BCLA CLEAR Presbyopia: Definitions.

Presbyopia is often the first sign of ageing experienced by humans. Standardising terminology and adopting it across the BCLA CLEAR Presbyopia reports, improves consistency in the communication of the evidence-based understanding of this universal physiological process. Presbyopia can be functionally and psychologically debilitating, especially for those with poor access to eyecare. Presbyopia was defined as occurring when the physiologically normal age-related reduction in the eye's focusing range reaches a point that, when optimally corrected for far vision, the clarity of vision at near is insufficient to satisfy an individual's requirements. Accommodation is the change in optical power of the eye due to a change in crystalline lens shape and position, whereas pseudo-accommodation is the attainment of functional near vision in an emmetropic or far-corrected eye without changing the refractive power of the eye. Other definitions specific to vision and lenses for presbyopia were also defined. It is recommended that these definitions be consistently adopted in order to standardise future research, clinical evaluations and education.

Cribado de Enfermedad Renal Crónica en Farmacia Comunitaria. Estudio CRIERFAC: descripción de la metodología / Screening for Chronic Kidney Disease in Community Pharmacy. CRIERFAC study: description of the methodology

La enfermedad renal crónica (ERC) es la presencia de alteraciones de estructura o función renal con consecuencias para la salud. Suele considerarse cuando el filtrado glomerular estimado (FGe) baja de 60 ml/min/1,73m2. Su progresión lleva al tratamiento renal sustitutivo (diálisis o trasplante) cuando baja de 15 ml/min/1,73m2. El cribado en poblaciones de riesgo ha demostrado ser coste-efectivo. El objetivo de este trabajo es hacer un cribado de ERC en farmacia comunitaria y en esta publicación exponemos la metodología de forma detallada y justificada.Metodología: los farmacéuticos de las farmacias comunitarias participantes seleccionan pacientes que cumplan criterios de inclusión y no de exclusión. Se les mide la creatinina mediante punción en el dedo y se calcula el FGe con la fórmula CKD-EPI. Si es menor de un determinado valor, que depende de la edad, se deriva al médico de atención primaria.Resultados: 141 de un total de 200 farmacias participaron en el estudio. 2.116 pacientes fueron reclutados y hubo una pérdida de 116 pacientes, alcanzando un tamaño muestral final de 2.000 pacientes.Discusión: El protocolo ha sido implementado con éxito por los farmacéuticos comunitarios y ha tenido una excelente acogida por parte de los usuarios de la farmacia comunitaria. El ajuste por edad de los puntos de corte para FGe aporta un filtro adicional novedoso, con el objetivo de no sobrecargar los centros de atención primaria con potenciales derivaciones de falsos positivos. La confirmación del diagnóstico queda sujeta a la comunicación voluntaria por parte del paciente al farmacéutico.(AU)

Clinically used broad-spectrum antibiotics compromise inflammatory monocyte-dependent antibacterial defense in the lung.

Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial therapy is a major risk factor for HAP, the underlying mechanism remains incompletely understood. Here, we demonstrate that antibiotic therapy in hospitalized patients is associated with decreased diversity of the gut microbiome and depletion of short-chain fatty acid (SCFA) producers. Infection experiments with mice transplanted with patient fecal material reveal that these antibiotic-induced microbiota perturbations impair pulmonary defense against MDR Klebsiella pneumoniae. This is dependent on inflammatory monocytes (IMs), whose fatty acid receptor (FFAR)2/3-controlled and phagolysosome-dependent antibacterial activity is compromized in mice transplanted with antibiotic-associated patient microbiota. Collectively, we characterize how clinically relevant antibiotics affect antimicrobial defense in the context of human microbiota, and reveal a critical impairment of IM´s antimicrobial activity. Our study provides additional arguments for the rational use of antibiotics and offers mechanistic insights for the development of novel prophylactic strategies to protect high-risk patients from HAP.

