PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII.

PGC-1α is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC-1α serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor α (ERRα), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes. We show that PGC-1α promotes pausing release in a two-arm mechanism (1) by recruiting the positive transcription elongation factor b (P-TEFb) and (2) by outcompeting the premature transcription termination complex Integrator. Using mice homozygous for five amino acid changes in the CBP80-binding motif (CBM) of PGC-1α that destroy CBM function, we show that efficient differentiation of primary myoblasts to myofibers and timely skeletal muscle regeneration after injury require PGC-1α binding to CBP80. Our findings reveal how PGC-1α activates stress-response gene transcription in a previously unanticipated pre-mRNA quality-control pathway.

Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.

A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem-the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor-kinase axis (ZBTB7B-RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region-specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Efficient quantum algorithm for dissipative nonlinear differential equations.

Nonlinear differential equations model diverse phenomena but are notoriously difficult to solve. While there has been extensive previous work on efficient quantum algorithms for linear differential equations, the linearity of quantum mechanics has limited analogous progress for the nonlinear case. Despite this obstacle, we develop a quantum algorithm for dissipative quadratic n-dimensional ordinary differential equations. Assuming [Formula: see text], where R is a parameter characterizing the ratio of the nonlinearity and forcing to the linear dissipation, this algorithm has complexity [Formula: see text], where T is the evolution time, ϵ is the allowed error, and q measures decay of the solution. This is an exponential improvement over the best previous quantum algorithms, whose complexity is exponential in T. While exponential decay precludes efficiency, driven equations can avoid this issue despite the presence of dissipation. Our algorithm uses the method of Carleman linearization, for which we give a convergence theorem. This method maps a system of nonlinear differential equations to an infinite-dimensional system of linear differential equations, which we discretize, truncate, and solve using the forward Euler method and the quantum linear system algorithm. We also provide a lower bound on the worst-case complexity of quantum algorithms for general quadratic differential equations, showing that the problem is intractable for [Formula: see text] Finally, we discuss potential applications, showing that the [Formula: see text] condition can be satisfied in realistic epidemiological models and giving numerical evidence that the method may describe a model of fluid dynamics even for larger values of R.

Safety Profile of Seven-Day Intra-articular Antibiotic Irrigation for the Treatment of Chronic Periprosthetic Joint Infection: A Prospective Randomized Phase II Comparative Study.

BACKGROUND: Systemic intravenous antimicrobials yield poor outcomes during treatment of periprosthetic joint infection due to the inability to obtain minimum biofilm eradication concentrations. This study evaluated the safety of a novel method of optimized local delivery of intra-articular antibiotics (IAAs). METHODS: This was a Phase II, multicenter, prospective randomized trial evaluating safety of a rapid (seven-day) two-stage exchange arthroplasty with IAA irrigation compared to standard two-stage exchange. The Experimental Group received irrigation using 80 mg tobramycin daily with a 2-hour soak, followed by hourly irrigation using 125 mg vancomycin with a 30-minute soak via an intramedullary irrigation device. The Control Group received an antibiotic-loaded cement spacer with vancomycin (average 8.4 g) and tobramycin (average 7.1 g, total 16 g antibiotics). Both groups received 12 weeks of systemic antibiotics following Stage 2. Safety measures included adverse events, peak vancomycin/tobramycin serum concentrations (Experimental Group), blood transfusion, and mortality. There were thirty-seven patients randomized to the Experimental Group and 39 to control. There was no difference in baseline demographics or comorbidities. RESULTS: There were no antibiotic medication-related adverse events and 2 serious adverse events related to antibiotic instillation. Of 188 vancomycin peak measurements, 69% had detectable serum level concentrations, with all concentrations well below the maximum acceptable trough threshold of 20 µg/mL. Of the 103 tobramycin peak measurements, 45% had detectable levels, with all below the maximum acceptable peak threshold of 18 to 24 µg/mL. There was no difference in blood transfused per subject (Experimental: 655 mL versus Control: 792 mL; P = .4188). There were two (2) deaths in the Experimental Group and four (4) in the control. CONCLUSIONS: The use of IAA is safe with minimal systemic antibiotic exposure. There was no difference in the rates or severity of serious adverse events between groups. Further research is being conducted to examine treatment efficacy.

Clinical Presentation and Outcomes of Kawasaki Disease in Children from Latin America: A Multicenter Observational Study from the REKAMLATINA Network.

