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Abstract 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.

Abstract 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.

Abstract Background Long COVID potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. Methods This study aims to assess the healthcare utilisation of individuals with long COVID. With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. Results We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.29, 95% CI: 7.74–8.87), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.48–1.51). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58–29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73–16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.66, 95% CI = 7.20–8.15), with costs being 44% higher than the comparator group (cost ratio = 1.44, 95% CI: 1.39–1.50). The long COVID group costs approximately £2500 per person per year (predicted mean cost: £2562.50, 95% CI: £2335.60–£2819.22), and the comparator group costs £1500 (predicted mean cost: £1527.43, 95% CI: £1404.33–1664.45). Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. Conclusions Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID.

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.

Key Clinical Message For diagnosis of osteoporosis, a T‐score of ≤−2.5 is recommended for all transgender and gender‐diverse patients aged 50 years or older, regardless of hormonal status. This case series presents 3 transgender individuals younger than 50 years undergoing gender‐affirming hormone therapy (GAHT) who had DXA scores suggestive of osteoporosis. We highlight possible discrepancies in DXA scan interpretations, especially in forearm bone mineral density measurements. We present the baseline (prior to beginning GAHT), 6‐month, and 1‐year follow‐up DXA data along with pertinent labs to include 25‐OH vitamin D, calcium, and alkaline phosphatase, for 2 transgender males (assigned female at birth) and 1 transgender female (assigned male at birth) undergoing GAHT who had low Z‐scores and T‐scores suggestive of osteoporosis. Multiple studies have analyzed the BMD data of individuals taking GAHT over time, which identify possible causes for low baseline Z‐scores for transgender females, but less so for transgender males. Other than positional statements, guidelines remain unclear regarding diagnostic approaches to osteoporosis and low Z‐scores in transgender individuals who are premenopausal or under 50 years of age. This case series addresses discrepancies in interpretation that may be encountered by clinicians with baseline and follow‐up DXAs, especially involving the forearm, during the course of GAHT. This highlights the importance of establishing clearer guidelines for the diagnosis and treatment of osteoporosis and low BMD for chronological age in the transgender population.

Background: Innovative Medicines Initiative (IMI) consortium IDEA-FAST is developing novel digital measures of fatigue, sleep quality, and impact of sleep disturbances for neurodegenerative diseases and immune-mediated inflammatory diseases. In 2022, the consortium met with the European Medicines Agency (EMA) to receive advice on its plans for regulatory qualification of the measures. This viewpoint reviews the IDEA-FAST perspective on developing digital measures for multiple diseases and the advice provided by the EMA. Summary: The EMA considered a cross-disease measure an interesting and arguably feasible concept. Developers should account for the need for a strong rationale that the clinical features to be measured are similar across diseases. In addition, they may expect increased complexity of study design, challenges when managing differences within and between disease populations, and the need for validation in both heterogeneous and homogeneous populations. Key Messages: EMA highlighted the challenges teams may encounter when developing a cross-disease measure, though benefits potentially include reduced resources for the technology developer and health authority, faster access to innovation across different therapeutic fields, and feasibility of cross-disease comparisons. The insights included here can be used by project teams to guide them in the development of cross-disease digital measures intended for regulatory qualification.

Abstract Background There is concern that the COVID-19 pandemic altered the management of common infections in primary care. This study aimed to evaluate infection-coded consultation rates and antibiotic use during the pandemic and how any change may have affected clinical outcomes. Methods With the approval of NHS England, a retrospective cohort study using the OpenSAFELY platform analysed routinely collected electronic health data from GP practices in England between January 2019 and December 2021. Infection coded consultations and antibiotic prescriptions were used estimate multiple measures over calendar months, including age-sex adjusted prescribing rates, prescribing by infection and antibiotic type, infection consultation rates, coding quality and rate of same-day antibiotic prescribing for COVID-19 infections. Interrupted time series (ITS) estimated the effect of COVID-19 pandemic on infection-coded consultation rates. The impact of the pandemic on non- COVID-19 infection-related hospitalisations was also estimated. Results Records from 24 million patients were included. The rate of infection-related consultations fell for all infections (mean reduction of 39% in 2020 compared to 2019 mean rate), except for UTI which remained stable. Modelling infection-related consultation rates highlighted this with an incidence rate ratio of 0.44 (95% CI 0.36–0.53) for incident consultations and 0.43 (95% CI 0.33–0.54) for prevalent consultations. Lower respiratory tract infections (LRTI) saw the largest reduction of 0.11 (95% CI 0.07–0.17). Antibiotic prescribing rates fell with a mean reduction of 118.4 items per 1000 patients in 2020, returning to pre-pandemic rates by summer 2021. Prescribing for LRTI decreased 20% and URTI increased 15.9%. Over 60% of antibiotics were issued without an associated same-day infection code, which increased during the pandemic. Infection-related hospitalisations reduced (by 62%), with the largest reduction observed for pneumonia infections (72.9%). Same-day antibiotic prescribing for COVID-19 infection increased from 1 to 10.5% between the second and third national lockdowns and rose again during 2022. Conclusions Changes to consultations and hospital admissions may be driven by reduced transmission of non-COVID-19 infections due to reduced social mixing and lockdowns. Inconsistencies in coding practice emphasises the need for improvement to inform new antibiotic stewardship policies and prevent resistance to novel infections.

