5'-Chalcogen-Substituted Nucleoside Pyrophosphate and Phosphate Monoester Analogues: Preparation and Hydrolysis Studies.

Novel sulfur and selenium substituted 5',5'-linked dinucleoside pyrophate analogues were prepared in a vibration ball mill from the corresponding persilylated monophosphate. The chemical hydrolysis of pyrophosphorochalcogenolate-linked dimers was studied over a wide pH-range. The effect of the chalcogeno-substitution on the reactivity of dinucleoside pyrophosphates was surprisingly modest, and the chemical stability is promising considering the potential therapeutic or diagnostic applications. The chemical stability of the precursor phosphorochalcogenolate monoesters was also investigated. Hydrolytic desilylation of these materials was effected in aqueous buffer at pH 3, 7 or 11 and resulted in phosphorus-chalcogen bond scission which was monitored using 31P NMR. The rate of dephosphorylation was dependent upon both the nature of the chalcogen and the pH. The integrity of the P-S bond in the corresponding phosphorothiolate was maintained at high pH but rapidly degraded at pH 3. In contrast, P-Se bond cleavage of the phosphoroselenolate monoester was rapid and the rate increased with alkalinity. The results obtained in kinetic experiments provide insight on the reactivity of the novel pyrophosphates studied as well as of other types of thiosubstituted biological phosphates. At the same time, these results also provide evidence for possible formation of unexpectedly reactive intermediates as the chalcogen-substituted analogues are metabolised.

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

Development of a generic wound care assessment minimum data set.

BACKGROUND: At present there is no established national minimum data set (MDS) for generic wound assessment in England, which has led to a lack of standardisation and variable assessment criteria being used across the country. This hampers the quality and monitoring of wound healing progress and treatment. AIM: To establish a generic wound assessment MDS to underpin clinical practice. METHOD: The project comprised 1) a literature review to provide an overview of wound assessment best practice and identify potential assessment criteria for inclusion in the MDS and 2) a structured consensus study using an adapted Research and Development/University of California at Los Angeles Appropriateness method. This incorporated experts in the wound care field considering the evidence of a literature review and their experience to agree the assessment criteria to be included in the MDS. RESULTS: The literature review identified 24 papers that contained criteria which might be considered as part of generic wound assessment. From these papers 68 potential assessment items were identified and the expert group agreed that 37 (relating to general health information, baseline wound information, wound assessment parameters, wound symptoms and specialists) should be included in the MDS. DISCUSSION: Using a structured approach we have developed a generic wound assessment MDS to underpin wound assessment documentation and practice. It is anticipated that the MDS will facilitate a more consistent approach to generic wound assessment practice and support providers and commissioners of care to develop and re-focus services that promote improvements in wound care.

Towards a spectroscopically accurate set of potentials for heavy hydride laser cooling candidates: Effective core potential calculations of BaH.

BaH (and its isotopomers) is an attractive molecular candidate for laser cooling to ultracold temperatures and a potential precursor for the production of ultracold gases of hydrogen and deuterium. The theoretical challenge is to simulate the laser cooling cycle as reliably as possible and this paper addresses the generation of a highly accurate ab initio (2)Σ(+) potential for such studies. The performance of various basis sets within the multi-reference configuration-interaction (MRCI) approximation with the Davidson correction is tested and taken to the Complete Basis Set (CBS) limit. It is shown that the calculated molecular constants using a 46 electron effective core-potential and even-tempered augmented polarized core-valence basis sets (aug-pCVnZ-PP, n = 4 and 5) but only including three active electrons in the MRCI calculation are in excellent agreement with the available experimental values. The predicted dissociation energy De for the X(2)Σ(+) state (extrapolated to the CBS limit) is 16,895.12 cm(-1) (2.094 eV), which agrees within 0.1% of a revised experimental value of <16,910.6 cm(-1), while the calculated re is within 0.03 pm of the experimental result.

Synthesis of Complex Druglike Molecules by the Use of Highly Functionalized Bench-Stable Organozinc Reagents.

The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. The high-fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug-discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable-space coverage.

Circulating serum-derived microparticles provide novel proteomic biomarkers of spontaneous preterm birth.

