Search

The emergence of biobank-level datasets offers new opportunities to discover novel biomarkers and develop predictive algorithms for human disease. Here, we present an ensemble machine-learning framework (machine learning with phenotype associations, MILTON) utilizing a range of biomarkers to predict 3,213 diseases in the UK Biobank. Leveraging the UK Biobank’s longitudinal health record data, MILTON predicts incident disease cases undiagnosed at time of recruitment, largely outperforming available polygenic risk scores. We further demonstrate the utility of MILTON in augmenting genetic association analyses in a phenome-wide association study of 484,230 genome-sequenced samples, along with 46,327 samples with matched plasma proteomics data. This resulted in improved signals for 88 known (P< 1 × 10−8) gene–disease relationships alongside 182 gene–disease relationships that did not achieve genome-wide significance in the nonaugmented baseline cohorts. We validated these discoveries in the FinnGen biobank alongside two orthogonal machine-learning methods built for gene–disease prioritization. All extracted gene–disease associations and incident disease predictive biomarkers are publicly available (http://milton.public.cgr.astrazeneca.com).

Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACDand RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.

There is a paucity of literature guiding trauma surgeons in the care of patients with active metastatic cancer (MC). Even less is known regarding outcomes for MC patients requiring emergent surgery after trauma. We hypothesized that trauma patients with active Metastatic Cancer (MC) have an increased mortality rate and undergo increased rates of withdrawal of care (WoC) within 72-hours following emergent operations, compared to similarly matched patients without MC.

Thermal annealing is the most common postdeposition technique used to crystallize antimony selenide (Sb2Se3) thin films. However, due to slow processing speeds and a high energy cost, it is incompatible with the upscaling and commercialization of Sb2Se3for future photovoltaics. Herein, for the first time, a fast-annealing technique that uses millisecond light pulses to deliver energy to the sample is adapted to cure thermally evaporated Sb2Se3films. This study demonstrates how photonic curing (PC) conditions affect the outcome of Sb2Se3phase conversion from amorphous to crystalline by evaluating the films’ crystalline, morphological, and optical properties. We show that Sb2Se3is readily converted under a variety of different conditions, but the zone where suitable films for optoelectronic applications are obtained is a small region of the parameter space. Sb2Se3annealing with short pulses (<3 ms) shows significant damage to the sample, while using longer pulses (>5 ms) and a 4–5 J cm–2radiant energy produces (211)- and (221)-oriented crystalline Sb2Se3with minimal to no damage to the sample. A proof-of-concept photonically cured Sb2Se3photovoltaic device is demonstrated. PC is a promising annealing method for large-area, high-throughput annealing of Sb2Se3with various potential applications in Sb2Se3photovoltaics.

Background: The increased contamination of illicit drugs with fentanyl in the United States drug market has contributed to escalating mortality from drug overdose. Leisure and hospitality service industry workers are encountering opioid-triggered overdoses in their workplaces, such as restaurants and bars. Consequently, this increases the need for overdose education and naloxone distribution (OEND) training, which has been limited. We aimed to describe the experiences among service industry workers encountering an overdose in their workplace.Methods: We conducted in-depth qualitative interviews with service industry workers in Little Five Points (L5P), Atlanta, between October 2019 and April 2020 and triangulated methods with participant observations and fieldwork. Purposive criterion sampling methods were applied to recruit from different establishments in the L5P commercial district, which comprised restaurants, bars, retail shops, and theaters. After an initial seed sample was identified by engaging key stakeholders during fieldwork (business owners, managers, and the business association), a snowball sample followed for a final sample of N= 15. To contextualize the local population of harm reduction workers, people who use drugs and/or obtain safer drug consumption supplies in L5P (sterile syringes, safer using kits, naloxone), and service industry workers and their customers in L5P, the first author volunteered with an Atlanta syringe services program from October 2019 to April 2020. The first author conducted participant observations during the syringe exchange program and field notes were taken during observation (44 hours). This engagement ensured a rich, thick description. We used a pragmatic approach to thematic data analysis for this study. Data were analyzed iteratively and inductively from interviews and observations. Two independent researchers reviewed transcripts to identify passages in the data related to the question of interest. The passages were contextualized within the full data set independently to understand the relationships in developing a theory of what was commonly occurring across participants’ experiences, and these relationships led to emerging salient themes regarding encountering an opioid overdose at work.Results: One salient theme related to overdose response emerged with the service industry workers included fear of negative consequences of overdose response, specifically, fear of disease transmission from artifacts of drug use and overdose response, including the spread of blood-borne disease, violence, and exposure to unintentional overdose. When discussing drug use, participants’ beliefs about the potential for personal danger from drug use artifacts (syringes and discarded drugs) and violence were identified as barriers to opioid overdose responses.Conclusions/Implications for Occupational Health Practice: Our findings provide valuable insights for tailoring OEND training for service industry workers to confront fears associated with opioid overdose response in their places of work to decrease mortality from the opioid epidemic. Harm reduction approaches need to be sensitive to the places in which overdose occurs and who the overdose responder is likely to be, which requires appropriately tailoring OEND training for service industry workers.

