Sublethal effects of a commercial Bt product and Bt cotton flowers on the bollworm (Helicoverpa zea) with impacts to predation from a lady beetle (Hippodamia convergens).

Insecticidal Bacillus thuringiensis Berliner (Bt) toxins produced by transgenic cotton (Gossypium hirsutum L.) plants have become an essential component of cotton pest management. Bt toxins are the primary management tool in transgenic cotton for lepidopteran pests, the most important of which is the bollworm (Helicoverpa zea Boddie) (Lepidoptera: Noctuidae) in the United States (U.S.). However, bollworm larvae that survive after consuming Bt toxins may experience sublethal effects, which could alter interactions with other organisms, such as natural enemies. Experiments were conducted to evaluate how sublethal effects of a commercial Bt product (Dipel) incorporated into artificial diet and from Bt cotton flowers impact predation from the convergent lady beetle (Hippodamia convergens Guérin-Méneville) (Coleoptera: Coccinellidae), common in cotton fields of the mid-southern U.S. Sublethal effects were detected through reduced weight and slower development in bollworm larvae which fed on Dipel incorporated into artificial diet, Bollgard II, and Bollgard 3 cotton flowers. Sublethal effects from proteins incorporated into artificial diet were found to significantly alter predation from third instar lady beetle larvae. Predation of bollworm larvae also increased significantly after feeding for three days on a diet incorporated with Bt proteins. These results suggest that the changes in larval weight and development induced by Bt can be used to help predict consumption of bollworm larvae by the convergent lady beetle. These findings are essential to understanding the potential level of biological control in Bt cotton where lepidopteran larvae experience sublethal effects.

Typology of employers offering line manager training for mental health.

BACKGROUND: Mental ill health has a high economic impact on society and employers. National and international policy advocates line manager (LM) training in mental health as a key intervention, but little is known about employer training provisions. AIMS: To explore the prevalence and characteristics of organizations that offer LM training in mental health. METHODS: Secondary analysis of existing longitudinal anonymised organizational-level survey data derived from computer-assisted telephone interview surveys collected in four waves (2020:1900 firms, 2021:1551, 2022:1904, 2023:1902) in England, before, during and after a global pandemic. RESULTS: The proportion of organizations offering LM training in mental health increased pre- to post-pandemic (2020:50%, 2023:59%) but 41% do not currently provide it. Logistic regression confirmed that LM training is more likely to be offered by large-sized enterprises, organizations with a larger proportion of employees who are younger (aged 25-49), female, disabled and from ethnic minority communities. Sector patterns were inconsistent, but in 2023, organizations from the 'Hospitality' and 'Business Services' sectors were more likely to provide LM training than other sectors. CONCLUSIONS: Continued efforts are needed to increase the proportion of employers offering LM training in mental health, particularly small- to medium-sized enterprises, and organizations with predominantly male, White and/or older workforces.

Clinical presentation, antimicrobial resistance, and treatment outcomes of Aeromonas human infections: A 14-year retrospective study and comparative genomics of two isolates from fatal cases.

BACKGROUND: Aeromonas virulence may not be entirely dependent on the host immune status. Pathophysiologic determinants of disease progression and severity remain unclear. METHODS: One hundred five patients with Aeromonas infections and 112 isolates were identified, their clinical presentations and outcomes analyzed, and their antimicrobial resistance (AMR) patterns assessed. Two isolates (A and B) from fatal cases of Aeromonas dhakensis bacteremia were characterized using whole genome sequence analysis. Virulence factor- and AMR-encoding genes from these isolates were compared with a well-characterized diarrheal isolate A. dhakensis SSU, and environmental isolate A. hydrophila ATCC_7966T. RESULTS: Skin and soft tissue infections, traumatic wound infections, sepsis, burns, and intraabdominal infections were common. Diabetes, malignancy, and cirrhosis were frequent comorbidities. Male sex, age ≥ 65 years, hospitalization, burns, and intensive care were associated with complicated disease. High rates of AMR to carbapenems and piperacillin-tazobactam were found. Treatment failure was observed in 25.7% of cases. Septic shock and hospital-acquired infections were predictors of treatment failure. All four isolates harbored assorted broad-spectrum AMR genes including blaOXA, ampC, cphA, and efflux pumps. Only clinical isolates possessed both polar and lateral flagellar genes, genes for various surface adhesion proteins, type 3- and -6 secretion systems and their effectors, and toxin genes, including exotoxin A. Both isolates A and B were resistant to colistin and harbored the mobile colistin resistance-3 (mcr-3) gene. CONCLUSIONS: Empirical therapy tailored to local Aeromonas antibiograms may facilitate more favorable outcomes, while advanced diagnostic methods may aid in identifying correct Aeromonas spp. of significant clinical importance.