OBJECTIVES: To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery aneurysm (CAA). STUDY DESIGN: An observational KD registry-based study was conducted in 64 participating pediatric centers across 19 Latin American countries retrospectively between January 1, 2009, and December 31, 2013, and prospectively from June 1, 2014, to May 31, 2017. Demographic and initial clinical and laboratory data were collected. Logistic regression incorporating clinical factors and maximum coronary artery z-score at initial presentation (between 10 days before and 5 days after intravenous immunoglobulin [IVIG]) was used to develop a prognostic model for CAA during follow-up (>5 days after IVIG). RESULTS: Of 1853 patients with KD, delayed admission (>10 days after fever onset) occurred in 16%, 25% had incomplete KD, and 11% were resistant to IVIG. Among 671 subjects with reported coronary artery z-score during follow-up (median: 79 days; IQR: 36, 186), 21% had CAA, including 4% with giant aneurysms. A simple prognostic model utilizing only a maximum coronary artery z-score ≥2.5 at initial presentation was optimal to predict CAA during follow-up (area under the curve: 0.84; 95% CI: 0.80, 0.88). CONCLUSION: From our Latin American population, coronary artery z-score ≥2.5 at initial presentation was the most important prognostic factor preceding CAA during follow-up. These results highlight the importance of early echocardiography during the initial presentation of KD.

Significance of Oct-4 transcription factor as a pivotal therapeutic target for CD44+ /24- mammary tumor initiating cells: Aiming at the root of the recurrence.

Breast cancer (BC) remains one of the deadliest and frequently diagnosed metastatic cancers worldwide. Cancer stem cells (CSCs) are the cell population within the tumor niche, having an epithelial to mesenchymal (EMT) transition phenotype, high self-renewal, vigorous metastatic capacity, drug resistance, and tumor relapse. Identification of targets for induction of apoptosis is essential to provide novel therapeutic approaches in BC. Our earlier studies showed that Vitamin C induces apoptotic cell death by losing redox balance in TNBC CSCs. In this study, we have attempted to identify previously unrecognized CSC survival factors that can be used as druggable targets for bCSCs apoptosis regulators isolated from the TNBC line, MDA MB 468. After a thorough literature review, Oct-4 was identified as the most promising marker for its unique abundance in cancer and absence in normal cells and the contribution of Oct-4 to the sustenance of cancer cells. We then validated a very high expression of Oct-4 in the MDA MB 468 bCSCs population using flow-cytometry. The loss of Oct-4 was carried out using small interfering RNA (siRNA)-mediated knockdown in the bCSCs, followed by assessing for cellular apoptosis. Our results indicated that Oct-4 knockdown induced cell death, changes in cellular morphology, inhibited mammosphere formation, and positive for Annexin-V expression, thereby indicating the role of Oct-4 in bCSC survival. Moreover, our findings also suggest the direct interaction between Oct-4 and Vitamin C using in silico docking. This data, hence, contributes towards novel information about Oct-4 highlighting this molecule as a novel survival factor in bCSCs.

Cardiovascular toxicities with pediatric tyrosine kinase inhibitor therapy: An analysis of adverse events reported to the Food and Drug Administration.

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

Fluoroalkoxylated C-3 and C-9 (S)-12-bromostepholidine analogues with D1R antagonist activity.

To illuminate the tolerance of fluoroalkoxylated groups at the C-3 and C-9 positions of tetrahydroprotoberberines (THPBs) on D1R activity, C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromostepholidine were prepared and evaluated. All compounds examined were D1R antagonists as measured by a cAMP assay. Our structure-activity studies herein indicate that the C-3 position tolerates a 1,1-difluoroethoxy substituent for D1R antagonist activity. Compound 13a was the most potent cAMP-based D1R antagonist identified and was also found to antagonize ß-arrestin translocation in a TANGO assay. Affinity assessments at other dopamine receptors revealed that 13a is selective for D1R and unlike other naturally-occurring THPBs such as (S)-stepholidine, lacks D2R affinity. In preliminary biopharmaceutical assays, excellent BBB permeation was observed for 13a. Further pharmacological studies are warranted on (S)-stepholidine congeners to harvest their potential as a source of novel, druggable D1R-targeted agents.

Rate of Recovery and Symptomatic Efficacy of a Polyherbal AYUSH Formulation in the Treatment of SARS-CoV-2 Disease: A Single-arm Trial.