Three nonhalogenated ionic liquids (ILs) dissolved in 2-ethylhexyl laurate (2-EHL), a biodegradable oil, are investigated in terms of their bulk and electro-interfacial nanoscale structures using small-angle neutron scattering (SANS) and neutron reflectivity (NR). The ILs share the same trihexyl(tetradecyl)phosphonium ([P6,6,6,14]+) cation paired with different anions, bis(mandelato)borate ([BMB]-), bis(oxalato)borate ([BOB]-), and bis(salicylato)borate ([BScB]-). SANS shows a high aspect ratio tubular self-assembly structure characterized by an IL core of alternating cations and anions with a 2-EHL-rich shell or corona in the bulk, the geometry of which depends upon the anion structure and concentration. NR also reveals a solvent-rich interfacial corona layer. Their electro-responsive behavior, pertaining to the structuring and composition of the interfacial layers, is also influenced by the anion identity. [P6,6,6,14][BOB] exhibits distinct electroresponsiveness to applied potentials, suggesting an ion exchange behavior from cation-dominated to anion-rich. Conversely, [P6,6,6,14][BMB] and [P6,6,6,14][BScB] demonstrate minimal electroresponses across all studied potentials, related to their different dissociative and diffusive behavior. A mixed system is dominated by the least soluble IL but exhibits an increase in disorder. This work reveals the subtlety of anion architecture in tuning bulk and electro-interfacial properties, offering valuable molecular insights for deploying nonhalogenated ILs as additives in biodegradable lubricants and supercapacitors.

Substituting precious elements in luminophores and photocatalysts by abundant first-row transition metals remains a significant challenge, and iron continues to be particularly attractive owing to its high natural abundance and low cost. Most iron complexes known to date face severe limitations due to undesirably efficient deactivation of luminescent and photoredox-active excited states. Two new iron(III) complexes with structurally simple chelate ligands enable straightforward tuning of ground and excited state properties, contrasting recent examples, in which chemical modification had a minor impact. Crude samples feature two luminescence bands strongly reminiscent of a recent iron(III) complex, in which this observation was attributed to dual luminescence, but in our case, there is clear-cut evidence that the higher-energy luminescence stems from an impurity and only the red photoluminescence from a doublet ligand-to-metal charge transfer (2LMCT) excited state is genuine. Photoinduced oxidative and reductive electron transfer reactions with methyl viologen and 10-methylphenothiazine occur with nearly diffusion-limited kinetics. Photocatalytic reactions not previously reported for this compound class, in particular the C–H arylation of diazonium salts and the aerobic hydroxylation of boronic acids, were achieved with low-energy red light excitation. Doublet–triplet energy transfer (DTET) from the luminescent 2LMCT state to an anthracene annihilator permits the proof of principle for triplet–triplet annihilation upconversion based on a molecular iron photosensitizer. These findings are relevant for the development of iron complexes featuring photophysical and photochemical properties competitive with noble-metal-based compounds.