OBJECTIVE: The purpose of this study was to determine whether the proteomic biosignature of circulating microparticles in maternal serum obtained in the second trimester could identify pregnancies that result in spontaneous preterm birth (SPTB). STUDY DESIGN: Microparticles were isolated from blinded biorepository-sourced serum samples from 48 pregnant women at 15 to 17 weeks of gestation. Microparticle proteins were extracted and analyzed using label-free liquid chromatography/mass spectrometry. Peptide features were analyzed to assess the association of specific protein patterns with subjects delivering at term (≥ 37 weeks gestation; n = 24) and those experiencing SPTB (≤ 34 weeks gestation; n = 24). RESULTS: We found 99 proteins that had statistically significant differences in signal intensity between term and SPTB women in both first (n = 26) and second (n = 22) singleton gestation pregnancy cohorts. Additional evaluation identified 18 biomarkers that met criteria for further priority evaluation (12 preterm, 6 term). Pathway analysis showed that differentiating SPTB biomarker proteins were predominantly associated with inflammation and cell injury, while differentiating term biomarkers were associated with cell growth and hematological parameters. CONCLUSION: This study shows for the first time that the proteomic content of serum microparticles isolated in the second trimester can identify with a high degree of accuracy pregnancies that result in SPTB.

Assessing health plan ownership.

In the emerging healthcare environment, providers will require many capabilities of traditional health plans simply to remain viable. Providers that are contemplating entering the health plan business should consider the likely strategic, structural, and cultural effects of such a strategy on their organizations. Providers that own health plans will need to determine how they will differentiate themselves in the markets to foster patient loyalty and which insurance lines of business they will pursue (e.g., individual, small group, large group, or other).

The integration aspiration.

Integration is a common goal when health systems acquire medical practices, but may take various forms and continue to evolve beyond the classic model. Characteristics of the classic model of integration include strong and committed physician leadership, an emphasis on care coordination, easy access to primary care, integrated IT and business intelligence, and a willingness to accept financial risk. Leaders of integrated delivery systems continue to strive for greater levels of coordination and leveraging of collected talents and resources.

The assault on common care models.

The U.S. healthcare system's focus on population health management is prompting experimental care models aimed at strategically filling gaps in care coordination for targeted patient populations. Examples include: Extensivists. Care coordinators. Home visits. Polyclinics. Reorganized hospitalists. Predictive modeling.

A synthetic connexin 43 mimetic peptide augments corneal wound healing.

The ability to safely and quickly close wounds and lacerations is an area of need in regenerative medicine, with implications toward healing a wide range of tissues and wounds. Using an in vivo corneal injury model, our study applied a newly developed peptide capable of promotion of wound healing and epithelial regeneration. The alpha-carboxy terminus 1 (αCT1) peptide is a 25 amino acid peptide from the C-terminus of connexin 43 (Cx43), modified to promote cellular uptake. Previous studies applying αCT1 to excisional skin wounds in porcine models produced tissues having an overall reduced level of scar tissue and decreased healing time. Rapid metabolism of αCT1 in previous work led to the investigation of extended release on wound healing rate used in this study. Here we delivered αCT1 both directly, in a concentrated pluronic solution, and in a sustained system, using polymeric alginate-poly-l-ornithine (A-PLO) microcapsules. Cell toxicity analysis showed minimal cell-loss with microcapsule treatment. Measurement of wound healing using histology and fluorescence microscopy indicated significant reduction in healing time of αCT1 microcapsule treated rat corneas compared with controls (88% vs. 38%). RT-PCR analysis showed an initial up regulation followed by down regulation of the gene keratin-19 (Krt19). Zonula occludens 1 (ZO-1) showed an opposite down regulation followed by an up regulation whereas Cx43 showed a biphasic response. Inflammatory indexes demonstrated a reduction in the inflammation of corneas treated with αCT1 microcapsules when compared with pluronic gel vehicle. These results suggest αCT1, when applied in a sustained release system, acts as a beneficial wound healing treatment.

Characterization of polymeric microcapsules containing a low molecular weight peptide for controlled release.

A need exists to prolong the release of rapidly metabolized peptides of a low molecular weight, while delivering this peptide without environmental interference. Previous studies have used bovine serum albumin (BSA) as a model peptide to study release characteristics from alginate microcapsules. BSA is 66 kDa in size, while the peptide of interest here, connexin-43 carboxyl-terminus mimetic peptide (αCT1), is only 3.4 kDa. Such a change in size results in a much different set of release parameters. Our overall goal is a sustained release over a 24+ h period. Prolonged application of the peptide to a wound site to investigate therapeutic effects is ideal. As a result, a diffusion method using alginate microcapsules, along with the addition of poly-l-lysine and poly-l-ornithine, has been explored. We first aimed to establish and characterize our parameters through a set of parametric tests. Variations in polymer coating, change in pH, and changes in loading ratio have previously been shown to effect release using model compounds. Here we test specific changes in these parameters to show effects on the release of αCT1. Additionally, the microcapsules were attached to several biomaterials and surgical implants by ultraviolet cross-linking to study the effectiveness of attachment and delivery. Analysis and measurements using phase contrast microscopy, scanning electron microscopy, and atomic force microscopy were used to characterize changes in microcapsule morphology.

