Low-Risk Staphylococcus aureus Bacteremia Patients Do Not Require Routine Diagnostic Imaging: A Multicenter, Retrospective, Cohort Study.

BACKGROUND: Stratification to categorize patients with Staphylococcus aureus bacteremia (SAB) as low or high risk for metastatic infection may direct diagnostic evaluation and enable personalized management. We investigated the frequency of metastatic infections in low-risk SAB patients, their clinical relevance, and whether omission of routine imaging is associated with worse outcomes. METHODS: We performed a retrospective cohort study at 7 Dutch hospitals among adult patients with low-risk SAB, defined as hospital-acquired infection without treatment delay, absence of prosthetic material, short duration of bacteremia, and rapid defervescence. Primary outcome was the proportion of patients whose treatment plan changed due to detected metastatic infections, as evaluated by both actual therapy administered and by linking a adjudicated diagnosis to guideline-recommended treatment. Secondary outcomes were 90-day relapse-free survival and factors associated with the performance of diagnostic imaging. RESULTS: Of 377 patients included, 298 (79%) underwent diagnostic imaging. In 15 of these 298 patients (5.0%), imaging findings during patient admission had been interpreted as metastatic infections that should extend treatment. Using the final adjudicated diagnosis, 4 patients (1.3%) had clinically relevant metastatic infection. In a multilevel multivariable logistic regression analysis, 90-day relapse-free survival was similar between patients without imaging and those who underwent imaging (81.0% versus 83.6%; adjusted odds ratio, 0.749; 95% confidence interval, .373-1.504). CONCLUSIONS: Our study advocates risk stratification for the management of SAB patients. Prerequisites are follow-up blood cultures, bedside infectious diseases consultation, and a critical review of disease evolution. Using this approach, routine imaging could be omitted in low-risk patients.

Large language models and their impact in ophthalmology.

The advent of generative artificial intelligence and large language models has ushered in transformative applications within medicine. Specifically in ophthalmology, large language models offer unique opportunities to revolutionise digital eye care, address clinical workflow inefficiencies, and enhance patient experiences across diverse global eye care landscapes. Yet alongside these prospects lie tangible and ethical challenges, encompassing data privacy, security, and the intricacies of embedding large language models into clinical routines. This Viewpoint highlights the promising applications of large language models in ophthalmology, while weighing up the practical and ethical barriers towards their real-world implementation. This Viewpoint seeks to stimulate broader discourse on the potential of large language models in ophthalmology and to galvanise both clinicians and researchers into tackling the prevailing challenges and optimising the benefits of large language models while curtailing the associated risks.

Granulocyte Colony-Stimulating Factor is a Determinant of Severe Bronchopulmonary Dysplasia and Coincident Retinopathy.

Bronchopulmonary dysplasia (BPD), also called chronic lung disease of immaturity, afflicts approximately one third of all extremely premature infants, causing lifelong lung damage. There is no effective treatment other than supportive care. Retinopathy of prematurity (ROP), which impairs vision irreversibly, is common in BPD, suggesting a related pathogenesis. However, specific mechanisms of BPD and ROP are not known. Herein, a neonatal mouse hyperoxic model of coincident BPD and retinopathy was used to screen for candidate mediators, which revealed that granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3, was up-regulated significantly in mouse lung lavage fluid and plasma at postnatal day 14 in response to hyperoxia. Preterm infants with more severe BPD had increased plasma G-CSF. G-CSF-deficient neonatal pups showed significantly reduced alveolar simplification, normalized alveolar and airway resistance, and normalized weight gain compared with wild-type pups after hyperoxic lung injury. This was associated with a marked reduction in the intensity, and activation state, of neutrophilic and monocytic inflammation and its attendant oxidative stress response, and protection of lung endothelial cells. G-CSF deficiency also provided partial protection against ROP. The findings in this study implicate G-CSF as a pathogenic mediator of BPD and ROP, and suggest the therapeutic utility of targeting G-CSF biology to treat these conditions.

The MOLES system to guide the management of melanocytic choroidal tumours: can optometrists apply it?