Light-triggered dissociation of ligands forms the basis for many compounds of interest for photoactivated chemotherapy (PACT), in which medicinally active substances are released or “uncaged” from metal complexes upon illumination. Photoinduced ligand dissociation is usually irreversible, and many recent studies performed in the context of PACT focused on ruthenium(II) polypyridines and related heavy metal complexes. Herein, we report a first-row transition metal complex, in which photoinduced dissociation and spontaneous recoordination of a ligand unit occurs. Two scorpionate-type tridentate chelates provide an overall six-coordinate arylisocyanide environment for chromium(0). Photoexcitation causes decoordination of one of these six ligating units and coordination of a solvent molecule, at least in tetrahydrofuran and 1,4-dioxane solvents, but far less in toluene, and below detection limit in cyclohexane. Transient UV–vis absorption spectroscopy and quantum chemical simulations point to photoinduced ligand dissociation directly from an excited metal-to-ligand charge-transfer state. Owing to the tridentate chelate design and the substitution lability of the first-row transition metal, recoordination of the photodissociated arylisocyanide ligand unit can occur spontaneously on a millisecond time scale. This work provides insight into possible self-healing mechanisms counteracting unwanted photodegradation processes and seems furthermore relevant in the contexts of photoswitching and (photo)chemical information storage.

The US National Seismic Hazard Model (NSHM) was updated in 2023 for all 50 states using new science on seismicity, fault ruptures, ground motions, and probabilistic techniques to produce a standard of practice for public policy and other engineering applications (defined for return periods greater than ∼475 or less than ∼10,000 years). Changes in 2023 time-independent seismic hazard (both increases and decreases compared to previous NSHMs) are substantial because the new model considers more data and updated earthquake rupture forecasts and ground-motion components. In developing the 2023 model, we tried to apply best available or applicable science based on advice of co-authors, more than 50 reviewers, and hundreds of hazard scientists and end-users, who attended public workshops and provided technical inputs. The hazard assessment incorporates new catalogs, declustering algorithms, gridded seismicity models, magnitude-scaling equations, fault-based structural and deformation models, multi-fault earthquake rupture forecast models, semi-empirical and simulation-based ground-motion models, and site amplification models conditioned on shear-wave velocities of the upper 30 m of soil and deeper sedimentary basin structures. Seismic hazard calculations yield hazard curves at hundreds of thousands of sites, ground-motion maps, uniform-hazard response spectra, and disaggregations developed for pseudo-spectral accelerations at 21 oscillator periods and two peak parameters, Modified Mercalli Intensity, and 8 site classes required by building codes and other public policy applications. Tests show the new model is consistent with past ShakeMap intensity observations. Sensitivity and uncertainty assessments ensure resulting ground motions are compatible with known hazard information and highlight the range and causes of variability in ground motions. We produce several impact products including building seismic design criteria, intensity maps, planning scenarios, and engineering risk assessments showing the potential physical and social impacts. These applications provide a basis for assessing, planning, and mitigating the effects of future earthquakes.

With the recent successful accounting of basin depth ground-motion adjustments in seismic hazard analyses for select areas of the western United States, we move toward implementing similar adjustments in the Atlantic and Gulf Coastal Plains by constructing a sediment thickness model and evaluating multiple relevant site amplification models for central and eastern United States seismic hazard analyses. We digitize and combine existing sediment thickness data sets into a composite surface that delineates the base of Cretaceous sediments under the Atlantic Coastal Plain and the base of Mesozoic sediments under the Gulf Coastal Plain. Amplification models dependent on sediment thickness, site natural period, and source-to-site path length are compared with data sets of observed ground motions to evaluate the ability of the new models to improve ground motion estimates. We find that the amplification models can account for observed trends in sediment-thickness and period-dependent residuals, but some tuning is required. For example, the model of Chapman and Guo requires a reference VS30, the time-averaged shear-wave velocity within 30 m of the Earth’s surface, for non-Coastal Plain sites, which we estimate to be between about 1 and 2 km/s. Along with our sediment thickness model, we estimate a velocity profile for application to the Harmon et al. site-natural-period-based model in order to best match the Chapman and Guo period dependence for a broad range of sediment thicknesses. The Next Generation of Attenuation models for the eastern United States Gulf Coast path-based adjustment models can also account for seismic attenuation in the Coastal Plain sediments and reduce the standard deviation of total residuals. If enacted in the U.S. Geological Survey National Seismic Hazard Model, these amplification models will reduce predicted short-period (<1 s) and increase predicted long-period (>1 s) ground motions in the Coastal Plains appreciably.

