Population Genomics of Adaptive Radiations: Exceptionally High Levels of Genetic Diversity and Recombination in an Endemic Spider From the Canary Islands.

The spider genus Dysdera has undergone a remarkable diversification in the oceanic archipelago of the Canary Islands, with ~60 endemic species having originated during the 20 million years since the origin of the archipelago. This evolutionary radiation has been accompanied by substantial dietary shifts, often characterised by phenotypic modifications encompassing morphological, metabolic and behavioural changes. Hence, these endemic spiders represent an excellent model for understanding the evolutionary drivers and to pinpoint the genomic determinants underlying adaptive radiations. Recently, we achieved the first chromosome-level genome assembly of one of the endemic species, D. silvatica, providing a high-quality reference sequence for evolutionary genomics studies. Here, we conducted a low coverage-based resequencing study of a natural population of D. silvatica from La Gomera island. Taking advantage of the new high-quality genome, we characterised genome-wide levels of nucleotide polymorphism, divergence and linkage disequilibrium, and inferred the demographic history of this population. We also performed comprehensive genome-wide scans for recent positive selection. Our findings uncovered exceptionally high levels of nucleotide diversity and recombination in this geographically restricted endemic species, indicative of large historical effective population sizes. We also identified several candidate genomic regions that are potentially under positive selection, highlighting relevant biological processes, such as vision and nitrogen extraction as potential adaptation targets. These processes may ultimately drive species diversification in this genus. This pioneering study of spiders that are endemic to an oceanic archipelago lays the groundwork for broader population genomics analyses aimed at understanding the genetic mechanisms driving adaptive radiation in island ecosystems.

The Motor Dysfunction Seen in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Isolated Rapid Eye Movement (REM) sleep Behavior Disorder (iRBD) requires quantitative tools to detect incipient Parkinson's disease (PD). METHODS: A motor battery was designed and compared with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) in people with iRBD and controls. This included two keyboard-based tests (BRadykinesia Akinesia INcoordination tap test and Distal Finger Tapping) and two dual tasking tests (walking and finger tapping). RESULTS: We included 33 iRBD patients and 29 controls. The iRBD group performed both keyboard-based tapping tests more slowly (P < 0.001, P = 0.020) and less rhythmically (P < 0.001, P = 0.006) than controls. Unlike controls, the iRBD group increased their walking duration (P < 0.001) and had a smaller amplitude (P = 0.001) and slower (P = 0.007) finger tapping with dual task. The combination of the most salient motor markers showed 90.3% sensitivity for 89.3% specificity (area under the ROC curve [AUC], 0.94), which was higher than the MDS-UPDRS-III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC, 0.81) for detecting motor dysfunction. CONCLUSION: Speed, rhythm, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Non-Dereliction in Evolution: Trophic Specialisation Drives Convergence in the Radiation of Red Devil Spiders (Araneae: Dysderidae) in the Canary Islands.

Natural selection plays a key role in deterministic evolution, as clearly illustrated by the multiple cases of repeated evolution of ecomorphological characters observed in adaptive radiations. Unlike most spiders, Dysdera species display a high variability of cheliceral morphologies, which has been suggested to reflect different levels of specialization to feed on isopods. In this study, we integrate geometric morphometrics and experimental trials with a fully resolved phylogeny of the highly diverse endemic species from the Canary Islands to 1) quantitatively delimit the different cheliceral morphotypes present in the archipelago, 2) test their association with trophic specialization, as reported for continental species, 3) reconstruct the evolution of these ecomorphs throughout the diversification of the group, 4) test the hypothesis of convergent evolution of the different morphotypes, and 5) examine whether specialization constitutes a case of evolutionary irreversibility in this group. We show the existence of 9 cheliceral morphotypes and uncovered their significance for trophic ecology. Further, we demonstrate that similar ecomorphs evolved multiple times in the archipelago, providing a novel study system to explain how convergent evolution and irreversibility due to specialization may be combined to shape phenotypic diversification in adaptive radiations.

A targeted gene phylogenetic framework to investigate diversification in the highly diverse yet geographically restricted red devil spiders (Araneae, Dysderidae).

