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  • Recoded E. coli strain shows that life can function with significantly compressed genetic code | Research

    Recoded E. coli strain shows that life can function with significantly compressed genetic code | Research

    A strain of Escherichia coli (E. coli) with a synthetic genetic code comprising just 57 codons, rather than the standard 64, is the most significantly recoded organism to date. The new strain, named Syn57, demonstrates that life can function with a significantly compressed genetic code.

    The researchers who carried out the work are based at the Medical Research Council’s Laboratory of Molecular Biology (LMB) in Cambridge, UK. They say that by freeing up codons – sequences of three nucleotide bases that correspond with specific amino acids – in the E. coli genome, Syn57 has more space to introduce unnatural amino acids. This could open up new applications, such as generating organisms that are resistant to viruses or produce new enzymes.

    The same team previously made Syn61 – a strain of E.coli with 61 codons – in 2019. But the researchers were keen to find out if living organisms could tolerate additional codon compression, taking them further away from their natural genetic sequence.

    ‘We wanted to know how deeply you could compress the genetic code, because if you can compress it, you can then free up some of the previously redundant codons to repurpose them for a new application,’ explains Wes Robertson, a synthetic biologist at the LMB and co-leader of the project. ‘The idea is we can then use cells to make things that chemists used to make in a flask, but now we can do it in a more programmable [and] bio-sustainable way.’

    To do this, the team started by developing a recoding scheme that would free up seven codons in the E. coli genome; four of the six codons which encode the amino acid serine, two of the four codons for the amino acid alanine and one stop codon. In total, this meant making more than 100,000 codon changes across the 4 million base pair genome of E. coli.

    To make the task more manageable they split the genome up into 38 fragments of around 100,000 base pairs each and synthesised them individually using homologous recombination in yeast to ensure that the recoding scheme would work.

    ‘It worked for about 75% of them. For the 25% where it didn’t work, we then went in and mapped, via a variety of new linkage mapping techniques that we developed,’ says Robertson. ‘Once we could pinpoint the problems, we added different synthetic DNA designs, which maintained compression, but were slightly different to our original design. ’

    They then stitched the fragments together, fixing potential problems as they went to enable the next step of the synthesis.

    While Syn57 didn’t grow as well as the original strain, Robertson notes that it ‘grew well enough for us to characterise it in the lab’. He adds that further modifications could provide Syn57 with a ‘genetic firewall’ that would prevent it interacting with genetic material from the wild-type E. coli. ‘So this will yield a virus-resistant strain which could be quite useful in industrial purposes,’ he says.

    Encoding new chemistry

    Martin Spinck, who also worked on the project, says the reassignment of the codons is limited only by their creativity. ‘All of these seven codons can be reassigned to any combination of seven or a subset of seven unnatural amino acids … and these can introduce quite a lot of new motives into biology that naturally would never exist and would never occur.’

    Farren Isaacs, an expert in molecular, cellular and developmental biology at Yale University in the US, describes the construction of a genome with 57 codons as a ‘significant’ accomplishment, although, he adds that the new functions that emerge will ultimately determine the impact of the work.

    ‘The key aspect of the design of this genome is to open up coding channels,’ he says. ‘There’s a number of potentially very useful properties that can emerge from organisms with a new genetic code: you can repurpose those codons to encode new chemistry, to create new kinds of synthetic proteins and polymers.’

    ‘They can confer resistance to viruses and other forms of horizontal gene transfer,’ he adds. ‘And you can also use them to engineer novel biocontainment solutions, where you can actually engineer these organisms to be dependent on synthetic amino acids preventing growth or escape in the wild.’

    ‘It’s the function that emerges that I think is most compelling for synthetic genomes with alternative codes.’

    However, Isaacs says there are still several questions yet to be answered. ‘What they haven’t done yet is knocked out tRNAs or release factors that decode those codons they have eliminated and see how the cell responds – does it completely eliminate that function from the cell or are there other translation factors that overlap and respond? … How might it impact growth and viability?’

    ‘That is going to be essential in actually realising the function of these organisms.’

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  • Authorities investigate botulism outbreaks linked to contaminated food in Italy

    Authorities investigate botulism outbreaks linked to contaminated food in Italy

    By&nbspEuronews

    Published on

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    Two separate outbreaks of botulism poisoning have been worrying Italy in recent weeks.

    In Calabria, the most serious cluster has resulted in two deaths and 12 hospitalisations, while other botulism cases have been reported in Sardinia. All of these cases can be traced back to contaminated food, including industrial and household preserves.

    Botulism is a rare but serious illness that can cause breathing problems, muscle paralysis, and death. People can get botulism by eating homemade foods that have not been properly canned, preserved, or fermented.

    Sardinia’s outbreak, for example, has been linked to contaminated industrial sauce.

    The outbreak in Calabria, which started between August 3 and 5 in Diamante in the Cosenza province, involved 18 people who ate sandwiches with sausage and turnip tops purchased from a street vendor. Two people died.

    The Paola public prosecutor’s office is investigating nine potential suspects, including the vendor, three managers from the companies that made the contaminated food, and five doctors from two health facilities in the Cosenza area.

    The alleged offences range from manslaughter to trading in harmful foodstuffs. The investigation is continuing; autopsies are planned and the food truck was seized for inspection.

    Another 14 patients who were hospitalised are in stable condition. Six are in intensive care, with one patient already extubated and breathing independently, while three children are in paediatric care and five patients are in other wards.

    The hospital has received several vials of botulinum toxin antidote, which is essential for the timely treatment of cases.

    Diamante Mayor Achille Ordine called the illnesses “circumscribed and limited”.

    Improper food canning raises risks of botulism

    Italy confirmed 452 cases of botulism between 2001 and 2020, the Italian National Institute of Health said. The average fatality rate was 3.1 per cent.

    Most of the cases (91 per cent) were foodborne, often related to the consumption of home canned foods.

    In 2023, Italy recorded 36 botulism cases, the highest number in Europe followed by France (15), Romania and Spain (14 each), and Germany (16).

    The Italian canning tradition, especially in southern regions, is one of the main causes of this high incidence. Home preservation of food, if not performed correctly, can promote the proliferation of Clostridium botulinum, the bacterium responsible for botulism.

    “There is no alarm, but prevention is essential, especially in the preparation of home preserves,” said Carlo Alessandro Locatelli, director of the Pavia Poison Control Centre.

    “Botulinum toxin is invisible and often does not alter the taste of food. The antidote is only effective in the early stages, when the toxin is still in the bloodstream”.

    Signs of botulism and how to prevent it

    Symptoms can occur from six hours up to seven days after eating contaminated food and include double vision, dilation of both pupils, drooping of the eyelids, difficulty speaking and swallowing, dry mouth, and constipation.

    In severe cases, it can impair breathing, necessitating intubation.

    Italian health authorities recommend carefully sterilising containers and tools for preserves, observing safe storage procedures, and avoiding giving honey and home-made preserves to children under one year old.

    In case of suspected intoxication, it is important to immediately contact the emergency room or the Pavia Poison Control Centre.

    Regarding the known outbreaks, health authorities are monitoring patients and have distributed doses of botulinum toxin antidote to the hospitals involved.

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  • Association of cataract history with dry eye disease signs and symptom

    Association of cataract history with dry eye disease signs and symptom

    Aaron T Zhao,1,2 Jocelyn He,2 Penny A Asbell,3 Vatinee Y Bunya,2 Gui-Shuang Ying2 On behalf of the DREAM Research Group

    1Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Ophthalmology, University of Memphis, Memphis, TN, USA

    Correspondence: Gui-Shuang Ying, Center for Preventive Ophthalmology and Biostatistics, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, 51 North 39 th Street, Philadelphia, PA, 19104, USA, Tel +1 215-662-9514, Email [email protected]

    Background: Dry eye disease (DED) and cataracts are highly prevalent ocular conditions, particularly among older adults. However, the relationship between cataracts, cataract surgery, and DED severity remains poorly understood. This study aimed to assess the associations between cataract history and DED signs and symptoms in participants with moderate-to-severe DED.
    Methods: This is a secondary analysis of data from a double-blind randomized control trial of participants (n = 535) with moderate-to-severe DED in the DREAM Study. At baseline, cataract history and patient characteristics were collected; DED signs and symptoms were assessed at baseline, 6 and 12 months. Cataract history was classified as: no history of cataracts, ongoing cataracts (clinically diagnosed cataracts without surgical intervention), or history of cataract surgery > 6 months prior to enrollment. Associations between cataract history and DED signs and symptoms were evaluated by univariate and multivariate regression analysis.
    Results: Among 1070 eyes from 535 participants, 646 eyes (60%) had no history of cataracts, 244 eyes (23%) had ongoing cataracts, and 180 eyes (17%) had a history of cataract surgery > 6 months prior. On univariate analysis of the combined data from baseline, 6 and 12 months, corneal staining scores were significantly worse in eyes with a history of cataract surgery than eyes with ongoing cataracts and eyes without history of cataracts (4.08 vs 3.63 vs 3.14; P=0.005). However, the difference became non-significant after adjustment by age alone (3.62 vs 3.38 vs 3.37, P=0.71) or by factors associated with DED severity (P=0.72). In multivariate analysis, meibomian gland dysfunction was significantly worse in eyes with no history of cataracts than in eyes with ongoing cataracts or with history of cataract surgery (3.1 vs 2.7 vs 2.6; P=0.02).
    Conclusion: Cataract surgery was not independently associated with worse DED symptoms and signs. This indicates that exacerbations of DED severity following cataract surgery are either age-related or transient in patients with moderate-to-severe DED.

    Plain Language Summary: Many older adults suffer from both dry eyes and cataracts, but doctors have not been sure if cataract surgery makes dry eye problems worse in the long term. Our research team studied 535 people with moderate-to-severe dry eye disease to find out.
    We compared dry eye symptoms and clinical signs among people with no cataracts, ongoing cataracts, and those who had undergone cataract surgery at least six months before joining our study.
    Our findings challenge the common belief that cataract surgery worsens dry eye. While patients who had cataract surgery initially appeared to have more severe dry eye signs, this difference disappeared when we accounted for their older age and other health factors.
    Interestingly, people who had undergone cataract surgery showed healthier oil-producing glands in their eyelids compared to those without cataracts. This might be because they were more likely to use anti-inflammatory eye drops that could help these glands recover.
    These results are reassuring for people with dry eyes who need cataract surgery. Any worsening of dry eye symptoms after surgery is likely temporary rather than permanent. This information helps eye doctors better counsel patients and manages their expectations regarding how cataract surgery might affect their pre-existing dry eye condition.