AbstractHigh-energy radiotherapy treatments of a medical Linear Accelerator (LinAc) generate secondary neutrons that can produce health damage on the human body as the induction of secondary cancers. The energy spectrum of these neutrons must be determined to estimate the extra dose received by patients inside a radiotherapy room during radiotherapy treatment. To quantify the neutron production, a Ludlum Bonner sphere spectrometer (BSS) is used for measurement at different points of a LinAc bunker at the Hospital Universitari i Politècnic La Fe de València. With the neutron measured data and a set of response detector curves obtained by Monte Carlo simulations with MCNP6.1.1, the Maximum Likelihood Expectation Maximization unfolding method is used to unfold the energy neutron spectrum. Unfolded neutron spectra at different locations were compared to those obtained by Monte Carlo simulation of the same setup, showing the same energetic behavior. The fluence rate decreases with source distance, and the shape changes from a fast neutron peak in the nearest LinAc head location to a prominent thermal neutron peak in the bunker maze region. Moreover, the neutron ambient equivalent dose was obtained from the unfolded spectra and compared to Berthold detector measurements, being consistent.

Harnessing sunlight via photosensitizing molecules is key for novel optical applications and solar-to-chemical energy conversion. Exploiting abundant metals such as iron is attractive but becomes challenging due to typically fast nonradiative relaxation processes. In this work, we report on the luminescence and excited-state reactivity of the heteroleptic [FeIII(pzTp)(CN)3]−complex (pzTp = tetrakis(pyrazolyl)borate), which incorporates a σ-donating trispyrazolyl chelate ligand and three monodentate σ-donating and π-accepting cyanide ligands. Contrary to the nonemissive [Fe(CN)6]3–, a broad emission band centered at 600 nm at room temperature has been recorded for the heteroleptic analogue attributed to the radiative deactivation from a 2LMCT excited state with a luminescence quantum yield of 0.02% and a lifetime of 80 ps in chloroform at room temperature. Bimolecular reactivity of the 2LMCT excited state was successfully applied to different alcohol photo-oxidation, identifying a cyanide–H bonding as a key reaction intermediate. Finally, this research demonstrated the exciting potential of [Fe(pzTp)(CN)3]−as a photo-oxidant, paving the way for further exploration and development of emissive Fe-based photosensitizers competent for photochemical transformations.

Epigenetic gene silencing induced by expanded repeats can cause diverse phenotypes ranging from severe growth defects in plants to genetic diseases such as Friedreich’s ataxia in humans. The molecular mechanisms underlying repeat expansion-induced epigenetic silencing remain largely unknown. Using a plant model with a temperature-sensitive phenotype, we have previously shown that expanded repeats can induce small RNAs, which in turn can lead to epigenetic silencing through the RNA-dependent DNA methylation pathway. Here, using a genetic suppressor screen and yeast two-hybrid assays, we identified novel components required for epigenetic silencing caused by expanded repeats. We show that FOURTH ULP GENE CLASS 1 (FUG1)—an uncharacterized SUMO protease with no known role in gene silencing—is required for epigenetic silencing caused by expanded repeats. In addition, we demonstrate that FUG1 physically interacts with ALFIN-LIKE 3 (AL3)—a histone reader that is known to bind to active histone mark H3K4me2/3. Loss of function of AL3abolishes epigenetic silencing caused by expanded repeats. AL3 physically interacts with the chromodomain protein LIKE HETEROCHROMATIN 1 (LHP1)—known to be associated with the spread of the repressive histone mark H3K27me3to cause repeat expansion-induced epigenetic silencing. Loss of any of these components suppresses repeat expansion-associated phenotypes coupled with an increase in IIL1expression with the reversal of gene silencing and associated change in epigenetic marks. Our findings suggest that the FUG1–AL3–LHP1 module is essential to confer repeat expansion-associated epigenetic silencing and highlight the importance of post-translational modifiers and histone readers in epigenetic silencing.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

Photoredox catalysis relies on light-induced electron transfer leading to a radical pair comprising an oxidized donor and a reduced acceptor in a solvent cage. For productive onward reaction to occur, the oxidized donor and the reduced acceptor must escape from that solvent cage before they undergo spontaneous reverse electron transfer. Here we show the decisive role that cage escape plays in three benchmark photocatalytic reactions, namely, an aerobic hydroxylation, a reductive debromination and an aza-Henry reaction. Using ruthenium(II)- and chromium(III)-based photocatalysts, which provide inherently different cage escape quantum yields, we determined quantitative correlations between the rates of photoredox product formation and the cage escape quantum yields. These findings can be largely rationalized within the framework of Marcus theory for electron transfer.