The family Dysderidae is a highly diverse group of nocturnal ground-dwelling and active-hunter spiders. Dysderids are mostly restricted to the Western Palearctic, and particularly rich and abundant around the Mediterranean region. Interestingly, the distribution of species richness among its 24 genera and three subfamilies is highly biased-80% of its 644 documented species belong to just two genera, Dysdera (326) and Harpactea (211). Dysderidae provides an excellent study case for evolutionary and ecological research. It includes cases of trophic specialization, which are uncommon among spiders, and exhibit other remarkable biological (e.g. holocentric chromosomes), behavioural (e.g. cryptic female choice), evolutionary (e.g. adaptive radiation) and ecological features (e.g. recurrent colonization of the subterranean environment). The lack of a quantitative hypothesis on its phylogenetic structure has hampered its potential as a testing ground for evolutionary, biogeographical and ecological hypotheses. Here, we present the results of a target, multi-locus phylogenetic analysis, using mitochondrial (cox1, 16s and 12s) and nuclear genes (h3, 28s and 18s), of the most exhaustive taxonomic sample within Dysderidae (104 spp.) to date and across related families (Synspermiata) (83 spp.). We estimate divergence times using a combination of fossil and biogeographic node calibrations and use this timeline to identify shifts in diversification rates. Our results support the monophyly of the Dysderidae subfamilies Rhodinae and Dysderinae but reject Harpacteinae as currently defined. Moreover, the clades recovered within Harpacteinae do not support its current taxonomy. The origin of the family most likely post-dated the break-up of Pangea, and cave colonization may be older than previously considered. After correcting for the taxonomic artefacts, we identified a significant shift in diversification rates at the base of the genus Dysdera. Although the unique coexistence of specialist and generalist diets within the lineage could be suggested as the potential driver for the rate acceleration, further quantitative analyses would be necessary to test this hypothesis.

Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones.

Asymmetric hydrogenation (AH) of tetrasubstituted olefins generating two stereocenters is still an open topic. There are only a few reports on the AH of tetrasubstituted olefins with conjugated functional groups, while this process can create useful intermediates for the subsequent elaboration of relevant end products. Most of the tetrasubstituted olefins successfully submitted to AH belong to a small number of functional classes; remarkably, the AH of tetrasubstituted acyclic enones still represents an unsolved challenge. Herein, we disclose a class of air-stable Ir-P,N catalysts, prepared in three steps from commercially available amino alcohols, that can hydrogenate, in minutes, a wide range of electronically and sterically diverse acyclic tetrasubstituted enones (including exocyclic ones) with high yields and high enantioselectivities. The factors responsible for the excellent selectivities were elucidated by combining deuterogenation experiments and theoretical calculations. The calculations indicated that the reduction follows an IrI /IrIII mechanism, in which enantioselectivity is controlled in the first migratory insertion of the hydride to the most electrophilic olefinic Cß and the formation of the hydrogenated product via reductive elimination takes place prior to the coordination of dihydrogen and the subsequent oxidative addition. The potential of the new catalytic systems is demonstrated by the derivatization of hydrogenation products.

In vitro dynamics and mechanisms of cefiderocol resistance development in wild-type, mutator and XDR Pseudomonas aeruginosa.

OBJECTIVES: To analyse the dynamics and mechanisms of stepwise resistance development to cefiderocol in Pseudomonas aeruginosa. METHODS: Cefiderocol resistance evolution was analysed in WT PAO1, PAOMS (mutS mutator derivate) and three XDR clinical isolates belonging to ST111, ST175 and ST235 clones. Strains were incubated in triplicate experiments for 24 h in iron-depleted CAMHB with 0.06-128 mg/L cefiderocol. Tubes from the highest antibiotic concentration showing growth were reinoculated into fresh medium containing concentrations up to 128 mg/L for 7 consecutive days. Two colonies per strain and experiment were characterized by determining the susceptibility profiles and WGS. RESULTS: Evolution of resistance was significantly enhanced in PAOMS, but was variable for the XDR strains, including levels similar to PAOMS (ST235), similar to PAO1 (ST175) or even below PAO1 (ST111). WGS revealed 2-5 mutations for PAO1 lineages and 35-58 for PAOMS. The number of mutations in the XDR clinical strains ranged from 2 to 4 except for one of the ST235 experiments in which a mutL lineage was selected, thus increasing the number of mutations. The most frequently mutated genes were piuC, fptA and pirR, related to iron uptake. Additionally, an L320P AmpC mutation was selected in multiple lineages and cloning confirmed its major impact on cefiderocol (but not ceftolozane/tazobactam or ceftazidime/avibactam) resistance. Mutations in CpxS and PBP3 were also documented. CONCLUSIONS: This work deciphers the potential resistance mechanisms that may emerge upon the introduction of cefiderocol into clinical practice, and highlights that the risk of resistance development might be strain-specific even for XDR high-risk clones.

