Bifunctional Imine Reductase Cascades for the Synthesis of Saturated N-Heterocycles.

Saturated N-heterocycles constitute a vital scaffold for pharmaceutical chemistry but are challenging to access synthetically, particularly asymmetrically. Here, we demonstrate how imine reductases can achieve annulation through tandem inter- and intramolecular reductive amination processes. Imine reductases were used in combination with further enzymes to access unsubstituted, α-substituted, and α,α'-disubstituted N-heterocycles from simple starting materials in one pot and under benign conditions. This work shows the remarkable flexibility of these enzymes to have broad activity against numerous substrates derived from singlular starting materials.

Protection efforts have resulted in ~10% of existing fish biomass on coral reefs.

The amount of ocean protected from fishing and other human impacts has often been used as a metric of conservation progress. However, protection efforts have highly variable outcomes that depend on local conditions, which makes it difficult to quantify what coral reef protection efforts to date have actually achieved at a global scale. Here, we develop a predictive model of how local conditions influence conservation outcomes on ~2,600 coral reef sites across 44 ecoregions, which we used to quantify how much more fish biomass there is on coral reefs compared to a modeled scenario with no protection. Under the assumptions of our model, our study reveals that without existing protection efforts there would be ~10% less fish biomass on coral reefs. Thus, we estimate that coral reef protection efforts have led to approximately 1 in every 10 kg of existing fish biomass.

Autistic psychiatrists' experiences of recognising themselves and others as autistic: a qualitative study.

BACKGROUND: Diagnosis of autism falls under the remit of psychiatry. Recognition that psychiatrists could be autistic is recent. Psychiatrists are the second largest specialty group in Autistic Doctors International, a peer support group for autistic doctors. AIMS: To explore the experiences of autistic psychiatrists in relation to recognising themselves and others as autistic. METHOD: This was a qualitative study using loosely structured interviews and an interpretive phenomenological analysis. RESULTS: Eight autistic senior psychiatrists based in the UK participated. One had a childhood diagnosis, two had been diagnosed in adulthood and the remainder self-identified as autistic as adults. Recognition of autism followed diagnosis of their children or encounters with autistic patients. Barriers to self-recognition included lack of autism training, the deficit-based diagnostic criteria and stereotypical views of autism. Recognising that they were autistic led to the realisation that many colleagues were also likely to be autistic, particularly in neurodevelopmental psychiatry. All participants reported the ability to quickly recognise autistic patients and to develop a good rapport easily, once they were aware of their own autistic identity. Difficulties recognising patients as autistic occurred before self-recognition when they shared autistic characteristics and experiences. 'If we don't recognise ourselves as autistic how on earth can we diagnose patients accurately?' CONCLUSIONS: Autistic psychiatrists face multiple barriers to recognising that they are autistic. Lack of self-recognition may impede diagnostic accuracy with autistic patients. Self-recognition and disclosure by autistic psychiatrists may be facilitated by reframing the traditional deficit-based view of autism towards a neurodiversity-affirmative approach, with consequent benefits for autistic patients.

A Perspective on Electrochemical Point Source Utilization of CO2 and Other Flue Gas Components to Value Added Chemicals.

Electrochemical CO2 reduction reaction (eCO2RR) has been explored extensively for mitigation of noxious CO2 gas generating C1 and C2+ hydrocarbons and oxygenates as value-added fuels and chemicals with remarkable selectivity. The source of CO2 being a pure CO2 feed, it does not fully satisfy the real-time digestion of industrial exhausts. Besides the detrimental effect of noxious gas mixture leading to global warming, there is a huge capital investment in purifying the flue gas mixtures from industries. The presence of other impurity gases affects the eCO2RR mechanism and its activity and selectivity toward C2+ products dwindle drastically. Impurities like NOx, SOx, O2, N2, and halide ions present in flue gas mixture reduce the conversion and selectivity of eCO2RR significantly. Instead of wiping out these impurities via separation processes, new strategies from material chemistry and electrochemistry can open new avenues for turning foes to friends! In this perspective, the co-electroreduction will vividly discussed and supporting role of different heteroatom-containing impurity gases with CO2, generating highly stable C─N, C─S, C─X bonds, and highlight the existing limitations and providing probable solutions for attaining further success in this field and translating this to industrial exhaust streams.

Managing nutrition-biodiversity trade-offs on coral reefs.