Estrategias de intervención motora sobre el control postural en niños y jóvenes con trastorno del espectro autista: una revisión sistemática / Motor intervention strategies on postural control in children and youth with autism spectrum disorder: A systematic review

El trastorno del espectro autista (TEA) posee características variadas con un impacto a nivel social, comunicativo y sensoriomotor (SM). Una característica SM son los problemas sobre el control postural (CP). Variadas son las estrategias de intervención motora (EIM), pero el beneficio sobre el CP es algo que se ha analizado de forma menos amplia. El objetivo fue describir las EIM y sus resultados sobre el CP de niños y adolescentes con TEA. Se realizó una búsqueda en PubMed, Scopus, Web of Science y Cochrane. Un total de ocho artículos cumplieron con los criterios de elegibilidad. Todas las EIM mostraron resultados beneficiosos sobre el mejoramiento del CP y fueron de diferente naturaleza (práctica de bailes, actividad física personalizada, videojuegos, Tai Chi Chuan, Taekwondo y realidad virtual). Es necesario mejorar los diseños y considerar los riesgos de sesgos, pues limitan el alcance de los resultados.(AU)

Autism spectrum disorder (ASD) has varied characteristics with an impact at the social, communicative and sensorimotor (SM) level. An SM feature is postural control (PC) problems. There are various motor intervention strategies (MIS), but the benefit over LC is something that has been analyzed less extensively. The objective was to describe the MIS and its results on the PC of children and adolescents with ASD. A search of PubMed, Scopus, Web of Science and Cochrane was performed. A total of eight articles met the eligibility criteria. All MIS showed beneficial results on the improvement of PC. The MIS were of a varied nature (dance practice, personalized physical activity, video games, Tai Chi Chuan, Taekwondo and virtual reality). It is necessary to improve the designs and consider the risks of bias, since they limit the scope of the results.(AU)

La fatiga en el daño cerebral sobrevenido / Fatigue in patients with acquired brain damage

La fatiga es un síndrome multidimensional, complejo y frecuente en los pacientes con daño cerebral sobrevenido, influyendo negativamente en el proceso de neurorrehabilitación. Aparece desde etapas tempranas luego de la lesión y puede permanecer en el tiempo, recuperadas o no las secuelas del daño. La fatiga depende de circuitos neuronales superiores y se define como una percepción anómala de sobreesfuerzo. Tiene una prevalencia de 29% a 77% tras el ictus, 18% a 75% tras el traumatismo craneoencefálico (TCE) y 47% a 97% tras tumores cerebrales. La fatiga se asocia a factores como sexo femenino, edad avanzada, familia disfuncional, antecedentes patológicos específicos, estado funcional (p. ej. fatiga previa a la lesión), comorbilidades, estado anímico, discapacidad secundaria y uso de ciertos fármacos. Su estudio se realiza sobre todo a partir de escalas como la Escala de severidad de fatiga (Fatigue Severity Scale). Hoy en día existen avances en herramientas de imagen para su diagnóstico como la resonancia magnética funcional. En cuanto a su tratamiento, no existe aún terapia farmacológica definitiva, sin embargo, existen resultados positivos con terapias dentro de la neurorrehabilitación convencional, terapia lumínica y el uso del neurofeedback, estimulación eléctrica y magnética transcraneal. Esta revisión tiene como objetivo ayudar al profesional dedicado a la neurorrehabilitación a reconocer factores asociados modificables, así como terapias a su alcance para disminuir sus efectos nocivos en el paciente. (AU)

Fatigue is a complex, multidimensional syndrome that is prevalent in patients with acquired brain damage and has a negative impact on the neurorehabilitation process. It presents from early stages after the injury, and may persist over time, regardless of whether sequelae have resolved. Fatigue is conditioned by upper neuronal circuits, and is defined as an abnormal perception of overexertion. Its prevalence ranges from 29% to 77% after stroke, from 18% to 75% after traumatic brain injury, and from 47% to 97% after brain tumours. Fatigue is associated with factors including female sex, advanced age, dysfunctional families, history of specific health conditions, functional status (eg, fatigue prior to injury), comorbidities, mood, secondary disability, and the use of certain drugs. Assessment of fatigue is fundamentally based on such scales as the Fatigue Severity Scale (FSS). Advances have recently been made in imaging techniques for its diagnosis, such as in functional MRI. Regarding treatment, no specific pharmacological treatment currently exists; however, positive results have been reported for some conventional neurorehabilitation therapies, such as bright light therapy, neurofeedback, electrical stimulation, and transcranial magnetic stimulation. This review aims to assist neurorehabilitation professionals to recognise modifiable factors associated with fatigue and to describe the treatments available to reduce its negative effect on patients. (AU)

G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?