    Introduction

    Affecting 5–50% of the global population, dry eye disease (DED) is a multifactorial ocular surface disease characterized by the loss of tear film and accompanied by visual disturbances and discomfort.1 The incidence of DED is known to increase with age: a recent meta-analysis estimated an incidence of 3.5% in the US population of 18 years and older compared with 7.8% in the US population of 68 years and older.2 Similarly, cataracts are often considered a disease of aging: the prevalence of cataracts in the global population has been estimated to range from 3% in the 20–39-year-old population to over 50% in the over-60-year-old population.3 Despite the high prevalence of both DED and cataracts in the older population, there is limited knowledge on how cataracts and cataract surgery may affect the severity of DED signs and symptoms.

    Cataract surgery may potentially affect DED through multiple mechanisms, including surgical trauma to the ocular surface, disruption of corneal innervation, and inflammatory responses that can alter tear film stability and composition.4,5 Patients with pre-existing DED often express concerns about potential worsening of their symptoms following cataract surgery, making evidence-based counseling crucial for informed decision-making.6

    While some reports suggest increased DED incidence following cataract surgery,5,7 no studies have investigated how cataract surgery can exacerbate DED severity in patients with pre-existing DED. This study aims to provide a comprehensive assessment for the associations of cataracts and cataract history with severity of DED signs and symptoms through a secondary analysis of rich data from the Dry Eye Assessment and Management (DREAM) study.8,9

    Materials and Methods

    DREAM Study

    The DREAM study was a multicenter randomized placebo-controlled trial assessing the efficacy of omega-3 supplementation for the treatment of DED (NCT02128763). The details of the DREAM study design and its primary results have previously been reported.8,9 The DREAM study was approved by the Institutional Review Board at each participating site, including approval from the University of Pennsylvania Institutional Review Board. The study followed the tenets of the Declaration of Helsinki, and informed consent was obtained from all participants. Only major features of DREAM study relevant to the study are described below.

    Participant Selection

    Individuals ≥18 years old with moderate-to-severe symptomatic DED, defined by having an Ocular Surface Disease Index (OSDI) of 25–80, were eligible for enrollment for the DREAM study. To enroll in the study, participants must have had symptoms of DED for at least 6 months prior to the initial screening visit and have used or had the desire to use artificial tears at least twice a day for the past two weeks before the initial screening visit. Participants also had to satisfy at least 2 of the following 4 criteria for dry eye signs in the same eye at two consecutive visits (screening and baseline visits within 2 weeks apart): 1) corneal fluorescein staining ≥4 (out of a possible 15 per eye); 2) conjunctival staining present ≥1 (out of a possible score of 6 per eye); 3) tear film break-up time (TBUT) ≤7 seconds; 4) Schirmer’s test ≥1 to ≤7 mm/5 minutes. Importantly, a recent history of ocular surgery, including laser-assisted in situ keratomileusis and cataract surgery within 6 months of the screening visit were ineligible for the study. The full comprehensive inclusion and exclusion criteria can be found in the DREAM Study protocol.9

    Study Measures

    Following the screening visit, relevant medical history and participant characteristics were collected at the baseline visit. Medical history included self-reported history of smoking, rosacea, Sjögren’s syndrome, peripheral vascular disease, thyroid dysfunction, hypertension, rheumatoid arthritis, irritable bowel, osteoarthritis, hypercholesterolemia, and depression. Other components of physical and mental health, including depression were assessed. Lastly, the use of ongoing treatments for dry eye disease, including, but not limited to artificial tears, cyclosporine drops, warm lid soaks, punctal plugs, and steroid eye drops, were recorded. Participants self-reported either no history of cataracts, ongoing cataracts (clinically diagnosed cataracts without surgical intervention), or the presence of a pseudophakic or aphakic eye (representing a history of cataract surgery >6 months prior to enrollment).

    Outcome measures of dry eye symptoms and signs were assessed at baseline, 6 months, and 12 months. Dry eye symptoms were measured using the OSDI score and the Brief Ocular Discomfort Inventory (BODI) score. The OSDI score ranged from 0–100, with a score of 0 indicating the lack of any ocular symptoms and 100 indicating the most severe symptoms of dry eye.10 The BODI score uses a similar rating system, with a rating scale of 0–100; it is often used as an alternative measure to OSDI for scoring dry eye symptoms, especially for patients with severe DED.11 Dry eye signs in each eye were evaluated using 6 different dry eye sign measures including: TBUT, Schirmer’s test, corneal staining score, conjunctival staining score, meibomian gland dysfunction, and tear osmolarity. TBUT was measured as the time it took for a break to appear in the tear film following a blink. Schirmer’s test involved using paper strips placed in the lower eyelid to measure the distance of wetting on the paper in 5 minutes. Corneal staining was performed using fluorescein staining, and the staining score was determined using the National Eye Institute grading scale, grading each of 5 cornea sections with a score of 0–3 and combining the score for a maximum of 15 points.12 Similarly, conjunctival staining score was evaluated on a scale of 0–3 in both the temporal and nasal sections of the conjunctiva with a maximum total score of 6 points. MGD was assessed using a TearScience Meibomian Gland Evaluator™ on silt-lamp examination, which evaluated the consistency of secretions and plugging on a 0–3 scale with a maximum total score of 6 points. Tear osmolarity was evaluated using a TearLab™ Osmolarity System (San Diego, CA), which measured the osmolarity level of the tear film from a range of 275 to 400 mOsm/L. Higher scores indicate more severe DED signs for corneal staining, conjunctival staining, MGD, and tear osmolarity, whereas lower scores indicate more severe DED signs for TBUT and Schirmer’s test. A composite severity score of DED signs from 0–1 was generated with the aforementioned measures by using a modified method from previous studies.13–15

    Statistical Analysis

    We evaluated associations between cataract history at baseline and DED symptoms and signs by grouping participants into three groups: 1) no history of cataracts; 2) ongoing cataracts; and 3) previous history of cataract surgery. We compared the DED signs and symptoms among these three cataract history groups using univariate and multivariate regression analyses. Multivariate analyses were adjusted for factors previously found to be associated with DED severity in the DREAM study, including age, gender, race, ethnicity, smoking status, Sjögren’s syndrome, facial rosacea, rheumatoid arthritis, peripheral artery disease, and depression (defined by a mental health component scale ≤42).16–20 These comparisons were based on combined data from baseline, 6 and 12 months, with correlation from repeated measures and inter-eye correlation (for comparison of signs) accounted for by using generalized estimating equations. Since the DREAM study did not find a significant treatment effect from ω-3 supplementation on DED symptoms and signs, these analyses were conducted on the two original study groups combined (ω-3 supplementation and placebo).8 Missing data were handled using available case analysis, with participants included if they had data for the specific outcome being analyzed.

    All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). Two-sided P<0.05 was considered statistically significant without adjustment for multiple comparisons.

    Results

    Participant Characteristics and Medical History

    Among the 535 participants (1070 eyes) enrolled in the DREAM study, 646 eyes (60%) had no history of cataracts, 244 eyes (23%) had ongoing cataracts, and 180 eyes (17%) had a history of cataract surgery >6 months prior (ie, pseudophakic/aphakic). Following the baseline evaluation, 479 participants (89.5%) completed the 6-month follow-up evaluation, and 486 (90.8%) participants completed the 12-month follow-up evaluation.

    A comprehensive comparison of the baseline participant characteristics among the three cataract history groups can be found in Table 1. The three groups were similar in gender (P = 0.07). However, participants with a history of cataract surgery were significantly older (P < 0.0001), less likely to identify as Hispanic or Latino (P < 0.0001), less likely to have never smoked (P = 0.03), and more likely to have ongoing hypertension (P < 0.0001), osteoarthritis (P < 0.0001) and hypercholesterolemia (P < 0.0001) than participants with ongoing cataracts or no history of cataracts. A significantly higher percentage of participants with a history of cataract surgery and with ongoing cataracts self-identified their race as white (P < 0.0001), have ongoing facial rosacea (P = 0.05), and have ongoing diabetes (P = 0.04) compared to participants with no history of cataracts. The prevalence of other notable comorbidities such as Sjögren’s syndrome, peripheral vascular disease, thyroid dysfunction, rheumatoid arthritis, irritable bowel syndrome, and depression were similar across the three groups (all P > 0.05).

    Table 1 Comparison of Baseline Characteristics by Baseline Cataract Status (n = 535 Patients, 1070 Eyes)

    At baseline, participants with a history of cataract surgery were more likely to use artificial tears or gels (93% vs 78% vs 76%, respectively; P = 0.001), lubricating ointment (22% vs 10% vs 10%, respectively; P = 0.03), and cyclosporine drops (31% vs 27% vs 14%, respectively; P<0.001) compared to participants with ongoing cataracts or no history of cataracts (Table 2). There was no significant difference in the use of other dry eye therapeutics among the three groups.