CLINICAL RELEVANCE: Although melanocytic choroidal tumours of the choroid are a common eye pathology, no standardised protocol exists for their management in the community. BACKGROUND: Choroidal naevi are found in approximately 6% of the adult White population, whereas choroidal melanomas are rare, with an annual incidence of 5-10/million/year. Multimodal imaging has advanced the understanding of malignancy imaging biomarkers, but distinguishing between a small melanoma and naevus remains difficult and an algorithm for their management by community practitioners has not been uniformly adopted. One of the authors (BD) devised the MOLES scoring system, which indicates malignancy likelihood according to mushroom shape, orange pigment, large size, enlargement, and subretinal fluid. When applied by ocular oncologists, the system accurately distinguishes choroidal naevi from melanomas. The aim of this study was to evaluate whether community optometrists can appropriately manage patients with melanocytic choroidal tumours using this system. METHODS: Clinical images of 25 melanocytic choroidal tumours were presented in an online survey, including colour fundus photographs, fundus autofluorescence, optical coherence tomography, and B-scan ultrasound images. Using the MOLES system, 39 optometrists diagnosed tumours as naevus or probable melanoma and decided between community monitoring and ophthalmologist referral. Responses were compared to MOLES grading of the same clinical images by ocular oncologists. RESULTS: Using MOLES, optometrists correctly identified 389/406 probable melanomas (95.8% sensitivity) and 331/516 choroidal naevi (64.1% specificity); correctly referred 773/778 tumours to an ophthalmologist (99.4% sensitivity); and correctly managed 80/144 lesions (55.6% specificity) in the community. CONCLUSION: Optometrists safely applied the MOLES scoring system in this survey. Further measures are indicated to reduce choroidal naevi over-referral and evaluate MOLES system usage in clinical optometric practice, where some imaging modalities may not be readily available.

TAK1 blockade as a therapy for retinal neovascularization.

Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-ß-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-ß1 and other proinflammatory cytokines. TAK1 is also a key mediator of proinflammatory signals and plays an important role in maintaining vascular integrity upon proinflammatory cytokine stimulation such as TNFα. However, its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. Here, we investigate the regulatory role of TAK1 in human endothelial cells responding to inflammatory stimuli and in a rat model of oxygen-induced retinopathy (OIR) featured retinal neovascularization. Using TAK1 knockout human endothelial cells that subjected to inflammatory stimuli, transcriptome analysis revealed that TAK1 is required for activation of NFκB signaling and mediates its downstream gene expression related to endothelial activation and angiogenesis. Moreover, pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol attenuated angiogenic activities of endothelial cells. Transcriptome analysis also revealed enrichment of TAK1-mediated NFκB signaling pathway in the retina of OIR rats and retinal neovascular membrane from patients with proliferative diabetic retinopathy. Intravitreal injection of 5Z-7-oxozeaenol significantly reduced hypoxia-induced inflammation and microglial activation, thus attenuating aberrant retinal angiogenesis in OIR rats. Our data suggest that inhibition of TAK1 may have therapeutic potential for the treatment of retinal neovascular pathologies.

The use and future perspective of Artificial Intelligence-A survey among German surgeons.

Purpose: Clinical abundance of artificial intelligence has increased significantly in the last decade. This survey aims to provide an overview of the current state of knowledge and acceptance of AI applications among surgeons in Germany. Methods: A total of 357 surgeons from German university hospitals, academic teaching hospitals and private practices were contacted by e-mail and asked to participate in the anonymous survey. Results: A total of 147 physicians completed the survey. The majority of respondents (n = 85, 52.8%) stated that they were familiar with AI applications in medicine. Personal knowledge was self-rated as average (n = 67, 41.6%) or rudimentary (n = 60, 37.3%) by the majority of participants. On the basis of various application scenarios, it became apparent that the respondents have different demands on AI applications in the area of "diagnosis confirmation" as compared to the area of "therapy decision." For the latter category, the requirements in terms of the error level are significantly higher and more respondents view their application in medical practice rather critically. Accordingly, most of the participants hope that AI systems will primarily improve diagnosis confirmation, while they see their ethical and legal problems with regard to liability as the main obstacle to extensive clinical application. Conclusion: German surgeons are in principle positively disposed toward AI applications. However, many surgeons see a deficit in their own knowledge and in the implementation of AI applications in their own professional environment. Accordingly, medical education programs targeting both medical students and healthcare professionals should convey basic knowledge about the development and clinical implementation process of AI applications in different medical fields, including surgery.

Case Series: Presumed Choroidal Melanoma Diagnosis Expedited by Documented Growth on Serial Optical Coherence Tomography.