'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.

Utility of artificial intelligence-based large language models in ophthalmic care.

PURPOSE: With the introduction of ChatGPT, artificial intelligence (AI)-based large language models (LLMs) are rapidly becoming popular within the scientific community. They use natural language processing to generate human-like responses to queries. However, the application of LLMs and comparison of the abilities among different LLMs with their human counterparts in ophthalmic care remain under-reported. RECENT FINDINGS: Hitherto, studies in eye care have demonstrated the utility of ChatGPT in generating patient information, clinical diagnosis and passing ophthalmology question-based examinations, among others. LLMs' performance (median accuracy, %) is influenced by factors such as the iteration, prompts utilised and the domain. Human expert (86%) demonstrated the highest proficiency in disease diagnosis, while ChatGPT-4 outperformed others in ophthalmology examinations (75.9%), symptom triaging (98%) and providing information and answering questions (84.6%). LLMs exhibited superior performance in general ophthalmology but reduced accuracy in ophthalmic subspecialties. Although AI-based LLMs like ChatGPT are deemed more efficient than their human counterparts, these AIs are constrained by their nonspecific and outdated training, no access to current knowledge, generation of plausible-sounding 'fake' responses or hallucinations, inability to process images, lack of critical literature analysis and ethical and copyright issues. A comprehensive evaluation of recently published studies is crucial to deepen understanding of LLMs and the potential of these AI-based LLMs. SUMMARY: Ophthalmic care professionals should undertake a conservative approach when using AI, as human judgement remains essential for clinical decision-making and monitoring the accuracy of information. This review identified the ophthalmic applications and potential usages which need further exploration. With the advancement of LLMs, setting standards for benchmarking and promoting best practices is crucial. Potential clinical deployment requires the evaluation of these LLMs to move away from artificial settings, delve into clinical trials and determine their usefulness in the real world.

Fatigue in patients with acquired brain damage.

Fatigue is a complex, multidimensional syndrome that is prevalent in patients with acquired brain damage and has a negative impact on the neurorehabilitation process. It presents from early stages after the injury, and may persist over time, regardless of whether sequelae have resolved. Fatigue is conditioned by upper neuronal circuits, and is defined as an abnormal perception of overexertion. Its prevalence ranges from 29% to 77% after stroke, from 18% to 75% after traumatic brain injury, and from 47% to 97% after brain tumours. Fatigue is associated with factors including female sex, advanced age, dysfunctional families, history of specific health conditions, functional status (eg, fatigue prior to injury), comorbidities, mood, secondary disability, and the use of certain drugs. Assessment of fatigue is fundamentally based on such scales as the Fatigue Severity Scale (FSS). Advances have recently been made in imaging techniques for its diagnosis, such as in functional MRI. Regarding treatment, no specific pharmacological treatment currently exists; however, positive results have been reported for some conventional neurorehabilitation therapies, such as bright light therapy, neurofeedback, electrical stimulation, and transcranial magnetic stimulation. This review aims to assist neurorehabilitation professionals to recognise modifiable factors associated with fatigue and to describe the treatments available to reduce its negative effect on patients.

[Motor intervention strategies on postural control in children and youth with autism spectrum disorder: A systematic review]. / Estrategias de intervención motora sobre el control postural en niños y jóvenes con trastorno del espectro autista: una revisión sistemática.

Autism spectrum disorder (ASD) has varied characteristics with an impact at the social, communicative and sensorimotor (SM) level. An SM feature is postural control (PC) problems. There are various motor intervention strategies (MIS), but the benefit over LC is something that has been analyzed less extensively. The objective was to describe the MIS and its results on the PC of children and adolescents with ASD. A search of PubMed, Scopus, Web of Science and Cochrane was performed. A total of eight articles met the eligibility criteria. All MIS showed beneficial results on the improvement of PC. The MIS were of a varied nature (dance practice, personalized physical activity, video games, Tai Chi Chuan, Taekwondo and virtual reality). It is necessary to improve the designs and consider the risks of bias, since they limit the scope of the results.

