Ligament augmentation repair is broadly applied across different orthopaedic subspecialities: an ISAKOS international survey of orthopaedic surgeons.

OBJECTIVES: To evaluate how ligament augmentation repair (LAR) techniques are currently used in different anatomic regions in orthopaedic sports medicine, and to identify the most common indications and limitations of LAR. METHODS: We sent survey invitations to 4,000 members of the International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine society. The survey consisted of 37 questions total, with members only receiving some branching questions specific to their area of specialisation. Data were analysed using descriptive statistics, and the significance between groups was evaluated using chi-square tests of independence. RESULTS: Of 515 surveys received, 502 were complete and included for the analysis (97% completion rate). 27% of respondents report from Europe, 26% South America, 23% Asia, 15% North America, 5.2% Oceania, and 3.4% Africa. 75% of all survey respondents report using LAR, most frequently using it for the anterior talofibular ligament ( 69%), acromioclavicular joint ( 58%), and the anterior cruciate ligament (51%). Surgeons in Asia report using LAR the most (80%), and surgeons in Africa the least (59%). LAR is most commonly indicated for additional stability (72%), poor tissue quality (54%), and more rapid return-to-play (47%). LAR users state their greatest limitation is cost (62%), while non-LAR users state their greatest reason not to use LAR is that patients do well without it (46%). We also find that the frequency of LAR use among surgeons may differ based on practice characteristics and training. For example, surgeons who treat athletes at the professional or Olympic level are significantly more likely to have a high annual use of LAR (20+ cases) compared to surgeons that treat only recreational athletes (45% and 25%, respectively, p â€‹= â€‹0.005). CONCLUSION: LAR is broadly applied in orthopaedics but its rate of use is not homogeneous. Outcomes and perceived benefits vary depending on factors such as surgeon specialty and treatment population. LEVEL OF EVIDENCE: Level V.

Publication trends in ligament augmentation techniques: current concepts.

IMPORTANCE: Ligament augmentation techniques (LATs) are surgical procedures, in which an anatomical ligament repair or reconstruction is strengthened with a synthetic material. During the last decade, LATs have increased in prevalence in clinical practice and academic literature. Observing the trends in LAT publications can be used to identify clusters of strong evidence for clinical practice and to highlight areas of the literature which need further development. OBJECTIVE: This article aims to define ligament augmentation as a technique category, observe anatomical, procedural, and temporal trends in LAT publication, and report on the state of current research in this field. EVIDENCE REVIEW: Primary literature in the English language, which describes ligament augmentation and reports on human, cadaveric, or biomechanical models, and published prior to May 24th, 2022, was targeted for analysis. PubMed, Embase, and Cochrane CENTRAL databases were explored using a focused keyword search strategy, and the resulting publications were reviewed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were collected and analysed using descriptive statistics. FINDINGS: Two hundred eighty-three publications reporting ligament augmentation techniques, published from May 1989 to May 2022, were included for final analysis. A wide technical and anatomical variety of procedures are reported. 36.8% of LAT publications describe knee ligaments, among which the anterior cruciate ligamenthas the highest focus in ligament augmentation publications (31.8% of articles). LAT literature has recently expanded in anatomical scope, with many contemporary articles describing the usage of a LAT in the ankle syndesmosis and coracoclavicular ligaments. 60.4% of LAT literature has been published since 2017. There has been an 11% average increase in the rate of LAT publication reports since 2015. Novel fixation devices-suture buttons and suture anchors-have gained wide popularity in the literature. CONCLUSIONS AND RELEVANCE: In this review, we define LATs and quantitatively describe the expansion of LAT use reported in the literature. This data will provide physicians an overview of the history of these methods, as well as illustrate the broad range of applications available for the use of LATs.

Variation of volatile organic compound levels within ambient room air and its impact upon the standardisation of breath sampling.

The interest around analysis of volatile organic compounds (VOCs) within breath has increased in the last two decades. Uncertainty remains around standardisation of sampling and whether VOCs within room air can influence breath VOC profiles. To assess the abundance of VOCs within room air in common breath sampling locations within a hospital setting and whether this influences the composition of breath. A secondary objective is to investigate diurnal variation in room air VOCs. Room air was collected using a sampling pump and thermal desorption (TD) tubes in the morning and afternoon from five locations. Breath samples were collected in the morning only. TD tubes were analysed using gas chromatography coupled with time-of-flight mass spectrometry (GC-TOF-MS). A total of 113 VOCs were identified from the collected samples. Multivariate analysis demonstrated clear separation between breath and room air. Room air composition changed throughout the day and different locations were characterized by specific VOCs, which were not influencing breath profiles. Breath did not demonstrate separation based on location, suggesting that sampling can be performed across different locations without affecting results.

Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia.

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure-activity relationships.

Ion Mobility Spectrometry Characterization of the Intermediate Hydrogen-Containing Gold Cluster Au7(PPh3)7H52.

We employ ion mobility spectrometry and density functional theory to determine the structure of Au7(PPh3)7H52+ (PPh3 = triphenylphosphine), which was recently identified by high mass resolution mass spectrometry. Experimental ion-neutral collision cross sections represent the momentum transfer between the ionic clusters and gas molecules averaged over the relative thermal velocities of the colliding pair, thereby providing structural insights. Theoretical calculations indicate the geometry of Au7(PPh3)7H52+ is similar to Au7(PPh3)7+, with three hydrogen atoms bridging two gold atoms and two hydrogen atoms forming single Au-H bonds. Collision-induced dissociation products observed during IMS experiments reveal that smaller hydrogen-containing clusters may be produced through fragmentation of Au7(PPh3)7H52+. Our findings indicate that hydrogen-containing species like Au7(PPh3)7H52+ act as intermediates in the formation of larger phosphine ligated gold clusters. These results advance the understanding and ability to control the mechanisms of size-selective cluster formation, which is necessary for scalable synthesis of clusters with tailored properties.

ESI-MS Identification of the Cationic Phosphine-Ligated Gold Clusters Au1-22: Insight into the Gold-Ligand Ratio and Abundance of Larger Clusters.

Triphenylphosphine (PPh3)-ligated gold nanoclusters are valuable for a number of potential applications due to their relative ease of synthesis and usefulness in forming advanced cluster architectures. While previous studies have reported cationic PPh3-ligated gold clusters with core sizes of Au1-4, Au6-11, and Au13-14, there has not been definitive identification by mass spectrometry of many larger clusters in the Au12-25 range. Herein, we survey a polydisperse solution of cationic PPh3-ligated gold clusters using high-mass-resolution (M/ΔM = 60,000) electrospray ionization mass spectrometry (ESI-MS). To improve the sensitivity and mass resolution of larger clusters for unambiguous identification, we increased the number of scan averages and reduced the range of mass collection windows to 200 m/z, thereby mitigating potential mass and ion abundance bias resulting from smaller "building block" gold clusters that are present in much higher abundance in solution. In addition to the previously reported clusters, we identify several new species including Au5(PPh3)5+, Au12(PPh3)9HCl2+, Au15(PPh3)9Cl2+, Au16(PPh3)10Cl22+, Au17(PPh3)113+, Au18(PPh3)102+, Au19(PPh3)10Cl2+, Au20(PPh3)12H33+, Au21(PPh3)10Cl2+, and Au22(PPh3)10Cl22+, indicating that a full range of clusters between Au1-22 may be observed in a single polydisperse solution. Considering all of the clusters observed, our findings provide evidence that the Au12-14 size range is a critical transition point in cluster nucleation. While smaller clusters exhibit a 1:1 gold-to-ligand ratio, larger clusters (beginning Au12-14) feature additional gold atoms without an equal number of accompanying ligands. Our results support previous evidence in the literature indicating that the "magic number" icosahedral Au13 geometry is the smallest cluster size where a ligand-less central gold atom is coordinated by a complete shell of 12 surrounding ligated gold atoms, thereby creating a stable "one-shell" cluster. Furthermore, our findings reinforce growing evidence that ligands may be used to actively direct gold cluster size and abundance during synthesis. While for PPh3-ligated systems the most abundant species are Au6-9 clusters, we find that for related methyldiphenylphosphine (PPh2Me) and dimethylphenylphosphine (PPhMe2)-ligated systems the most abundant cluster sizes are Au10-11 and Au12-14, respectively. Together, we demonstrate that reducing the range of m/z collection windows and increasing the number of scan averages dramatically improves instrument sensitivity for cationic gold clusters, enabling thorough characterization of polydisperse solutions that is not possible using conventional techniques.

Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment.

Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer 'Donors' (n = 52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). 'Recipients' randomized to Intervention (IR, n = 40) or Control (CR, n = 35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitized frequently to limit large droplet and contact transmission. One transmitted infection was confirmed by serology in a CR, yielding a secondary attack rate of 2.9% among CR, 0% in IR (p = 0.47 for group difference), and 1.3% overall, significantly less than 16% (p<0.001) expected based on a proof-of-concept study secondary attack rate and considering that there were twice as many Donors and days of exposure. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols.

Evaluation of an early discharge from hospital scheme focussing on patients' housing needs: The ASSIST Project.