    Table 2 Comparison of Treatments for Dry Eye Disease by Baseline Cataract Status

    Cataract History and DED Signs and Symptoms

    In the univariate analysis (Table 3), corneal staining scores were significantly worse in eyes with a history of cataract surgery compared to eyes with ongoing cataracts and eyes with no history of cataracts (mean ± SE: 4.1 ± 0.3 vs 3.6 ± 0.2 vs 3.1 ± 0.1 respectively; P=0.005). However, this difference became non-significant after adjusting by factors previously found to be associated with DED severity (adjusted mean ± SE: 3.6 ± 0.3 vs 3.3 ± 0.2 vs 3.4 ± 0.1 respectively; P = 0.72) (Table 4) and was not significant after being adjusted by age alone (adjusted mean ± SE: 3.6 ± 0.3 vs 3.4 ± 0.2 vs 3.4 ± 0.2, respectively; P = 0.70) (Supplementary Table 1). In univariate analysis, tear osmolarity was significantly worse in eyes with a history of cataract surgery than in eyes with ongoing cataracts and eyes with no history of cataracts (mean ± SE: 305.7 ± 1.4 vs 304.0 ± 1.1 vs 301.8 ± 0.7 respectively; P=0.03) but was not significant in multivariate analysis (adjusted mean ± SE: 304.7 ± 1.5 vs 303.6 ± 1.1 vs 302.5 ± 0.8, respectively; P = 0.42) (Table 4). MGD was not different among the three groups in univariate analysis (P=0.67), but in multivariate analysis (Table 4), the MGD score was significantly higher in eyes with no history of cataracts than in eyes with cataracts and eyes with a history of cataract surgery (adjusted mean ± SE: 3.1 ± 0.1 vs 2.7 ± 0.1 vs 2.6 ± 0.2, respectively; P = 0.02). There was no significant difference in TBUT, Schirmer’s test, conjunctival staining score, and composite dry eye severity (all P > 0.11) among the 3 groups in both univariable and multivariable analyses. Cataract history was not associated with any dry eye symptoms, assessed by OSDI (P=0.98), BODI (P = 0.18), and BODI pain scores (P = 0.46) (Table 3).

    Table 3 Univariate Analysis for the Comparison of DED Symptoms and Signs at Baseline, 6 month, 12 month Combined by Baseline History of Cataract

    Table 4 Multivariate Analysis for the Comparison of DED Symptoms and Signs at Baseline, 6 month, 12 month Combined by Baseline History of Cataract

    Discussion

    Our study evaluated associations between cataract history and DED severity among well-characterized participants with moderate-to-severe DED. While corneal staining and tear osmolarity were significantly worse in participants with a history of cataract surgery, these associations were not significant upon adjusting for age and other factors previously found to be associated with DED. Interestingly, our study found an atypical association between cataract history and MGD, where eyes with a history of cataract surgery tended to have less severe MGD than eyes with no history of cataracts.

    Contrary to studies suggesting increased DED incidence after cataract surgery, our findings indicate that DED exacerbations are likely transient.21,22 Our study found that a history of cataract surgery was not independently associated with worse DED signs and symptoms in participants with moderate-to-severe DED. The use of eye drops, particularly ones containing benzalkonium chloride preservatives, are commonly administered during the postoperative period following cataract surgery. Studies have shown that preservative eye drops can significantly increase DED signs compared to non-preservative eye drops in patients not previously affected by DED.23,24 It is plausible that our patients may have experienced increased DED signs and symptoms immediately after cataract surgery due to a combination of the surgical trauma and usage of postoperative preservative eye drops, which were alleviated after the discontinuation of preservative eye drops in the following months, allowing for the recovery of the ocular surface.

    Our findings suggest that exacerbations of DED signs and symptoms associated with cataract surgery are time-limited and reversible. Previous research indicates that corneal sensitivity and tear functions return to preoperative levels within 1–3 months post-surgery.25,26 This theorized timeframe of recovery is consistent with other recent studies as well: a 2024 study of patients with mild-to-moderate DED found that after six months of cataract surgery, signs of dry eye significantly improved compared to signs of dry eye immediately post-surgery in both patients who used eye drops with or without preservatives postoperatively.27 While this seems to suggest that the ocular surface of patients with DED will eventually recover from cataract surgery, it is important to note that it is yet to be elucidated whether these transient exacerbations of DED signs and symptoms post-surgery affect eyes with pre-existing DED for longer than healthy eyes. The presence of significantly worse corneal staining scores in participants with a history of cataract surgery that disappeared upon adjusting solely for age suggests that DED severity, if associated with cataract surgery, is more related to the age of the patient population than the surgery itself. The lack of significant difference in DED signs and symptoms in patients with ongoing cataracts and patients with no history of cataracts also suggests that the development of the cataract itself does not increase DED severity.

    Interestingly, in our study, MGD was significantly less severe in participants with a history of cataract surgery than patients with no history of cataracts. This is counter to what the prevailing consensus is in the literature—studies in the literature suggest that there is an exacerbation of MGD, with lower meibum expressibility and lower meibum quality, in patients following cataract surgery.28 One possible explanation of our findings is that in the months following cataract surgery, and before enrollment, participants with a history of cataract surgery had time for any damaged meibomian glands to heal. Past studies have shown that MGD aggravation due to cataract surgery normally resolves by 3 months post-surgery.29 Some studies report that meibomian gland expressibility and meibum quality return as soon as 1 month post-operatively.30 Additionally, in our study, participants with a history of cataract surgery were significantly more likely to use cyclosporine A eye drops as treatment for DED. Cyclosporine A is a calcineurin inhibitor known to suppress T-cell mediated immune responses, and these anti-inflammatory effects may alleviate MGD.31 For example, a randomized control trial of 33 patients with MGD found that patients who were randomized to topical cyclosporine A had significantly lower number of meibomian gland inclusions, improved tarsal telangiectasis, and improved lid margin vascularity—all indications of MGD severity—compared to the placebo group at 3 months.32 This seems to indicate that cyclosporine A not only treats the accompanying DED signs and symptoms but can also treat the underlying MGD as well. However, while the greater usage of cyclosporine A in participants with a history of cataract surgery can be a possible explanation of our finding, we cannot conclusively determine why participants with a history of cataract surgery had significantly better MGD compared to the other two groups. Future studies are needed to better understand the role cataract surgery plays in MGD in patients with DED.

    There were some limitations to our study. First, cataract history was self-reported, which may introduce recall bias. Second, participants who enrolled in the DREAM study could not have undergone cataract surgery within 6 months of the initial baseline visit. Therefore, we could only evaluate the long-lasting association of cataract surgery with DED severity. The short-term effects of cataract surgery on DED severity could be investigated through a future study which includes patients with a recent history of cataract surgery (ie <6 months). Third, we did not collect data on specific surgical techniques or intraoperative medications that might influence DED outcomes. Fourth, the DREAM study only enrolled patients with moderate-to-severe DED; thus, we were unable to assess how cataract surgery is associated with DED severity in patients with mild DED. Fifth, we did not adjust for multiple comparisons across many dry eye outcome measures, which may increase the risk of Type I error. However, our primary analyses focused on clinically meaningful differences rather than statistical significance alone. Additionally, our study did not evaluate the molecular and cellular effects of cataract surgery on the tear film. Future studies that investigate how cataract surgery impacts the cornea on a cellular level in patients with DED would be helpful in our understanding of how cataract surgery impacts DED. A study of 48 eyes that underwent phacoemulsification found that while TBUT improved significantly and returned to pre-operative levels 1-month following the surgery, goblet cell density was significantly decreased at 1 day, 1 month, and 3 months post-surgery.33 Thus, while the exacerbation of signs and symptoms of DED may be transiently induced in cataract surgery, the decrease in goblet cell density post-surgery could have a longer-lasting effect on the eyes of DED patients. Finally, in our study, participants with a history of cataract surgery were significantly more likely to use artificial tears, gels, cyclosporine drops, and lubricating ointment than participants without history of cataracts. These therapeutics are known to attenuate DED signs and symptoms (eg, artificial tears lower OSDI scores) and thus may have masked the effect of phacoemulsification on DED severity in our participants.34–36 Moreover, past studies have shown that the usage of topical medications such as cyclosporine A or artificial tears has improved DED symptoms (as measured by OSDI) in patients post-phacoemulsification.37 Future studies that evaluate the microscopic ocular surface changes in post-cataract surgery patients with DED can better evaluate the effect of cataract surgery on DED signs and symptoms without confounders (ie, therapeutics alleviating dry eye signs and symptoms).

    Conclusions

    In patients with moderate-to-severe DED, cataracts and a history of cataract surgery were not independently associated with more severe DED symptoms and signs. However, this study was limited to long-term effects because participants with recent cataract surgery (<6 months) were excluded. This lack of association suggests that increased DED severity following phacoemulsification is either related to patient age and/or are transient in DED patients. The use of anti-inflammatory eye drops may be able to mitigate MGD after cataract surgery in patients with moderate-to-severe DED. However, this merits further investigation. Additional studies are needed to better understand how cataract surgery affects DED severity and MGD in patients with DED.

    Acknowledgments

    This work was supported by National Eye Institute Grants U10EY022879, U10EY022881, R21EY031338, and an unrestricted grant from Research to Prevent Blindness (RPB). The funding organization had no role in the design or conduct of this research. Previously presented at the World Ophthalmology Congress 2024, Vancouver, CA.

    Collaborators

    Please see supplementary material for The members of the DREAM Study Research Group.

    Disclosure

    Dr Penny Asbell reports personal fees from Iolyx, outside the submitted work. Dr Vatinee Bunya is part of the advisory board for Kowa (paid) and Sjogren’s Foundation (unpaid), outside the submitted work. The authors report no other conflicts of interest in this work.

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    7. Naderi K, Gormley J, O’Brart D. Cataract surgery and dry eye disease: a review. Eur J Ophthalmol. 2020;30(5):840–855. doi:10.1177/1120672120929958

    8. Asbell PA, Maguire MG, Pistilli M, et al. n-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378(18):1681–1690. doi:10.1056/NEJMoa1709691

    9. Asbell PA, Maguire MG, Peskin E, Bunya VY, Kuklinski EJ. Dry eye assessment and management (DREAM©) study: study design and baseline characteristics. Contemporary Clin Trials. 2018;71:70–79. doi:10.1016/j.cct.2018.06.002

    10. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the ocular surface disease index. Archives of Ophthalmology. 2000;118(5):615–621. doi:10.1001/archopht.118.5.615

    11. Pistilli M, Ying G-S, Maguire MG, et al. Symptom questionnaires for dry eye disease: a comparative rasch analysis of the OSDI, BODI and IDEEL. Invest Ophthalmol Visual Sci. 2011;52(14):3865.

    12. Lemp MA. Report of the national eye institute/industry workshop on clinical trials in dry eyes. Clao J. 1995;21(4):221–232.

