Large language models approach expert-level clinical knowledge and reasoning in ophthalmology: A head-to-head cross-sectional study.

Large language models (LLMs) underlie remarkable recent advanced in natural language processing, and they are beginning to be applied in clinical contexts. We aimed to evaluate the clinical potential of state-of-the-art LLMs in ophthalmology using a more robust benchmark than raw examination scores. We trialled GPT-3.5 and GPT-4 on 347 ophthalmology questions before GPT-3.5, GPT-4, PaLM 2, LLaMA, expert ophthalmologists, and doctors in training were trialled on a mock examination of 87 questions. Performance was analysed with respect to question subject and type (first order recall and higher order reasoning). Masked ophthalmologists graded the accuracy, relevance, and overall preference of GPT-3.5 and GPT-4 responses to the same questions. The performance of GPT-4 (69%) was superior to GPT-3.5 (48%), LLaMA (32%), and PaLM 2 (56%). GPT-4 compared favourably with expert ophthalmologists (median 76%, range 64-90%), ophthalmology trainees (median 59%, range 57-63%), and unspecialised junior doctors (median 43%, range 41-44%). Low agreement between LLMs and doctors reflected idiosyncratic differences in knowledge and reasoning with overall consistency across subjects and types (p>0.05). All ophthalmologists preferred GPT-4 responses over GPT-3.5 and rated the accuracy and relevance of GPT-4 as higher (p<0.05). LLMs are approaching expert-level knowledge and reasoning skills in ophthalmology. In view of the comparable or superior performance to trainee-grade ophthalmologists and unspecialised junior doctors, state-of-the-art LLMs such as GPT-4 may provide useful medical advice and assistance where access to expert ophthalmologists is limited. Clinical benchmarks provide useful assays of LLM capabilities in healthcare before clinical trials can be designed and conducted.

Respiratory protein-driven selectivity during the Permian-Triassic mass extinction.

Extinction selectivity determines the direction of macroevolution, especially during mass extinction; however, its driving mechanisms remain poorly understood. By investigating the physiological selectivity of marine animals during the Permian-Triassic mass extinction, we found that marine clades with lower O2-carrying capacity hemerythrin proteins and those relying on O2 diffusion experienced significantly greater extinction intensity and body-size reduction than those with higher O2-carrying capacity hemoglobin or hemocyanin proteins. Our findings suggest that animals with high O2-carrying capacity obtained the necessary O2 even under hypoxia and compensated for the increased energy requirements caused by ocean acidification, which enabled their survival during the Permian-Triassic mass extinction. Thus, high O2-carrying capacity may have been crucial for the transition from the Paleozoic to the Modern Evolutionary Fauna.

Modeling the economic impact for Chile of an import ban on genetically modified maize.

We estimate producer and consumer surplus changes due to a possible GM maize import ban in Chile, which produces only non-GM grains for internal use. Without foreign non-GM sources, the ban's effect on domestic maize prices would be so significant as to induce Chile to switch from net exporter to net importer of animal products. Fixed factor owners in farm production would benefit significantly, although non-GM maize imports would moderate gains. Total social welfare measures would decline considerably, requiring large offsetting noneconomic benefits for a ban's political viability. Without non-GM imports, internal maize prices would likely eliminate domestic animal product industries; with possible imports, industries and final consumers would suffer, but much less. Currently, the country is a net importer of grain and a net exporter of pork and poultry, and so most welfare losses on the demand side of the market for maize would be in terms of the economic rents generated by the pork and poultry sectors. International competition would protect final consumers to the extent that animal product imports based on GM feed were permitted.

US-guided EM tracked system for HDR brachytherapy: A first in-men randomized study for whole prostate treatment.

PURPOSE: An electromagnetic tracking device (EMT) has been integrated in an HDR 3D ultrasound guidance system for prostate HDR. The aim of this study was to compare the efficiency of HDR workflows with and without EM tracking. METHODS AND MATERIALS: A total of 58 patients with a 15 Gy HDR prostate boost were randomized in two arms and two operation room (OR) procedures using: (1) the EMT investigational device, and (2) the Oncentra prostate system (OCP). OR times were compared for both techniques. RESULTS: The overall procedure median time was about 20% shorter for EMT (63 min) compared to OCP (79 min). The US acquisition and contouring was longer for OCP compared to EMT (23 min vs. 16 min). The catheter reconstruction's median times were 23 min and 13 min for OCP and EMT respectively. For the automatic reconstruction with EMT, 62% of cases required no or few manual corrections. Using the EM technology in an OR environment was challenging. In some cases, interferences or the stiffness of the stylet introduced errors in the reconstruction of catheters. The last step was the dosimetry with median times of 11 min (OCP) and 15.5 min (EMT). Finally, it was observed that there was no learning curve associated with the introduction of this new technology. CONCLUSIONS: The EMT device offers an efficient solution for automatic catheter reconstruction for HDR prostate while reducing the possibility of mis-reconstructed catheters caused by issues of visualization in the US images. Because of that, the overall OR times was shorter when using the EMT system.

