Large Language Models as Molecular Design Engines.

The design of small molecules is crucial for technological applications ranging from drug discovery to energy storage. Due to the vast design space available to modern synthetic chemistry, the community has increasingly sought to use data-driven and machine learning approaches to navigate this space. Although generative machine learning methods have recently shown potential for computational molecular design, their use is hindered by complex training procedures, and they often fail to generate valid and unique molecules. In this context, pretrained Large Language Models (LLMs) have emerged as potential tools for molecular design, as they appear to be capable of creating and modifying molecules based on simple instructions provided through natural language prompts. In this work, we show that the Claude 3 Opus LLM can read, write, and modify molecules according to prompts, with impressive 97% valid and unique molecules. By quantifying these modifications in a low-dimensional latent space, we systematically evaluate the model's behavior under different prompting conditions. Notably, the model is able to perform guided molecular generation when asked to manipulate the electronic structure of molecules using simple, natural-language prompts. Our findings highlight the potential of LLMs as powerful and versatile molecular design engines.

The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance.

ABSTRACT: As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX's antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain.

Self-Described Training Needs of Special Operations Forces Medics and the Birth of the TACMED Division.

Training needs of Special Operations Forces (SOF) medics were surveyed and new training initiatives have been created to meet their needs. SOF medics perform an array of medical procedures in austere environments with minimal supervision. Medical skills decay over time after initial training and the perceived training needs of active SOF medics were unclear. To fill this gap, active SOF medics (n=57) completed a survey that included confidence ratings and indications of whether additional training would make them more proficient in 70 medical knowledge and procedural skills, assembled into categories by a panel of experts (airway, trauma, neuro, differential diagnosis, administrative, infection, critical care, environmental, other). Data were analyzed with analysis of variance (ANOVA) and nonparametric statistics at P<.05. Confidence was highest in the trauma, administrative, and airway categories, and lowest in the infection, differential diagnosis, and neuro categories (P<.05 or less). Categories indicating the greatest need for additional training were environmental and critical care, while those indicating lowest need were the airway and trauma categories (P=.05). Additional training was endorsed by >75% of participants in each category. SOF medics also wanted additional training in all areas, preferably hands-on with live patients in realistic scenarios, taught by experienced medics. Findings highlight the training needs of SOF medics and demonstrate the value of bottom-up feedback toward optimizing sustainment training. Based on present findings, two TACMED (Tactical Medicine) Divisions at the SOF Echelon III level were created to meet the sustainment training needs of SOF medics.

Jumping Performance and Behavior of the Globular Springtail Dicyrtomina minuta.

Springtails are among the most abundant arthropods on earth and they exhibit unique latch-mediated spring-actuated jumping behaviors and anatomical systems. Despite this, springtail jumps have not been well described, especially for those with a globular body plan. Here, we provide a complete description and visualization of jumping in the globular springtail Dicyrtomina minuta. A furca-powered jump results in an average take-off velocity of 1 ms-1 in 1.7 ms, with a fastest acceleration to liftoff of 1938 ms-2. All jumps involve rapid backwards body rotation throughout, rotating on average at 282.2 Hz with a peak rate of 368.7 Hz. Despite body lengths of 1-2 mm, jumping resulted in a backwards trajectory traveling up to 102 mm in horizontal distance and 62 mm in vertical. Escape jumps in response to posterior stimulation did not elicit forward-facing jumps, suggesting that D. minuta is incapable of directing a jump off a flat surface within the 90° heading directly in front of them. Finally, two landing strategies were observed: collophore-anchoring, which allows for an immediate arrest and recovery, and uncontrolled landings where the springtail chaotically tumbles. In comparison to other fast jumping arthropods, linear performance measures globular springtail jumps place them between other systems like fleas and froghoppers. However, in angular body rotation, globular springtails like D. minuta surpass all other animal systems. Given the extraordinary performance measures, unique behavioral responses, and understudied nature of these species, globular springtails present promising opportunities for further description and comparison.

Health and social care: The link between social care deficiencies and health care pressures.

In the United Kingdom, demand on the social care sector is rising coupled with a significant reduction in funding making it difficult to meet these needs. The aim of this two-part commentary is to provide a critical evaluation of the evidence base in relation to solutions to tackle the growing demands on health and social care. Part 1 focuses on the evidence from a systematic review around the association between the availability and supply of social care and healthcare on utilisation for older adults in high income countries. Part 1 Health and social care The link between social care deficiencies and health care pressures: An evidence summary based on the following systematic review:Spiers G, Matthews FE, Moffatt S, Barker RO, Jarvis H, Stow D, Kingston A, Hanratty B (2019) Impact of social care supply on healthcare utilisation by older adults: a systematic review and meta-analysis. Age and Ageing 48(1):57-66. https://doi.org/10.1093/ageing/afy147.