High-throughput crystallographic fragment screening of Zika virus NS3 Helicase.

The Zika virus (ZIKV), discovered in Africa in 1947, swiftly spread across continents, causing significant concern due to its recent association with microcephaly in newborns and Guillain-Barré syndrome in adults. Despite a decrease in prevalence, the potential for a resurgence remains, necessitating urgent therapeutic interventions. Like other flaviviruses, ZIKV presents promising drug targets within its replication machinery, notably the NS3 helicase (NS3Hel) protein, which plays critical roles in viral replication. However, a lack of structural information impedes the development of specific inhibitors targeting NS3Hel. Here we applied high-throughput crystallographic fragment screening on ZIKV NS3Hel, which yielded structures that reveal 3D binding poses of 46 fragments at multiple sites of the protein, including 11 unique fragments in the RNA-cleft site. These fragment structures provide templates for direct design of hit compounds and should thus assist the development of novel direct-acting antivirals against ZIKV and related flaviviruses, thus opening a promising avenue for combating future outbreaks.

Crystallographic fragment screening delivers diverse chemical scaffolds for Zika virus NS2B-NS3 protease inhibitor development.

Zika virus (ZIKV) infections cause microcephaly in new-borns and Guillain-Barre syndrome in adults raising a significant global public health concern, yet no vaccines or antiviral drugs have been developed to prevent or treat ZIKV infections. The viral protease NS3 and its co-factor NS2B are essential for the cleavage of the Zika polyprotein precursor into individual structural and non-structural proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 48 binders with diverse chemical scaffolds were identified in the active site of the protease, with another 6 fragment hits observed in a potential allosteric binding site. Our work provides potential starting points for the development of potent NS2B-NS3 protease inhibitors. Furthermore, we have structurally characterized a potential allosteric binding pocket, identifying opportunities for allosteric inhibitor development.

Crystallographic Fragment Screen of Coxsackievirus A16 2A Protease identifies new opportunities for the development of broad-spectrum anti-enterovirals.

Enteroviruses are the causative agents of paediatric hand-foot-and-mouth disease, and a target for pandemic preparedness due to the risk of higher order complications in a large-scale outbreak. The 2A protease of these viruses is responsible for the self-cleavage of the poly protein, allowing for correct folding and assembly of capsid proteins in the final stages of viral replication. These 2A proteases are highly conserved between Enterovirus species, such as Enterovirus A71 and Coxsackievirus A16 . Inhibition of the 2A protease deranges capsid folding and assembly, preventing formation of mature virions in host cells and making the protease a valuable target for antiviral activity. Herein, we describe a crystallographic fragment screening campaign that identified 75 fragments which bind to the 2A protease including 38 unique compounds shown to bind within the active site. These fragments reveal a path for the development of non-peptidomimetic inhibitors of the 2A protease with broad-spectrum anti-enteroviral activity.

Fantasy football points capture performance declines in National Football League offensive skill players following an ankle injury.

Background: The ankle is one of the anatomic sites most frequently injured in National Football League (NFL) players. Ankle injuries have previously been shown to have long-lasting negative impacts, and have been associated with impaired athletic performance. The aim of this study was to use fantasy football points as a metric to evaluate the impact of ankle injuries on NFL offensive skill player performance. Methods: An open-access online database was used to identify NFL players who sustained ankle injuries from 2009 to 2020. Another public online database was used to determine fantasy points and other performance metrics for injured offensive skill players in the seasons before and after their ankle injury. Injured players were matched to a healthy control by position, age, and BMI. Paired T-tests were performed to evaluate performance metrics before and after the ankle injury. An ANCOVA was performed to assess the effect of return to play (RTP) time and injury type on fantasy performance. Results: 303 players with ankle injuries were included. Fantasy output, including average points per game (PPG) and total fantasy points accrued in one season, significantly decreased in the season following a player's ankle injury (p < 0.0001). In running backs, tight ends, and wide receivers, performance significantly decreased in every metric evaluated (p < 0.0001). In quarterbacks, there was no significant change in performance, except for a decrease in the number of games played (p = 0.0033) and in the number of interceptions thrown (p = 0.029). Conclusion: Assessing fantasy football output revealed a decrease in player performance in the season following an ankle injury, especially in route-running players. These results can be used to inform injury prevention and rehabilitation practices in the NFL.

