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Various excitation-induced loss mechanisms have been identified during the development of direct-gap semiconductor lasers. Recently, indirect-gap laser sources, particularly germanium (Ge) or GeSn based, have emerged due to silicon industry compatibility. Tensile strain is crucial for optical gain or low-threshold room-temperature operation in such media. This study investigates an excitation-induced optical loss mechanism of mechanical origin in Ge-based micro-cavities with all-around stressor layers, a popular platform for strain-engineered laser sources. Using Raman spectroscopy, photoluminescence, and simulations, we find that excitation lowers the optical gain by altering the strain profile. Heating causes Ge micro-cavities to expand within a constraining stressor layer, inducing compressive strain, which is explained by the mismatch in thermal expansion coefficients.

Abstract The continuous emergence of multidrug‐resistant bacterial pathogens poses a major global healthcare challenge, with Klebsiella pneumoniae being a prominent threat. We conducted a comprehensive study on K. pneumoniae’s antibiotic resistance mechanisms, focusing on outer membrane vesicles (OMVs) and polymyxin, a last‐resort antibiotic. Our research demonstrates that OMVs protect bacteria from polymyxins. OMVs derived from Polymyxin B (PB)‐stressed K. pneumoniae exhibited heightened protective efficacy due to increased vesiculation, compared to OMVs from unstressed Klebsiella. OMVs also shield bacteria from different bacterial families. This was validated ex vivo and in vivo using precision cut lung slices (PCLS) and Galleria mellonella. In all models, OMVs protected K. pneumoniae from PB and reduced the associated stress response on protein level. We observed significant changes in the lipid composition of OMVs upon PB treatment, affecting their binding capacity to PB. The altered binding capacity of single OMVs from PB stressed K. pneumoniae could be linked to a reduction in the lipid A amount of their released vesicles. Although the amount of lipid A per vesicle is reduced, the overall increase in the number of vesicles results in an increased protection because the sum of lipid A and therefore PB binding sites have increased. This unravels the mechanism of the altered PB protective efficacy of OMVs from PB stressed K. pneumoniae compared to control OMVs. The lipid A‐dependent protective effect against PB was confirmed in vitro using artificial vesicles. Moreover, artificial vesicles successfully protected Klebsiella from PB ex vivo and in vivo. The findings indicate that OMVs act as protective shields for bacteria by binding to polymyxins, effectively serving as decoys and preventing antibiotic interaction with the cell surface. Our findings provide valuable insights into the mechanisms underlying antibiotic cross‐protection and offer potential avenues for the development of novel therapeutic interventions to address the escalating threat of multidrug‐resistant bacterial infections.

Introduction There is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) pilot trial, the aim of the main SAFER trial is to establish whether population screening for AF reduces incidence of stroke risk.Methods and analysis Approximately 82 000 people aged 70 years and over and not on oral anticoagulation are being recruited from general practices in England. Patients on the palliative care register or residents in a nursing home are excluded. Eligible people are identified using electronic patient records from general practices and sent an invitation and consent form to participate by post. Consenting participants are randomised at a ratio of 2:1 (control:intervention) with clustering by household. Those randomised to the intervention arm are sent an information leaflet inviting them to participate in screening, which involves use of a handheld single-lead ECG four times a day for 3 weeks. ECG traces identified by an algorithm as possible AF are reviewed by cardiologists. Participants with AF are seen by a general practitioner for consideration of anticoagulation. The primary outcome is stroke. Major secondary outcomes are: death, major bleeding and cardiovascular events. Follow-up will be via electronic health records for an average of 4 years. The primary analysis will be by intention-to-treat using time-to-event modelling. Results from this trial will be combined with follow-up data from the cluster-randomised pilot trial by fixed-effects meta-analysis.Ethics and dissemination The London—Central National Health Service Research Ethics Committee (19/LO/1597) provided ethical approval. Dissemination will include public-friendly summaries, reports and engagement with the UK National Screening Committee.Trial registration number ISRCTN72104369.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016–0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 – 2056) (FXV). Clinical trial number: NCT03842800