Domestication through clandestine cultivation constrained genetic diversity in magic mushrooms relative to naturalized populations.

Fungi that are edible or fermentative were domesticated through selective cultivation of their desired traits. Domestication is often associated with inbreeding or selfing, which may fix traits other than those under selection, and causes an overall decrease in heterozygosity. A hallucinogenic mushroom, Psilocybe cubensis, was domesticated from its niche in livestock dung for production of psilocybin. It has caused accidental poisonings since the 1940s in Australia, which is a population hypothesized to be introduced from an unknown center of origin. We sequenced genomes of 38 isolates from Australia and compared them with 86 genomes of commercially available cultivars to determine (1) whether P. cubensis was introduced to Australia, and (2) how domestication has impacted commercial cultivars. Our analyses of genome-wide SNPs and single-copy orthologs showed that the Australian population is naturalized, having recovered its effective population size after a bottleneck when it was introduced, and it has maintained relatively high genetic diversity based on measures of nucleotide and allelic diversity. In contrast, domesticated cultivars generally have low effective population sizes and hallmarks of selfing and clonal propagation, including low genetic diversity, low heterozygosity, high linkage disequilibrium, and low allelic diversity of mating-compatibility genes. Analyses of kinship show that most cultivars are founded from related populations. Alleles in the psilocybin gene cluster are identical across most cultivars of P. cubensis with low diversity across coding sequence; however, unique allelic diversity in Australia and some cultivars may translate to differences in biosynthesis of psilocybin and its analogs.

Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases.

Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.

The Genetics of Coronary Artery Disease: A Vascular Perspective.

Genome-wide association studies (GWAS) have identified a large number of genetic loci for coronary artery disease (CAD), with many located close to genes associated with traditional CAD risk pathways, such as lipid metabolism and inflammation. It is becoming evident with recent CAD GWAS meta-analyses that vascular pathways are also highly enriched and present an opportunity for novel therapeutics. This review examines GWAS-enriched vascular gene loci, the pathways involved and their potential role in CAD pathogenesis. The functionality of variants is explored from expression quantitative trait loci, massively parallel reporter assays and CRISPR-based gene-editing tools. We discuss how this research may lead to novel therapeutic tools to treat cardiovascular disorders.

Health-related quality of life in patients accessing medicinal cannabis in Australia: The QUEST initiative results of a 3-month follow-up observational study.

AIMS: Patients with chronic health conditions not responding to conventional treatment can access medicinal cannabis (MC) prescriptions from clinicians in Australia. We aimed to assess overall health-related quality of life (HRQL), pain, fatigue, sleep, anxiety, and depression in a large real-world sample of patients accessing prescribed medicinal cannabis. We hypothesized that all patient-reported outcomes (PROs) would improve from baseline to 3-months. METHODS: The QUEST Initiative is a large prospective multicenter study of patients with any chronic health condition newly prescribed medicinal cannabis between November 2020 and December 2021. Eligible patients were identified by 120 clinicians at medical centers across six Australian states. Consenting participants completed the EuroQol Group EQ-5D-5L health status questionnaire; European Organization for Research & Treatment of Cancer Quality of Life questionnaire (QLQ-C30); Patient-Reported Outcomes Measurement Information System (PROMIS) Short Forms in Fatigue and Sleep Disturbance, and the Depression Anxiety Stress Scale (DASS-21) before starting therapy, at 2-weeks titration, then monthly for 3-months. RESULTS: Of the 2762 consenting participants, 2327 completed baseline and at least one follow-up questionnaire. Ages ranged between 18-97 years (mean 51y; SD = 15.4), 62.8% were female. The most commonly treated conditions were chronic pain (n = 1598/2327; 68.7%), insomnia (n = 534/2327; 22.9%), generalized anxiety (n = 508/2327; 21.5%), and mixed anxiety and depression (n = 259/2327; 11%). Across the whole cohort both EQ-5D-5L utility scores and QLQ-C30 summary scores showed clinically meaningful improvement in HRQL from baseline to mean follow-up with d = 0.54 (95%CI:0.47 to 0.59) and d = 0.64 (95%CI:0.58 to 0.70) respectively; and clinically meaningful improvement in fatigue (d = 0.54; 95%CI:0.48 to 0.59). There was clinically meaningful reduction of pain for those with chronic pain (d = 0.65; 95%CI:0.57 to 0.72); significant improvements for those with moderate to extremely severe anxiety (X2 = 383; df = 4; p<0.001) and depression (X2 = 395; df = 4; p<0.001); and no changes in sleep disturbance. CONCLUSIONS: We observed statistically significant, clinically meaningful improvements in overall HRQL and fatigue over the first 3-months in patients with chronic health conditions accessing prescribed medical cannabis. Anxiety, depression, and pain also improved over time, particularly for those with corresponding health conditions. The study continues to follow-up patients until 12-months to determine whether improvements in PROs are maintained long-term. TRAIL REGISTRATION: Study registration - Australian New Zealand Clinical Trials Registry: ACTRN12621000063819. https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000063819.