Serum carboxymethyllysine concentration is associated with erosive hand osteoarthritis.

OBJECTIVE: Carboxymethyllysine (CML) and homocitrulline (HCit) are the products of two non-enzymatic post-translational modifications of protein, a process related to age. We investigated whether serum CML and HCit concentrations were associated with hand osteoarthritis (HOA), especially erosive HOA. DESIGN: Serum CML and HCit were measured by using liquid chromatography coupled with tandem mass spectrometry at inclusion in 386 patients included in the DIGItal Cohort Design (DIGICOD) cohort. We investigated whether serum CML and/or HCit concentrations were associated with erosive HOA or with HOA clinical and radiological features. Moreover, we compared the tissular concentrations of CML and HCit in OA and non-OA cartilage from proximal interphalangeal and metacarpo-phalangeal (MCP) joints from human cadaveric donors. RESULTS: Median (IQR) serum CML concentration was lower in patients with erosive HOA than those with non-erosive HOA (178.7 [157.1-208.8] vs 194.7 [168.9-217.1] µmol/mol Lys, P = 0.002), but median HCit concentration did not differ between the groups (193.9 [162.9-232.0] vs 193.9 [155.9-224.6] µmol/mol Lys). Cartilage HCit and CML concentrations were not correlated with clinical features. Serum CML concentration was higher in OA than non-OA MCPs (7.0 vs 4.0 mmol/mol Lys, P = 0.01). CONCLUSIONS: Serum CML concentration was lower in erosive HOA than non-erosive HOA, and cartilage CML concentration was higher in OA than non-OA cartilage. These results encourage further studies to test whether serum CML could be a new prognostic biomarker in HOA.

Neural predictors of cognitive-behavior therapy outcome in anxiety-related disorders: a meta-analysis of task-based fMRI studies.

BACKGROUND: Cognitive-behavior therapy (CBT) is a well-established first-line intervention for anxiety-related disorders, including specific phobia, social anxiety disorder, panic disorder/agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Several neural predictors of CBT outcome for anxiety-related disorders have been proposed, but previous results are inconsistent. METHODS: We conducted a systematic review and meta-analysis of task-based functional magnetic resonance imaging (fMRI) studies investigating whole-brain predictors of CBT outcome in anxiety-related disorders (17 studies, n = 442). RESULTS: Across different tasks, we observed that brain response in a network of regions involved in salience and interoception processing, encompassing fronto-insular (the right inferior frontal gyrus-anterior insular cortex) and fronto-limbic (the dorsomedial prefrontal cortex-dorsal anterior cingulate cortex) cortices was strongly associated with a positive CBT outcome. CONCLUSIONS: Our results suggest that there are robust neural predictors of CBT outcome in anxiety-related disorders that may eventually lead (probably in combination with other data) to develop personalized approaches for the treatment of these mental disorders.

Development of Immobilized Carreira (Phosphoramidite, Olefin) Ligands and Application in Iridium-Catalyzed Asymmetric Allylic Amination.

A family of polystyrene-supported (phosphoramidite, olefin) ligands L1-L4, based on the original design by Defieber and Carreira, has been developed and applied in iridium-catalyzed asymmetric allylic amination of unmasked allylic alcohols (27 examples, up to 99% ee). Among them, functional resins L1 and L4 exhibit important advantages such as easy preparation, ligand recyclability, and easy handling for sequential use. As a distinctive advantage, the catalytic use of the iridium complexes of L1 and L4 allows the straightforward reuse of a high percentage of the expensive iridium metal involved in the complexes, which is not achievable under homogeneous conditions with the corresponding monomeric complexes.

Structure-based Design of Novel Hepatitis B Virus Capsid Assembly Modulators.

Small-molecule capsid assembly modulators (CAMs) have been recently recognized as promising antiviral agents for curing chronic hepatitis B virus (HBV) infection. A target-based in silico screening study is described, aimed towards the discovery of novel HBV CAMs. Initial optimization of four weakly active screening hits was performed via focused library synthesis. Lead compound 42 and close analogues 56 and 57 exhibited in vitro potency in the sub- and micromolar range along with good physico-chemical properties and were further evaluated in molecular docking and mechanism of action studies.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications.