The term "social licence" has been used to describe which uses and users of health data the public supports - and under what conditions. From November 2022 to January 2023, Health Data Research Network Canada was funded by the Public Health Agency of Canada to explore whether there was consensus among experienced public and patient advisors on: (i) uses of health data that all members supported or opposed and (ii) what constitutes an essential requirement for a health data use or user to be within social licence. The project was conducted in English and French in collaboration with the Interdisciplinary Research Group in Health Informatics (GRIIS) at the University of Sherbrooke. It involved 20 public/patient advisor "participants" and an additional 13 public/patient advisors who served as peer-reviewers, all of whom had prior experience working in a health-related field and/or with health data. The process followed inclusive design principles in that it captured views held by the majority and minority of participants, including views expressed by only one or two participants. After two 2-hour facilitated sessions, participants agreed that it is within social licence for health data to be used (i) by healthcare practitioners to improve patient care, (ii) by governments and administrators to improve the health system, and (iii) by university-based researchers to understand disease and well-being. There was consensus opposition to (i) an individual or organisation selling someone else's identified health data and (ii) health data being used for a purpose that has no public or societal benefit. There was no consensus about what constitutes an essential requirement for a use or users of health data to be with social licence. The results of the process have been published in a non-peer-reviewed report co-authored with participants. This paper has been co-authored with a subset of the participants and peer-reviewers to present a high-level summary of the findings, methodological details, and templates to enable other groups to adapt the process to their own settings. It also presents the results of an anonymous evaluation of the process using the Public and Patient Engagement Evaluation Tool (PPEET), which were mostly positive and identified some areas for improvement.

IntroductionThe Red Sea is a narrow rift basin characterized by latitudinal environmental gradients which shape the diversity and distribution of reef-dwelling organisms. Studies on Symbiodiniaceae associated with select hard coral taxa present species- specific assemblages and concordant variation patterns from the North to southeast Red Sea coast at depths shallower than 30 m. At mesophotic depths, however, algal diversity studies are rare. Here, we characterize for the first-time host-associated algal communities of a mesophotic specialist coral species, Leptoseris cf. striatus, along the Saudi Arabian Red Sea coast.MethodsWe sampled 56 coral colonies spanning the eastern Red Sea coastline from the Northern Red Sea to the Farasan Banks in the South, and across two sampling periods, Fall 2020 and Spring 2022. We used Next Generation Sequencing of the ITS2 marker region in conjunction with SymPortal to denote algal assemblages.Results and discussionOur results show a relatively stable coral species-specific interaction with algae from the genus Cladocopium along the examined latitudinal gradient, with the appearance, in a smaller proportion, of presumed thermally tolerant algal taxa in the genera Symbiodinium and Durusdinium during the warmer season (Fall 2020). Contrary to shallow water corals, our results do not show a change in Symbiodiniaceae community composition from North to South in this mesophotic specialist species. However, our study highlights for the first time that symbiont communities are subject to change over time at mesophotic depth, which could represent an important phenomenon to address in future studies.

Health benefits from urban greening are assumed to translate into reduced healthcare expenditure, yet few studies have tested this. A total of 110,134 participants in the Sax Institute’s 45 and Up Study in the Australian cities of Sydney, Newcastle, or Wollongong were linked with hospital cost data for cardiovascular disease (CVD) events (e.g., acute myocardial infarctions) up to 30 June 2018. Associations between percentages of total green space, tree canopy, and open grass within 1.6 km of participants homes and annual per person measured CVD-related hospital costs were analysed using generalised linear model (GLM) with gamma density as a component of a two-part mixture model, adjusting for confounders. Overall, 26,243 participants experienced a CVD-related hospitalisation. Incidence was lower among participants with 10 % more tree canopy (OR 0.98, 95 %CI 0.96, 0.99), but not with higher total green space or open grass percentages. Total costs of hospitalisations per year were lower with 10 % more tree canopy (means ratio 0.96, 95 %CI 0.95, 0.98), but also higher with 10 % more open grass (means ratio 1.04, 95 %CI 1.02, 1.06). It was estimated that raising tree canopy cover to 30 % or more for individuals with currently less than 10 % could lead to a within-sample annual saving per person of AU$ 193 overall and AU$ 569 for those who experienced one or more CVD-related hospital admissions. This projects to an estimated annual health sector cost reduction of AU$ 19.3 million per 100,000 individuals for whom local tree canopy cover is increased from less than 10 % to 30 % or higher. In conclusion, this longitudinal study is among the first to analyse measured healthcare cost data in relation to urban green space in general, and with differentiation between major types of greenery relevant to urban planning policies in cities around the world. In sum, this study advances an increasingly important and international focus of research by reporting on the lower burden of CVD and fewer associated hospitalisations stemming from upstream investments that protect and restore urban tree canopy, which not only translates into substantial reduced costs for the health sector, but also helps to create regenerative cities and flourishing communities.

IntroductionHigh sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT.MethodsHere, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment.ResultsIn total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week.DiscussionThese case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

Abstract: We determine the mod $p$ cohomological invariants for several affine group schemes $G$ in characteristic $p$. These are invariants of $G$-torsors with values in étale motivic cohomology, or equivalently in Kato’s version of Galois cohomology based on differential forms. In particular, we find the mod 2 cohomological invariants for the symmetric groups and the orthogonal groups in characteristic 2, which Serre computed in characteristic not 2. We also determine all operations on the mod $p$ étale motivic cohomology of fields, extending Vial’s computation of the operations on the mod $p$ Milnor K-theory of fields.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.