Atypical Intrahepatic Cholestasis of Pregnancy: A Red Herring.

Intrahepatic cholestasis of pregnancy is an intrahepatic etiology of acute cholestasis commonly defined by pruritus and increased bile acids, liver transaminases, and, occasionally, bilirubin. Azathioprine is an immunosuppressive agent associated with various forms of hepatoxicity, ranging from transient rises in serum aminotransferase levels, acute cholestatic injury, and chronic hepatic injury. In this report, we present a 20-year-old pregnant woman who presented with cholestatic liver injury due to intrahepatic cholestasis of pregnancy with a clinical picture complicated by increased levels of azathioprine metabolites.

Appropriateness of Ophthalmology Recommendations From an Online Chat-Based Artificial Intelligence Model.

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

A Bacteriophage Cocktail Targeting Yersinia pestis Provides Strong Post-Exposure Protection in a Rat Pneumonic Plague Model.

Yersinia pestis , one of the deadliest bacterial pathogens ever known, is responsible for three plague pandemics and several epidemics, with over 200 million deaths during recorded history. Due to high genomic plasticity, Y. pestis is amenable to genetic mutations as well as genetic engineering that can lead to the emergence or intentional development of pan-drug resistant strains. The dissemination of such Y. pestis strains could be catastrophic, with public health consequences far more daunting than those caused by the recent COVID-19 pandemic. Thus, there is an urgent need to develop novel, safe, and effective treatment approaches for managing Y. pestis infections. This includes infections by antigenically distinct strains for which vaccines, none FDA approved yet, may not be effective, and those that cannot be controlled by approved antibiotics. Lytic bacteriophages provide one such alternative approach. In this study, we examined post-exposure efficacy of a bacteriophage cocktail, YPP-401, to combat pneumonic plague caused by Y. pestis CO92. YPP-401 is a four-phage preparation with a 100% lytic activity against a panel of 68 genetically diverse Y. pestis strains. Using a pneumonic plague aerosol challenge model in gender-balanced Brown Norway rats, YPP-401 demonstrated ∼88% protection when delivered 18 hours post-exposure for each of two administration routes (i.e., intraperitoneal and intranasal) in a dose-dependent manner. Our studies suggest that YPP-401 could provide an innovative, safe, and effective approach for managing Y. pestis infections, including those caused by naturally occurring or intentionally developed strains that cannot be managed by vaccines in development and antibiotics.

An established abdominal wall multidisciplinary team improves patient care and aids surgical decision making with complex ventral hernia patients.

INTRODUCTION: Abdominal wall reconstruction (AWR) is an emerging subspecialty within general surgery. The practice of multidisciplinary team (MDT) meetings to aid decision making and improve patient care has been demonstrated, with widespread acceptance. This study presents our initial experience of over 150 cases of complex hernia patients discussed in a newly established MDT setting. METHODS: From February 2020 to July 2022 (30-month period), abdominal wall MDTs were held bimonthly. Key stakeholders included upper and lower gastrointestinal surgeons, a gastrointestinal specialist radiologist, a plastic surgeon, a high-risk anaesthetist and two junior doctors integrated into the AWR clinical team. Meetings were held online, where patient history, past medical and surgical history, hernia characteristics and up-to-date computed tomography scans were discussed. RESULTS: Some 156 patients were discussed over 18 meetings within the above period. Ninety-five (61%) patients were recommended for surgery, and 61 (39%) patients were recommended for conservative management or referred elsewhere. Seventy-eight (82%) patients were directly waitlisted, whereas seventeen (18%) required preoperative optimisation: three (18%) for smoking cessation, eleven (65%) for weight-loss management and three (18%) for specialist diabetic assessment and management. In total, 92 (59%) patients (including operative and nonoperative management) have been discharged to primary care. DISCUSSION: A multidisciplinary forum for complex abdominal wall patients is a safe process that facilitates decision making, promotes education and improves patient care. As the AWR subspecialty evolves, our view is that the "complex hernia MDT" will become commonplace. We present our experience and share advice for others planning to establish an AWR centre.