This study calculated a return on investment of an early discharge from hospital scheme focussing on improved responses to patients' housing needs. The study identified critical success factors of the scheme that will inform potential spread of the intervention to other localities. Financial return on investment based on service costs and benefits were calculated and the critical success factors were identified through interviews with key stakeholders. The annualised return on investment of the scheme was £3.03 for each £1 invested. Close working relationships between health and housing and aspects of the local housing stock (such as direct local control) were key to realising the return on investment.

Supporting the UN's Sustainable Development Goals: reconceptualising a 'sustainable development assessment tool' for the health and care system in England.

AIM:: As one of the biggest organisations in the world, the National Health Service (NHS) in England can contribute considerably to the United Nations' Sustainable Development Goals (UN's SDGs). In order to optimise this, this study evaluated and reconceptualised a sustainable development assessment tool for health and care settings in England. METHODS:: A quantitative survey and user/expert discussion panels were conducted to evaluate and reconceptualise the existing sustainable development assessment tool used by the NHS in England, the so-called 'Good Corporate Citizenship Assessment Tool', including potential improvements such as the integration of the UN's SDGs. RESULTS:: A reconceptualised self-assessment tool integrating the UN's SDGs was developed and implemented online as the 'Sustainable Development Assessment Tool' (SDAT). Further improvements included a process-oriented redesign and the creation of new modules and cross-sections aligning them with the leads responsible for the implementation of key initiatives in NHS organisations, which would contribute to achieving the targets of the SDGs. CONCLUSION:: User/expert involvement has enabled an informed approach to a reconceptualisation of a sustainable assessment tool for health and care settings. The tool will support organisations to build their mandatory Sustainable Development Management Plans, as part of the National Public Health Outcomes Framework. Alignment of the tool to the UN's SDGs provides an opportunity for health and care organisations to demonstrate accountability and progress against the UN's set of transformational goals. Furthermore, the tool could be adapted to other public service providers.

CoREST Complex-Selective Histone Deacetylase Inhibitors Show Prosynaptic Effects and an Improved Safety Profile To Enable Treatment of Synaptopathies.

Synaptic dysfunction is a pathological feature in many neurodegenerative disorders, including Alzheimer's disease, and synaptic loss correlates closely with cognitive decline. Histone deacetylases (HDACs) are involved in chromatin remodeling and gene expression and have been shown to regulate synaptogenesis and synaptic plasticity, thus providing an attractive drug discovery target for promoting synaptic growth and function. To date, HDAC inhibitor compounds with prosynaptic effects are plagued by known HDAC dose-limiting hematological toxicities, precluding their application to treating chronic neurologic conditions. We have identified a series of novel HDAC inhibitor compounds that selectively inhibit the HDAC-co-repressor of repressor element-1 silencing transcription factor (CoREST) complex while minimizing hematological side effects. HDAC1 and HDAC2 associate with multiple co-repressor complexes including CoREST, which regulates neuronal gene expression. We show that selectively targeting the CoREST co-repressor complex with the representative compound Rodin-A results in increased spine density and synaptic proteins, and improved long-term potentiation in a mouse model at doses that provide a substantial safety margin that would enable chronic treatment. The CoREST-selective HDAC inhibitor Rodin-A thus represents a promising therapeutic strategy in targeting synaptic pathology involved in neurologic disorders.

GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like.

The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC50 of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC50 = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.

Sickness presenteeism: measurement and management challenges.

Since work can be restorative to health, attending work when unwell should not be viewed as an inherently negative phenomenon. However, the functional benefits are likely to depend on the health condition, and the psychosocial quality of the work provided. The current study used a workforce survey to explore differences in the pattern of presenteeism and absenteeism by health condition, the association of psychosocial work factors with presenteeism compared to absenteeism, and their interaction to predict health. Findings indicate that instead of substituting absenteeism for presenteeism, the two tend to coincide, but the balance differs by health condition. Presenteeism is more likely to occur in poorer psychosocial environments, reinforcing the importance of ensuring work is designed and managed in ways that are beneficial rather than detrimental to health. The findings also highlight the methodological importance of differentiating between the act and impact of presenteeism in future research and practice. Practitioner Summary: Effective management of work-related health requires that practitioners manage both sickness absence and presence together, since employees tend to fluctuate between the two when unwell. Interventions should be tailored to the specific health concern, paying particular attention to the psychosocial environment in enabling employees to continue working without exacerbating health.

GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2).

The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.

Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance.

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance.

Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637).

CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.

Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains.

The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.

In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition.

In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. Using microdialysis, we show that 3mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3mg/kg (p.o.) corresponding to 59-86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications.

Development of methyl isoxazoleazepines as inhibitors of BET.

In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.