Abstract Sustainably managing fisheries requires regular and reliable evaluation of stock status. However, most multispecies reef fisheries around the globe tend to lack research and monitoring capacity, preventing the estimation of sustainable reference points against which stocks can be assessed. Here, combining fish biomass data for >2000 coral reefs, we estimate site-specific sustainable reference points for coral reef fisheries and use these and available catch estimates to assess the status of global coral reef fish stocks. We reveal that >50% of sites and jurisdictions with available information have stocks of conservation concern, having failed at least one fisheries sustainability benchmark. We quantify the trade-offs between biodiversity, fish length, and ecosystem functions relative to key benchmarks and highlight the ecological benefits of increasing sustainability. Our approach yields multispecies sustainable reference points for coral reef fisheries using environmental conditions, a promising means for enhancing the sustainability of the world’s coral reef fisheries.

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.

Abstract Premise Low‐cost, repairable lab equipment is rare within the biological sciences. By lowering the costs of entry using 3D printing and open‐source hardware, our goal is to empower both amateur and professional scientists to conduct research. Methods We developed a modular system of 3D‐printable designs called COBLE (Collection of Bespoke Laboratory Equipment), including novel and remixed 3D‐printable lab equipment that can be inexpensively printed, assembled, and repaired for a fraction of the cost of retail equivalents. Results Here we present novel tools that utilize 3D printing to enable a wide range of scientific experiments. We include additional resources for scientists and labs that are interested in utilizing 3D printing for their research. Discussion By describing the broad potential that 3D‐printed designs can have in the biological sciences, we hope to inspire others to implement and improve upon these designs, improving accessibility and enabling science for all.

The notion that mitochondria cannot be lost was shattered with the report of an oxymonad Monocercomonoides exilis, the first eukaryote arguably without any mitochondrion. Yet, questions remain about whether this extends beyond the single species and how this transition took place. The Oxymonadida is a group of gut endobionts taxonomically housed in the Preaxostyla which also contains free-living flagellates of the genera Trimastix and Paratrimastix. The latter two taxa harbour conspicuous mitochondrion-related organelles (MROs). Here we report high-quality genome and transcriptome assemblies of two Preaxostyla representatives, the free-living Paratrimastix pyriformis and the oxymonad Blattamonas nauphoetae. We performed thorough comparisons among all available genomic and transcriptomic data of Preaxostyla to further decipher the evolutionary changes towards amitochondriality, endobiosis, and unstacked Golgi. Our results provide insights into the metabolic and endomembrane evolution, but most strikingly the data confirm the complete loss of mitochondria for all three oxymonad species investigated (M. exilis, B. nauphoetae, and Streblomastix strix), suggesting the amitochondriate status is common to a large part if not the whole group of Oxymonadida. This observation moves this unique loss to 100 MYA when oxymonad lineage diversified.

ABSTRACTAnticipation of futures using transdisciplinary approaches is critical to provide the basis for appropriate action to cope with current and future risks and to foster sustainability transformations. Coasts in the Global South in particular are subjected to severe environmental and societal challenges exacerbated by climate change. Yet, traditional research methods and epistemologies may not reflect the need for envisioning radically different sustainable futures. To gain an overview of and identify gaps in the current practices of transformational transdisciplinary research in coastal regions of the Global South, we conducted a systematic literature review of empirical English-language research articles (n = 256). Our results showed that most of the articles reviewed focused on past and current state analysis. Those articles using anticipation methods rarely analysed or established a link between anticipation and sustainability transformation. Yet, transdisciplinary and anticipation research have synergistic effects to foster sustainability transformation. A combination of these approaches may integrate pluralistic voices and values of stakeholders and foster potential alternative visions to counter unsustainable narratives. Thereby, the visions for possible futures may become more inclusive and reflective of realities in the Global South. Anticipation of the future using transdisciplinary approaches can provide a basis for adaptive management of future environmental and societal challenges. It may provide the knowledge-base which can be used to identify, reduce or prevent governance actions that result in undesirable states of the future. The inclusion of anticipation and foresight in transdisciplinary research creates the potential for achieving or progressing towards innovative and sustainable visions of the future.

Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.

Marine fishes can substantially contribute to the inorganic carbon cycle through the excretion of intestinally precipitated carbonates, but the underlying drivers remain largely unknown. This study identifies the environmental factors and fish traits that predict carbonate excretion rate and mineralogical composition in tropical reef fishes.