SIGNIFICANCE: These cases highlight the importance of monitoring choroidal nevi with benign imaging characteristics and the potential to quantify horizontal growth using optical coherence tomography (OCT), in the absence of color fundus photography. PURPOSE: This study aimed to present reports of two patients with pigmented choroidal tumors with low malignant potential based on their multimodal imaging features at the time of referral, but access to prior OCT imaging confirmed horizontal growth consistent with melanoma. CASE REPORTS: Two patients with pigmented, dome-shaped, subfoveal tumors were referred. Both tumors had basal diameters greater than 5 mm but no other risk factor for growth at the time of referral. Screening OCT scans had been taken of each patient's macula more than 5 years before referral, but color fundus photography was not available for either. Repeat OCT scanning at the time of referral showed horizontal growth of the tumors consistent with melanoma. As per the "To Find Small Ocular Melanoma-Do Imaging" risk factor assessment, the 5-year risk of growth of both tumors would be estimated at 11% at the time of referral, and in the absence of the documented horizontal growth on OCT scanning, the patients would have been monitored for growth. After discussion of the risks and benefits, both patients elected for their tumors to be managed as choroidal melanomas and underwent ruthenium plaque brachytherapy. CONCLUSIONS: Horizontal growth of choroidal tumors can be established using sequential OCT scans in the absence of color fundus photography. Access to prior imaging can expedite the diagnosis of choroidal melanoma, potentially allowing patients to be treated earlier.

An Experimental Model of Bronchopulmonary Dysplasia Features Long-Term Retinal and Pulmonary Defects but Not Sustained Lung Inflammation.

Bronchopulmonary dysplasia (BPD) is a severe lung disease that affects preterm infants receiving oxygen therapy. No standardized, clinically-relevant BPD model exists, hampering efforts to understand and treat this disease. This study aimed to evaluate and confirm a candidate model of acute and chronic BPD, based on exposure of neonatal mice to a high oxygen environment during key lung developmental stages affected in preterm infants with BPD. Neonatal C57BL/6 mouse pups were exposed to 75% oxygen from postnatal day (PN)-1 for 5, 8, or 14 days, and their lungs were examined at PN14 and PN40. While all mice showed some degree of lung damage, mice exposed to hyperoxia for 8 or 14 days exhibited the greatest septal wall thickening and airspace enlargement. Furthermore, when assessed at PN40, mice exposed for 8 or 14 days to supplemental oxygen exhibited augmented septal wall thickness and emphysema, with the severity increased with the longer exposure, which translated into a decline in respiratory function at PN80 in the 14-day model. In addition to this, mice exposed to hyperoxia for 8 days showed significant expansion of alveolar epithelial type II cells as well as the greatest fibrosis when assessed at PN40 suggesting a healing response, which was not seen in mice exposed to high oxygen for a longer period. While evidence of lung inflammation was apparent at PN14, chronic inflammation was absent from all three models. Finally, exposure to high oxygen for 14 days also induced concurrent outer retinal degeneration. This study shows that early postnatal exposure to high oxygen generates hallmark acute and chronic pathologies in mice that highlights its use as a translational model of BPD.

The immunological link between neonatal lung and eye disease.

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are two neonatal diseases of major clinical importance, arising in large part as a consequence of supplemental oxygen therapy used to promote the survival of preterm infants. The presence of coincident inflammation in the lungs and eyes of neonates receiving oxygen therapy indicates that a dysregulated immune response serves as a potential common pathogenic factor for both diseases. This review examines the current state of knowledge of immunological dysregulation in BPD and ROP, identifying similarities in the cellular subsets and inflammatory cytokines that are found in the alveoli and retina during the active phase of these diseases, indicating possible mechanistic overlap. In addition, we highlight gaps in the understanding of whether these responses emerge independently in the lung and retina as a consequence of oxygen exposure or arise because of inflammatory spill-over from the lung. As BPD and ROP are anatomically distinct, they are often considered discreet disease entities and are therefore treated separately. We propose that an improved understanding of the relationship between BPD and ROP is key to the identification of novel therapeutic targets to treat or prevent both conditions simultaneously.

Localised cervical lymphadenopathy: a rare presenting sign of syphilis.