Coral reefs support an incredible abundance and diversity of fish species, with reef-associated fisheries providing important sources of income, food, and dietary micronutrients to millions of people across the tropics. However, the rapid degradation of the world's coral reefs and the decline in their biodiversity may limit their capacity to supply nutritious and affordable seafood while meeting conservation goals for sustainability. Here, we conduct a global-scale analysis of how the nutritional quality of reef fish assemblages (nutritional contribution to the recommended daily intake of calcium, iron, and zinc contained in an average 100 g fish on the reef) relates to key environmental, socioeconomic, and ecological conditions, including two key metrics of fish biodiversity. Our global analysis of more than 1,600 tropical reefs reveals that fish trophic composition is a more important driver of micronutrient concentrations than socioeconomic and environmental conditions. Specifically, micronutrient density increases as the relative biomass of herbivores and detritivores increases at lower overall biomass or under high human pressure. This suggests that the provision of essential micronutrients can be maintained or even increase where fish biomass decreases, reinforcing the need for policies that ensure sustainable fishing, and that these micronutrients are retained locally for nutrition. Furthermore, we found a negative association between micronutrient density and two metrics of fish biodiversity, revealing an important nutrition-biodiversity trade-off. Protecting reefs with high levels of biodiversity maintains key ecosystem functions, whereas sustainable fisheries management in locations with high micronutrient density could sustain the essential supply of micronutrients to coastal human communities.

The experiences of autistic adults who were previously diagnosed with borderline or emotionally unstable personality disorder: A phenomenological study.

LAY ABSTRACT: Autistic people face many barriers to receiving an autism diagnosis. Often, they may be misdiagnosed with borderline personality disorder instead. For our study, we interviewed 10 autistic adults who had previously been diagnosed with borderline personality disorder. This helped us to better understand their experiences. They explained how borderline personality disorder is quite stigmatised and may suggest that people are to blame for their differences in behaviour. They found the treatments they had to try for borderline personality disorder to be harmful. For example, these treatments promoted 'masking'. Previous research showed that masking can be harmful for autistic people, linking it to risk of suicide. This diagnosis also led to healthcare professionals neglecting them and discounting their beliefs. Once they were diagnosed with borderline personality disorder, it was hard to access an autism assessment. When they did receive their autism diagnoses, this was much more positive. This diagnosis was validating. It also improved their mental health, as they were no longer expected to mask - their differences were now accepted. They still felt that autism was stigmatised in society. However, this was very different to the stigma around borderline personality disorder. They felt autism stigma was more about their competence as people, whereas borderline personality disorder stigma was about how they were broken and might be harmful to others. This study is important because it allows their stories to be heard by researchers and healthcare professionals alike. Adding their voices helps to humanise them, promoting positive change in mental health services. More research is now needed.

Characterization of the SUF FeS cluster synthesis machinery in the amitochondriate eukaryote Monocercomonoides exilis.

Monocercomonoides exilis is the first known amitochondriate eukaryote. Loss of mitochondria in M. exilis ocurred after the replacement of the essential mitochondrial iron-sulfur cluster (ISC) assembly machinery by a unique, bacteria-derived, cytosolic SUF system. It has been hypothesized that the MeSuf pathway, in cooperation with proteins of the cytosolic iron-sulfur protein assembly (CIA) system, is responsible for the biogenesis of FeS clusters in M. exilis, yet biochemical evidence is pending. Here, we address the M. exilis MeSuf system and show that SUF genes, individually or in tandem, support the loading of iron-sulfur (FeS) clusters into the reporter protein IscR in Escherichia coli. The Suf proteins MeSufB, MeSufC, and MeSufDSU interact in vivo with one another and with Suf proteins of E. coli. In vitro, the M. exilis Suf proteins form large complexes of varying composition and hence may function as a dynamic biosynthetic system in the protist. The putative FeS cluster scaffold MeSufB-MeSufC (MeSufBC) forms multiple oligomeric complexes, some of which bind FeS clusters and form selectively only in the presence of adenosine nucleotides. The multi-domain fusion protein MeSufDSU binds a PLP cofactor and can form higher-order complexes with MeSufB and MeSufC. Our work demonstrates the biochemical property of M. exilis Suf proteins to act as a functional FeS cluster assembly system and provides insights into the molecular mechanism of this unique eukaryotic SUF system.

Germany's Approach for the Secondary Use of Federated Real-World Data in the German Portal for Medical Research Data.

