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ABSTRACTIntroductionSeladelpar (MBX-8025) is a once-daily administered highly specific PPAR-δ agonist in Phase 3 and extension trials for use in patients with primary biliary cholangitis (PBC).Areas coveredThis review provides background on current treatment options for PBC, and summarizes clinical trial data regarding the safety and effectiveness of seladelpar within the context of these treatments.Expert opinionClinical trials results demonstrate the safety and tolerability of seladelpar use for PBC, including in patients with cirrhosis. The primary composite endpoint (ALP <1.67 times ULN, decrease ≥ 15% from baseline, and TB ≤ULN) was met in 61.7% of the patients treated with seladelpar and in 20% receiving placebo (p < 0.001). Moreover, pruritus – a cardinal and often intractable symptom of PBC – was improved with seladelpar treatment, as were overall quality of life measurements. Improvements in markers of inflammation were likewise observed. These biochemical and clinical findings therefore represent landmark developments in PBC treatment and offer a therapeutic option for PBC.

AbstractA popular but contested view is that mass rezoning is an essential policy measure to address housing affordability. Often obscured in debates about this measure is that rezoning involves the privatization of public space. We clarify the nature of the policy by recognizing that property rights over land are, conceptually, a bundle of socially negotiated rights to parcels of airspace. This view shows that rezoning to provide rights to airspace for existing landowners is not costless. It involves transferring valuable property rights from the public to existing private landowners for free, creating a more unequal distribution of property rights ownership without necessarily generating faster housing development. We argue that giving away public rights to airspace should not be done for free and explore what policy measures retain value from residential rezoning for the public.

RationaleHeterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported.ObjectivesWe investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes.MethodsHierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters.Measurements and main resultsWe identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes.ConclusionsThese findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes.Trial registration numberISRCTN20769191, ISRCTN12776039.

BackgroundFibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD).MethodsDescription of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure.ResultsThe target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results.ConclusionBy using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis.Design: Multicentre three-arm randomised controlled trial.Setting: UK NHS hospitals.Target population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis.Health technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed.Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice.

Low-frequency Raman spectroscopy was used to characterize variably substituted hydroxyapatites with Sr2+, F–, and CO32–as the substituting species in the crystalline and amorphous forms. These samples were characterized for substitution and crystallinity using methods previously explored in the literature (XRPD, IR, and Raman spectroscopy) to demonstrate a range of substitutions, and the levels of crystallinity were achieved. The sample series was characterized with low-frequency Raman spectroscopy where clear differences between amorphous and crystalline forms along with systematic changes in the crystalline spectra with the level of substitution were observed. Solid-state density functional theory was used to identify and characterize the observed low-frequency Raman modes, and principal component analysis further explored the trends in the data set. A new crystallinity index (CI) was proposed using the ratio of intensities at 140 and 110 cm–1(CILFRintensityStokes) or −140 and −110 cm–1(CILFRintensityanti-Stokes). When correlated to the XRPD-based CI, better correlation was observed with CILFRintensityStokes(NRMSE = 0.11, R2= 0.85) and CILFRintensityanti-Stokes(NRMSE = 0.11, R2= 0.88) compared to the previously used CIIR(NRMSE = 0.24, R2= 0.03) or CIRaman(NRMSE = 0.15, R2= 0.66) methods, which were particularly sensitive to the degree of substitution interfering with the level of crystallinity, thus making this a promising method for estimating crystallinity when dealing with variably substituted apatites.

The vibrational and electronic properties of six systematically altered donor–acceptor dyes were investigated with density functional theory (DFT), spectroscopy, and electrochemical techniques. The dyes incorporated a carbazole donor connected to a dithieno[3,2-b:2′,3′-d]thiophene linker at either the C2(m) or C3(p) position. Indane-based acceptors contained either dimalononitrile (IndCN), ketone and malononitrile (InOCN) or diketone (IndO) electron accepting groups. Molecular geometries modeled by DFT using the BLYP functional and def2-TZVP basis set showed planar geometries containing large, extended π-systems and produced Raman spectra consistent with the experimental data. Electronic absorption spectra had transitions with π–π* character at wavelengths below 325 nm and a charge transfer (CT) transition region from 500 to 700 nm. The peak wavelength was dependent on the donor and acceptor architecture, with each modulating the HOMO and LUMO levels, respectively, supported by TD-DFT estimates using the LC-ωPBE* functional and 6-31g(d) basis set. The compounds showed emission in solution with quantum yields ranging from 0.004 to 0.6 and lifetimes of less than 2 ns. These were assigned to either π–π* or CT emissive states. Signals attributed to CT states exhibited positive solvatochromism and thermochromism. The spectral emission behavior of each compound trended with the acceptor unit moieties, where malononitrile units lead to greater π–π* character and ketones exhibited greater CT character.

Control over the populations of singlet and triplet excitons is key to organic semiconductor technologies. In different contexts, triplets can represent an energy loss pathway that must be managed (i.e., solar cells, light-emitting diodes, and lasers) or provide avenues to improve energy conversion (i.e., photon upconversion and multiplication systems). A key consideration in the interplay of singlet and triplet exciton populations in these systems is the rate of intersystem crossing (ISC). In this work, we design, measure, and model a series of new electron acceptor molecules and analyze them using a combination of ultrafast transient absorption and ultrafast broadband photoluminescence spectroscopies. We demonstrate that intramolecular triplet formation occurs within several hundred picoseconds in solution and is accelerated considerably in the solid state. Importantly, ISC occurs with sufficient rapidity to compete with charge formation in modern organic solar cells, implicating triplets in intrinsic exciton loss channels in addition to charge recombination. Density functional theory calculations reveal that ISC occurs in triplet excited states characterized by local deviations from orbital π-symmetry associated with rotationally flexible thiophene rings. In disordered films, structural distortions, therefore, result in significant increases in spin–orbit coupling, enabling rapid ISC. We demonstrate the generality of this proposal in an oligothiophene model system where ISC is symmetry-forbidden and show that conformational disorder introduced by the formation of a solvent glass accelerates ISC, outweighing the lower temperature and increased viscosity. This proposal sheds light on the factors responsible for facile ISC and provides a simple framework for molecular control over spin states.

ABSTRACTThe World Anti-Doping Code (2021) includes a substance on the prohibited list if it meets at least two of the following: (1) it has the potential to enhance or enhances sport performance; (2) it represents an actual or potential health risk to the athlete; (3) it violates the spirit of sport. This paper uses a case study to illustrate points of tension between this code and enhancements that are appropriate to ban; we argue that there are banned drugs (e.g., acetazolamide and dexamethasone) the use of which we have good reason to not only permit but encourage for high-altitude sports. Drawing on lessons from this case study, we propose a reformulation of the Code that requires (1–3) be met but offers preferable ways of unpacking conditions (1) and (3) – and in a way that better preserves how the spirit of sport condition should be indexed to particular sports. Our formulation is inclusive enough to rule in drugs like acetazolamide and dexamethasone as permissible in high-altitude sports while at the same time ruling out problem cases – including many drugs already on the prohibited list. The result is an attempted alignment between the conditions specified and those drugs that should be banned.