Recognising syphilis can be challenging due to enormous variability in disease presentation. We present a case of 56-year-old female patient, without any medical history, with unilateral cervical lymphadenopathy and night sweats since 3 weeks. Initial differential diagnosis consisted of infectious disease, lymphoproliferative disease and autoimmune disease. Despite considerable diagnostic efforts, including serological tests for common infectious diseases, a CAT scan and histologic examination, no diagnosis was found. After reconsideration, serologic testing for syphilis was performed and was positive. Hereby, the final diagnosis of syphilis was made. Neurosyphilis and HIV coinfection were ruled out before treatment with benzylpenicillin was initiated. After which our patient made a full recovery. Treatment delay could have been considerably diminished if the localised lymphadenopathy was recognised as possible syphilitic disease. In future cases this could not only prevent further dissemination and potential morbidity in the individual patient as well as further emergence within the population.

Estimating malignancy risk of melanocytic choroidal tumours detected in the Australian National Eye Health Survey.

Clinical relevance: The malignant potential of choroidal melanocytic tumours detected incidentally in the community is thought to be low, but this has not been assessed using a validated screening tool. An accurate characterisation of the malignant potential of these lesions has implications for resource allocation, service provision, education, and training.Background: MOLES (Mushroom shape, Orange Pigment, Large size, Enlargement, and Subretinal fluid) categorises tumours as 'common naevus', 'low-risk naevus', 'high-risk naevus', and 'probable melanoma'. The MOLES system recommends that patients with common naevi (score = 0) undergo review by a community optometrist every two years, ideally with sequential colour photography. For the remaining patients (score ≥ 1), specialist imaging and assessment are recommended, with referral triaged as non-urgent for patients with low-risk (score = 1) or high-risk naevi (score = 2) and urgent for patients with probable melanoma (score > 2).Methods: Lesions flagged as choroidal melanocytic tumours on retinal photographs taken during the Australian National Eye Health Survey were retrospectively analysed by an ocular oncologist. Each lesion was assigned a MOLES score and categorised as common, low-risk, high-risk or probable melanoma.Results: Seventy-seven choroidal naevi were identified. Seventy-five (97%) of the choroidal naevi were categorised as common naevi, with a MOLES score of 0. Two (3%) choroidal naevi had a score of 1 and diagnosed as low-risk naevi due to their size. No naevi had a score of 2 or more.Conclusion: All choroidal naevi detected in this nationally representative population survey were innocuous. This suggests that the vast majority of choroidal melanocytic tumours that are incidentally detected in Australia can be managed in primary eye care settings without the need for specialist referral. MOLES provides a simple evidence-based method for choroidal naevi assessment in primary care.

A survey of clinicians on the use of artificial intelligence in ophthalmology, dermatology, radiology and radiation oncology.

Artificial intelligence technology has advanced rapidly in recent years and has the potential to improve healthcare outcomes. However, technology uptake will be largely driven by clinicians, and there is a paucity of data regarding the attitude that clinicians have to this new technology. In June-August 2019 we conducted an online survey of fellows and trainees of three specialty colleges (ophthalmology, radiology/radiation oncology, dermatology) in Australia and New Zealand on artificial intelligence. There were 632 complete responses (n = 305, 230, and 97, respectively), equating to a response rate of 20.4%, 5.1%, and 13.2% for the above colleges, respectively. The majority (n = 449, 71.0%) believed artificial intelligence would improve their field of medicine, and that medical workforce needs would be impacted by the technology within the next decade (n = 542, 85.8%). Improved disease screening and streamlining of monotonous tasks were identified as key benefits of artificial intelligence. The divestment of healthcare to technology companies and medical liability implications were the greatest concerns. Education was identified as a priority to prepare clinicians for the implementation of artificial intelligence in healthcare. This survey highlights parallels between the perceptions of different clinician groups in Australia and New Zealand about artificial intelligence in medicine. Artificial intelligence was recognized as valuable technology that will have wide-ranging impacts on healthcare.

Lung and Eye Disease Develop Concurrently in Supplemental Oxygen-Exposed Neonatal Mice.

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are two debilitating disorders that develop in preterm infants exposed to supplemental oxygen to prevent respiratory failure. Both can lead to lifelong disabilities, such as chronic obstructive pulmonary disease and vision loss. Due to the lack of a standard experimental model of coincident disease, the underlying associations between BPD and ROP are not well characterized. To address this gap, we used the robust mouse model of oxygen-induced retinopathy exposing C57BL/6 mice to 75% oxygen from postnatal day 7 to 12. The cardinal features of ROP were replicated by this strategy, and the lungs of the same mice were simultaneously examined for evidence of BPD-like lung injury, investigating both the short- and long-term effects of early-life supplemental oxygen exposure. At postnatal days 12 and 18, mild lung disease was evident by histopathologic analysis together with the expected vasculopathy in the inner retina. At later time points, the lung lesion had progressed to severe airspace enlargement and alveolar simplification, with concurrent thinning in the outer layer of the retina. In addition, critical angiogenic oxidative stress and inflammatory factors reported to be dysregulated in ROP were similarly impaired in the lungs. These data shed new light on the interconnectedness of these two neonatal disorders, holding potential for the discovery of novel targets to treat BPD and ROP.

Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells.

The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.

A biocompatible reverse thermoresponsive polymer for ocular drug delivery.

Age-related macular degeneration (AMD) is a leading cause of vision loss, the treatment of which may require monthly intravitreal injections. This is a burden on patients and health services, and new delivery modalities that reduce injection frequency are required. To that end, we investigated the suitability of a novel reverse thermoresponsive polymer (RTP) as an ocular drug-delivery vehicle. In this work, we detail the structure and synthesis of a novel RTP, and determine drug release curves for two drugs commonly used in the treatment of AMD, bevacizumab and aflibercept. Biocompatibility of the RTP was assessed in vitro in human and rat cell lines and in vivo following intravitreal injection in rats. Bevacizumab demonstrated a more appropriate release profile than aflibercept, with 67% released within 14 days and 78% released in total over a 183-day period. No toxic effects of RTP were seen in human or rat cells in up to 14 days of co-culture with RTP. Following intravitreal injection, intraocular pressure was unaffected by the presence of RTP and no changes in retinal function or structure were observed at 1 week or 1 month post-injection. RTP injection did not cause inflammation, gliosis or apoptosis in the retina. This work demonstrates the potential suitability of the novel RTP as a sustained-release vehicle for ocular drug delivery for anti-neovascular therapies. Optimization of polymer chemistry for optimal drug loading and release is needed.

Prevalence of glaucoma in the Australian National Eye Health Survey.

AIM: To estimate the prevalence of glaucoma in Australia. METHODS: This was a population-based study of 3098 non-Indigenous Australians (50-98 years) and 1738 Indigenous Australians (40-92 years) stratified by remoteness. Each participant underwent a standard examination that included visual field assessment, tonometry and non-mydriatic fundus photography. Two fellowship-trained glaucoma specialists independently assessed relevant case notes (past ocular history, best-corrected visual acuity, frequency doubling technology visual fields, Van Herick grade, intraocular pressure and optic disc-centred photographs) and assigned a diagnosis ranked on a scale of certainty: none, possible, probable or definite glaucoma. RESULTS: A total of 4792 (99.1%, 3062 non-Indigenous and 1730 Indigenous) participants had retinal photographs in at least one eye that were gradable for glaucoma. The weighted prevalence of glaucoma (definite) in non-Indigenous Australians and Indigenous Australians was 1.5% (95% CI 1.0 to 2.2) and 0.6% (95% CI 0.4 to 1.1), respectively. When definite and probable cases of glaucoma were combined, rates were 3.4% (95% CI 2.7 to 4.3) among non-Indigenous and 1.6% (95% CI 1.1 to 2.3) in Indigenous Australians. Only 52.4% of non-Indigenous Australians and 28.0% of Indigenous Australians with glaucoma self-reported a known history of glaucoma. CONCLUSION: We estimate that 198 923 non-Indigenous Australians aged 50 years and over and 2139 Indigenous Australians aged 40 years and over have glaucoma. Given the high rates of undiagnosed glaucoma coupled with a significant ageing of the Australian population, improvements in case detection and access to low vision rehabilitation services may be required to cope with the growing burden of glaucoma.

Early worsening of diabetic retinopathy due to intensive glycaemic control.

The prevalence of diabetes and diabetic retinopathy is increasing around the world. Glycaemic control is important in reducing the long-term risk of complications of diabetes, however intensive glycaemic control, particularly in patients with longstanding and poorly controlled diabetes, is associated with the risk of early worsening of diabetic retinopathy and vision loss. We present two clinical cases to illustrate the presentation of early worsening and to highlight a role for intravitreal anti-vascular endothelial growth factor therapies in ameliorating this phenomenon, as well as a review of the current understanding of this phenomenon. We emphasise the importance of identifying individuals at risk of early worsening of diabetic retinopathy and recommend regular ophthalmological review during the period of intensive glycaemic control to ensure optimal visual outcomes.