In the light of big data driven clinical research, fair access to real world clinical health data enables evidence to improve patient care. Germany's healthcare system provides an abundant data resource but unique challenges due to its federated nature, heterogeneity and high data-protection standards. The Medical Informatics Initiative (MII) developed concepts that are being implemented in the German Portal for Medical Research Data (FDPG) to grant access to distributed data-sources across state borders. The portal currently provides access to more than 10 million patient resources containing hundreds of millions of laboratory parameters, diagnostic reports, administered medications, procedures and specimens. Upcoming datasets include among others oncological data, molecular analysis results and microbiological findings. Here, we describe the philosophy, implementation and experience behind the framework: standardized access processes, interoperable fair data, software for in depth feasibility requests, tools to support researchers and hospital stakeholders alike as well as transparency measures to provide data use information for patients. Challenges remain to improve data quality and automatization of technical and organizational processes.

Development of a Maturity Model for Medical Patient Registries - A Community Approach.

OBJECTIVE: Development of a generic model to visualize the potential for use and further development of registries to assess the suitability of the registry for a specific purpose. METHODS: Multi-stage community approach. RESULTS: The maturity model has 9 categories with 105 items. The purpose of the registry is mapped via potential usage dimensions. CONCLUSION: Important for acceptance is the appropriateness of the requirements in relation to the purposes.

Individual mangrove trees provide alternative reef fish habitat on backreefs.

Mangrove trees occur in a variety of geomorphic and sedimentary settings. Yet, studies investigating their role as habitat providers often focus on the most common biophysical types, such as deltaic, estuarine, open coast or lagoonal mangroves on soft sediments, disregarding less typical environments. Here, we investigated the influence of individual mangrove trees growing on a consolidated backreef system (Laucala Bay, Fiji) on habitat use by reef fishes. Combining field surveys and an experiment, we quantified the extent to which reef mangrove trees serve as habitat for solitary or shoaling reef fishes. Using mangrove tree mimics, we disentangled effects attributable to the physical structure of trees from those related to their bio-chemical properties. We found that fish numbers were 3.7 times higher within close proximity to the mangrove trees than at control sites and correlated significantly with root system perimeter. The roots of larger trees sheltered aggregations of juveniles and adults at incoming and high tides. Mangrove trees and mimics attracted fishes alike. We show that mangrove trees on backreefs provide habitat for shoaling and adult reef fishes in addition to serving as nursery areas, an ecosystem service otherwise lacking on backreef areas with low structural complexity.

Evaluating the Effectiveness of African School of Hypertension for Non-Physician Health Workers, a Qualitative Study: QuASH Hypertension Study.

Background: The implementation of task sharing and shifting (TSTS) policy as a way of addressing the shortage of physicians and reducing the burden of hypertension in Africa birthed the idea of the African School of Hypertension (ASH). The ASH is saddled with the responsibility of training non-physician health workers across Africa continent in the management of uncomplicated hypertension. Aim: To get feedback from some faculty members and students who participated in the first ASH programme. Methods: This was a cross-sectional exploratory qualitative study conducted among eight students and eight faculty members. Feedback from the program was obtained by conducting in-depth interviews centred on description of course content; expectations and knowledge acquired from ASH; level of interaction between students and faculty members; challenges faced during the ASH; level of implementation of acquired training; and suggestions to improve subsequent ASH programs. Results: The course content of the ASH was described as simple, appropriate and adequate while interaction between students and faculty members were highly cordial and engaging. New knowledge about hypertension management was acquired by the students with different levels of implementation post-graduation. Some identified challenges with the ASH program were poor internet connectivity during lectures, non-uniformity of TSTS policies and hypertension management guidelines across Africa, technical problems with hypertension management app and low participation from other African countries apart from Nigeria. Some recommendations to improve ASH program were development of a uniform hypertension management guideline for Africans, wider publicity of the ASH, interpretation of lectures into French and Portuguese languages and improvement of internet connectivity. Conclusion: The ASH programme has largely achieved its objectives with the very encouraging feedback received from both faculty members and the students. Steps should be taken to address the identified challenges and implement the suggested recommendations in subsequent ASH program to sustain this success.

Feasibility of Artificial Intelligence Powered Adverse Event Analysis: Using a Large Language Model to Analyze Microwave Ablation Malfunction Data.