Synthesis of Partially Fluorinated Alkyl Triflates by Electrochemical Fluorination (Simons Process).

A scalable straightforward synthesis of monofluoro- and difluoromethyl triflate CF3 SO2 OCH2 F (MH2F ) and CF3 SO2 OCHF2 (MHF2 ) through electrochemical fluorination (ECF, Simons process) of methyl triflate MH3 in anhydrous hydrogen fluoride at nickel anodes is presented. The ECF method is also feasible for the preparation of the deuterated analogues CF3 SO2 OCD2 F (MD2F ) and CF3 SO2 OCDF2 (MD2F ). Surprisingly, no H/D exchange occurs during ECF of CF3 SO2 OCD3 (MD3 ); this provides further evidence for a NiF3 /NiF4 -mediated ECF mechanism. The ECF of selected partially fluorinated ethyl triflates is described, and electrochemical fluorination of CF3 SO2 OCH2 CF3 (EH2F3 ) leads to the until now unknown chiral CF3 SO2 OCHFCF3 (EHFF3 ). The analogous fluoromethyl and fluoroethyl nonaflates are also accessible by ECF. This study contains detailed spectroscopic, structural, and thermal data on (fluoro)methyl and fluoro(ethyl) triflates.

Assessing the utility of ChatGPT as an artificial intelligence-based large language model for information to answer questions on myopia.

PURPOSE: ChatGPT is an artificial intelligence language model, which uses natural language processing to simulate human conversation. It has seen a wide range of applications including healthcare education, research and clinical practice. This study evaluated the accuracy of ChatGPT in providing accurate and quality information to answer questions on myopia. METHODS: A series of 11 questions (nine categories of general summary, cause, symptom, onset, prevention, complication, natural history, treatment and prognosis) were generated for this cross-sectional study. Each question was entered five times into fresh ChatGPT sessions (free from influence of prior questions). The responses were evaluated by a five-member team of optometry teaching and research staff. The evaluators individually rated the accuracy and quality of responses on a Likert scale, where a higher score indicated greater quality of information (1: very poor; 2: poor; 3: acceptable; 4: good; 5: very good). Median scores for each question were estimated and compared between evaluators. Agreement between the five evaluators and the reliability statistics of the questions were estimated. RESULTS: Of the 11 questions on myopia, ChatGPT provided good quality information (median scores: 4.0) for 10 questions and acceptable responses (median scores: 3.0) for one question. Out of 275 responses in total, 66 (24%) were rated very good, 134 (49%) were rated good, whereas 60 (22%) were rated acceptable, 10 (3.6%) were rated poor and 5 (1.8%) were rated very poor. Cronbach's α of 0.807 indicated good level of agreement between test items. Evaluators' ratings demonstrated 'slight agreement' (Fleiss's κ, 0.005) with a significant difference in scoring among the evaluators (Kruskal-Wallis test, p < 0.001). CONCLUSION: Overall, ChatGPT generated good quality information to answer questions on myopia. Although ChatGPT shows great potential in rapidly providing information on myopia, the presence of inaccurate responses demonstrates that further evaluation and awareness concerning its limitations are crucial to avoid potential misinterpretation.