Background: The COVID-19 pandemic, caused by the human coronavirus, SARS-CoV-2, has led to the death of millions across the globe. The SARS-CoV-2 virus is highly infectious, and mutates rapidly. This creates additional challenges for the development of robust therapeutic solutions. Along with modern healthcare, there is a need to explore natural, plant-based antiviral compounds that can be used in the treatment of COVID-19. Objective: The present feasibility study investigates the efficacy of a 13-ingredient Ayurvedic polyherbal formulation, NOQ19, in the management of COVID-19. Methodology: A single-arm, open-label study design was adopted for this feasibility study. 161 RT-PCR-positive COVID-19 patients were enrolled. The enrolled participants were provided with the Ayurvedic intervention - two tablets of NOQ19 thrice daily along with the standard of care treatment. Follow-up COVID-19 RT-PCR tests were conducted on days 5, 10, and 14 or until the patient tested negative. The time taken to turn RT-PCR negative or become asymptomatic was noted. Setting: The study was conducted at Sri Sri Institute for Advanced Research from April 2021 to June 2021. Participants: A total of 161 COVID-19 patients isolating at home were assessed. Intervention: The NOQ19 preparation is a combination of 13 Ayurvedic herbs. Outcomes Measured: RT-PCR tests, the turnaround time to becoming asymptomatic, and regular symptoms assessment. Results: The analysis demonstrated that 74% of the patients tested negative on the RT-PCR within five days of taking NOQ19. Additionally, 98% of the subjects tested negative on the RT-PCR on day 10 after taking NOQ19 and standard of care treatment (as necessary). None of the participants reported any adverse events or side-effects due to NOQ19 medication. Conclusion: The NOQ19 Ayurvedic polyherbal formulation can be an effective and safe option for the symptomatic management of COVID-19.

Lessons Learned From the Comprehensive Care for Joint Replacement Model at an Academic Tertiary Center: The Good, the Bad, and the Ugly.

BACKGROUND: Our institution participated in the Comprehensive Care for Joint Replacement (CJR) model from 2016 to 2020. Here we review lessons learned from a total joint arthroplasty (TJA) care redesign at a tertiary academic center amid changing: (1) CJR rules; (2) inpatient only rules; and (3) outpatient trends. METHODS: Quality, financial, and patient demographic data from the years prior to and during participation in CJR were obtained from institutional and Medicare reconciled CJR performance data. RESULTS: Despite an increase in true outpatients and new challenges that arose from changing inpatient-only rules, there was significant improvement in quality metrics: decreased length of stay (3.48-1.52 days, P < .001), increased home discharge rate (70.2-85.5%, P < .001), decreased readmission rate (17.7%-5.1%, P < .001), decreased complication rate (6.5%-2.0%, P < .001), and the Centers for Medicare and Medicaid Services (CMS) Composite Quality Score increased from 4.4 to 17.6. Over the five year period, CMS saved an estimated $8.3 million on 1,486 CJR cases, $7.5 million on 1,351 non-CJR cases, and $600,000 from the voluntary classification of 371 short-stay inpatients as outpatient-a total savings of $16.4 million. Despite major physician time and effort leading to marked improvements in efficiency, quality, and large cost savings for CMS, CJR participation resulted in a net penalty of $304,456 to our institution, leading to zero physician gainsharing opportunities. CONCLUSION: The benefits of CJR were tempered by malalignment of incentives among payer, hospital, and physician as well as a lack of transparency. Future payment models should be refined based on the successes and challenges of CJR.

An improved synthesis of [18 F]VAT and its precursor.