IntroductionCoral bleaching immediately impacts the reef benthos, but effects on fish communities are less well understood because they are often delayed and confounded by anthropogenic interactions.MethodsWe assessed changes in fish abundance, biomass and community composition before and after the 2015/16 coral bleaching event at Aldabra Atoll, Seychelles, where local human impacts are minimal, but reefs suffered 50% bleaching-induced coral mortality. We monitored 12 shallow (2–5 m water depth) and nine deep (15 m water depth) permanent survey sites using two survey methods: indicator surveys recording 84 taxa over six years (pre-: 2014; post-bleaching: 2016–2019, 2021), sizing fish based on six size-class categories, and extended fish surveys recording 198 taxa over two years (pre-: 2015; post-bleaching: 2020) with size estimates to the nearest cm (excluding fish < 8 cm).ResultsDuring indicator surveys, mean fish abundance did not change on deep reefs. However, abundance increased by 77% on shallow reefs between 2014 and 2016, which was mainly driven by increases in herbivores and omnivores, likely as a response to elevated turf algae cover following coral mortality. Overall (and functional group-specific) indicator fish biomass did not differ between 2014 and 2016 and remained at or above pre-bleaching levels throughout 2016–2021. In contrast, extended fish surveys in 2015 and 2020 showed a 55–60% reduction in overall abundance on shallow and deep reefs, and a 69% reduction in biomass on shallow reefs, with decreases in biomass occurring in all functional groups. Biomass on deep reefs did not differ between 2015 and 2020. Multivariate analysis of both data sets revealed immediate and long-lasting differences between pre- and post-bleaching fish community compositions, driven largely by herbivorous, omnivorous and piscivorous taxa.DiscussionResults from the indicator surveys suggest that the bleaching event had limited impact on fish abundance and biomass, while the extended surveys recorded changes in abundance and biomass which would otherwise have gone undetected. Our findings improve understanding of the shift a broad community of fish undergoes following a mass coral bleaching event and highlights the value of survey methods that include the full suite of species to detect ecological responses to environmental drivers.

Prostate cancer represents one of the most common malignant tumors in male patients in Germany. The pathological reporting of radical prostatectomy specimens following a structured process constitutes an excellent prototype for the introduction of software-based standardized structured reporting in pathology. This can lead to reports of higher quality and could create a fundamental improvement for future AI applications. A software-based reporting template was used to generate standardized structured pathological reports of radical prostatectomy specimens of patients treated at the University Hospital Klinikum rechts der Isar of Technische Universität München, Germany. Narrative reports (NR) and standardized structured reports (SSR) were analyzed with regard to completeness, and clinicians’ satisfaction with each report type was evaluated. SSR show considerably higher completeness than NR. A total of 10 categories out of 32 were significantly more complete in SSR than in NR (p < 0.05). Clinicians awarded overall high scores in NR and SSR reports. One rater acknowledged a significantly higher level of clarity and time saving when comparing SSR to NR. Our findings highlight that the standardized structured reporting of radical prostatectomy specimens, qualifying as level 5 reports, significantly increases objectively measured content quality and the level of completeness. The implementation of nationwide SSR in Germany, particularly in oncologic pathology, can serve pathologists, clinicians, and patients.

IntroductionMedicine may select for autistic characteristics. As awareness and diagnosis of autism are growing, more medical students and doctors may be discovering they are autistic. No studies have explored the experiences of autistic doctors. This study aimed to fill that gap.MethodsThis is a cross-sectional study. A participatory approach was used to identify the need for the project and to modify a pre-existing survey for use exploring the experiences of autistic doctors.ResultsWe received 225 responses. 64% had a formal diagnosis of autism. The mean age of receiving a formal diagnosis was 36 (range 3–61). Most were currently working as doctors (82%). The most common specialties were general practice / family medicine (31%), psychiatry (18%), and anesthesia (11%). Almost half of those working had completed specialty training (46%) and 40% were current trainees. 29% had not disclosed being autistic to anyone at work. 46% had requested adjustments in the workplace but of these, only half had them implemented.Three quarters had considered suicide (77%), one quarter had attempted suicide (24%) and half had engaged in self-harm (49%). 80% reported having worked with another doctor they suspected was autistic, but only 22% reported having worked with another doctor they knew was autistic. Having never worked with a potentially autistic colleague was associated with having considered suicide.Most preferred to be called “autistic doctors” (64%). Most considered autism to be a difference (83%). Considering autism to be a disorder was associated with preference for the term “doctors with autism,” and with having attempted suicide.ConclusionAutistic doctors reported many challenges in the workplace. This may have contributed to a culture of nondisclosure. Mental health was poor with high rates of suicidal ideation, self-harm, and prior suicide attempts. Despite inhospitable environments, most were persevering and working successfully. Viewing autism as a disorder was associated with prior suicide attempts and a preference for person-first language. A neurodiversity-affirmative approach to autism may lead to a more positive self-identity and improved mental health. Furthermore, providing adequate supports and improving awareness of autistic medical professionals may promote inclusion in the medical workforce.

Dynamic oxygen-17 (17O) magnetic resonance imaging (MRI) is an imaging method that enables a direct and non-invasive assessment of cerebral oxygen metabolism and thus potentially the distinction between viable and non-viable tissue employing a three-phase inhalation experiment. The purpose of this investigation was the first application of dynamic 17O MRI at 7 Tesla (T) in a patient with stroke. In this proof-of-concept experiment, dynamic 17O MRI was applied during 17O inhalation in a patient with early subacute stroke. The analysis of the relative 17O water (H217O) signal for the affected stroke region compared to the healthy contralateral side revealed no significant difference. However, the technical feasibility of 17O MRI has been demonstrated paving the way for future investigations in neurovascular diseases.