Oral health and related outcomes in children and adolescents with cystic fibrosis: a scoping review.

PURPOSE: Good oral health is important for children and adolescents with cystic fibrosis (CF). The purpose of this scoping review is to describe the existing evidence base regarding oral health in children and adolescents with CF and provide recommendations for future research. METHODS: Using a scoping review framework, a comprehensive search was undertaken using medline, embase, and PubMed. The search strategy included broad terms relating to CF, oral health, and children and adolescents and included only papers written in English. RESULTS: 61 articles were included. Topics investigated included dental caries, enamel defects, periodontal health, dental staining, oral health related quality of life, dental management, and dental development of children and adolescents with CF. CONCLUSION: Dental outcomes of children and adolescents with CF differ from the healthy population. The current literature describing dental health in children and adolescents with CF includes predominately descriptive analyses. A shift to hypothesis-based studies to explore causal relationships that explain the differences in dental outcomes seen in the CF population offers an opportunity to better understand the problems faced by children and adolescents with CF. Research that actively engages stakeholders, including children and adolescents with CF and their families will enable evidence-based recommendations to improve their oral health.

Local genetic adaptation to habitat in wild chimpanzees.

How populations adapt to their environment is a fundamental question in biology. Yet we know surprisingly little about this process, especially for endangered species such as non-human great apes. Chimpanzees, our closest living relatives, are particularly interesting because they inhabit diverse habitats, from rainforest to woodland-savannah. Whether genetic adaptation facilitates such habitat diversity remains unknown, despite having wide implications for evolutionary biology and conservation. Using 828 newly generated exomes from wild chimpanzees, we find evidence of fine-scale genetic adaptation to habitat. Notably, adaptation to malaria in forest chimpanzees is mediated by the same genes underlying adaptation to malaria in humans. This work demonstrates the power of non-invasive samples to reveal genetic adaptations in endangered populations and highlights the importance of adaptive genetic diversity for chimpanzees.

Phosphorylation of mammalian cytosolic and mitochondrial malate dehydrogenase: insights into regulation.

Malate dehydrogenase (MDH) is a key enzyme in mammalian metabolic pathways in cytosolic and mitochondrial compartments. Regulation of MDH through phosphorylation remains an underexplored area. In this review we consolidate evidence supporting the potential role of phosphorylation in modulating the function of mammalian MDH. Parallels are drawn with the phosphorylation of lactate dehydrogenase, a homologous enzyme, to reveal its regulatory significance and to suggest a similar regulatory strategy for MDH. Comprehensive mining of phosphorylation databases, provides substantial experimental (primarily mass spectrometry) evidence of MDH phosphorylation in mammalian cells. Experimentally identified phosphorylation sites are overlaid with MDH's functional domains, offering perspective on how these modifications could influence enzyme activity. Preliminary results are presented from phosphomimetic mutations (serine/threonine residues changed to aspartate) generated in recombinant MDH proteins serving as a proof of concept for the regulatory impact of phosphorylation. We also examine and highlight several approaches to probe the structural and cellular impact of phosphorylation. This review highlights the need to explore the dynamic nature of MDH phosphorylation and calls for identifying the responsible kinases and the physiological conditions underpinning this modification. The synthesis of current evidence and experimental data aims to provide insights for future research on understanding MDH regulation, offering new avenues for therapeutic interventions in metabolic disorders and cancer.

Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain.

Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

An Adaptive Pragmatic Randomized Controlled Trial of Emergency Department Acupuncture for Acute Musculoskeletal Pain Management.

STUDY OBJECTIVE: Acute musculoskeletal pain in emergency department (ED) patients is frequently severe and challenging to treat with medications alone. The purpose of this study was to determine the feasibility, acceptability, and effectiveness of adding ED acupuncture to treat acute episodes of musculoskeletal pain in the neck, back, and extremities. METHODS: In this pragmatic 2-stage adaptive open-label randomized clinical trial, Stage 1 identified whether auricular acupuncture (AA; based on the battlefield acupuncture protocol) or peripheral acupuncture (PA; needles in head, neck, and extremities only), when added to usual care was more feasible, acceptable, and efficacious in the ED. Stage 2 assessed effectiveness of the selected acupuncture intervention(s) on pain reduction compared to usual care only (UC). Licensed acupuncturists delivered AA and PA. They saw and evaluated but did not deliver acupuncture to the UC group as an attention control. All participants received UC from blinded ED providers. Primary outcome was 1-hour change in 11-point pain numeric rating scale. RESULTS: Stage 1 interim analysis found both acupuncture styles similar, so Stage 2 continued all 3 treatment arms. Among 236 participants randomized, demographics and baseline pain were comparable across groups. When compared to UC alone, reduction in pain was 1.6 (95% confidence interval [CI]: 0.7 to 2.6) points greater for AA+UC and 1.2 (95% CI: 0.3 to 2.1) points greater for PA+UC patients. Participants in both treatment arms reported high satisfaction with acupuncture. CONCLUSION: ED acupuncture is feasible and acceptable and can reduce acute musculoskeletal pain better than UC alone.