The vesicular acetylcholine transporter (VAChT) in the brain is an important presynaptic cholinergic biomarker, and neuroimaging studies of VAChT may provide in vivo information about psychiatric and neurologic conditions including Alzheimer's disease that are not accessible by other methods. The 18 F-labeled radiotracer, ((-)-(1-(-8-(2-[18 F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone ([18 F]VAT, 1), was reported as a selective and high affinity ligand for the in vivo imaging of VAChT. The synthesis of [18 F]VAT has been reported in a two-step procedure with total 140 min, which includes preparation of 2-[18 F]fluoroethyltosylate and alkylation of benzovesamicol (-)-5 precursor with this radiosynthon using two different automated production modules consecutively. A multiple step synthetic route was employed for the synthesis of stereospecific precursor benzovesamicol (-)-5, which is difficult to be adapted for scale-up. To make the production of this tracer more amenable for clinical imaging, we present an improved total synthesis protocol to attain [18 F]VAT: (1) a tosylethoxy group being pre-installed tosylate precursor (-)-8 is synthesized to render a simple one-step radiofluorination under mild conditions; (2) The key optically active intermediate benzovesamicol (-)-5 was obtained via the regio- and enantio-enriched ring-opening amination of meso-epoxide 3 with 4-phenylpiperidine derivative 2 under catalysis of a chiral salenCo(III) catalyst 4b, which dramatically simplifies the synthetic route of the tosylate precursor (-)-8. [18 F]VAT 1 was prepared within ~65 min with desired chemical and radiochemical purities, via a fully automated procedure, using a commercial PET tracer production module. The final drug product was obtained as a sterile, pyrogen-free solution that conforms United States Pharmacopeia (USP) <823> requirements.

Structure-Activity Relationship Studies on 6-Chloro-1-phenylbenzazepines Leads to the Identification of a New Dopamine D1 Receptor Antagonist.

The 1-phenylbenzazepine template has yielded a number of D1R-like ligands, which, though useful as pharmacological tools, have significant drawbacks in terms of selectivity versus D5R as well as pharmacokinetic behavior. A number of 1-phenylbenzazepines contain a 6-chloro functional group, but extensive SAR studies around the 6-chloro-1-phenylbenzazepine framework have not been reported in the literature. To further understand the tolerance of the 6-chloro-1-phenylbenzazepine template for various substituent groups towards affinity and selectivity at D1R, we synthesized two series of analogs with structural variations at the C-7, C-8, N-3, C-3' and C-4' positions. The series 2 analogs differed from series 1 analogs in possessing a nitrogenated functionality at C-8 and lacked a C-4' substituent, but were otherwise similar. Analogs were assessed for affinity at D1R, D2R and D5R. For both series, we found that the analogs lacked affinity for D2R and showed modest D1R versus D5R selectivity. For series 1 analogs, an N-3 methyl substituent group was better tolerated than N-H or an N-3 allyl substituent. The C-8 position appears to be tolerant of amino and methanesulfonamide substituents for high D1R affinity, but C-8 amides displayed low to moderate D1R affinities. A C-3' methyl substituent appeared to be critical for the D1R affinity of some analogs, but the C-4' substituents tried (hydroxy and methoxy; series 1) did not result in any significant boost in D1R affinity. Compound 15a was the most potent and selective D1R ligand identified from these studies (Ki at D1R = 30 nM; 6-fold selectivity versus D5R). Further functional activity assessments indicate that 15a functions as a D1R antagonist towards cAMP-mediated signaling. The predicted drug-like properties of 15a are encouraging for further pharmacological assessments on the compound.

A Physician-led Care Redesign Blunts Predictors of Length of Stay after Total Hip and Knee Arthroplasty.

We questioned to what extent traditional predictors of care team burden (via increased length of stay [LOS] after total joint arthroplasty [TJA]) were able to be mitigated through alteration of the care pathway. The impact on LOS of traditional patient risk factors, as well as encounter variables, were analyzed for a consecutive set of patients undergoing surgery before and after a physician-initiated arthroplasty care pathway redesign. We analyzed the impact of these variables on LOS, discharge disposition, and 90-day readmission; separate analyses were performed pre- and post-redesign for LOS. Several patient factors (Risk Assessment and Prediction Tool, body mass index, age, insurance type, smoking) predicted longer LOS in the pre-redesign cohort; post-redesign, only ambulation on the day of surgery and anticoagulation type were predictive. The redesign also lessened the aggregate impact of the patient-specific risk factors, resulting in reduced variation in LOS. Physician leadership of care pathways can reduce the impact of factors that have portended longer LOS, thereby reducing variability in LOS and costs for disparate patient populations while driving improvements in value-based care indices. (Journal of Surgical Orthopaedic Advances 32(2):097-101, 2023).

Outcome of tracheostomy among COVID-19 patients in a tertiary hospital setting: Our experience.