Background: The coronavirus disease 2019 (COVID-19) vaccination programme in England was extended to include all adolescents and children by April 2022. The aim of this paper is to describe trends and variation in vaccine coverage in different clinical and demographic groups amongst adolescents and children in England by August 2022. Methods: With the approval of NHS England, a cohort study was conducted of 3.21 million children and adolescents’ records in general practice in England, in situ and within the infrastructure of the electronic health record software vendor TPP using OpenSAFELY. Vaccine coverage across various demographic (sex, deprivation index and ethnicity) and clinical (risk status) populations is described. Results: Coverage is higher amongst adolescents than it is amongst children, with 53.5% adolescents and 10.8% children having received their first dose of the COVID-19 vaccine. Within those groups, coverage varies by ethnicity, deprivation index and risk status; there is no evidence of variation by sex. Conclusion: First dose COVID-19 vaccine coverage is shown to vary amongst various demographic and clinical groups of children and adolescents.

Optically pumped magnetometers (OPMs) are an emerging lightweight and compact sensor that can measure magnetic fields generated by the human brain. OPMs enable construction of wearable magnetoencephalography (MEG) systems, which offer advantages over conventional instrumentation. However, when trying to measure signals at low frequency, higher levels of inherent sensor noise, magnetic interference and movement artefact introduce a significant challenge. Accurate characterisation of low frequency brain signals is important for neuroscientific, clinical, and paediatric MEG applications and consequently, demonstrating the viability of OPMs in this area is critical. Here, we undertake measurement of theta band (4–8 Hz) neural oscillations and contrast a newly developed 174 channel triaxial wearable OPM-MEG system with conventional (cryogenic-MEG) instrumentation. Our results show that visual steady state responses at 4 Hz, 6 Hz and 8 Hz can be recorded using OPM-MEG with a signal-to-noise ratio (SNR) that is not significantly different to conventional MEG. Moreover, we measure frontal midline theta oscillations during a 2-back working memory task, again demonstrating comparable SNR for both systems. We show that individual differences in both the amplitude and spatial signature of induced frontal-midline theta responses are maintained across systems. Finally, we show that our OPM-MEG results could not have been achieved without a triaxial sensor array, or the use of postprocessing techniques. Our results demonstrate the viability of OPMs for characterising theta oscillations and add weight to the argument that OPMs can replace cryogenic sensors as the fundamental building block of MEG systems.

Bandyopadhyay, Schips et al. model the factors contributing to overloading of healthcare facilities during the first COVID-19 wave in Italy. They predict that an early test and isolate intervention could have reduced healthcare usage and death rates but would not have kept hospitalizations within pre-pandemic hospital limits.

Abstract Background The plastid genomes of the green algal order Chlamydomonadales tend to expand their non-coding regions, but this phenomenon is poorly understood. Here we shed new light on organellar genome evolution in Chlamydomonadales by studying a previously unknown non-photosynthetic lineage. We established cultures of two new Polytoma-like flagellates, defined their basic characteristics and phylogenetic position, and obtained complete organellar genome sequences and a transcriptome assembly for one of them. Results We discovered a novel deeply diverged chlamydomonadalean lineage that has no close photosynthetic relatives and represents an independent case of photosynthesis loss. To accommodate these organisms, we establish the new genus Leontynka, with two species (L. pallida and L. elongata) distinguishable through both their morphological and molecular characteristics. Notable features of the colourless plastid of L. pallida deduced from the plastid genome (plastome) sequence and transcriptome assembly include the retention of ATP synthase, thylakoid-associated proteins, the carotenoid biosynthesis pathway, and a plastoquinone-based electron transport chain, the latter two modules having an obvious functional link to the eyespot present in Leontynka. Most strikingly, the ~362 kbp plastome of L. pallida is by far the largest among the non-photosynthetic eukaryotes investigated to date due to an extreme proliferation of sequence repeats. These repeats are also present in coding sequences, with one repeat type found in the exons of 11 out of 34 protein-coding genes, with up to 36 copies per gene, thus affecting the encoded proteins. The mitochondrial genome of L. pallida is likewise exceptionally large, with its >104 kbp surpassed only by the mitogenome of Haematococcus lacustris among all members of Chlamydomonadales hitherto studied. It is also bloated with repeats, though entirely different from those in the L. pallida plastome, which contrasts with the situation in H. lacustris where both the organellar genomes have accumulated related repeats. Furthermore, the L. pallida mitogenome exhibits an extremely high GC content in both coding and non-coding regions and, strikingly, a high number of predicted G-quadruplexes. Conclusions With its unprecedented combination of plastid and mitochondrial genome characteristics, Leontynka pushes the frontiers of organellar genome diversity and is an interesting model for studying organellar genome evolution.