•Rare variants causal of recessive hemostasis disorders have clinical consequences in carriers.•Common variants modify these consequences and are one of the reasons for different phenotypic expressivity.

Background Patients with peritoneal carcinomatosis (PC) can develop malignant bowel obstructions (MBOs) requiring inpatient admission and nasogastric tube decompression. Palliative decompressive gastrostomy tubes (G-tubes) may affect patient disposition, allowing for self-management and reduction in inpatient services. Therefore, we sought to assess disposition and inpatient readmission rates in patients admitted with PC and MBO following G-tube placement.Methods The Vizient® Clinical Data Base was queried for inpatient admissions from October 2018 to May 2022 utilizing ICD-10 codes to identify patients admitted with PC and bowel obstruction, with or without G-tube placement. Demographics and hospital outcomes were recorded. Descriptive statistics and multivariate logistic regression analysis were performed.Results From 750 patients, 59 (7.9%) had a G-tube placed. Compared to patients without G-tubes, those with G-tubes had lower rates of disposition to home (32.2% vs 70.0%, P< .001) and higher rates of disposition to hospice (home: 30.5% vs 7.8%, P< .001, facility: 10.2% vs 3.9%, P= .02). There was no significant difference in the rate (17.3% vs 22.3%, P= .40) or risk (OR = 1.44, 95% CI .69-3.01) of 30-day readmissions with G-tubes. However, palliative care consultation (OR 33.77, 95% CI 19.16-59.52) and G-tube placement (OR 5.82, 95% CI 2.56-13.25) were independent predictors for hospice.Discussion Placement of G-tubes in patients with PC and MBO was associated with higher rates of disposition to hospice but there is no difference in 30-day readmission rates compared to those without G-tubes. Further prospective studies are needed to understand the role of G-tube placement in patients with MBO in relation to outcomes and disposition.

Visible-light-driven reduction of CO2to both CO and formate (HCOO–) was achieved in acetonitrile solutions using a homobimetallic Cu bisquaterpyridine complex. In the presence of a weak acid (water) as coreactant, the reaction rate was enhanced, and a total of ca. 766 TON (turnover number) was reached for the CO2reduction, with 60% selectivity for formate and 28% selectivity for CO, using Ru(phen)32+as a sensitizer and amines as sacrificial electron donors. Mechanistic studies revealed that with the help of cooperativity between two Cu centers, a bridging hydride is generated in the presence of a proton source (water) and further reacts with CO2to give HCOO–. A second product, CO, was also produced in a parallel competitive pathway upon direct coordination of CO2to the reduced complex. Mechanistic studies further allowed comparison of the observed reactivity to the monometallic Cu quaterpyridine complex, which only produced CO, and to the related homobimetallic Co bisquaterpyridine complex, that has been previously shown to generate formate following a mechanism not involving the formation of an intermediate hydride species.

Eutectic mixtures of choline chloride, urea, and water in deep eutectic solvent (DES)/water molar hydration ratios (w) of 2, 5, and 10, with dissolved cerium salt, were measured using neutron diffraction with isotopic substitution. Structures were modeled using empirical potential structure refinement (EPSR). Ce3+was found to form highly charged complexes with a mean coordination number between 7 and 8, with the shell containing mostly chloride, followed by water. The shell composition is strongly affected by the molar ratio of dilution, as opposed to the mass or volume fraction, due to the high affinity of Cl–and H2O ligands that displace less favorable interactions with ligands such as urea and choline. The presence of Ce3+salt disrupted the bulk DES structure slightly, making it more electrolyte-like. The measured coordination shell of choline showed significant discrepancies from the statistical noninteracting distribution, highlighting the nonideality of the blend. Cluster analysis revealed the trace presence of percolating water clusters (25 ≥ n≥ 2) in solvent compositions of 5 and 10wfor the first time.

Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets1–4. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype–protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort5. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene–protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into transpQTLs across multiple biological domains, highlight genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABOblood group and FUT2secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public–private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.