    13. Ong ES, Felix ER, Levitt RC, Feuer WJ, Sarantopoulos CD, Galor A. Epidemiology of discordance between symptoms and signs of dry eye. Br J Ophthalmol. 2018;102(5):674–679. doi:10.1136/bjophthalmol-2017-310633

    14. Sullivan BD, Whitmer D, Nichols KK, et al. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010;51(12):6125–6130. doi:10.1167/iovs.10-5390

    15. Vehof J, Sillevis Smitt-Kamminga N, Nibourg SA, Hammond CJ. Predictors of discordance between symptoms and signs in dry eye disease. Ophthalmology. 2017;124(3):280–286. doi:10.1016/j.ophtha.2016.11.008

    16. Gill SC, Butterworth P, Rodgers B, Mackinnon A. Validity of the mental health component scale of the 12-item short-form health survey (MCS-12) as measure of common mental disorders in the general population. Psychiatry Res. 2007;152(1):63–71. doi:10.1016/j.psychres.2006.11.005

    17. Yu K, Bunya V, Maguire M, Asbell P, Ying GS. Systemic conditions associated with severity of dry eye signs and symptoms in the dry eye assessment and management study. Ophthalmology. 2021;128(10):1384–1392. doi:10.1016/j.ophtha.2021.03.030

    18. Zhou Y, Murrough J, Yu Y, et al. Association between depression and severity of dry eye symptoms, signs, and inflammatory markers in the DREAM study. JAMA Ophthalmol. 2022;140(4):392–399. doi:10.1001/jamaophthalmol.2022.0140

    19. Zhao M, Yu Y, Roy NS, Ying GS, Asbell P, Bunya VY. Sex-related differences and hormonal effects in the dry eye assessment and management (DREAM) study. Br J Ophthalmol. 2023;108(1):23–29. doi:10.1136/bjo-2022-322238

    20. Zhao M, Yu Y, Ying GS, Asbell PA, Bunya VY. Age associations with dry eye clinical signs and symptoms in the dry eye assessment and management (DREAM) study. Ophthalmol Sci. 2023;3(2):100270. doi:10.1016/j.xops.2023.100270

    21. Gomes JAP, Azar DT, Baudouin C, et al. TFOS DEWS II iatrogenic report. Ocular Surf. 2017;15(3):511–538. doi:10.1016/j.jtos.2017.05.004

    22. Sidaraite A, Mikalauskiene L, Grzybowski A, Zemaitiene R. Evaluation of ocular surface after cataract surgery-A prospective study. J Clin Med. 2022;11(15):4562. doi:10.3390/jcm11154562

    23. Muzyka-Woźniak M, Stróżecki Ł, Przeździecka-Dołyk J. Assessment of the eye surface and subjective symptoms after using 0.1% dexamethasone drops with and without preservatives in patients after cataract surgery. Sci Rep. 2023;13(1):18625. doi:10.1038/s41598-023-44939-1

    24. Walsh K, Jones L. The use of preservatives in dry eye drops. Clin Ophthalmol. 2019;13:1409–1425. doi:10.2147/opth.S211611

    25. Khanal S, Tomlinson A, Esakowitz L, et al. Changes in corneal sensitivity and tear physiology after phacoemulsification. Ophthalmic Physiol Opt. 2008;28(2):127–134. doi:10.1111/j.1475-1313.2008.00539.x

    26. Shimabukuro M, Maeda N, Koh S, Abe K, Kobayashi R, Nishida K. Effects of cataract surgery on symptoms and findings of dry eye in subjects with and without preexisting dry eye. Jpn J Ophthalmol. 2020;64(4):429–436. doi:10.1007/s10384-020-00744-1

    27. Jensen P, Nilsen C, Gundersen M, et al. A preservative-free approach – effects on dry eye signs and symptoms after cataract surgery. Clin Ophthalmol. 2024;18:591–604. doi:10.2147/opth.S446804

    28. Han KE, Yoon SC, Ahn JM, et al. Evaluation of dry eye and meibomian gland dysfunction after cataract surgery. Am J Ophthalmol. 2014;157(6):1144–1150.e1. doi:10.1016/j.ajo.2014.02.036

    29. Song P, Sun Z, Ren S, et al. Preoperative management of MGD alleviates the aggravation of MGD and dry eye induced by cataract surgery: a prospective, randomized clinical trial. Biomed Res Int. 2019;2019:2737968. doi:10.1155/2019/2737968

    30. Eom Y, Na KS, Hwang HS, et al. Clinical efficacy of eyelid hygiene in blepharitis and meibomian gland dysfunction after cataract surgery: a randomized controlled pilot trial. Sci Rep. 2020;10(1):11796. doi:10.1038/s41598-020-67888-5

    31. Qiao J, Yan X. Emerging treatment options for meibomian gland dysfunction. Clin Ophthalmol. 2013;7:1797–1803. doi:10.2147/opth.S33182

    32. Perry HD, Doshi-Carnevale S, Donnenfeld ED, Solomon R, Biser SA, Bloom AH. Efficacy of commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction. Cornea. 2006;25(2):171–175. doi:10.1097/01.ico.0000176611.88579.0a

    33. Oh T, Jung Y, Chang D, Kim J, Kim H. Changes in the tear film and ocular surface after cataract surgery. Jpn J Ophthalmol. 2012;56(2):113–118. doi:10.1007/s10384-012-0117-8

    34. Ames P, Galor A. Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence. Clin Investig. 2015;5(3):267–285. doi:10.4155/cli.14.135

    35. Jeon J, Park S. Comparison of the efficacy of eyelid warming masks and artificial tears for dry eye symptoms in contact lens wearers. Contact Lens Anterior Eye. 2021;44(1):30–34. doi:10.1016/j.clae.2020.02.013

    36. Semp DA, Beeson D, Sheppard AL, Dutta D, Wolffsohn JS. Artificial Tears: a Systematic Review. Clin Optom. 2023;15:9–27. doi:10.2147/opto.S350185

    37. Cetinkaya S, Mestan E, Acir NO, Cetinkaya YF, Dadaci Z, Yener HI. The course of dry eye after phacoemulsification surgery. BMC Ophthalmol. 2015;15(1):68. doi:10.1186/s12886-015-0058-3

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  • AMC earnings Q2 2025 narrow losses

    AMC earnings Q2 2025 narrow losses

    People walk past an AMC theatre in Manhattan in New York City, U.S., February 25, 2025. 

    Jeenah Moon | Reuters

    Shares of AMC Entertainment rose 8% in early trading Monday after the movie theater chain reported stronger-than-expected second-quarter results.

    The company posted revenue of nearly $1.4 million, up about 35% year over year and topping the $1.35 billion Wall Street estimate, according to LSEG.

    AMC reported a net loss of $4.7 million, or just 1 cent per share, notably narrower than the loss of $32.8 million, or 10 cents per share, the company reported in the second quarter of 2024.

    On an adjusted, per-share basis, AMC reported breaking even. Wall Street analysts had expected AMC to report an adjusted loss per share of 8 cents, per LSEG.

    AMC also said it saw a 26% increase in moviegoers’ attendance compared to last year.

    CEO Adam Aron said the company’s results are indicative of a “recovering industry-wide box office” after previously struggling to pare losses amid dual writers’ and actors’ strikes and an overall post-pandemic decline in movie attendance.

    The company is also navigating a significant debt load.

    “We’ve now addressed all of our 2026 debt maturities pushing them out to 2029,” Aron said. “In so doing, we have put in place a solid foundation to capitalize on what we believe will be our industry’s continued growth momentum, especially evident in the fourth quarter of 2025 and continuing deep into 2026.”

    Aron also said the company saw consolidated admissions revenue per patron topping $12 for “the first time ever,” with total consolidated revenue per patron reaching an “unprecedented” $22.26.

    The company reported significant growth in its premium offerings, including its AMC Go Plan, with premium auditoriums operating at nearly three times the occupancy of regular auditoriums.

    “The combination of a resurgent box office, our unparalleled theatre footprint with premium experiences galore, our compelling marketing programs and our increasing financial strength have a flywheel impact when they all are happening simultaneously,” Aron said.

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  • ‘Empathie’ Renewed For Season 2 At Crave & Canal+

    ‘Empathie’ Renewed For Season 2 At Crave & Canal+

    EXCLUSIVE: Canada’s Crave and France’s Canal+ are going in for another round of empathy.

    The French and Canadian players have recommissioned Empathie from creator and star Florence Longpré shortly before Season 1 launches on Canal+.

    Exploring the depths of mental illness, Empathie tells the story of Suzanne (Longpré), a criminologist-turned-psychiatrist who goes to work at the Institut psychiatrique Mont-Royal. There, she befriends Mortimer, an intriguing security officer, and meets a variety of patients with compelling stories.

    Empathie is Crave and Canal+’s first joint project. Season 1 has been a hit for Crave, with the Bell Media-owned streamer saying it is the second most popular original series since the launch of the platform and the top-watched Crave original this year across all languages in Canada. Empathie won the Audience Award at France’s Séries Mania earlier this year. Season 1 launches on Canal+ on September 1.

    “Putting ourselves in someone else’s shoes, understanding them, and sharing their feelings is the greatest journey we can take from the couches in our living rooms,” said Longpré.

    Suzane Landry, Bell Media’s Vice-President, Content Development, Programming and News, added: “Building on the phenomenal success of Empathie on Crave, we are proud to present this remarkable work to a new  audience. Our partnership with Canal+ illustrates Bell Media’s focus on making great original series that resonate at home and abroad.”

    Produced by Trio Orange in collaboration with Bell, Empathie is written by Longpré and directed by Guillaume Lonergan. The series is produced with the participation of the SODEC (Société de développement des entreprises culturelles) Film and Television Tax Credit, the Canada Media Fund, the Canadian Film or Video Production Tax Credit, SODEC Québec, the TELUS Fund, the Quebecor Fund and the Independent Production Fund for COGECO. International distribution in French-speaking territories is handled by Trio Orange, while other territories are handled by Beta Group.