Accurate prediction of crop production is essential in effectively managing the food security and economic resilience of agricultural countries. This study evaluates the performance of statistical and machine learning-based methods for large-scale crop production forecasting. We predict the quarterly production of 325 crops (including fruits, vegetables, cereals, non-food, and industrial crops) across 83 provinces in the Philippines. Using a comprehensive dataset of 10,949 time series over 13 years, we demonstrate that a global forecasting approach using a state-of-the-art deep learning architecture, the transformer, significantly outperforms popular tree-based machine learning techniques and traditional local forecasting approaches built on statistical and baseline methods. Our results show a significant 84.93%, 80.69%, and 79.54% improvement in normalized root mean squared error (NRMSE), normalized deviation (ND), and modified symmetric mean absolute percentage error (msMAPE), respectively, over the next-best methods. By leveraging cross-series information, our proposed method is scalable and works well even with time series that are short, sparse, intermittent, or exhibit structural breaks/regime shifts. The results of this study further advance the field of applied forecasting in agricultural production and provide a practical and effective decision-support tool for policymakers that oversee crop production and the agriculture sector on a national scale.

Post-task responses (PTRs) are transitionary responses occurring for several seconds between the end of a stimulus/task and a period of rest. The most well-studied of these are beta band (13 – 30 Hz) PTRs in motor networks following movement, often called post-movement beta rebounds, which have been shown to differ in patients with schizophrenia and autism. Previous studies have proposed that beta PTRs reflect inhibition of task-positive networks to enable a return to resting brain activity, scaling with cognitive demand and reflecting cortical self-regulation. It is unknown whether PTRs are a phenomenon of the motor system, or whether they are a more general self-modulatory property of cortex that occur following cessation of higher cognitive processes as well as movement. To test this, we recorded magnetoencephalography (MEG) responses in 20 healthy participants to a working-memory task, known to recruit cortical networks associated with higher cognition. Our results revealed PTRs in the theta, alpha and beta bands across many regions of the brain, including the dorsal attention network (DAN) and lateral visual regions. These PTRs increased significantly (p < 0.05) in magnitude with working-memory load, an effect which is independent of oscillatory modulations occurring over the task period as well as those following individual stimuli. Furthermore, we showed that PTRs are functionally related to reaction times in left lateral visual (p < 0.05) and left parietal (p < 0.1) regions, while the oscillatory responses measured during the task period are not. Importantly, motor PTRs following button presses did not modulate with task condition, suggesting that PTRs in different networks are driven by different aspects of cognition. Our findings show that PTRs are not limited to motor networks but are widespread in regions which are recruited during the task. We provide evidence that PTRs have unique properties, scaling with cognitive load and correlating significantly with behaviour. Based on the evidence, we suggest that PTRs inhibit task-positive network activity to enable a transition to rest, however, further investigation is required to uncover their role in neuroscience and pathology.

Eruptive dynamics of the 1060 CE rhyolitic eruption of Big Glass Mountain (BGM), USA, are investigated with field observations, hydrogen isotope and H2O content analysis of pyroclastic obsidian chips and lavas. Field relations at BGM reveal evidence for hybrid eruption, defined as synchronous explosive venting and effusive emplacement of vast obsidian lava flows. This activity is particularly well manifested by extensive breccia zones implanted within the BGM obsidian lavas, which may represent rafted tephra cones, in addition to remnants of airfall tephra on the lava. Rhyolitic obsidians collected from a 2.5-m-thick fall deposit and co-eruptive lava flow were studied by FTIR and TCEA methods to elucidate the eruption’s degassing history. The data, along with VolcDeGas program simulations, demonstrate a correlation between H2O content and H-isotopic composition (δD) that likely reflects ever-increasing amounts of volatile loss via repetitive close-system steps, best described as batched degassing.

BackgroundData analysis is used to identify signals suggestive of variation in treatment choice or clinical outcome. Analyses to date have generally focused on a hypothesis-driven approach. ObjectiveThis study aimed to develop a hypothesis-free approach to identify unusual prescribing behavior in primary care data. We aimed to apply this methodology to a national data set in a cross-sectional study to identify chemicals with significant variation in use across Clinical Commissioning Groups (CCGs) for further clinical review, thereby demonstrating proof of concept for prioritization approaches. MethodsHere we report a new data-driven approach to identify unusual prescribing behaviour in primary care data. This approach first applies a set of filtering steps to identify chemicals with prescribing rate distributions likely to contain outliers, then applies two ranking approaches to identify the most extreme outliers amongst those candidates. This methodology has been applied to three months of national prescribing data (June-August 2017). ResultsOur methodology provides rankings for all chemicals by administrative region. We provide illustrative results for 2 antipsychotic drugs of particular clinical interest: promazine hydrochloride and pericyazine, which rank highly by outlier metrics. Specifically, our method identifies that, while promazine hydrochloride and pericyazine are barely used by most clinicians (with national prescribing rates of 11.1 and 6.2 per 1000 antipsychotic prescriptions, respectively), they make up a substantial proportion of antipsychotic prescribing in 2 small geographic regions in England during the study period (with maximum regional prescribing rates of 298.7 and 241.1 per 1000 antipsychotic prescriptions, respectively). ConclusionsOur hypothesis-free approach is able to identify candidates for audit and review in clinical practice. To illustrate this, we provide 2 examples of 2 very unusual antipsychotics used disproportionately in 2 small geographic areas of England.