Numerous studies have explored the kinetics of light-induced charge separation and thermal charge recombination in donor–acceptor compounds, but quantum efficiencies have rarely been investigated. Here, we report on two essentially isomeric molecular triads, both comprising a π-extended tetrathiafulvalene (ExTTF) donor, a ruthenium(II)-based photosensitizer, and a naphthalene diimide (NDI) acceptor. The key difference between the two triads is how the NDI acceptor is connected. Linkage at the NDI core provides stronger electronic coupling to the other molecular components than connection via the nitrogen atoms of NDI. This change in molecular connectivity is expected to accelerate both energy-storing charge separation and energy-wasting charge recombination processes, but it is not a priori clear how this will affect the triad’s ability to store photochemical energy; any gain resulting from faster charge separation could potentially be (over)compensated by losses through accelerated charge recombination. The new key insight emerging from our study is that the quantum yield for the formation of a long-lived charge-separated state increases by a factor of 5 when going from nitrogen- to core-connected NDI, providing the important proof of concept that better molecular connectivity indeed enables more efficient photochemical energy storage. The physical origin of this behavior seems to root in different orbital connectivity pathways for charge separation and charge recombination, as well as in differences in the relevant orbital interactions depending on NDI connection. Our work provides guidelines for how to discriminate between energy-storing and energy-wasting electron transfer reactions in order to improve the quantum yields for photochemical energy storage and solar energy conversion.

A subset of patients with marginal ulcers after Roux-en-Y gastric bypass (RNYGB) is refractory to medical management. Here we report a retrospective review of a single institution cohort (N = 10) of video- or robotic-assisted thoracoscopic (VATS or RATS) truncal vagotomies performed between 2013 and 2018. All patients had recurrent marginal ulcers following RNYGB complicated by bleeding or perforation, refractory to medical management for a median of 3.5 months prior to undergoing truncal vagotomy. With a median of 23 months’ follow-up, only three patients had continued symptoms (70% symptom resolution) post-operatively. Only one patient who had repeat endoscopy after the procedure had documented endoscopic evidence of recurrent marginal ulcer (83% endoscopic resolution). VATS or RATS truncal vagotomy is a safe and effective method to treat complicated marginal ulceration after RNYGB. After an average duration of unsuccessful medical treatment lasting three months, vagotomy led to successful resolution in 70-83% of patients.

Sensitized triplet–triplet annihilation upconversion is a promising strategy to use visible light for chemical reactions requiring the energy input of UV photons. This strategy avoids unsafe ultraviolet light sources and can mitigate photo-damage and provide access to reactions, for which filter effects hamper direct UV excitation. Here, we report a new approach to make blue-to-UV upconversion more amenable to photochemical applications. The tethering of a naphthalene unit to a cyclometalated iridium(III) complex yields a bichromophore with a high triplet energy (2.68 eV) and a naphthalene-based triplet reservoir featuring a lifetime of 72.1 μs, roughly a factor of 20 longer than the photoactive excited state of the parent iridium(III) complex. In combination with three different annihilators, consistently lower thresholds for the blue-to-UV upconversion to crossover from a quadratic into a linear excitation power dependence regime were observed with the bichromophore compared to the parent iridium(III) complex. The upconversion system composed of the bichromophore and the 2,5-diphenyloxazole annihilator is sufficiently robust under long-term blue irradiation to continuously provide a high-energy singlet-excited state that can drive chemical reactions normally requiring UV light. Both photoredox and energy transfer catalyses were feasible using this concept, including the reductive N–O bond cleavage of Weinreb amides, a C–C coupling reaction based on reductive aryl debromination, and two Paternò–Büchi [2 + 2] cycloaddition reactions. Our work seems relevant in the context of developing new strategies for driving energetically demanding photochemistry with low-energy input light.

Nicotinamide adenine nucleotide (NADH) is involved in many biologically relevant redox reactions, and the photochemical regeneration of its oxidized form (NAD+) under physiological conditions is of interest for combined photo- and biocatalysis. Here, we demonstrate that tri-anionic, water-soluble variants of typically very lipophilic iridium(III) complexes can photo-catalyze the reduction of an NAD+mimic in a comparatively efficient manner. In combination with a well-known rhodium co-catalyst to facilitate regioselective reactions, these iridium(III) photo-reductants outcompete the commonly used [Ru(bpy)3]2+(bpy = 2,2′-bipyridine) photosensitizer in water by up to 1 order of magnitude in turnover frequency. This improved reactivity is attributable to the strong excited-state electron donor properties and the good chemical robustness of the tri-anionic iridium(III) sensitizers, combined with their favorable Coulombic interaction with the di-cationic rhodium co-catalyst. Our findings seem relevant in the greater context of photobiocatalysis, for which access to strong, efficient, and robust photoreductants with good water solubility can be essential.