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  • Two-Decade Retrospective Analysis of Postoperative Endophthalmitis at

    Two-Decade Retrospective Analysis of Postoperative Endophthalmitis at

    Introduction

    Postoperative endophthalmitis is a particularly serious complication of ophthalmic surgery. Severe and irreversible visual loss can occur in a large proportion of cases, particularly if diagnosis and proper treatment are delayed. Although culture methods may fail to identify the causative pathogen, clinical signs of disease can be sufficient to recognize this condition and initiate treatment.

    The most common types of intraocular surgeries performed worldwide are cataract extraction, glaucoma filtration surgery, pars plana vitrectomy (PPV), and intravitreal injection (IVI). The reported incidence of acute-onset postoperative endophthalmitis ranges from 0.036% to 0.36% of eyes undergoing intraocular surgery.1–3 Additionally, the incidence of post-injection endophthalmitis is reportedly 0.049%–0.056%.4

    Since 2000, intraocular surgery underwent substantial changes, such as increased numbers of cataract surgeries and PPVs. Surgical advancements included small clear corneal incision cataract surgery, manual small incision cataract surgery, sutureless small-gauge PPV (instead of 20-gauge PPV), and an exponential increase in the use of intravitreal injections for ophthalmic treatment. These developments may influence the incidence of postoperative endophthalmitis.5,6

    Categorization helps to predict the causative organism and underlying etiology. According to the Endophthalmitis Vitrectomy Study, acute-onset postoperative endophthalmitis is defined as an infection arising within 6 weeks after surgery. Conversely, delayed-onset postoperative endophthalmitis is defined as an infection occurring more than 6 weeks after surgery.7

    This study was performed to evaluate the clinical features, causative organisms, treatment modalities, and visual outcomes associated with acute-onset and delayed-onset postoperative endophthalmitis during the past 20 years at a university referral center.

    Ramathibodi Hospital, a tertiary referral facility in central Thailand, receives endophthalmitis cases from local and distant areas. This single-center retrospective study focused on postoperative endophthalmitis cases from the surrounding region.

    Materials and Methods

    This study adhered to the tenets of the Declaration of Helsinki and was approved by the Mahidol University Ethics Committee for Human Research (MURA2023/888). Informed consent was waived due to the retrospective nature of the study. No identifiable patient data or images are included in this publication. A retrospective review was conducted involving the medical records of all patients who received treatment for postoperative endophthalmitis at Ramathibodi Hospital between 2001 and 2022. The study included patients with the following International Classification of Diseases and Related Health Problems-10 codes: H44.0 for purulent endophthalmitis, H44.1 for other endophthalmitis, H45.1 for endophthalmitis in diseases classified elsewhere, H59.8 for other postprocedural disorders of the eye and adnexa, such as keratoplasty-associated endophthalmitis and bleb-associated endophthalmitis, and T89.1 for unspecified procedure complications. Diagnoses of endophthalmitis were based on clinical signs and symptoms, including eye pain, vision loss, eyelid edema, conjunctival hyperemia and chemosis, anterior chamber inflammation (eg, flare, cells, hypopyon, pupillary fibrin membrane), blebitis, vitritis, and vitreous opacity on B-scan ultrasonography. In our study, follow-up was defined as the period from the initial diagnosis of endophthalmitis to at least nine months after treatment. The main outcome measurement was the evaluation at nine months post-treatment; therefore, patients who were lost to follow-up before this timepoint were excluded from the analysis.

    For all suspected cases of endophthalmitis, demographic data were recorded; these data included age, sex, underlying diseases, laterality, onset and duration, best-corrected visual acuity (VA) at initial presentation (defined as the VA measured at the patient’s first visit to our hospital at the time of endophthalmitis diagnosis) and after recovery, pathogen etiology, type of intraocular surgery and associated complications, culture results, and treatments.

    Prior to initiating treatment, vitreous and/or aqueous samples were collected for microbiological analysis in all cases. In patients undergoing intravitreal tapping, undiluted vitreous samples were aspirated using a 23-gauge needle attached to a syringe under aseptic conditions at the operating microscope. For patients treated with PPV, undiluted vitreous specimens were obtained at the start of the procedure before infusion was initiated, using the vitrectomy cutter connected to a sterile syringe or tubing. Standard 20- or 23-gauge systems were used, and all procedures were performed by experienced vitreoretinal surgeons. Collected specimens were immediately submitted for microbiological workup, which included inoculation on blood agar, chocolate agar, Sabouraud dextrose agar, and thioglycollate broth to detect aerobic and anaerobic bacteria and fungi. In some cases, molecular testing using 16S and 18S rRNA gene polymerase chain reaction (PCR) assays were performed to enhance pathogen detection. However, molecular diagnostics were not consistently available during the first five years of the study period due to laboratory limitations. Bacterial detection was performed using primers 27F and 519R, commonly applied for broad-range bacterial identification.8 For fungi, the internal transcribed spacer (ITS1–ITS2) region was amplified using ITS1 and ITS2 primers, which are widely recommended for broad fungal coverage.9 Immediate PPV was defined as surgery performed within 24 hours of endophthalmitis diagnosis, whereas delayed PPV was performed more than 24 hours after diagnosis in cases where there was no clinical improvement or worsening following primary vitreous tapping and antimicrobial injection. In cases of bacterial infection, ceftazidime and vancomycin were prescribed as empiric therapy, whereas amphotericin or voriconazole were administered in cases of fungal infection. Specific treatments for each patient were determined based on culture results.

    To facilitate statistical analysis, Snellen VA measurements were converted to logarithm of the minimum angle of resolution (logMAR) values. Poor VA measurements were assigned logMAR values of 2.0, 2.3, 2.5, 2.7, and 3.0 for counting fingers, hand motion, light projection, light perception, and no light perception, respectively. The primary outcome measure was VA assessed at nine months, which was used as the reference point for determining the final visual outcome after endophthalmitis management.10

    Statistical Analysis

    Categorical data (eg, sex, laterality, underlying diseases, prior surgeries, and treatment modalities) are shown as numbers and percentages. Continuous variables are presented as means and standard deviations; for variables with skewed distributions, medians and interquartile ranges (IQRs) are presented. Normally distributed continuous variables were analyzed using t-tests. For skewed distributions, the Mann–Whitney U-test was used. Categorical variables were analyzed using the Pearson chi-squared test or Fisher’s exact test. Multivariate logistic regression analysis was utilized to identify factors associated with poor visual prognosis. Multilevel linear random intercepts and random slope regression models were used to analyze the mean difference in VA (logMAR) from preoperative to postoperative across the three treatment groups. The models also compared the mean preoperative VA (logMAR) among the treatment groups and accounted for variations between individual participants at the preoperative stage (intercepts). Additionally, the models calculated the mean difference in the effect over time (slopes) on VA (logMAR) between preoperative and postoperative stages across the three groups. Statistical analysis was performed using STATA version 14.0 (Stata Corp LP, College Station, TX, USA). P-values <0.05 were considered statistically significant.

    Results

    This study initially included 181 patients with suspected endophthalmitis, according to their electronic medical records. After the exclusion of 18 patients (Figure 1) due to incomplete records, altered diagnoses, or loss to follow-up, 163 eyes of 163 patients were analyzed (Table 1). The participants comprised 89 men and 74 women with a mean age of 64.8±13.0 years. Endophthalmitis involved the right eye in 82 cases (50.3%). The two most prevalent underlying diseases were hypertension and diabetes mellitus, observed in 53% and 31% of cases, respectively, as presented in Table 1.

    Table 1 Demographic Data of 163 Patients with Postoperative Endophthalmitis

    Figure 1 Post-operative endophthalmitis inclusion and subgroup treatment analysis flow diagram.

    Abbreviations: EMRs, electronic medical records; ICD10, 10th revision of the International Classification of Diseases; IVI, intravitreal injection; PPV, pars plana vitrectomy.

    Notes: Bold text in the diagram indicates the total number of eyes included in the study cohort.

    All included patients had postoperative endophthalmitis; 53% of eyes (87 of 163) were acute-onset. The median intervals from surgery to presentation were 8 days (IQR, 3–14) and 730 days (IQR, 125–1753) in the acute and chronic postoperative endophthalmitis groups, respectively. Cataract surgery was the primary procedure associated with the highest incidence of postoperative endophthalmitis (94 cases, 57.7%). Eighteen eyes (11%) received vitreous tapping and intravitreal antibiotics at the referring hospital prior to presentation at our center. Of these, 14 were in the cataract surgery group, 2 in the PPV group, and 1 each in the glaucoma and IVI groups. Among these, 10 cataract cases and all PPV and glaucoma cases were culture negative.

    Microbiological investigations of vitreous fluid were performed for all patients prior to treatment. The treatment modalities utilized in this study, including intravitreal or intracameral injections, immediate PPV, delayed PPV, and enucleation, are summarized in Table 2. All PPV procedures were combined with antimicrobial intravitreal injection (IVI). Immediate PPV was the most common approach, employed in 98 eyes (60.1%), followed by vitreous tapping with IVI alone in 50 eyes (30.7%). Delayed PPV was performed in 12 eyes (7.4%) following initial IVI due to clinical deterioration. The mean time to delayed PPV after initial presentation was 3.9 days (range 2–10 days). Intracameral injection was performed in two eyes (1.2%), when the anterior and posterior chambers were considered as a single chamber, either due to prior scleral fixation of an intraocular lens procedure or the aphakic status of the patient.

    Table 2 Trends in Treatment Modalities and Antimicrobial Agents for Endophthalmitis Across Different Time Periods

    Additionally, trends in treatment modalities for endophthalmitis from 2001 to present are summarized in Table 2. A shift in management strategies was observed over the years. Immediate PPV became the predominant approach in recent years, particularly after 2016. In contrast, vitreous tapping IVI alone and delayed PPV were more frequently employed in earlier years, especially before 2010.

    Variations in drug treatment for postoperative endophthalmitis are presented in Table 2. Antimicrobial agents were administered to all patients based on suspected pathogens. The most commonly used intravitreal antibiotic regimens for bacterial infections were combinations of ceftazidime and vancomycin. Among the 163 total cases, 141 (86.5%) received systemic antibiotics, predominantly second- or third-generation fluoroquinolones, administered primarily via the oral route. Furthermore, 33 of 141 cases received intravenous antibiotics, predominantly involving a combination of ceftazidime and vancomycin.