INTRODUCTION: The COVID-19 pandemic is unprecedented. Amongst those who contracted COVID-19, a number required intubation and prolonged ventilation. This increased the number of ventilated patients in the hospital and increased the requirement for tracheostomy of severe COVID-19 patients. Our objective is to study the outcome of patients with COVID-19 who underwent tracheostomy. MATERIALS AND METHODS: This study is a novel retrospective study in a tertiary centre in Malaysia. Case notes of COVID- 19 patients who underwent tracheostomy in Hospital Ampang were collected using the electronic Hospital Information System. Data were analysed using the SPSS system. RESULTS: From a total of 30 patients, 15 patients survived. All patients underwent either open or percutaneous tracheostomy. The median age is 53 (range: 28-69) with a significant p-value of 0.02. Amongst comorbidities, it was noted that diabetes mellitus was significant with a p-value of 0.014. The median time from the onset of COVID-19 to tracheostomy is 30 days. The median duration of intensive care unit (ICU) stay is 30.5 days, with the median duration of hospital length of stay of 44 days (p = 0.009 and <0.001, respectively). No complications that contributed to patient death were found. Survivors had a median of 29.5 days from tracheostomy to oxygen liberation. CONCLUSION: Tracheostomy in COVID-19 patients that requires prolonged ventilation is unavoidable. It is a safe procedure and mortality is not related to the procedure. Mortality is primarily associated with COVID-19.

A vegetative storage protein improves drought tolerance in maize.

Vegetative storage proteins (VSPs) are known to serve as nitrogen reserves in many dicot plants but remain undiscovered in grasses, most widely grown group of crops globally. We identified and characterized a VSP in maize and demonstrated that its overexpression improved drought tolerance. Nitrogen supplementation selectively induced a mesophyll lipoxygenase (ZmLOX6), which was targeted to chloroplasts by a novel N-terminal transit peptide of 62 amino acids. When ectopically expressed under the control of various tissue-specific promoters, it accumulated to a fivefold higher level upon expression in the mesophyll cells than the wild-type plants. Constitutive expression or targeted expression specifically to the bundle sheath cells increased its accumulation by less than twofold. The overexpressed ZmLOX6 was remobilized from the leaves like other major proteins during grain development. Evaluated in the field over locations and years, transgenic hybrids overexpressing ZmLOX6 in the mesophyll cells significantly outyielded nontransgenic sibs under managed drought stress imposed at flowering. Additional storage of nitrogen as a VSP in maize leaves ameliorated the effect of drought on grain yield.

Semisynthetic Transformations on (+)-Boldine Reveal a 5-HT2A/2CR Antagonist.

Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HT2CR ligands. 1,2,9,10-Tetraoxygenated aporphine alkaloids in particular have demonstrated good affinity for 5-HTRs. In continued efforts to understand the impacts of structural modification of the 1,2,9,10-tetraoxygenated aporphine template on affinity, selectivity, and activity at 5-HT2R subtypes, we used (+)-boldine (8) as a semisynthetic feedstock in the preparation of C-2-alkoxylated (+)-predicentrine analogues. Compound 10n, which contains a benzyloxy group at C-2, has been identified as a novel 5-HT2CR ligand with strong affinity (4 nM) and moderate selectivity versus 5-HT2BR and 5-HT2AR (12-fold and 6-fold, respectively). Compound 10n functions as an antagonist at 5-HT2A and 5-HT2C receptors. Computational experiments indicate that several hydrophobic interactions as well as strong H-bond and salt bridge interactions between the protonated amine moiety in 10n and Asp134 are responsible for the potent 5-HT2CR affinity of this compound. Furthermore, compound 10n displays favorable predicted drug-like characteristics, which is encouraging toward future optimization.

Further studies on C2'-substituted 1-phenylbenzazepines as dopamine D1 receptor ligands.

The 1-phenylbenzazepine scaffold has yielded several D1R targeting ligands, but some gaps remain in our understanding of the structure-activity relationships in this scaffold. In particular, there is a paucity of studies that have investigated the effects of substituents at the C2' position of 1-phenylbenzazepines on their affinity and selectivity towards D1R. In this study, a set of methyl- and fluoro- C2'-substituted 1-phenylbenzazepines, with ring A catechol or 8-hydroxy-7-methoxy moieties in tandem with N-methyl or N-allyl substituent groups, was synthesized and evaluated for affinity at a subset of dopamine receptors - D1R, D2R and D5R. These studies indicate that an N-methyl group is generally preferred over N-unsubstituted or N-allyl groups for strong D1R affinity. In addition, it was revealed that compounds with a ring A 8-hydroxy-7-methoxy motif displayed stronger D1R affinity than analogous compounds with a ring A catechol moiety. Furthermore, the presence of a C2' substituent does not significantly impact D1R selectivity over D5R. However, for all analogs assessed, D1R selectivity over D2R was maintained. D1R vs D5R selectivity was generally poor or modest (less than 10-fold) among members of the series. A new high affinity selective D1R ligand - 10b (Ki = 5.7 nM), was identified in this study; further pharmacological characterization indicates that 10b is an antagonist at D1R (IC50 = 10.7 nM). Docking studies on 10b indicate that a number of interactions with hydrophobic residues (Trp321, Val317, Phe313, Phe289, Phe288, Phe285, Phe203, Tyr194, Leu190, Ser188, His 164, Ile104, Val100 and Trp99) in addition to the typical N-Asp103 salt bridge are important for its D1R affinity.