Brood Parasites That Care: Alternative Nesting Tactics in a Subsocial Wasp.

AbstractHosts and brood parasites are a classic example of conflict. Parasites typically provide no offspring care after laying eggs, imposing costs on hosts. Female subsocial wasps (Ammophila pubescens) alternate between initiating their own nests and using an "intruder" tactic of replacing eggs in nests of unrelated conspecifics. Hosts can respond by substituting new eggs of their own, with up to eight reciprocal replacements. Remarkably, intruders usually provision offspring in host nests, often alongside hosts. We used field data to investigate why intruders provision and to understand the basis of interactions. We found that intruders could not increase their fitness payoffs by using the typical brood parasite tactic of not provisioning offspring. Intruders using the typical tactic would benefit when hosts provisioned in their stead, but their offspring would starve when hosts failed to provision. Although some hosts obtained positive payoffs when intruders mistakenly provisioned their offspring, on average utilizing a conspecific nest represents parasitism: hosts pay costs while intruders benefit. Hosts and intruders used the same tactic of egg replacement, but intruders more often laid the final egg. Selection should favor better discrimination of offspring, which could lead to repeated cycles of costly egg replacement.

A Monte Carlo dose recalculation pipeline for durable datasets: an I-125 LDR prostate brachytherapy use case.

Monte Carlo (MC) dose datasets are valuable for large-scale dosimetric studies. This work aims to build and validate a DICOM-compliant automated MC dose recalculation pipeline with an application to the production of I-125 low dose-rate prostate brachytherapy MC datasets. Built as a self-contained application, the recalculation pipeline ingested clinical DICOM-RT studies, reproduced the treatment into the Monte Carlo simulation, and outputted a traceable and durable dose distribution in the DICOM dose format. MC simulations with TG43-equivalent conditions using both TOPAS andegs_brachyMC codes were compared to TG43 calculations to validate the pipeline. The consistency of the pipeline when generating TG186 simulations was measured by comparing simulations made with both MC codes. Finally,egs_brachysimulations were run on a 240-patient cohort to simulate a large-scale application of the pipeline. Compared to line source TG43 calculations, simulations with both MC codes had more than 90% of voxels with a global difference under ±1%. Differences of 2.1% and less were seen in dosimetric indices when comparing TG186 simulations from both MC codes. The large-scale comparison ofegs_brachysimulations with treatment planning system dose calculation seen the same dose overestimation of TG43 calculations showed in previous studies. The MC dose recalculation pipeline built and validated against TG43 calculations in this work efficiently produced durable MC dose datasets. Since the dataset could reproduce previous dosimetric studies within 15 h at a rate of 20 cases per 25 min, the pipeline is a promising tool for future large-scale dosimetric studies.

Atypical B cells and impaired SARS-CoV-2 neutralization following heterologous vaccination in the elderly.

Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here, we show that individuals 70 years or older (median age 73, range 70-75) who received a primary two-dose schedule with AZD1222 and booster third dose with mRNA vaccine achieve significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared with those younger than 70 (median age 66, range 54-69) at 1 month post booster. Impaired neutralization potency and breadth post third dose in the elderly is associated with circulating "atypical" spike-specific B cells expressing CD11c and FCRL5. However, when considering individuals who received three doses of mRNA vaccine, we did not observe differences in neutralization or enrichment in atypical B cells. This work highlights the finding that AdV and mRNA COVID-19 vaccine formats differentially instruct the memory B cell response.

Mapping the neuroethological signatures of pain, analgesia, and recovery in mice.

Ongoing pain is driven by the activation and modulation of pain-sensing neurons, affecting physiology, motor function, and motivation to engage in certain behaviors. The complexity of the pain state has evaded a comprehensive definition, especially in non-verbal animals. Here, in mice, we used site-specific electrophysiology to define key time points corresponding to peripheral sensitivity in acute paw inflammation and chronic knee pain models. Using supervised and unsupervised machine learning tools, we uncovered sensory-evoked coping postures unique to each model. Through 3D pose analytics, we identified movement sequences that robustly represent different pain states and found that commonly used analgesics do not return an animal's behavior to a pre-injury state. Instead, these analgesics induce a novel set of spontaneous behaviors that are maintained even after resolution of evoked pain behaviors. Together, these findings reveal previously unidentified neuroethological signatures of pain and analgesia at heightened pain states and during recovery.

Accelerated waning of the humoral response to COVID-19 vaccines in obesity.