Objectives: Determine if a large language model (LLM, GPT-4) can label and consolidate and analyze interventional radiology (IR) microwave ablation device safety event data into meaningful summaries similar to humans. Methods: Microwave ablation safety data from January 1, 2011 to October 31, 2023 were collected and type of failure was categorized by human readers. Using GPT-4 and iterative prompt development, the data were classified. Iterative summarization of the reports was performed using GPT-4 to generate a final summary of the large text corpus. Results: Training (n = 25), validation (n = 639), and test (n = 79) data were split to reflect real-world deployment of an LLM for this task. GPT-4 demonstrated high accuracy in the multiclass classification problem of microwave ablation device data (accuracy [95% CI]: training data 96.0% [79.7, 99.9], validation 86.4% [83.5, 89.0], test 87.3% [78.0, 93.8]). The text content was distilled through GPT-4 and iterative summarization prompts. A final summary was created which reflected the clinically relevant insights from the microwave ablation data relative to human interpretation but had inaccurate event class counts. Conclusion: The LLM emulated the human analysis, suggesting feasibility of using LLMs to process large volumes of IR safety data as a tool for clinicians. It accurately labelled microwave ablation device event data by type of malfunction through few-shot learning. Content distillation was used to analyze a large text corpus (>650 reports) and generate an insightful summary which was like the human interpretation.

Transcatheter Axial Pump Use in Pediatric Patients on Veno-Arterial Extracorporeal Membrane Oxygenation: An ACTION Collaborative Experience.

We report the largest pediatric multicenter experience with Impella pump use and peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. Utilizing the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) collaborative database, we conducted a retrospective, multicenter study of all patients with cardiogenic shock requiring VA-ECMO support with subsequent Impella implant between October 2014 and December 2021. The primary outcome was defined as death while on Impella support. Secondary outcomes were recovery, transplantation, and transition to durable ventricular assist device (VAD) at the time of Impella explantation. Adverse events were defined according to the ACTION registry criteria. Twenty subjects were supported with Impella; Impella 2.5 (n = 3), CP (n = 12), 5.0/5.5 (n = 5). The median Interquartile range (IQR) age, weight, and body surface area at implantation were 15.6 years (IQR = 13.9-17.2), 65.7 kg (IQR = 53.1-80.7), and 1.74 m2 (IQR = 1.58-1.98). Primary cardiac diagnoses were dilated cardiomyopathy/myocarditis in nine (45%), congenital heart disease in four (20%), graft failure/rejection in four (20%), and three (15%) others. Most common adverse events included hemolysis (50%) and bleeding (20%). There were two deaths (10%) in the cohort. Nine patients (45%) were explanted for recovery, eight (40%) were transitioned to a durable VAD, and one (5%) underwent heart transplantation. Impella percutaneous pump support should be considered in the older pediatric population supported with peripheral VA-ECMO, as a means of left heart decompression, and a strategy to come off ECMO to achieve endpoints of myocardial recovery, transition to a durable VAD, or transplantation.

Risk of emergency hospital admission related to adverse events after antibiotic treatment in adults with a common infection: impact of COVID-19 and derivation and validation of risk prediction models.

BACKGROUND: With the global challenge of antimicrobial resistance intensified during the COVID-19 pandemic, evaluating adverse events (AEs) post-antibiotic treatment for common infections is crucial. This study aims to examines the changes in incidence rates of AEs during the COVID-19 pandemic and predict AE risk following antibiotic prescriptions for common infections, considering their previous antibiotic exposure and other long-term clinical conditions. METHODS: With the approval of NHS England, we used OpenSAFELY platform and analysed electronic health records from patients aged 18-110, prescribed antibiotics for urinary tract infection (UTI), lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI), sinusitis, otitis externa, and otitis media between January 2019 and June 2023. We evaluated the temporal trends in the incidence rate of AEs for each infection, analysing monthly changes over time. The survival probability of emergency AE hospitalisation was estimated in each COVID-19 period (period 1: 1 January 2019 to 25 March 2020, period 2: 26 March 2020 to 8 March 2021, period 3: 9 March 2021 to 30 June 2023) using the Kaplan-Meier approach. Prognostic models, using Cox proportional hazards regression, were developed and validated to predict AE risk within 30 days post-prescription using the records in Period 1. RESULTS: Out of 9.4 million patients who received antibiotics, 0.6% of UTI, 0.3% of URTI, and 0.5% of LRTI patients experienced AEs. UTI and LRTI patients demonstrated a higher risk of AEs, with a noted increase in AE incidence during the COVID-19 pandemic. Higher comorbidity and recent antibiotic use emerged as significant AE predictors. The developed models exhibited good calibration and discrimination, especially for UTIs and LRTIs, with a C-statistic above 0.70. CONCLUSIONS: The study reveals a variable incidence of AEs post-antibiotic treatment for common infections, with UTI and LRTI patients facing higher risks. AE risks varied between infections and COVID-19 periods. These findings underscore the necessity for cautious antibiotic prescribing and call for further exploration into the intricate dynamics between antibiotic use, AEs, and the pandemic.