    Table 3 presents the preoperative and postoperative VA across the three treatment groups: vitreous tapping with IVI, immediate PPV, and delayed PPV. Two eyes that received intracameral injections were included in the IVI group. The mean initial VA before treatment was 2.0 logMAR in the immediate PPV group and 1.7 logMAR in both the IVI and delayed PPV group. Significant VA improvements were observed in the immediate PPV and delayed PPV groups, with mean improvements of 0.8 logMAR (p < 0.001) and 0.9 logMAR (p = 0.001), respectively. Multilevel linear regression models with random intercepts and slopes were used to analyze the mean differences in VA changes between treatment groups. The IVI group showed significantly less VA improvement compared to the immediate PPV group (mean difference: 0.6 logMAR, p < 0.001) and the delayed PPV group (mean difference: 0.7 logMAR, p = 0.029). No statistically significant difference in VA improvement was found between the immediate and delayed PPV groups.

    Table 3 Mean VA (Log MAR) Value and Mean Difference of Participants From Initial and Final Visual Acuity of Three Different Treatment Groups

    Among acute-onset cases, 60 of 87 eyes (69%) underwent immediate PPV with IVI, whereas in delayed-onset cases, 38 of 76 eyes (50%) underwent the same treatment. One patient with a prior history of corneal transplantation required immediate enucleation due to severe infection. During the follow-up period, five additional eyes required enucleation due to inadequate response to treatment. For patients who retained their eye, the median final VA was 20/200, corresponding to 0.9 (0.3, 2.3) logMAR. VA improved by more than five letters in 61.2% of cases, remained stable in 11.5%, and declined by more than five letters in 27.4%.

    Prior Intraocular Surgeries

    We analyzed the relationships between prior intraocular surgeries and postoperative endophthalmitis (Table 4). Our results showed that cataract surgery was the most common procedure among the 94 eyes (57.7%) with postoperative endophthalmitis. Within this group, complicated surgeries involving posterior capsular rupture occurred in 12 eyes (12.8%). Other procedures included glaucoma surgeries (trabeculectomy and glaucoma drainage devices) in 23 eyes (14.1%), vitrectomy in 16 eyes (9.8%), corneal transplantation (penetrating keratoplasty and keratoprosthesis implantation) in 10 eyes (6.1%), and IVI in eight eyes (4.9%). Twelve eyes (7.4%) had undergone combined cataract surgery with other procedures, such as vitrectomy and trabeculectomy.

    Table 4 Different Prior Intraocular Surgeries with Their Associated Factors and Visual Outcomes

    The median age at presentation for patients undergoing glaucoma surgery was 61 years, the lowest among all surgical groups. Conversely, the highest median age at presentation was 70 years, observed in the corneal transplantation group. The interval between surgery and endophthalmitis diagnosis varied among procedures. Most patients with cataract surgery–, combined cataract surgery–, or intravitreal injection–related postoperative endophthalmitis presented with acute disease. Conversely, most patients who underwent prior glaucoma surgeries or corneal transplantation presented with chronic disease.

    Furthermore, we examined variations in globe salvage rates across surgical groups. The lowest rate was observed in the prior glaucoma surgery group (87%), whereas the highest rates were observed in the IVI and combined cataract surgery groups (100%). After the exclusion of cases requiring enucleation, the most favorable visual outcomes were achieved in the cataract and vitrectomy groups: median (IQR) VA of 0.5 (0.2–2.0) logMAR and 0.5 (0.5–2.3) logMAR, respectively. In subgroup analysis focusing on cataract surgery, the final median (IQR) VA after endophthalmitis treatment was less favorable in cases involving complicated cataract surgery (1.15 [IQR 0.60–2.15] logMAR) than in non-complicated cases (0.40 [IQR 0.20–2.0] logMAR). However, this difference in VA was not statistically significant (p=0.06). The least favorable visual outcome was observed in the prior corneal transplantation group, with a median (IQR) VA of 3.0 (2.0–3.0) logMAR.

    Causative Microorganisms

    Positive cultures were obtained in 52 of 163 eyes (31.9%). Bacteria were isolated in 42 eyes (80.7%), fungi were isolated in five eyes (9.6%), multiple bacterial organisms were isolated in one eye (2.0%), and mixed causative organisms in four eyes (7.7%). Notably, seven bacterial infections were identified through 16S rRNA analysis and negative culture methods, whereas two fungal infections were identified through 18S rRNA analysis and negative culture methods. The specific causative organisms, classified according to onset timing, and their visual outcomes are presented in Table 5. When considering the previous surgical procedures, the positive-culture rate was highest in the glaucoma surgery group (52.2%) and lowest in the vitrectomy group (25.0%). In acute postoperative endophthalmitis, positive cultures were obtained in 26 of 87 eyes (29.9%). The most frequently identified microorganism was coagulase-negative Staphylococcus (CoNS; 15/26, 57.7%), followed by Enterococcus faecalis (4/26, 15.9%).

    Table 5 Culture-Positive Pathogen Results According to Onset, Ocular-Related Surgeries and Visual Acuity

    Among cases of delayed-onset postoperative endophthalmitis, positive cultures were obtained in 22 of 76 eyes (29.0%). CoNS was again the most frequently identified microorganism (4/22, 18.2%). Most culture-positive delayed-onset postoperative endophthalmitis cases were associated with glaucoma surgery (11/21, 52.4%), and Streptococcus species were the predominant organisms in three cases. Pseudomonas aeruginosa infection was the most virulent organism, causing final VA of no light perception in all three affected patients. Staphylococcus aureus and CoNS were comparatively less virulent, with the best median final VA.

    Among five eyes with culture-proven fungal endophthalmitis, three were infected with Aspergillus spp., one with Penicillium, and one with Rigidoporus. Based on initial treatment modality, one eye received IVI (amphotericin and voriconazole) without vitrectomy and achieved successful infection control (Penicillium). Two eyes underwent immediate PPV (Aspergillus) and both were successfully salvaged. The remaining two eyes received only IVI as delayed PPV was not feasible due to uncontrolled infection and poor corneal clarity; both subsequently required enucleation (Aspergillus and Rigidoporus). The remaining three cases with preserved eyes, the median VA was 2.4 logMAR. All fungal infection cases exhibited delayed onset, with mean and median intervals from surgery (two keratoprostheses, one trabeculectomy, one phacoemulsification, and one scleral fixation of an intraocular lens) to diagnosis of 96.6 and 56.4 weeks, respectively.

    Subsequently, participants were categorized into two groups based on visual outcomes, as determined by the median final VA (Table 6). These groups had VA better than 20/200 and VA equal to or less than 20/200; six enucleation cases were excluded from the analysis. Univariate analysis revealed that diabetes mellitus, initial VA of 20/200 or worse, hypopyon at initial presentation, and delayed-onset postoperative endophthalmitis were factors significantly associated with poor visual outcomes. No significant differences in visual outcomes were observed based on other factors, such as sex, immunocompetence, end-stage renal disease status, culture results, and vitrectomy status. Stepwise logistic regression analysis confirmed significant associations of poor visual outcomes with diabetes mellitus (odds ratio [OR]=2.65; 95% confidence interval [CI], 1.17–5.96), VA at initial presentation of 20/200 or worse (OR=35.87; 95% CI, 7.15–179.89), and delayed-onset postoperative endophthalmitis (OR=3.9; 95% CI, 1.79–8.50).

    Table 6 Factors Associated with Final Visual Outcome After Treatment of Postoperative Endophthalmitis by Univariate and Multivariate Analysis (Enucleation Eyes Were Excluded)

    In this study, six patients underwent enucleation due to uncontrolled infection after treatment, representing a globe salvage rate of 96.3%. The infections occurred after three postoperative trabeculectomies, one phacoemulsification, one vitrectomy with scleral fixation, and one keratoprosthesis implantation.

    Discussion

    In cases of postoperative endophthalmitis, intraocular fluid smears and cultures remain the gold standard for identifying causative organisms. The culture-positive rate in our study was lower than typically reported in the literature, where postoperative endophthalmitis culture yields generally range from 40% to 70%.11–13 Several factors may explain this finding. Eighteen eyes (11%) had received intravitreal antibiotics prior to referral, potentially suppressing organism growth by the time of sample collection. Additionally, limited vitreous volume in some cases and the use of conventional culture methods without molecular diagnostics could have reduced detection sensitivity. Culture-positive rates also varied by prior surgery type, with higher rates in the glaucoma group and lower rates in the cataract and PPV groups. This may be partly due to pre-referral treatment: 14 of the 18 pretreated eyes were in the cataract group (10 culture-negative), and all pretreated PPV and glaucoma cases were also culture-negative. Differences in sample size across surgical subgroups may also have contributed to the variability in culture positivity.

    The Endophthalmitis Vitrectomy Study (1995) showed that early vitrectomy significantly improved outcomes in patients with light perception vision, with a threefold greater chance of achieving 20/40 vision.14 Since then, advances in surgical techniques have increased the success of PPV, which has become more widely adopted in managing endophthalmitis.5 The Complete and Early Vitrectomy for Endophthalmitis (CEVE) approach is now recommended as a primary treatment, especially when the fundus view is obscured or macular involvement cannot be excluded.15 We compared VA at initial presentation among three groups: IVI alone, immediate PPV with IVI, and delayed PPV with IVI. Initial VA was generally better in the IVI and delayed PPV groups, likely reflecting clinical decisions to reserve immediate PPV for eyes with more severe vitritis.

    Post-treatment outcomes showed significant visual improvement in both the immediate and delayed PPV groups, while the IVI group showed no significant change. Visual improvement was also significantly greater in the PPV groups compared to the IVI group. These findings suggest that PPV—whether performed initially or after IVI—offers superior visual outcomes, particularly in patients with poor baseline vision or severe vitritis. This aligns with previous studies reporting that immediate PPV results in better visual outcomes compared to IVI alone in cases of postoperative endophthalmitis presenting with poor vision or severe vitritis.15,16

    The limited improvement in the IVI group may be due to the absence of mechanical clearance of infectious and inflammatory material. Additionally, less severe initial presentations in this group may have led to smaller observed gains in visual acuity. The difference in outcomes between immediate and delayed PPV was not statistically significant, likely due to the small sample size in the delayed PPV group. These findings underscore the need for individualized treatment based on disease severity, with close monitoring to allow timely surgical intervention when needed.