Coordination complexes of precious metals with the d6valence electron configuration such as Ru(II), Os(II) and Ir(III) are used for lighting applications, solar energy conversion and photocatalysis. Until now, d6complexes made from abundant first-row transition metals with competitive photophysical and photochemical properties have been elusive. While previous research efforts focused mostly on Fe(II), we disclose that isoelectronic Cr(0) gives access to higher photoluminescence quantum yields and excited-state lifetimes when compared with any other first-row d6metal complex reported so far. The luminescence behaviour of the metal-to-ligand charge transfer excited states of these Cr(0) complexes is competitive with Os(II) polypyridines. With these Cr(0) complexes, the metal-to-ligand charge transfer states of first-row d6metal complexes become exploitable in photoredox catalysis, and benchmark chemical reductions proceed efficiently under low-energy red illumination. Here we demonstrate that appropriate molecular design strategies open up new perspectives for photophysics and photochemistry with abundant first-row d6metals.

ObjectivesPalliative care (PC) for patients with advanced cancer has been associated with improved symptom burden and quality of life (QoL). This study aimed to characterise postoperative symptoms of cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) patients and to assess PC impact by analysing symptom burden before and after PC interventions.MethodsCRS/HIPEC patients with two PC visits within 5 months postoperatively (2016–2021) at a tertiary care centre were identified from a retrospective database. For each patient, documentation of QoL-associated symptoms at the initial PC visit and changes in symptomatology at the second PC visit were recorded. Descriptive statistics were performed.Results46 patients were included in this study. Median age was 62.2 (range 31.9–84.6) years. Median peritoneal cancer index was 23.5 (range 0–39). The most common histologies were colorectal (32.6%) and appendiceal (30.4%). Symptoms most frequently reported were pain (84.8%), fatigue (54.3%) and appetite loss/change (52.2%). Following PC interventions, most symptoms were stable or improved. The mean number of symptoms per patient was 3.7, with an average of 3.5 improved/stable and 0.5 worse/new onset at follow-up (p<0.001).ConclusionCRS/HIPEC patients experienced a high QoL-associated symptom burden. Following postoperative PC interventions, significantly more symptoms were reported as improved/stable, compared with worse/new onset.

Square-planar NiIIcomplexes and their electronically excited states play key roles in cross-coupling catalysis and could offer new opportunities to complement well-known isoelectronic PtIIluminophores. Metal-to-ligand charge transfer (MLCT) excited states and their deactivation pathways are particularly relevant in these contexts. We sought to extend the lifetimes of 3MLCT states in square-planar NiIIcomplexes by creating coordination environments that seemed particularly well adapted to the 3d8valence electron configuration. Using a rigid tridentate chelate ligand, in which a central cyclometalated phenyl unit is flanked by two coordinating N-heterocyclic carbenes, along with a monodentate isocyanide ligand, a very strong ligand field is created. Bulky substituents at the isocyanide backbone furthermore protect the NiIIcenter from nucleophilic attack in the axial directions. UV–Vis transient absorption spectroscopies reveal that upon excitation into 1MLCT absorption bands and ultrafast intersystem crossing to the 3MLCT excited state, the latter relaxes onward into a metal-centered triplet state (3MC). A torsional motion of the tridentate ligand and a NiII-carbon bond elongation facilitate 3MLCT relaxation to the 3MC state. The 3MLCT lifetime gets longer with increasing ligand field strength and improved steric protection, thereby revealing clear design guidelines for square-planar NiIIcomplexes with enhanced photophysical properties. The longest 3MLCT lifetime reached in solution at room temperature is 48 ps, which is longer by a factor of 5–10 compared to previously investigated square-planar NiIIcomplexes. Our study contributes to making first-row transition metal complexes with partially filled d-orbitals more amenable to applications in photophysics and photochemistry.