Ankle Telemedicine Planning Considerations.

A virtual medical visit, also known as telemedicine or telehealth, is a valuable alternative method of providing health care to patients who do not have easy access to a hospital, or during times when limited social interaction is crucial such as our current COVID-19 pandemic. A virtual approach to evaluating musculoskeletal system ailments is particularly challenging, for diagnosis of these conditions generally rely greatly on physical examination, which may be challenging. However, a properly planned and executed telemedicine visit will yield successful results in most cases. Our aim is to produce a document with instructions and suggestions, including physical examination maneuvers, to help physicians carry out a proper virtual medical visit with patients complaining of ankle musculoskeletal problems. Virtual visits should not be thought of as a replacement for traditional face-to-face medical consultations, but rather a complementary method to provide health care when deemed appropriate. By following this guide, and tailoring it to the specific case at hand, medical providers should be able to effectively carry out a successful telemedicine consultation for musculoskeletal ailments relating to the ankle.Levels of Evidence: Level V.

Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.

Identification of the functional domain of the dense core vesicle biogenesis factor HID-1.

Large dense core vesicles (LDCVs) mediate the regulated release of neuropeptides and peptide hormones. HID-1 is a trans-Golgi network (TGN) localized peripheral membrane protein contributing to LDCV formation. There is no information about HID-1 structure or domain architecture, and thus it remains unknown how HID-1 binds to the TGN and performs its function. We report that the N-terminus of HID-1 mediates membrane binding through a myristoyl group with a polybasic amino acid patch but lacks specificity for the TGN. In addition, we show that the C-terminus serves as the functional domain. Indeed, this isolated domain, when tethered to the TGN, can rescue the neuroendocrine secretion and sorting defects observed in HID-1 KO cells. Finally, we report that a point mutation within that domain, identified in patients with endocrine and neurological deficits, leads to loss of function.

Diurnal variation of optical coherence tomography-based macular fluid in exudative age-related macular degeneration.

BACKGROUND: Significant diurnal fluctuation of optical coherence tomography (OCT)-based macular fluid occurs in patients with several macular conditions including diabetic macular edema (DME) and cystoid macular edema due to retinal venous occlusion (RVO). OCT imaging and analysis of macular fluid status plays a central role in clinical management of exudative age-related macular degeneration (eAMD), however diurnal variation of eAMD OCT findings has not yet been formally studied. Herein, we investigate whether clinically meaningful fluctuation of OCT-based macular fluid occurs in patients with eAMD. METHODS: Prospective observational study. Patients with eAMD and intra- and/or sub-retinal fluid on early AM OCT were enrolled to receive two consecutive OCT scans at least four hours later. Retinal layers were manually segmented on all OCT rasters and AM-to-PM and PM-to-PM image pairs were analyzed for total retinal and neurosensory retinal volume changes within the central 1 and 3 mm ETDRS subfields. Finally, two masked retinal specialists analyzed all OCT image pairs for qualitative differences that may impact clinical management. RESULTS: 21 patients with eAMD and fluid on OCT were recruited between January 2020 and November 2021. There was no mean difference between AM and PM central 3 mm total retinal volume (p = 0.56), central 3 mm neurosensory retinal volume (p = 0.25), central 1 mm total retinal mean thickness (p = 0.96), or central 1 mm neurosensory retinal mean thickness (p = 0.63), nor were any differences identified in PM-to-PM control comparisons. Qualitative analysis by two masked experts identified no clinically significant differences between any AM-to-PM OCT image pairs. CONCLUSIONS: No significant diurnal variation in OCT-based macular fluid or thickness was identified in patients with eAMD, either quantitatively or qualitatively.

Enablers and barriers to mental health initiatives in construction SMEs.