Editorial Commentary: Allogenic Dermal Fibroblasts in Collagen Matrix Scaffold Enhance Rotator Cuff Repair in an Animal Model.

There has been a recent surge of interest on the use of biologic supplements to facilitate rotator cuff repair healing. Experimental evidence appears to support use of allogenic dermal fibroblasts (ADFs), either in the form of local injection or tenocytes embedded in collagen matrix scaffold, to enhance healing of a repaired rotator cuff tendon tear in an animal model. When compared with the ADFs, the platelet-rich plasma (PRP)-induced response seems to be limited in terms of the specific increases in local collagen 1 concentration, thus resulting in a bone-tendon healing response that is inferior in both biology and biomechanical behavior under the same laboratory conditions. While on the one hand, there is pilot data supporting use of dermal fibroblast in the clinical setting, thus reinforcing the animal study findings, on the other hand, we are also aware of the encouraging biologic changes that occurred in the retrieved acellular dermal matrix (ADM) allograft that was used for superior capsular reconstruction as a treatment of irreparable rotator cuff tears. In theory, ADFs locally instilled as an injection should further enhance the healing response compared to the ADM. However, this needs to be further studied to be able to be widely applicable clinically.

High-Level Athletes Who Did Not Return to Sport for Reasons Unrelated to Their Hip Achieve Successful Midterm Outcomes With a Benchmarking Against High-Level Athletes Who Returned to Sport.

PURPOSE: 1) To report minimum 2- and 5-year outcomes of high-level athletes who did not return to sport (RTS) after hip arthroscopy for reasons unrelated to their hip (T athletes) and 2) to benchmark these findings against a propensity-matched control group of high-level athletes who returned to sport (RTS athletes). METHODS: Data were prospectively collected and retrospectively reviewed for professional, collegiate, and high school athletes between April 2008 and October 2015, who underwent primary hip arthroscopy. Athletes were considered eligible if they did not return to sport for reasons unrelated to their hip such as loss of interest, graduation, or a lifestyle transition (T athletes). Inclusion criteria were preoperative and minimum 5-year postoperative patient-reported outcomes (PROs) for the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sports Specific Subscale (HOS-SSS), and the visual analog scale (VAS) for pain. Clinical outcomes were assessed using the minimal clinically important difference (MCID) and maximum outcome improvement satisfaction threshold (MOIST). T athletes were then propensity-matched to a control group of high-level athletes who returned to sport after hip arthroscopy (RTS athletes) for comparison. RESULTS: Twenty-seven T hips (25 patients) were included in the analysis with a mean follow-up time of 38.9 ± 16.8 and 72.1 ± 16.8 months for minimum 2- and 5-year outcomes, respectively. They demonstrated significant improvement in all measured PROs. When compared to a propensity-matched control group of RTS athletes, T athletes demonstrated similar improvement in PROs (mHHS, NAHS, and HOS-SSS) and achieved MCID at similar rates for NAHS (T: 77.8% vs RTS: 68.8%; P = .570) and HOS-SSS (T: 70.3% vs RTS: 76.6%, P = .824) compared to RTS athletes; however T athletes demonstrated higher rates of achieving MCID for mHHS (T: 88.9% vs RTS: 72.9% P = .033). CONCLUSION: Athletes who did not return to sport for reasons unrelated to their hip demonstrated favorable outcomes at minimum 2- and 5-year follow-up. They had similar PROs and rates of achieving MCID for HOS-SSS compared to a propensity-matched control group of high-level athletes who returned to sport. Return to sport status may not necessarily be correlated to the patient's perception of their own outcome. LEVEL OF EVIDENCE: III, retrospective cohort study.