Introduction The growing worldwide prevalence of Alzheimer’s disease (AD) and the lack of effective treatments pose a dire medical challenge. Sleep disruption is also prevalent in the ageing population and is increasingly recognised as a risk factor and an early sign of AD. The ALFASleep project aims to characterise sleep with subjective and objective measurements in cognitively unimpaired middle/late middle-aged adults at increased risk of AD who are phenotyped with fluid and neuroimaging AD biomarkers. This will contribute to a better understanding of the pathophysiological mechanisms linking sleep with AD, thereby paving the way for the development of non-invasive biomarkers and preventive strategies targeting sleep.Methods and analysis We will invite 200 participants enrolled in the ALFA+ (for ALzheimer and FAmilies) prospective observational study to join the ALFASleep study. ALFA+ participants are cognitively unimpaired middle-aged/late middle-aged adults who are followed up every 3 years with a comprehensive set of evaluations including neuropsychological tests, blood and cerebrospinal fluid (CSF) sampling, and MRI and positron emission tomography acquisition. ALFASleep participants will be additionally characterised with actigraphy and CSF–orexin-A measurements, and a subset (n=90) will undergo overnight polysomnography. We will test associations of sleep measurements and CSF–orexin-A with fluid biomarkers of AD and glial activation, neuroimaging outcomes and cognitive performance. In case we found any associations, we will test whether changes in AD and/or glial activation markers mediate the association between sleep and neuroimaging or cognitive outcomes and whether sleep mediates associations between CSF–orexin-A and AD biomarkers.Ethics and dissemination The ALFASleep study protocol has been approved by the independent Ethics Committee Parc de Salut Mar, Barcelona (2018/8207/I). All participants have signed a written informed consent before their inclusion (approved by the same ethics committee). Study findings will be presented at national and international conferences and submitted for publication in peer-reviewed journals.Trial registration number NCT04932473.

Summary: We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid and interstitial fluid around the brain, facilitating solute transport. Models enable hypothesis development and predictions of transport, with clinical applications including drug delivery, stroke, cardiac arrest, and neurodegenerative disorders like Alzheimer’s disease. We sort existing models into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, and links to neuronal activity. Needs and opportunities for future work are highlighted wherever possible; new models, expanded models, and novel experiments to inform models could all have tremendous value for advancing the field.

Fiber-feedback optical parametric oscillators (OPOs) incorporate intracavity fibers to provide a compact high-energy wavelength-tunable laser platform; however, dispersive effects can limit operation to the sub-picosecond regime. In this research article, we modeled pulse propagation through systems of cascaded fibers, incorporating SMF-28 and ultra-high numerical aperture (UHNA) fibers with complementary second-order dispersion coefficients. We found that the pulse duration upon exiting the fiber system is dominated by uncompensated third-order effects, with UHNA7 presenting the best opportunity to realise a cascaded-fiber-feedback OPO.

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Germinal centers (GCs) are transient structures where affinity maturation of B cells gives rise to high affinity plasma and memory cells. The mechanism of GC shutdown is unclear, despite being an important phenomenon maintaining immune homeostasis. In this study, we used a mathematical model to identify mechanisms that can independently promote contraction of GCs leading to shutdown. We show that GC shutdown can be promoted by antigen consumption by B cells, antigen masking by soluble antibodies, alterations in follicular dendritic cell (FDC) network area, modulation of immune complex cycling rate constants, alterations in T follicular helper signaling, increased terminal differentiation and reduced B cell division capacity. Proposed mechanisms promoted GC contraction by ultimately decreasing the number of B cell divisions and recycling cells. Based on the in-silico predictions, we suggest a combination of experiments that can be potentially employed by future studies to unravel the mechanistic basis of GC shutdown such as measurements of the density of pMHC presentation of B cells, FDC network size per B cell, fraction of cells expressing differentiation markers. We also show that the identified mechanisms differentially affect the efficiency of GC reaction estimated based on the quantity and quality of resulting antibodies.

Ipsilateral sensorimotor (iSM1) cortex negative BOLD responses (NBR) are observed to unilateral tasks and are thought to reflect a functionally relevant component of sensorimotor inhibition. Evidence suggests that sensorimotor inhibitory mechanisms degrade with age, along with aspects of motor ability and dexterity. However, understanding of age-related changes to NBR is restricted by limited comparisons between young vs old adults groups with relatively small samples sizes. Here we analysed a BOLD fMRI dataset (obtained from the CamCAN repository) of 581 healthy subjects, gender-balanced, sampled from the whole adult lifespan performing a motor response task to an audiovisual stimulus. We aimed to investigate how sensorimotor and default-mode NBR characteristics of magnitude, spatial extent and response shape alter at every decade of the aging process. We observed a linear decrease in iSM1 NBR magnitude across the whole lifespan, whereas the contralateral sensorimotor (cSM1) PBR magnitude was unchanged. An age-related decrease in the spatial extent of NBR and an increase in the ipsilateral positive BOLD response (PBR) was observed. This occurred alongside an increasing negative correlation between subject's iSM1 NBR and cSM1 PBR magnitude, reflecting a change in the balance between cortical excitation and inhibition. Conventional GLM analysis, using a canonical haemodynamic response (HR) function, showed disappearance of iSM1 NBR in subjects over 50 years of age. However, a deconvolution analysis showed that the shape of the iSM1 HR altered throughout the lifespan, with significantly delayed time-to-peak and decreased magnitude. The most significant decreases in iSM1 HR magnitude occurred in older age (>60 years) but the first changes in HR shape and timing occurred as early as 30 years, suggesting the possibility of separate mechanisms underlying these alterations. Reanalysis using data-driven HRs for each decade detected significant sensorimotor NBR into late older age, showing the importance of taking changes in HR morphology into account in fMRI aging studies. These results may reflect fMRI measures of the age-related decreases in transcollosal inhibition exerted upon ipsilateral sensorimotor cortex and alterations to the excitatory-inhibitory balance in the sensorimotor network.

