MRSA cells also secrete micrococcal nuclease (Nuc1) which degrades double-stranded DNA. In this study we used a nuc1 mutant strain to investigate the role of Nuc1 in MRSA biofilm formation and dispersal. Biofilm was quantitated in microplates using a crystal violet binding assay. Extracellular DNA (eDNA) was isolated from colony biofilms and analyzed by agarose gel electrophoresis. In some experiments, broth or agar was supplemented with sub-MIC amoxicillin to induce biofilm formation. Biofilm erosion was quantitated by culturing biofilms on rods, transferring the rods to fresh broth, and enumerating CFUs that detached from the rods. Biofilm sloughing was investigated by culturing biofilms in glass tubes perfused with broth and measuring the sizes of the detached cell aggregates. We found that a nuc1 mutant strain produced significantly more biofilm and more eDNA than a wild-type strain in both the absence and presence of sub-MIC amoxicillin, nuc1 mutant biofilms grown on rods detached significantly less than wild-type biofilms. Detachment was restored by exogenous DNase or a wild-type nuc1 gene on a plasmid. In the sloughing assay, nuc1 mutant biofilms released cell aggregates that were significantly larger than those released by wild-type biofilms. Our results suggest that Nuc1 modulates biofilm formation, biofilm detachment, and the sizes of detached cell aggregates. These processes may play a role in the spread and subsequent survival of MRSA biofilms during biofilm-related infections.

Selective demethylation of O-aryl glycosides by iridium-catalyzed hydrosilylation.

The cleavage of alkyl ethers by hydrosilylation is a powerful synthetic tool for the generation of silyl ethers. Previous attempts to apply this transformation to carbohydrate derivatives have been constrained by poor selectivity and preferential reduction of the anomeric position. O-Aryl glycosides are found to be stable under iridium- and borane-catalyzed hydrosilylation conditions, allowing for alkyl ether cleavage without loss of anomeric functionality. A cationic bis(phosphine)iridium complex catalyzes the selective 3-demethylation of a variety of 2,3,4-tri-O-methyl pyranoses, offering a unique approach to 3-hydroxy or 3-acetyl 2,4-di-O-methylpyranoses.

Levelling Education Outcomes for Students With Medical and Mental Health Needs.

Students' educational and behavioural outcomes can be adversely impacted by the unique challenges posed by chronic health conditions. As some children and adolescents may live with these challenges throughout their education, hospital-based educators play a crucial role in reducing the impacts of health conditions on educational outcomes. This study assessed the extent to which the support provided by the School of Special Educational Needs: Medical and Mental Health (SSEN:MMH, Western Australia) attenuated the negative association between higher absences and lower student outcomes. Administrative education records relating to absences, student behaviour, achievement outcomes, and level of support provided by the SSEN:MMH were used to assess the study questions. Regression models revealed no significant association between higher levels of teaching support and student outcomes after controlling for baseline characteristics. However, the negative association between higher absences and lower academic achievement was lower among students receiving higher levels of liaison. Additional analysis highlighted challenges in evaluating student outcomes, including the finding that most students receiving support missed at least two weeks of school over a year but received less than the equivalent of two days of teaching support, suggesting that the available measures were not sensitive to the level of teaching support provided. Together, the findings of this study suggest that liaison services informing schools about the educational needs of students are an important tool for supporting students academically and that the process of supporting students with chronic health conditions is not a simple task given the varying complexity of student needs and behaviours.