BACKGROUND: Mental ill-health is prevalent in the construction industry, and workers in small- to medium-sized enterprises (SMEs) are at high risk. Knowledge about the implementation of mental health initiatives in construction SMEs is limited. AIMS: To explore enablers and barriers to implementing mental health initiatives within UK SME construction firms from the perspective of the business owners, directors and managers with responsibilities for workplace mental health. METHODS: Qualitative study involving semi-structured interviews conducted with company owners/managers with responsibilities for workforce mental health. Participants were sampled from construction SMEs in the UK. RESULTS: Eleven construction professionals were interviewed (10 men, 1 woman; aged 34-55 years, M = 40.6) representing UK SME construction firms that were micro (<10 employees, n = 8), small (<50 employees, n = 1) and medium (<250 employees, n = 2) sized organizations. Reflexive thematic analysis generated four themes: (i) traditional views and macho culture, identified as barriers to implementation; (ii) mental health awareness, knowledge and education; (iii) valuing good mental health and (iv) a reactive or proactive approach to mental health, which all served as both enablers and barriers depending on perspective and context. CONCLUSIONS: This study sheds light on an under-researched but high-risk category of workers experiencing poor mental health. We provide recommendations for policy and practice with a 'call to action' for SME owners, industry and policymakers to embark on workplace mental health implementation projects in SME settings.

Medical Encounters and Treatment Outcomes in Ironman-Distance Triathlon.

PURPOSE: This study aimed to examine the injury and illness characteristics, treatments, and outcomes at elite ultraendurance triathlon events. METHODS: We quantified participant demographics, injury types, treatments, and disposition for medical encounters at 27 Ironman-distance triathlon championships from 1989 to 2019. We then calculated the likelihood of concurrent medical complaints in each encounter. RESULTS: We analyzed 10,533 medical encounters among 49,530 race participants for a cumulative incidence of 221.9/1000 participants (95% confidence interval [CI] = 217.7-226.2). Younger (<35 yr; 259.3/1000, 95% CI = 251.6-267.2) and older athletes (70+ yr; 254.0/1000, 95% CI = 217.8-294.4) presented to the medical tent at higher rates than middle-age adults (36-69 yr; 180.1/1000, 95% CI = 175.4-185.0). Female athletes also presented at higher rates when compared with males (243.9/1000, 95% CI = 234.9-253.2 vs 198.0/1000, 95% CI = 193.4-202.6). The most common complaints were dehydration (438.7/1000, 95% CI = 426.2-451.6) and nausea (400.4/1000, 95% CI = 388.4-412.6). Intravenous fluid was the most common treatment (483/1000; 95% CI = 469.8-496.4). Of the athletes who received medical care, 116.7/1000 (95% CI = 110.1-123.4) did not finish the race, and 17.1/1000 (95% CI = 14.7-19.8) required hospital transport. Athletes rarely presented with an isolated medical condition unless their injury was dermatologic or musculoskeletal in nature. CONCLUSIONS: Ultraendurance triathlon events have high rates of medical encounters among female athletes, as well as both younger and older age categories. Gastrointestinal and exertional-related symptoms are among the most common complaints. Intravenous infusions were the most common treatment after basic medical care. Most athletes entering the medical tent finished the race, and a small percentage were dispatched to the hospital. A more thorough understanding of common medical occurrences, including concurrent presentations and treatments, will allow for improved care and optimal race management.

Ultrasound simulation training to meet the 2021 Royal College of Radiologists' curriculum for radiology trainees: South East London experience.

AIM: To enhance ultrasound teaching delivery to radiology trainees using a simulation course matched to the 2021 Royal College of Radiologists (RCR) curriculum. MATERIAL AND METHODS: An ultrasound simulation training course was designed for specialty trainees (ST) 1 in radiology, which was based on the 2021 RCR curriculum and covered the top ultrasound training priorities. The course was piloted initially on two occasions in a 1-day format to the August 2021 and the March 2022 ST1 intake trainees. Based on the feedback, a comprehensive 4-day course was developed and delivered between October and December 2022 for the August 2022 ST1 intake, funded by Health Education England. The outcomes measured were subjective trainee feedback using numerical scores and free text. RESULTS: All King's College Hospital NHS Foundation Trust radiology ST1 trainees from the August 2021 to the August 2022 intake participated in ultrasound simulation training. The training matched the RCR curriculum and increased the trainees' confidence and competency in medical ultrasound. CONCLUSIONS: Ultrasound simulation training can be successfully delivered to ST1 trainees to match the 2021 RCR curriculum and enhance training in medical ultrasound for radiologists.