Abstract Premature-born infants have impaired amygdala structure, presumably due to increased stress levels of premature birth mediated by the amygdala. However, accounting for lifelong plasticity of amygdala, it is unclear whether such structural changes persist into adulthood. To address this problem, we stated the following questions: first, are whole amygdala volumes reduced in premature-born adults? And second, as adult anxiety traits are often increased after prematurity and linked with amygdala structure, are alterations in amygdala associated with adults’ anxiety traits after premature birth? We addressed these questions by automated amygdala segmentation of MRI volumes in 101 very premature-born adults (

Abstract Background SARS-CoV-2 has induced a worldwide pandemic and subsequent non-pharmaceutical interventions (NPIs) to control the spread of the virus. As in many countries, the SARS-CoV-2 pandemic in Germany has led to a consecutive roll-out of different NPIs. As these NPIs have (largely unknown) adverse effects, targeting them precisely and monitoring their effectiveness are essential. We developed a compartmental infection dynamics model with specific features of SARS-CoV-2 that allows daily estimation of a time-varying reproduction number and published this information openly since the beginning of April 2020. Here, we present the transmission dynamics in Germany over time to understand the effect of NPIs and allow adaptive forecasts of the epidemic progression. Methods We used a data-driven estimation of the evolution of the reproduction number for viral spreading in Germany as well as in all its federal states using our model. Using parameter estimates from literature and, alternatively, with parameters derived from a fit to the initial phase of COVID-19 spread in different regions of Italy, the model was optimized to fit data from the Robert Koch Institute. Results The time-varying reproduction number (R t) in Germany decreased to

Dyslexia impacts upon reading and writing, but not upon intelligence. Little research has explored dyslexia in medicine. An online questionnaire was emailed to all medical students within a single medical school, inviting them to participate. Results were analysed using descriptive statistics. Statistical significance was calculated for any differences between gender, age group, or year-group cohorts. 123 individuals responded. Most reported a good understanding of dyslexia, and feelings that their peers with it should be supported. However, a minority reported feelings of jealously, and dissatisfaction – feeling that students with dyslexia should not be supported, as this gives them an unfair advantage. In some, this seemed to stem from a belief that dyslexia were not real, or that their peers were “faking it”. “I think it is a poor excuse for students to be favoured advantageously and receive tremendous benefits. It is certainly not a medical problem.”

This article situates emerging three-dimensional (3D) visualization technologies in the health sciences within the broader historical context of the stereoscope. Although 3D visualization technologies enhance pedagogy and deepen student engagement, they are generally cost-prohibitive and therefore inaccessible for many institutions. In light of this issue, the authors consider the work of American gynecologist and founding member of The Johns Hopkins Hospital in Baltimore, Maryland, Dr. Howard Atwood Kelly (1858–1943). A monumental work, Kelly’s The Stereo Clinic is a multivolume publication whose focal point was the stereoscope, an image-viewing device that can be seen as a prototype for present-day 3D technologies. Each installment presents a step-by-step overview of a specific surgical procedure using a didactic narrative and corresponding stereoscopic images that illustrate the clinical practices. Significantly, Kelly understood The Stereo Clinic as an egalitarian project that provided high-quality educational resources to students and practicing physicians who did not have access to world-class clinical suites and teaching institutions. Furthermore, he viewed The Stereo Clinic as a remedy to the commonplace frustrations of medical education, such as crowded surgical suites, and the hazards of in-person observation. The Stereo Clinic is an important case study because it reveals a medical profession at the turn of the twentieth century preoccupied with 3D visualization. Inventive clinicians such as Kelly did not only advocate for this technology on the strength of its pedagogical value; they also articulated the equalitarian nature of this medium and produced 3D technology accessible to a wide audience.

The purpose of this study was to investigate which social groups are perceived as a threat target and which are perceived as a threat source during the COVID-19 outbreak. In a German sample ('N' = 1454) we examined perceptions of social groups ranging from those that are psychologically close and smaller (family, friends, neighbors) to those that are more distal and larger (people living in Germany, humankind). We hypothesized that psychologically closer groups would be perceived as less affected by COVID-19 as well as less threatening than more psychologically distal groups. Based on social identity theorizing, we also hypothesized that stronger identification with humankind would change these patterns. Furthermore, we explored how these threat perceptions relate to adherence to COVID-19 health guidelines. In line with our hypotheses, latent random-slope modelling revealed that psychologically distal and larger groups were perceived as more affected by COVID-19 and as more threatening than psychologically closer and smaller groups. Including identification with humankind as a predictor into the threat target model resulted in a steeper increase in threat target perception patterns, whereas identification with humankind did not predict differences in threat source perceptions. Additionally, an increase in threat source perceptions across social groups was associated with more adherence to health guidelines, whereas an increase in threat target perceptions was not. We fully replicated these findings in a subgroup from the original sample ('N' = 989) four weeks later. We argue that societal recovery from this and other crises will be supported by an inclusive approach informed by a sense of our common identity as human beings.

