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.

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.

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.

Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

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.

BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain.

The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription.

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.

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.

EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis.

BACKGROUND: Preoperative diagnosis of solid pancreatic lesions remains challenging despite advancement in imaging technologies. EUS has the benefit of being a minimally invasive, well-tolerated procedure, although results are operator-dependent. The addition of FNA (EUS-guided FNA) provides samples for cytopathologic analysis, a major advantage over other imaging techniques. OBJECTIVE: To determine the diagnostic accuracy of EUS-FNA for pancreatic cancer. DESIGN: This is a meta-analysis of published studies assessing the diagnostic capability of EUS-FNA. Relevant studies were identified via MEDLINE and were included if they used a reference standard of definitive surgical histology or clinical follow-up of at least 6 months. MAIN OUTCOME MEASUREMENTS: Data from selected studies were analyzed by using test accuracy meta-analysis software, providing a pooled value for sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve. Cytology results were classified as inadequate, benign, atypical, suspicious, or malignant. Predefined subgroup analysis was performed. RESULTS: Thirty-three studies published between 1997 and 2009 were included, with a total number of 4984 patients. The pooled sensitivity for malignant cytology was 85% (95% confidence interval [CI], 84-86), and pooled specificity was 98% (95% CI, 0.97-0.99). If atypical and suspicious cytology results were included to determine true neoplasms, the sensitivity increased to 91% (95% CI, 90-92); however, the specificity was reduced to 94% (95% CI, 93-96). The diagnostic accuracy of EUS-FNA was enhanced in prospective, multicenter studies. LIMITATION: Publication bias was not a significant determinant of pooled accuracy. CONCLUSION: This meta-analysis demonstrates that EUS-FNA is a highly accurate diagnostic test for solid neoplasms of the pancreas and should be considered when algorithms for investigating solid pancreatic lesions are being planned.

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.

Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine, a dual serotonin and dopamine reuptake inhibitor.

The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.

Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor.

The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.

Discovery of N-methyl-1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor.

Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC(50) ≤ 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.

Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors.

The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.

Novel drug OMS103HP reduces pain and improves joint motion and function for 90 days after arthroscopic meniscectomy.

PURPOSE: This phase 2 study compared OMS103HP (Omeros, Seattle, WA) with control (lactated Ringer's) irrigation solution in patients undergoing arthroscopic partial meniscectomy. METHODS: This was a prospective, multicenter, double-blind, randomized, vehicle-controlled, parallel-group study. Safety and postoperative pain, range of motion, and self-reported function were evaluated for 90 days. Statistical results were based on univariate analysis of variance and repeated-measures analyses. RESULTS: Mean visual analog scale (VAS) pain scores within 24 hours after discharge from the recovery room showed more pain in the control group beginning at 2 hours and peaking at 8 hours. Univariate analysis of variance of mean VAS scores over the 24-hour period did not meet statistical significance. Repeated-measures analysis yielded a statistically significant difference (P = .004) for time-by-treatment interaction, showing a clear drug benefit over time based on VAS scores. There were statistically significant differences at day 7 between the groups in passive flexion without pain (P = .022). The proportion of patients achieving flexion of 95° or greater, 110°, and 125° was greater for the OMS103HP group. The Knee Injury and Osteoarthritis Outcome Score (KOOS) showed statistically significant differences (P ≤ .05) between the OMS103HP and control groups for 4 of 5 outcomes (symptoms, pain, sport and recreation, and knee-based quality of life but not activities of daily living). All scores showed a treatment effect through day 90. The overall incidence of adverse events and abnormal laboratory values for the OMS103HP and control groups was similar. Serious adverse events occurred in 1 control patient. CONCLUSIONS: In this study of patients with meniscal tears who underwent simple debridement, the use of OMS103HP resulted in reduced acute postoperative pain (measured by VAS over the first 24 hours postoperatively), reduced pain during recovery (measured by the KOOS pain subscale, which measures both background levels of pain and exacerbations caused by movements or activities), improved postoperative knee motion, and improved functional outcomes as assessed with the KOOS Knee Survey. Clinical benefits of OMS103HP were consistent and sustained throughout 90 days of postoperative follow-up. LEVEL OF EVIDENCE: Level I, prospective, randomized, controlled trial.

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.

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.

The kinetic isotope effect in the search for deuterated drugs.

The kinetic isotope effect has long been exploited by physical organic chemists to study reaction mechanisms due to its effect on reaction rates when cleavage of a C-isotope bond is rate determining. Medicinal chemists have also used the deuterium kinetic isotope effect to slow the cytochrome P450 metabolism of the deuterated versions of drug candidates, with the first in vitro microsome studies of deuterated morphine appearing in the literature in the 1960s, and a deuterated alanine compound from Merck going all the way to phase IIb in the 1970s. The recent emergence of companies such as Concert Pharmaceuticals and Auspex Pharmaceuticals, based solely on the idea of deuterium-for-hydrogen versions of existing drugs, has reinvigorated the backers of the deuterium camp, and established the strategy as a viable low-risk approach to drug development. A history of the deuterium kinetic isotope effect is presented, along with examples of deuterated drugs that span 50 years, from 1960 to present day. Specific examples of compounds from the Concert and Auspex pipelines are also analyzed and the pros and cons of their approach are discussed.

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.