    Intravitreal antibiotics are essential for initial management of postoperative endophthalmitis and are often combined with topical and systemic agents. Vancomycin and ceftazidime are commonly used due to their broad-spectrum coverage. Vancomycin targets gram-positive bacteria, including methicillin-resistant strains, while ceftazidime is preferred for gram-negative coverage and is safer than amikacin.17 The use of topical and systemic antibiotics alongside intravitreal therapy in postoperative endophthalmitis depends on disease severity and patient factors. The EVS recommends systemic antibiotics in cases with severe presentation, such as dense hypopyon or poor initial vision. The 2013 ESCRS guidelines also advise that if systemic antibiotics are used for severe acute-onset cases, they should align with the spectrum of intravitreal agents.18 In our study, systemic antibiotics were used in 87% of cases, primarily via oral administration. Intravenous antibiotics were given in 20%, typically for more severe presentations. While intravenous antibiotics may be perceived as beneficial in advanced cases, their efficacy remains uncertain, especially in milder disease, as existing studies have not shown a clear advantage.

    Cataract surgery was the most common procedure among the 94 eyes with endophthalmitis. Previous studies have identified posterior capsule rupture as a significant risk factor for post-cataract endophthalmitis.13,19–26 In our study, we were unable to calculate the true incidence of posterior capsule rupture; therefore, we could not analyze its relationship with endophthalmitis. Of the 94 cataract cases, 82 (87.2%) were uncomplicated and 12 (12.8%) were complicated. Final median VA was poorer in the complicated group (1.15 logMAR) compared to the uncomplicated group (0.40 logMAR), though this difference was not statistically significant.

    In our cohort, the median time from surgery to presentation in the chronic group was 730 days, which is longer than the typical duration of two to three months but remains plausible given that delayed-onset chronic endophthalmitis can present months to years after surgery. These indolent cases may remain subclinical for prolonged periods before eventually manifesting with signs of inflammation, as described in previous reports.27–29 The timing of endophthalmitis onset varied by procedure. Acute-onset cases were more common after cataract surgery, combined cataract procedures, and IVI, while delayed-onset cases occurred more frequently after glaucoma surgery or corneal transplantation. Our findings align with prior reports indicating that bleb-associated endophthalmitis occurs in 0.2% to 9.6% of glaucoma filtering surgeries, typically presenting more than one month postoperatively.30–32 Delayed-onset cases often have poor outcomes despite infection control and 22% requiring enucleation or evisceration.30,32

    Our study included 10 cases of delayed-onset post-keratoplasty endophthalmitis, with one requiring enucleation. The remaining cases had a median final VA of 3.0 logMAR, reflecting poor outcomes. Similarly, Tran et al reported unfavorable visual outcomes in patients with delayed-onset endophthalmitis following penetrating keratoplasty.33

    In this study, the spectrum of endophthalmitis isolates predominantly comprised gram-positive microorganisms, such as CoNS (Staphylococcus epidermidis), E. faecalis and Staphylococcus aureus. In culture-positive acute-onset cases, CoNS was the most common isolate (57.7%). This aligns with their known role as common skin and ocular surface flora, which may be introduced during intraocular procedures. Although consistent with prior studies,34–36 our data underscore the continued predominance of CoNS in postoperative endophthalmitis and highlight the need for meticulous perioperative aseptic precautions to minimize contamination risk.

    Delayed-onset postoperative endophthalmitis is typically caused by Propionibacterium spp., CoNS, and fungi.37–39 In the present study, CoNS remained the predominant microorganisms among cases of delayed-onset postoperative endophthalmitis (18.18% of culture-positive cases); our findings reinforce previous reports that CoNS constitute common pathogens in chronic cases of postoperative endophthalmitis. We also identified three cases each of S. aureus, E. faecalis, and fungal isolates. Notably, over half of delayed-onset culture-positive cases followed glaucoma surgery, with Streptococcus spp. being the most frequent, aligning with previous findings in bleb-associated infections.30 The prevalence of other bacterial species can vary in delayed-onset endophthalmitis, highlighting the importance of understanding the microbial profile to ensure effective treatment.

    All five cases of fungal postoperative endophthalmitis in our study presented with delayed onset. Two required enucleations, while the remaining eyes were salvaged but had poor final visual acuity. This aligns with prior reports that fungal endophthalmitis often results in poor visual outcomes.40 Aspergillus is known for its aggressive course and high risk of vision loss, whereas data on Penicillium and Rigidoporus remain limited. Current strategies involve PPV, intravitreal amphotericin (5–10 mg/0.1 mL) or voriconazole, and systemic antifungal therapy.41,42 Given the indolent nature of delayed-onset fungal infections, prolonged systemic treatment (6 weeks to 6 months) may be warranted to improve outcomes.42

    Importantly, clinical outcomes vary among bacterial species. P. aeruginosa infections were associated with the worst visual outcomes, as indicated by the absence of light perception in all three affected patients. Similarly, Lin et al43 reported dismal visual outcomes in cases of P. aeruginosa endophthalmitis, such that nearly all patients experienced final VA of counting fingers or worse; additionally, the rate of evisceration was high. In contrast, S. aureus and CoNS exhibited less virulence, resulting in better median final VA. These findings emphasize the importance of identifying specific microbial profiles to predict clinical outcomes and tailor treatment strategies.

    Retinal detachment (RD) was identified in a small proportion of eyes with postoperative endophthalmitis (4.9%), though underreporting may have contributed to this low rate. All culture-positive RD cases involved bacterial pathogens and had poor visual outcomes (median final VA: 2.3 logMAR). Zhang et al44 also reported worse prognosis and higher complication rates in eyes with RD. At our center, silicone oil is routinely used in eyes with concurrent RD for its antimicrobial and tamponade properties, which may help reduce RD recurrence. Other studies have shown that the risk of RD is reduced in eyes with adjuvant silicone oil implantation.45,46

    In this study, several factors were identified as significantly influencing visual outcomes in postoperative endophthalmitis. These factors included diabetes mellitus (OR=2.7), VA at initial presentation of 20/200 or worse (OR=35.9) and delayed-onset postoperative endophthalmitis (OR=3.9). Diabetic patients may be more susceptible to infection due to impaired neutrophil function and hyperglycemia-related immune dysfunction.47,48 An additional reported risk factor is renal disease.16 Despite the significant morbidity associated with infectious endophthalmitis, this study highlights the potential benefits for microbiological analysis and prompt, tailored antimicrobial and/or surgical interventions in improving visual outcomes, even in cases with poor initial VA.

    Conclusions

    Postoperative endophthalmitis most commonly followed cataract surgery. Coagulase-negative Staphylococcus species were the leading causative microorganisms in both acute- and delayed-onset cases. Immediate PPV with intravitreal injection was the most frequent treatment, yielding significant improvements in VA, with a median final VA of 20/200 and a globe salvage rate of 96.3%. Visual improvement was achieved in most cases, though factors such as diabetes mellitus, poor VA at initial presentation and delayed-onset endophthalmitis were significantly associated with worse outcomes. These findings underscore the importance of timely and appropriate management to optimize visual and anatomical outcomes.

    Abbreviations

    CI, confidence interval; CoNS, coagulase-negative Staphylococcus; ESCRS, European Society of Cataract and Refractive Surgeons; EVS, Endophthalmitis Vitrectomy Study; IQR, interquartile range; IVI, intravitreal injection; logMAR: logarithm of the minimum angle of resolution; OR, odd ratio; PPV, pars plana vitrectomy; RD, retinal detachment; RNA, ribonucleic acid; rRNA, ribosomal RNA; VA, visual acuity.

    Funding

    There is no funding to report.

    Disclosure

    The authors report no conflicts of interest in this work.

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    22. Wong T, Chee S. Risk factors of acute endophthalmitis after cataract extraction: a case-control study in Asian eyes. Br J Ophthalmol. 2004;88(1):29–31. doi:10.1136/bjo.88.1.29

    23. Mayer E, Cadman D, Ewings P, et al. A 10 year retrospective survey of cataract surgery and endophthalmitis in a single eye unit: injectable lenses lower the incidence of endophthalmitis. Br J Ophthalmol. 2003;87(7):867–869. doi:10.1136/bjo.87.7.867

    24. Norregaard JC, Thoning H, Bernth-Petersen P, Andersen TF, Javitt JC, Anderson GF. Risk of endophthalmitis after cataract extraction: results from the international cataract surgery outcomes study. Br J Ophthalmol. 1997;81(2):102–106. doi:10.1136/bjo.81.2.102

    25. Javitt JC, Vitale S, Canner JK, et al. National outcomes of cataract extraction: endophthalmitis following inpatient surgery. Arch Ophthalmol. 1991;109(8):1085–1089. doi:10.1001/archopht.1991.01080080045025

    26. Kamalarajah S, Ling R, Silvestri G, et al. Presumed infectious endophthalmitis following cataract surgery in the UK: a case–control study of risk factors. Eye. 2007;21(5):580–586. doi:10.1038/sj.eye.6702368

    27. Clark WL, Kaiser PK, Flynn HW Jr, Belfort A, Miller D, Meisler DM. Treatment strategies and visual acuity outcomes in chronic postoperative Propionibacterium acnes endophthalmitis. Ophthalmology. 1999;106(9):1665–1670. doi:10.1016/S0161-6420(99)90348-2

    28. Poon E, Poon A, McKelvie P, Levitz L, Zamir E. Delayed bacterial endotheliitis and endophthalmitis 11 years after cataract surgery. Case Rep Ophthalmol. 2023;14(1):376–381. doi:10.1159/000531501

    29. Lazzarini TA, Al-Khersan H, Patel NA, et al. Chronic, recurrent bacterial endophthalmitis caused by Achromobacter xylosoxidans: clinical features and management. Int Med Case Rep Jo. 2020;Volume 13:265–269. doi:10.2147/IMCRJ.S259899

    30. Kangas TA, Greenfield DS, Flynn JHW, Parrish IIRK, Palmberg P. Delayed-onset endophthalmitis associated with conjunctival filtering blebs. Ophthalmology. 1997;104(5):746–752. doi:10.1016/S0161-6420(97)30238-3

    31. Phillips WB, Wong TP, Bergren RL, Friedberg MA, Benson WE. Late onset endophthalmitis associated with filtering blebs. Slack Incorporated Thorofare. 1994;88–91.