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.

Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging.

The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (TFH) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. Here we show that TFH cell localization is critical for the quality of the antibody response and for the expansion of the FDC network upon immunization. The smaller GC and compressed FDC network in aged mice were corrected by provision of TFH cells that colocalize with FDCs using CXCR5. This demonstrates that the age-dependent defects in the GC response are reversible and shows that TFH cells support stromal cell responses to vaccines.

Indigenous Peoples and Organization Studies.

This essay encourages scholars of management and organization studies (MOS) to critically reflect on how Indigenous peoples and their knowledges have been, and continue to be, systemically discriminated against. This discrimination is the result of colonization; it has deeply impacted and continues to affect which knowledges and practices are valued and embraced. The impact of colonization is mirrored in MOS via processes and actions within the academic setting and our business schools. The result is the continued marginalization of Indigenous peoples and their knowledges. We propose a shift in how MOS scholars approach research in relation to non-western societies to counter, and hopefully end, these continued practices of discrimination in our business schools. Specifically, we argue that demarginalizing Indigenous research in academia and going beyond 'cosmetic indigenization' in our business schools are new, collaborative ways of rethinking indigeneity and breaking down the current barriers in MOS that reinforce and perpetuate the systemic discrimination against Indigenous peoples, their knowledges and practices.

How predictable are mass extinction events?

Many modern extinction drivers are shared with past mass extinction events, such as rapid climate warming, habitat loss, pollution and invasive species. This commonality presents a key question: can the extinction risk of species during past mass extinction events inform our predictions for a modern biodiversity crisis? To investigate if it is possible to establish which species were more likely to go extinct during mass extinctions, we applied a functional trait-based model of extinction risk using a machine learning algorithm to datasets of marine fossils for the end-Permian, end-Triassic and end-Cretaceous mass extinctions. Extinction selectivity was inferred across each individual mass extinction event, before testing whether the selectivity patterns obtained could be used to 'predict' the extinction selectivity exhibited during the other mass extinctions. Our analyses show that, despite some similarities in extinction selectivity patterns between ancient crises, the selectivity of mass extinction events is inconsistent, which leads to a poor predictive performance. This lack of predictability is attributed to evolution in marine ecosystems, particularly during the Mesozoic Marine Revolution, associated with shifts in community structure alongside coincident Earth system changes. Our results suggest that past extinctions are unlikely to be informative for predicting extinction risk during a projected mass extinction.

ChAdOx1 nCoV-19 vaccination generates spike-specific CD8+ T cells in aged mice.

Effective vaccines have reduced the morbidity and mortality caused by severe acute respiratory syndrome coronavirus-2 infection; however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8+ T cells are important for killing virally infected cells, and vaccines that induce antigen-specific CD8+ T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titers are suboptimal, as can occur in older individuals. Here, we show that in aged mice, spike epitope-specific CD8+ T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV-19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV-19 elicits a good CD8+ T-cell response in older bodies, but that typical age-associated features are evident on these vaccine reactive T cells.

Estradiol withdrawal following a hormone simulated pregnancy induces deficits in affective behaviors and increases ∆FosB in D1 and D2 neurons in the nucleus accumbens core in mice.

In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an "estrogen withdrawal" state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estradiol withdrawal on several behavioral measures of anxiety and motivation. We found that estradiol withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estradiol withdrawal. In the social motivation test, estradiol withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ∆FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ∆FosB expression in the nucleus accumbens core, but ∆FosB expression did not vary across hormone conditions in the nucleus accumbens shell. Using transgenic reporter mice, we found that this increase in ∆FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ∆FosB in the NAc core.

Touch neurons underlying dopaminergic pleasurable touch and sexual receptivity.

Pleasurable touch is paramount during social behavior, including sexual encounters. However, the identity and precise role of sensory neurons that transduce sexual touch remain unknown. A population of sensory neurons labeled by developmental expression of the G protein-coupled receptor Mrgprb4 detects mechanical stimulation in mice. Here, we study the social relevance of Mrgprb4-lineage neurons and reveal that these neurons are required for sexual receptivity and sufficient to induce dopamine release in the brain. Even in social isolation, optogenetic stimulation of Mrgprb4-lineage neurons through the back skin is sufficient to induce a conditioned place preference and a striking dorsiflexion resembling the lordotic copulatory posture. In the absence of Mrgprb4-lineage neurons, female mice no longer find male mounts rewarding: sexual receptivity is supplanted by aggression and a coincident decline in dopamine release in the nucleus accumbens. Together, these findings establish that Mrgprb4-lineage neurons initiate a skin-to-brain circuit encoding the rewarding quality of social touch.

A Randomised Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Palovarotene Ophthalmic Solution.