Little research exists concerning dyslexia in medical education. A qualitative study highlighted issues such as bullying and a lack of support. This project aimed to quantify those findings. An online survey was sent to junior doctors in parts of the United Kingdom. Seventy-five participated. Most (53%) were diagnosed with dyslexia at university / medical school. Most reported that dyslexia impacted upon their selfimage (59%) and self-esteem (73%). Nearly half (46%) felt it influenced their career pathway choices within medicine. Participants reported bullying at medical school – from peers (24%), from academic teachers (14%), and from clinical teachers (27%); and also at work – from peers (25%), from academic teachers (13%), and from clinical teachers (23%). 88% reported that foundation schools provided no support, 92% that NHS Trusts provided none, and 90% that their deaneries provided none. The sorts of supports which seemed to be lacking were “psychological” or “pastoral” supports.

Abstract Background Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer. Methods Study design: “RACE IT” (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11–15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy. Planned sample size: 33 patients, interim analysis after 11 patients. Discussion This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019. Trial registration Protocol Code RACE IT: AB 65/18; EudraCT: 2018–001823-38; Clinicaltrials.gov: NCT03529890; Date of registration: 27 June 2018.

Oxidation is one of the most important processes used by the chemical industry. However, many of the methods that are used pose significant sustainability and environmental issues. Biocatalytic oxidation offers an alternative to these methods, with a now significant enzymatic oxidation toolbox on offer to chemists. Oxidases are one of these options, and as they only depend on molecular oxygen as a terminal oxidant offer perfect atom economy alongside the selectivity benefits afforded by enzymes. This review will focus on examples of oxidase biocatalysts that have been used for the sustainable production of important molecules and highlight some important processes that have been significantly improved through the use of oxidases. It will also consider emerging classes of oxidases, and how they might fit in a future biorefinery approach for the sustainable production of important chemicals.

Purpose: Discordance between pre-operative biopsy and final pathology for Upper Tract Urothelial Carcinoma (UTUC) is high and optimal management remains controversial. The aim of this study is to evaluate the accuracy of pre-operative biopsy, to identify prognostic factors and to evaluate the effect of adjuvant chemotherapy on survival and oncologic outcome in UTUC.Methods: We analyzed records of patients receiving surgical treatment for UTUC. Pathology of pre-operative biopsy was compared to surgical specimen. We used Kaplan-Meier method to estimate survival probabilities and Cox's proportional hazards models to estimate the association between covariates and event times. Primary endpoint was overall survival (OS). A matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy.Results: 151 patients underwent surgical treatment (28% open, 36% laparoscopic, 17% robotic radical nephroureterectomy; 14% segmental ureteral resections and 5% palliative nephrectomy) for UTUC and were included in the analysis. Upstaging from

Antibody diversification and selection of B cells occur in dynamic structures called germinal centers (GCs). Passively administered soluble antibodies regulate the GC response by masking the antigen displayed on follicular dendritic cells (FDCs). This suggests that GCs might intercommunicate via naturally produced soluble antibodies, but the role of such GC–GC interactions is unknown. In this study, we performed in silico simulations of interacting GCs and predicted that intense interactions by soluble antibodies limit the magnitude and lifetime of GC responses. With asynchronous GC onset, we observed a higher inhibition of late formed GCs compared to early ones. We also predicted that GC–GC interactions can lead to a bias in the epitope recognition even in the presence of equally dominant epitopes due to differences in founder cell composition or initiation timing of GCs. We show that there exists an optimal range for GC–GC interaction strength that facilitates the affinity maturation towards an incoming antigenic variant during an ongoing GC reaction. These findings suggest that GC–GC interactions might be a contributing factor to the unexplained variability seen among individual GCs and a critical factor in the modulation of GC response to antigenic variants during viral infections.

Abstract. Transgender surgeries are increasingly performed across the globe and in the United States. Although comprehensive centers exist, which are well equipped to cater and tailor to the needs of this population subset, quite often their resultant complications are handled at a different institution owing to the acuity of the condition. However, interestingly the psychosocial needs, medical pathophysiology, available surgical procedures, and their resultant complications are still not a part of the regular medical curriculum. This translates into inadequate care when physicians from vast majority of institutions that do not routinely perform transgender surgery encounter these patients with complications from gender-affirming surgeries. We present a case of a patient who underwent complex multiple gender-affirming surgeries, presenting to our emergency department with an acute abdomen; this resulted in a diagnostic and management dilemma and review of brief pertinent literature. We recommend that transgender medicine and its basics needs should be exposed to currently practicing physicians by continuing medical education, trainees and medical students alike via incorporation into their curriculum, to decrease health disparities among the lesbian, gay, bisexual, transgender, and queer community.