This Review compiles the evolution, mechanistic understanding, and more recent advances in enantioselective Pd-catalyzed allylic substitution and decarboxylative and oxidative allylic substitutions. For each reaction, the catalytic data, as well as examples of their application to the synthesis of more complex molecules, are collected. Sections in which we discuss key mechanistic aspects for high selectivity and a comparison with other metals (with advantages and disadvantages) are also included. For Pd-catalyzed asymmetric allylic substitution, the catalytic data are grouped according to the type of nucleophile employed. Because of the prominent position of the use of stabilized carbon nucleophiles and heteronucleophiles, many chiral ligands have been developed. To better compare the results, they are presented grouped by ligand types. Pd-catalyzed asymmetric decarboxylative reactions are mainly promoted by PHOX or Trost ligands, which justifies organizing this section in chronological order. For asymmetric oxidative allylic substitution the results are grouped according to the type of nucleophile used.

An enantio- and diastereoselective approach to indoloquinolizidines in continuous flow.

Merging polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor has been used as the key, enantiodetermining step in a short synthesis of indoloquinolizidines. Using this approach, a highly enantioselective, solvent-free and rapid conjugate addition of dimethyl malonate to a diverse family of cinnamaldehydes in continuous flow, allowing the preparation of relevant oxodiesters in multigram amounts has been developed. The obtained Michael adducts have been used to complete an expedient diastereoselective synthesis of indoloquinolizidine via cascade Pictet-Splengler cyclisation-lactamisation in continuous flow. The conversion of enantiopure Michael adducts into δ-lactones via telescoped reduction/cyclisation in continuous flow has also been explored.

The interplay between infection risk factors of SARS-CoV-2 and mortality: a cross-sectional study from a cohort of long-term care nursing home residents.

BACKGROUND: Covid-19 pandemic has particularly affected older people living in Long-term Care settings in terms of infection and mortality. METHODS: We carried out a cross-sectional analysis within a cohort of Long-term care nursing home residents between March first and June thirty, 2020, who were ≥ 65 years old and on whom at least one PCR test was performed. Socio-demographic, comorbidities, and clinical data were recorded. Facility size and community incidence of SARS-CoV-2 were also considered. The outcomes of interest were infection (PCR positive) and death. RESULTS: A total of 8021 residents were included from 168 facilities. Mean age was 86.4 years (SD = 7.4). Women represented 74.1%. SARS-CoV-2 infection was detected in 27.7% of participants, and the overall case fatality rate was 11.3% (24.9% among those with a positive PCR test). Epidemiological factors related to risk of infection were larger facility size (pooled aOR 1.73; P < .001), higher community incidence (pooled aOR 1.67, P = .04), leading to a higher risk than the clinical factor of low level of functional dependence (aOR 1.22, P = .03). Epidemiological risk factors associated with mortality were male gender (aOR 1.75; P < .001), age (pooled aOR 1.16; P < .001), and higher community incidence (pooled aOR 1.19, P = < 0.001) whereas clinical factors were low level of functional dependence (aOR 2.42, P < .001), Complex Chronic Condition (aOR 1.29, P < .001) and dementia (aOR 1.33, P <0.001). There was evidence of clustering for facility and health area when considering the risk of infection and mortality (P < .001). CONCLUSIONS: Our results suggest a complex interplay between structural and individual factors regarding Covid-19 infection and its impact on mortality in nursing-home residents.

Systematic use of short unicortical epiphyseal locking screws versus full-length unicortical locking screws in distal radius fracture volar plating: A prospective and comparative study.

PURPOSE: Volar locking plates, used in distal radius fracture (DRF), present a risk of injuring extensor tendons with screws penetrating the dorsal cortex of the radius. Actually, even when aiming to use maximum-length unicortical locking screws, some still could be bicortical. We hypothesize the use of only short unicortical screws would allow a proper stabilization of the radial epiphysis without the risk of dorsal cortex penetration. MATERIALS AND METHODS: A prospective monocentric non-randomized study was conducted. Patients with DRF (excepted for partial dorsal joint fractures) were treated in group A with short locking epiphyseal screws (16 mm for females, 18 mm for males) and in group B with full-length unicortical locking screws. Ultrasound was done 3 months postoperatively to evaluate the number and length of prominent dorsal screws. X-rays were performed after 6 weeks to assess stability according to volar tilt and radial inclination variations. RESULTS: There were 37 patients in group A and 39 in group B with 148 and 156 epiphyseal screws, respectively. In group A, there were 0% of dorsal penetrating screws against 6.5% (10 screws from 8 patients) in group B (p < 0.05). There was no significant difference for the stability between the groups: mean volar tilt variation ( - 0.6° vs. - 0.7°) and mean radial inclination variation ( - 0.4° vs. - 0.4°). CONCLUSION: For a same stability with volar locking plates for DRF, short epiphyseal locking screws should be preferred to full-length unicortical screws in order to prevent extensor tendon injuries. Based on 75% of distal radial average anteroposterior width for each sex, screw lengths of 16 mm for females and 18 mm for males seem to be the length to use. LEVEL OF EVIDENCE 2: Prospective, Comparisons made, non-randomized.

Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants.

Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings. However, it is unclear whether the splicing imbalance of this exon is associated with cancer risk. Here we identify a common genetic variant in intron 10, rs5820483 (NC_000017.11:g.43095106_43095108dup), which is associated with exon 11 isoform expression and alternative splicing, and with the risk of breast cancer, but not ovarian cancer, in BRCA1 pathogenic variant carriers. The identification of this genetic effect was confirmed by analogous observations in mouse cells and tissue in which a loxP sequence was inserted in the syntenic intronic region. The prediction that the rs5820483 minor allele variant would create a binding site for the splicing silencer hnRNP A1 was confirmed by pull-down assays. Our data suggest that perturbation of BRCA1 exon 11 splicing modifies the breast cancer risk conferred by pathogenic variants of this gene.

Monophyly, Taxon Sampling, and the Nature of Ranks in the Classification of Orb-Weaving Spiders (Araneae: Araneoidea).

We address some of the taxonomic and classification changes proposed by Kuntner et al. (2019) in a comparative study on the evolution of sexual size dimorphism in nephiline spiders. Their proposal to recircumscribe araneids and to rank the subfamily Nephilinae as a family is fundamentally flawed as it renders the family Araneidae paraphyletic. We discuss the importance of monophyly, outgroup selection, and taxon sampling, the subjectivity of ranks, and the implications of the age of origin criterion to assign categorical ranks in biological classifications. We explore the outcome of applying the approach of Kuntner et al. (2019) to the classification of spiders with emphasis on the ecribellate orb-weavers (Araneoidea) using a recently published dated phylogeny. We discuss the implications of including the putative sister group of Nephilinae (the sexually dimorphic genus Paraplectanoides) and the putative sister group of Araneidae (the miniature, monomorphic family Theridiosomatidae). We propose continuation of the phylogenetic classification put forth by Dimitrov et al. (2017), and we formally rank Nephilinae and Phonognathinae as subfamilies of Araneidae. Our classification better reflects the understanding of the phylogenetic placement and evolutionary history of nephilines and phonognathines while maintaining the diagnosability of Nephilinae. It also fulfills the fundamental requirement that taxa must be monophyletic, and thus avoids the paraphyly of Araneidae implied by Kuntner et al. (2019).

Repeated colonization, adaptive radiation and convergent evolution in the sheet-weaving spiders (Linyphiidae) of the south Pacific Archipelago of Juan Fernandez.

We report on the colonization and diversification of linyphiid spiders in the Pacific oceanic archipelago of Juan Fernandez. About 50 spider species occur naturally in these islands, most of them endemic and about half of them are linyphiids. Linyphiidae includes no fewer than 15 species of Laminacauda and three of Neomaso (with several additional undescribed species in the latter genus), all of them single island endemics. There are three additional linyphiid endemic genera, two monotypic and one, Juanfernandezia, with two species. Unlike the rather uniform somatic morphology and small ground sheet webs of the continental Laminacauda and Neomaso species, the Juan Fernandez endemics exhibit morphological features and life history traits that are very rare or unknown in any other linyphiids. A multi-locus phylogenetic analysis confirms at least five independent Juan Fernandez colonizations of Linyphiidae, two within the same genus, and three of which underwent subsequent local diversification. Different calibrations suggest alternative colonization timelines, some at odds with island ages, but all agree on similar diversification timings of the endemic lineages. Rare phenotypic traits (e.g. gigantism, massive chelicerae or elongated legs) evolved multiple times independently within the islands. Based on the remarkable levels of eco-phenotypic differentiation in locally diversified species showing densely packed distributions, we propose that Laminacauda, and probably Neomaso, constitute a case of adaptive radiation.