BACKGROUND AND OBJECTIVE: Palovarotene, a selective retinoic acid receptor γ agonist, is under investigation for the treatment of dry eye disease. This study aimed to determine the ocular and systemic safety, tolerability and pharmacokinetics of palovarotene ophthalmic solution (PVO-OS) in healthy adults. METHODS: This was a randomised, vehicle-controlled phase I study (NCT04762355; retrospectively registered). Participants received either PVO-OS (at 0.025, 0.05 or 0.10 mg/mL) or a vehicle (placebo-to-match PVO-OS) once-daily or twice-daily for seven consecutive days. Safety was assessed by ocular and systemic assessments. Blood samples for pharmacokinetic assessments were collected before and after dose administration. RESULTS: Thirty-six participants were randomised to PVO-OS and 12 to the vehicle. Overall, 89 treatment-emergent ocular adverse events (TEOAEs) were reported by 22 participants (61.1%) receiving PVO-OS and ten TEOAEs were reported by five participants (41.7%) receiving the vehicle. Erythema, irritation and skin dryness of the eyelid were the most common TEOAEs in participants receiving PVO-OS. The incidence of TEOAEs and eyelid-related findings in the PVO-OS groups increased with ascending dose and frequency compared with participants treated with the vehicle. All TEOAEs were mild (96.6%) or moderate (3.4%) and resolved without sequelae. Plasma palovarotene concentrations were generally measurable for up to 3-4 h for 0.025 mg/mL and 0.05 mg/mL and up to 12 h for 0.10 mg/mL dose regimens, independent of the frequency of administration. CONCLUSIONS: PVO-OS was generally well tolerated at doses up to and including 0.10 mg/mL twice daily. Similar pharmacokinetic profiles were observed for the once-daily and twice-daily regimens following multiple ascending doses of PVO-OS.

Palaeoecology of the Hiraiso Formation (Miyagi Prefecture, Japan) and implications for the recovery following the end-Permian mass extinction.

The Hiraiso Formation of northeast Japan represents an important and under-explored archive of Early Triassic marine ecosystems. Here, we present a palaeoecological analysis of its benthic faunas in order to explore the temporal and spatial variations of diversity, ecological structure and taxonomic composition. In addition, we utilise redox proxies to make inferences about the redox state of the depositional environments. We then use this data to explore the pace of recovery in the Early Triassic, and the habitable zone hypothesis, where wave aerated marine environments are thought to represent an oxygenated refuge. The age of the Hiraiso Formation is equivocal due to the lack of key biostratigraphical index fossils, but new ammonoid finds in this study support an early Spathian age. The ichnofossils from the Hiraiso Formation show an onshore-offshore trend with high diversity and relatively large faunas in offshore transition settings and a low diversity of small ichnofossils in basinal settings. The body fossils do not, however, record either spatial or temporal changes, because the shell beds represent allochthonous assemblages due to wave reworking. The dominance of small burrow sizes, presence of key taxa including Thalassinoides, Rhizocorallium and Holocrinus, presence of complex trace fossils, and both erect and deep infaunal tiering organisms suggests that the benthic fauna represents an advanced stage of ecological recovery for the Early Triassic, but not full recovery. The ecological state suggests a similar level of ecological complexity to late Griesbachian and Spathian communities elsewhere, with the Spathian marking a globally important stage of recovery following the mass extinction. The onshore-offshore distribution of the benthic faunas supports the habitable zone hypothesis. This gradient is, however, also consistent with onshore-offshore ecological gradients known to be controlled by oxygen gradients in modern tropical and subtropical settings. This suggests that the habitable zone is not an oxygenated refuge that is only restricted to anoxic events. The lack of observed full recovery is likely a consequence of a persistent oxygen-limitation (dysoxic conditions), hot Early Triassic temperatures and the lack of a steep temperature/water-depth gradient within the habitable zone.

Tfh cells and the germinal center are required for memory B cell formation & humoral immunity after ChAdOx1 nCoV-19 vaccination.

Emergence from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been facilitated by the rollout of effective vaccines. Successful vaccines generate high-affinity plasma blasts and long-lived protective memory B cells. Here, we show a requirement for T follicular helper (Tfh) cells and the germinal center reaction for optimal serum antibody and memory B cell formation after ChAdOx1 nCoV-19 vaccination. We found that Tfh cells play an important role in expanding antigen-specific B cells while identifying Tfh-cell-dependent and -independent memory B cell subsets. Upon secondary vaccination, germinal center B cells generated during primary immunizations can be recalled as germinal center B cells again. Likewise, primary immunization GC-Tfh cells can be recalled as either Tfh or Th1 cells, highlighting the pluripotent nature of Tfh cell memory. This study demonstrates that ChAdOx1 nCoV-19-induced germinal centers are a critical source of humoral immunity.