New insights in presbyopia: impact of correction strategies.

Presbyopia occurs when the physiologically normal age-related reduction in the eyes focusing range reaches a point, when optimally corrected for distance vision, that the clarity of vision at near is insufficient to satisfy an individual's requirements. Hence, it is more about the impact it has on an individual's visual ability to function in their environment to maintain their lifestyle than a measured loss of focusing ability. Presbyopia has a significant impact on an individual's quality of life and emotional state. While a range of amelioration strategies exist, they are often difficult to access in the developing world and prescribing is generally not optimal even in developed countries. This review identified the need for a standardised definition of presbyopia to be adopted. An appropriate battery of tests should be applied in evaluating presbyopic management options and the results of clinical trials should be published (even if unsuccessful) to accelerate the provision of better outcomes for presbyopes.

Biofilm formation on human immune cells is a multicellular predation strategy of Vibrio cholerae.

Biofilm formation is generally recognized as a bacterial defense mechanism against environmental threats, including antibiotics, bacteriophages, and leukocytes of the human immune system. Here, we show that for the human pathogen Vibrio cholerae, biofilm formation is not only a protective trait but also an aggressive trait to collectively predate different immune cells. We find that V. cholerae forms biofilms on the eukaryotic cell surface using an extracellular matrix comprising primarily mannose-sensitive hemagglutinin pili, toxin-coregulated pili, and the secreted colonization factor TcpF, which differs from the matrix composition of biofilms on other surfaces. These biofilms encase immune cells and establish a high local concentration of a secreted hemolysin to kill the immune cells before the biofilms disperse in a c-di-GMP-dependent manner. Together, these results uncover how bacteria employ biofilm formation as a multicellular strategy to invert the typical relationship between human immune cells as the hunters and bacteria as the hunted.

Effect of peripheral defocus on axial growth and modulation of refractive error in children with anisohyperopia.

PURPOSE: To establish whether axial growth and refractive error can be modulated in anisohyperopic children by imposing relative peripheral hyperopic defocus (RPHD) using multifocal soft contact lenses. METHODS: This study is a prospective, controlled paired-eye study with anisohyperopic children. Axial growth and refractive error were observed without intervention for the first 6 months of the 3-year trial with participants wearing single vision spectacles. Then, participants wore a centre-near, multifocal, soft contact lens (+2.00 D add) in their more hyperopic eye for 2 years, with a single vision contact lens worn in the fellow eye if required. The 'centre-near' portion of the contact lens in the more hyperopic eye corrected distance refractive error while the 'distance' portion imposed hyperopic defocus in the peripheral retina. Participants reverted to single vision spectacles for the final 6 months. RESULTS: Eleven participants, mean age of 10.56 years (SD 1.43; range 8.25-13.42), completed the trial. No increase in axial length (AL) was found during the first 6 months in either eye (p > 0.99). Axial growth across the 2-year intervention period was 0.11 mm (SEM 0.03; p = 0.06) in the test eye versus 0.15 mm (SEM 0.03; p = 0.003) in the control eye. AL was invariant during the final 6 months in both eyes (p > 0.99). Refractive error was stable during the first 6 months in both eyes (p = 0.71). Refractive error change across the 2-year intervention period was -0.23 D (SEM 0.14; p = 0.32) in the test eye versus -0.30 D (SEM 0.14; p = 0.61) in the control eye. Neither eye demonstrated a change in refractive error during the final 6 months (p > 0.99). CONCLUSIONS: Imposing RPHD using the centre-near, multifocal, contact lens specified here did not accelerate axial growth nor reduce refractive error in anisohyperopic children.

Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis.

Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles (Legionella pneumophila, Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, Streptococcus pneumoniae) and observed comparable NF-κB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for Klebsiella, E.coli and Salmonella OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free Clear coli OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion, Klebsiella, E.coli and Salmonella OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome. Video Abstract.