The smallest worthwhile effect on pain intensity of exercise therapy for people with chronic low back pain: a discrete choice experiment study.

OBJECTIVE: To identify the smallest worthwhile effect (SWE) of exercise therapy for people with non-specific chronic low back pain (CLBP). DESIGN: Discrete choice experiment. METHODS: The SWE was estimated as the lowest reduction in pain that participants would consider exercising worthwhile, compared to not exercising i.e., effects due to natural history and other components (e.g., regression to the mean). We recruited English-speaking adults in Australia with non-specific CLBP to our online survey via email obtained from a registry of previous participants and advertisements on social media. We used discrete choice experiment to estimate the SWE of exercise compared to no exercise for pain intensity. We analysed the discrete choice experiment using a mixed logit model, and mitigated hypothetical bias through certainty calibration, with sensitivity analyses performed with different certainty calibration thresholds. RESULTS: Two-hundred and thirteen participants completed the survey. The mean age (±SD) was 50.7±16.5, median (IQR) pain duration 10 years (5-20), and mean pain intensity (±SD) was 5.8±2.3 on a 0-10 numerical rating scale. For people with CLBP the SWE of exercise was a between-group reduction in pain of 20%, compared to no exercise. In the sensitivity analyses, the SWE varied with different levels of certainty calibration; from 0% without certainty calibration to 60% with more extreme certainty calibration. CONCLUSION: This patient-informed threshold of clinical importance could guide the interpretation of findings from randomised trials and meta-analyses of exercise therapy compared to no exercise.

Prehospital Needle Decompression of Suspected Tension Pneumothorax: Outcomes and Consequences.

Tension pneumothorax (TPT) identified in the prehospital setting requires prehospital needle decompression (PHND). This study aimed to evaluate complications from PHND when it was performed without meeting clinical criteria. A retrospective review was performed of patients undergoing (PHND) from 2016 through 2022 at a level 1 trauma center. Patient data who received PHND were reviewed. Of 115 patients, 85 did not meet at least one clinical criterion for PHND. The majority of patients in this cohort 76 (89%) required a chest tube and 22 (25%) had an iatrogenic pneumothorax from PHND. 5 patients (6%) were admitted due to iatrogenic PHND. Two vascular injuries in this population were directly due to PHND and required emergency operative repair. This study shows the negative consequences of PHND when performed without clear indications. Several patients underwent unnecessary procedures with significant clinical consequences.

68 Ga-DOTATATE and 18 F-FDG PET Imaging of a Rare Chordoid Meningioma With Intracranial Recurrence and Extracranial Metastases.

ABSTRACT: Chordoid meningiomas, rare meningioma variants, are characterized by their histopathological features and clinical behavior resembling that of other chondroid/myxoid neoplasms. We present a case of pathology-proven chordoid meningioma imaged with both 68 Ga-DOTATATE and 18 F-FDG PET images during a complicated postoperative course with multiple episodes of local recurrence and, ultimately, extracranial metastasis. This case underscores the aggressive behavior of chordoid meningiomas while highlighting how molecular imaging plays an important role in clinical monitoring and guidance of management.

A field programmable gate array based Langmuir probe system for measurement of plasma parameters at 500 kHz in a high-power impulse magnetron sputtering plasma.

By utilizing Field Programmable Gate Arrays in a configuration similar to that of the Mirror Langmuir Probe, it is possible to bias a single probe at three precise voltages in sequence. These voltages can be dynamically adjusted in real-time based on the measured plasma electron temperature to ensure the transition region is always sampled. The first results have been obtained by employing this method and have generated real-time outputs of electron temperature, ion saturation current, and floating potential on a low temperature pulsed-DC magnetron at 500 kHz. These results are in good agreement with the analysis of a conventionally swept Langmuir probe. This probe is designed with the intention of being implemented on MAST-U to aid in the study of exhaust physics and enable further investigation into filamentary behavior.

Method considerations for school psychology from longitudinal research on gifted students.

This article draws from longitudinal research on gifted students to provide method considerations for school psychology research. First, we provide some background of gifted and talented education in the United States. Then, drawing from multiple longitudinal samples of gifted students, in particular the Study of Mathematically Precocious Youth (SMPY), we illustrate the role of replications, including constructive replications. In the middle two sections, we highlight methodological design features focused first on predictors, and then on outcomes, considering types, magnitude, and breadth. Finally, we provide additional considerations and future directions, including expanding the outcome domain, overcoming the limitations of past gifted and talented research studies, and suggesting possibilities for future research. Our article may help improve school psychology research as well as assist school psychology researchers interested in conducting their own longitudinal studies using gifted samples.