The big deal about big data.

Big data is a concept that is being widely applied in the retail industries as a means to understand customers' purchasing habits and preferences for followup promotional activity. It is characterized by vast amounts of diverse and rapidly multiplying data that are available at or near real-time. Conversations with executives of leading healthcare organizations provide a barometer for understanding where the industry stands in its adoption of big data as a means to meet the critical information requirements of value-based health care.

The healthcare cost curve can be bent.

The nation's annual growth rate of medical costs could be halved if the nation were to rigorously pursue the following initiatives, among others: Move rapidly from fee-for-service to value-based contracting. Increase the supply and effective utilization of primary care physicians and physician extenders. Focus more on chronic disease management. Pass tort reform. Encourage the formation of multispecialty group practices and integrated systems. Reduce administrative complexity.

When a health system develops its own road map.

Key considerations facing a hypothetical and typical health system as it transitions to value-based payment provide a guide for systems as they undertake this transition. The health system's first step is to review its current environment and strategies and the building blocks it has in place. Next, the system needs to add more building blocks, build a financial cushion, and revise targets and dashboards. Next steps include testing value-based payment contracting, realigning incentives, implementing new care management strategies, and communicating extensively. All of these steps will be unique to each organization.

Assessing the environmental impact of an anastomotic leak care pathway.

Background: The healthcare sector faces increasing pressure to improve environmental sustainability whilst continuing to meet the needs of patients. One strategy is to lower the avoidable demand on healthcare services, by reducing the number of surgical complications, such as anastomotic leak (AL). The aim of this study was to assess the environmental impact associated with the care pathway of AL. Methods: An environmental impact assessment was performed according to the Sustainable Healthcare Coalition (SHC) guidelines. A care pathway, describing the typical steps involved in the diagnosis and treatment of AL was developed. Activity and emission data for each stage of the care pathway were used to calculate the climate, water and waste impact of the treatment of AL patients. Results: The environmental impact assessment shows that AL is associated with an average climate, water and waste impact per patient of 1303 kg CO2-eq, 1803 m3 of water and 123 kg waste, respectively. Grade C leaks are associated with the greatest environmental impact, contributing to 89.3 %, 79.4 % and 97.9 % of each impact, respectively. A breakdown of the environmental impact of each activity shows that stoma home management is the largest contributor to the total climate (46.6 %) and waste (47.3 %) impact of AL patients, whilst in-patient hospital stay contributes greatest to the total water impact (46.7 %). Conclusions: The treatment of AL is associated with a substantial environmental impact. This study is, to our knowledge, the first to assess the environmental impact associated with the treatment of AL.

Pharmacokinetic studies in women of 2 novel oral formulations of tranexamic acid therapy for heavy menstrual bleeding.

Two randomized, open-label clinical studies involving healthy female volunteers aged 18-45 years (study 1, N = 32; study 2, N = 40) are described, which characterize the pharmacokinetics and steady-state dosage regimen performance of 2 novel, modified-release tranexamic acid tablet formulations. The objective of these studies was to identify the optimum product formulation to advance into late-phase clinical trials for heavy menstrual bleeding. For study 1, participants received single 1.3-g doses (2 650-mg tablets) of tranexamic acid modified-immediate-release (MIR) and tranexamic acid delayed-release (DR) formulations under fasting conditions compared with nonfasting conditions (after breakfast). For study 2, participants received tranexamic acid MIR or tranexamic acid DR as a single 1.3-g dose followed by a dosage regimen of 1.3 g every 8 hours for 5 days. Plasma tranexamic acid concentrations reached minimum effective levels (≥5 µg/mL) within 1.5 hours and within 3 hours after a 1.3-g tranexamic acid MIR and tranexamic acid DR dose, respectively. Food did not appreciably influence tranexamic acid MIR pharmacokinetics, whereas a high-fat meal significantly lowered the maximum concentration produced with tranexamic acid DR. Peak systemic exposure and maintenance of plasma tranexamic acid concentrations within the therapeutic range (5-15 µg/mL) were optimally achieved with 1.3 g of the MIR formulation dosed every 8 hours. The MIR and DR formulations were well tolerated. Peak-to-trough steady-state performance of the tranexamic acid MIR 1.3-g product (dosed every 8 hours, or 3 times daily, for up to 5 days) supported its advancement to late-phase clinical trials in women with heavy menstrual bleeding.

How business intelligence can improve value.

Case studies of three healthcare organizations reinforce the premise that business intelligence--the ability to convert data into actionable information for decision making--is critical to demonstrating improved value.

Correction to "SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial".

[This corrects the article DOI: 10.1016/j.lansea.2022.100036.].