Changes in sick notes associated with COVID-19 from 2020 to 2022: a cohort study in 24 million primary care patients in OpenSAFELY-TPP.

OBJECTIVES: Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called 'fit notes') are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19. DESIGN: Cohort study. SETTING: With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database. PARTICIPANTS: People 18-64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673). PRIMARY OUTCOME MEASURE: Receipt of a sick note in primary care. RESULTS: Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia. CONCLUSIONS: Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

Tandem One-Pot Biocatalytic Oxidation and Wittig Reaction in Water.

We explore biocatalytic aldehyde generation under aqueous conditions, concomitantly delivering access to a one-pot Wittig reaction using stabilized phosphoranes and granting diverse alkene products. Using a recombinant choline oxidase mutant, we first undertake biocatalytic alcohol oxidation across a range of functional aliphatic primary alcohols, demonstrating a remarkable substrate tolerance for this enzyme, including chloride, bromide, azide, S-methyl, and alkynyl groups. Following this, we extend capability and deliver a practicable milligram-scale one-pot Wittig reaction in water.

The safety of antivirals and neutralising monoclonal antibodies used in prehospital treatment of Covid-19.

OBJECTIVE: This proof-of-principle pharmacovigilance study used Electronic Health Record (EHR) data to examine the safety of sotrovimab, paxlovid and molnupiravir in prehospital treatment of Covid-19. METHOD: With NHS England approval, we conducted an observational cohort study using OpenSAFELY-TPP, a secure software-platform which executes analyses across EHRs for 24 million people in England. High-risk individuals with Covid-19 eligible for prehospital treatment were included. Adverse events (AEs) were categorised into events in the drug's Summary of Product Characteristics (SmPC), drug-reactions and immune-mediated. Cox models compared risk across treatments. A pre-pandemic record analysis was performed for comparative purposes. RESULTS: Between 2021-2023, 37,449 patients received sotrovimab, paxlovid or molnupiravir whilst 109,647 patients made up an eligible-but-untreated population. The 28-day rates of AEs were low: SmPC 0.34 per 1000 patient-years (95% CI 0.32-0.36); drug-reactions 0.01 (95% CI 0.01-0.02) and immune-mediated 0.03 (95% CI 0.03-0.04), and similar or lower than the pre-pandemic period. Compared with the eligible but untreated population, sotrovimab and paxlovid associated with a risk of SmPC AE [adjHR 1.36 (95% CI 1.15-1.62) and 1.28 (95% CI 1.05-1.55), respectively], whilst sotrovimab associated with a risk of drug-reactions [adjHR 2.95 (95% CI 1.56-5.55)] and immune-mediated events [adjHR 3.22 (95% CI 1.86-5.57)]. CONCLUSION: Sotrovimab, paxlovid and molnupiravir demonstrate acceptable safety profiles. Although the risk of AEs was greatest with sotrovimab, event rates were lower than comparative pre-pandemic period.

Trace metal pollution gradients in a tropical seagrass ecosystem.

Trace metals are one of the most serious pollutants in tropical seagrass meadows given their persistence and toxicity. Whereas quantity is frequently measured, there is no information on the spatial extent of metal pollution in these systems. Here, we use an island in Indonesia (Barang Lompo) as a model system to study the impact radius of two major and eight trace metals in sediment and seagrass leaves. We provide evidence for exponential decay in both the metal pollution index and concentrations of most metals with increasing distance from the island (k = -0.01 to -0.08 m-1). Consequently, there is an impact radius of approximately 100 m around the island. The comparative analysis of both seagrass species further revealed interspecific differences in metal loads. This study highlights the importance of assessing the spatial extent of metal pollution in addition to its quantity.

Accessing Active Fragments for Drug Discovery Utilising Nitroreductase Biocatalysis.

Biocatalysis has played a limited role in the early stages of drug discovery. This is often attributed to the limited substrate scope of enzymes not affording access to vast areas of novel chemical space. Here, we have shown a promiscuous nitroreductase enzyme (NR-55) can be used to produce a panel of functionalised anilines from a diverse panel of aryl nitro starting materials. After screening on analytical scale, we show that sixteen substrates could be scaled to 1 mmol scale, with several poly-functional anilines afforded with ease under the standard conditions. The aniline products were also screened for activity against several cell lines of interest, with modest activity observed for one compound. This study demonstrates the potential for nitroreductase biocatalysis to provide access to functional fragments under benign conditions.