Converging on the orb: denser taxon sampling elucidates spider phylogeny and new analytical methods support repeated evolution of the orb web.

High throughput sequencing and phylogenomic analyses focusing on relationships among spiders have both reinforced and upturned long-standing hypotheses. Likewise, the evolution of spider webs-perhaps their most emblematic attribute-is being understood in new ways. With a matrix including 272 spider species and close arachnid relatives, we analyze and evaluate the relationships among these lineages using a variety of orthology assessment methods, occupancy thresholds, tree inference methods and support metrics. Our analyses include families not previously sampled in transcriptomic analyses, such as Symphytognathidae, the only araneoid family absent in such prior works. We find support for the major established spider lineages, including Mygalomorphae, Araneomorphae, Synspermiata, Palpimanoidea, Araneoidea and the Retrolateral Tibial Apophysis Clade, as well as the uloborids, deinopids, oecobiids and hersiliids Grade. Resulting trees are evaluated using bootstrapping, Shimodaira-Hasegawa approximate likelihood ratio test, local posterior probabilities and concordance factors. Using structured Markov models to assess the evolution of spider webs while accounting for hierarchically nested traits, we find multiple convergent occurrences of the orb web across the spider tree-of-life. Overall, we provide the most comprehensive spider tree-of-life to date using transcriptomic data and use new methods to explore controversial issues of web evolution, including the origins and multiple losses of the orb web.

Computational Studies Suggest Promiscuous Candida antarctica Lipase B as an Environmentally Friendly Alternative for the Production of Epoxides.

Environmentally friendly processes are nowadays a trending topic to get highly desired chemical compounds and, in this sense, the use of enzyme-catalyzed routes is becoming a promising alternative to traditional synthetic methods. In the present paper, a hybrid quantum mechanics/molecular mechanics (QM/MM) computational study on the epoxidation of alkenes catalyzed by the Ser105Ala variant of the promiscuous Candida antarctica lipase B (CALB) is presented in an attempt to search for alternative paths to get useful intermediates in industries. The catalyzed reaction, described at the atomistic level with a model of the full solvated in a box of water molecules, is compared with the alternative epoxidation of alkenes by peroxy acids in chloroform. Free-energy profiles obtained at the density functional theory (DFT)/MM level show how Ser105Ala CALB is capable of epoxide short alkenes in a two-step process with free-energy barriers, in agreement with available experimental data, that are significantly lower than those of the single-step reaction in solution. The possible (R)-enantioselectivity dictated by the binding step, explored by means of alchemical QM/MM free-energy perturbation (FEP) methods, and the preference for the (S)-enantiomer derived from the free-energy landscape of the chemical steps would cancel out, thus predicting the lack of enantioselectivity experimentally observed. In general, our results provide general information on the molecular mechanism employed by a highly promiscuous enzyme, with potential applications in biotechnology.

The provision of hospital at home care: Results of a national survey of UK hospitals.

BACKGROUND: Hospital at home (HaH) replicates elements of hospital-based care in the community, to facilitate the safe management of a broad spectrum of acute illness in the patient's usual environment. The extent to which this model of care has been adopted in the United Kingdom is unknown. METHODS: The Society for Acute Medicine Benchmarking Audit is a day of care survey undertaken annually within the United Kingdom. Participation is open to all hospital in the United Kingdom receiving acutely unwell medical patients. A questionnaire is used to collect hospital-level data on the structure and organisation of acute care delivery. The survey included questions designed to quantify the number of hospitals that offered HaH. When present, further questions were asked to clarify the characteristics of the HaH service in terms of workforce, range of diagnostic test and interventions. This information was used to build a picture of HaH service provision on a national scale. RESULTS: A total of 130 hospitals contributed organisational data to SAMBA19. The capability to refer to a hospital at home service was recognised by 46.9% (n = 61) of units. The majority of these services, 83.3% (n = 50) were nurse-led. The capability to provide a physician review at home was reported in 23.3% (n = 14). The majority of services could provide intravenous antibiotics at home, but access to other simple interventions, such as intravenous diuretics or acute supplemental oxygen, is limited. CONCLUSION: At present, few acute hospitals for consitency in the United Kingdom have access to a hospital at home service capable of replicating essential elements of inpatient care. Our study suggests organisational change in acute care delivery and significant investment would be required to establish equal access to hospital-at-home care within the United Kingdom.