    32. Song A, Scott IU, Flynn MHW, Budenz DL. Delayed-onset bleb-associated endophthalmitis: clinical features and visual acuity outcomes. Ophthalmology. 2002;109(5):985–991. doi:10.1016/S0161-6420(02)00965-X

    33. Tran KD, Yannuzzi NA, Si N, et al. Clinical features, antimicrobial susceptibilities, and treatment outcomes of patients with culture positive endophthalmitis after penetrating keratoplasty. Am J Ophthalmol Case Rep. 2018;9:62–67. doi:10.1016/j.ajoc.2018.01.011

    34. Gentile RC, Shukla S, Shah M, et al. Microbiological spectrum and antibiotic sensitivity in endophthalmitis: a 25-year review. Ophthalmology. 2014;121(8):1634–1642. doi:10.1016/j.ophtha.2014.02.001

    35. Benz MS, Scott IU, Flynn HW Jr, Unonius N, Miller D. Endophthalmitis isolates and antibiotic sensitivities: a 6-year review of culture-proven cases. Am J Ophthalmol. 2004;137(1):38–42. doi:10.1016/S0002-9394(03)00896-1

    36. Recchia FM, Busbee BG, Pearlman RB, Carvalho-Recchia CA, Ho AC. Changing trends in the microbiologic aspects of postcataract endophthalmitis. Archives of Ophthalmol. 2005;123(3):341–346. doi:10.1001/archopht.123.3.341

    37. Maalouf F, Abdulaal M, Hamam RN. Chronic postoperative endophthalmitis: a review of clinical characteristics, microbiology, treatment strategies, and outcomes. Int J Inf. 2012;2012:1–6. doi:10.1155/2012/313248

    38. Shirodkar AR, Pathengay A, Flynn HW Jr, et al. Delayed-versus acute-onset endophthalmitis after cataract surgery. Am J Ophthalmol. 2012;153(3):391–398.e2. doi:10.1016/j.ajo.2011.08.029

    39. Fox GM, Joondeph BC, Flynn HW, Pflugfelder SC, Roussel TJ. Delayed-onset pseudophakic endophthalmitis: reply. Am J Ophthalmol. 1991;111(5):656–657. doi:10.1016/S0002-9394(14)73723-7

    40. Narang S, Gupta A, Gupta V, et al. Fungal endophthalmitis following cataract surgery: clinical presentation, microbiological spectrum, and outcome. Am J Ophthalmol. 2001;132(5):609–617. doi:10.1016/S0002-9394(01)01180-1

    41. Weishaar PD, Flynn HW Jr, Murray TG, et al. Endogenous Aspergillus endophthalmitis: clinical features and treatment outcomes. Ophthalmology. 1998;105(1):57–65. doi:10.1016/S0161-6420(98)71225-3

    42. Chakrabarti A, Shivaprakash MR, Singh R, et al. Fungal endophthalmitis: fourteen years’ experience from a center in India. Retina. 2008;28(10):1400–1407. doi:10.1097/IAE.0b013e318185e943

    43. Lin J, Huang S, Liu M, Lin L, Gu J, Duan F. Endophthalmitis caused by pseudomonas aeruginosa: clinical characteristics, outcomes, and antibiotics sensitivities. Journal of Ophthalmol. 2022;2022:1–6. doi:10.1155/2022/1265556

    44. Zhang WF ZX, Meng LH, Chen H, Chen YX, Chen Y-X. Endophthalmitis at a tertiary referral center: characteristics and treatment outcomes over three decades. Front Cell Dev Biol. 2022;10:952375. doi:10.3389/fcell.2022.952375

    45. Nagpal M, Jain P, Nagpal K. Pars plana vitrectomy with or without silicone oil endotamponade in surgical management of endophthalmitis. Asia-Pac J Ophthalmol. 2012;1:216–221. doi:10.1097/APO.0b013e31826000cd

    46. Do T, Hon D, Aung T, Hien N, Cowan C. Bacterial endogenous endophthalmitis in Vietnam: a randomized controlled trial comparing vitrectomy with silicone oil versus vitrectomy alone. Clin Ophthalmol. 2014;8:1633–1640. doi:10.2147/OPTH.S67589

    47. Pozzilli P, Leslie RD. Infections and diabetes: mechanisms and prospects for prevention. Diabet Med. 1994;11(10):935–941. doi:10.1111/j.1464-5491.1994.tb00250.x

    48. Geerlings S, Hoepelman A. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol med microbio. 2000;26:259–265. doi:10.1111/j.1574-695X.1999.tb01397.x

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  • A Machine learning Model Integrating Preoperative Blood-Based Indices

    A Machine learning Model Integrating Preoperative Blood-Based Indices

    Introduction

    Endometrial cancer (EC) is a common gynecologic malignancy affecting women’s health, its incidence rising in many countries over recent decades. According to the 2022 cancer statistics from the National Cancer Center of China, the incidence rate of EC stands at 6.84 per 100,000, with a mortality rate of 1.05 per 100,000.1 This increase is hypothesized to be associated with the increasing prevalence of obesity and changes in female reproductive patterns.2,3 EC develops through a multistep progression originating from normal or hyperplastic endometrium. Endometrial hyperplasia (EH), is histologically characterized by an abnormal increase in the gland-to-stroma ratio accompanied by architectural irregularities in glandular morphology, including variations in both shape and size. This pathological transformation is predominantly driven by prolonged exposure to unopposed estrogen stimulation.4 Clinical evidence indicates that untreated EH carries a significant risk of malignant transformation.5 The prognosis of EC is critically dependent on the disease stage at diagnosis. Although approximately 70% of early-stage EC cases are detected due to abnormal vaginal bleeding, nearly 30% of patients present with advanced-stage disease due to the asymptomatic, resulting in significantly poorer clinical outcomes.6,7 Consequently, early detection of EC is important for improving patient prognosis and survival rates.

    Recent studies have shown that both in the treatment and screening of EC, it is recommended to minimize damage for patients and non-invasive,8 but the absence of a simple, non-invasive screening protocol for EC represents a significant clinical challenge. While hysteroscopy and diagnostic curettage remain the most frequently utilized methods for evaluating endometrial lesions, these approaches are associated with several substantial limitations: invasive, procedural complexity and substantial healthcare costs. Furthermore, repeated applications of these techniques may increase the risk of lesion metastasis and induce intrauterine adhesions –that are particularly relevant for young, nulliparous women. Although fine-needle aspiration offers a minimally invasive method, its diagnostic reliability is compromised, which typically evaluates less than 50% of the uterine cavity. Transvaginal ultrasound (TVUS) remains the first-line imaging modality for evaluating endometrial abnormalities, offering high sensitivity for detecting hyperplasia or polyps. However, its specificity for differentiating benign lesions from early-stage malignancies remains suboptimal. Magnetic resonance imaging (MRI), while superior in assessing myometrial invasion and tumor staging, is cost-prohibitive for routine screening. These limitations underscore the need for complementary non-invasive tools to refine preoperative risk stratification.9 Previous studies has identified several biomarkers associated with EC clinical features and prognosis;7,10,11 however, their diagnostic performance remains suboptimal when used in isolation. These diagnostic limitations present substantial challenges in differentiating between endometrial hyperplasia (EH) and early-stage EC. In densely populated nations such as China, there is an urgent need to develop robust, quantitative and cost-efficient predictive models for EC. Such advancements could facilitate timely intervention, and ultimately improve patient outcomes through personalized risk stratification.

    Uncontrolled inflammation plays a pivotal role in both the initiation and progression of tumors, with the inflammatory state often reflected in alterations of serum inflammatory markers.12 Beyond traditional markers such as white blood cells, lymphocytes, and platelets, emerging indices including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), as well as the more recently developed systemic immune-inflammation index (SII)13 and systemic inflammatory response index (SIRI)14 have been recognized as valuable indicators of systemic inflammatory response.15 These peripheral blood-based markers have demonstrated significant roles in systemic inflammation and cancer biology, encompassing cancer prediction, progression, and survival prognosis.16–20 While these biomarkers have been studied as prognostic indicators in EC,17 their potential utility in the diagnosis and prediction of EC remains underexplored.

    Machine Learning (ML) algorithms have increasingly been integrated into the medical field for disease prediction, offering significant advantages over traditional statistical methods. ML algorithm is capable of processing large and complex datasets, identifying implicit relationships among various relevant features, and thereby enabling more accurate disease risk prediction.21 The current landscape of EC risk assessment reveals a paucity of robust predictive models that base on real-world data. Our objective is to develop a non-invasive preoperative tool utilizing peripheral blood indices and ultrasound to predict EC risk, reduce the need for the invasive diagnostic interventions.

    Materials and Methods

    Study Participants

    The study included women treated at the Third Affiliated Hospital of SYSU between January 2014 to August 2024, who were diagnosed by histopathology.

    Inclusion Criteria:

    1. Patients diagnosed with EH or EC confirmed by diagnostic curettage or surgical pathology.

    2. Patients with complete clinical information and data.

    Exclusion Criteria:

    1. Patients with severe dysfunction of the heart, liver, kidney, or other major organs.

    2. Patients with other malignant tumors or conditions affecting serum tumor marker and inflammatory marker levels.

    3. Patients without complete blood cell count data available one week prior to surgery.

    4. Patients with a history of fertility-preserving treatment for EC who were receiving hormone therapy.

    Data Collection

    Feature selection was guided by evidence-based approach: (1) established clinical relevance (eg, age, BMI, and menopausal status as known EC risk factors); (2) systematic review of biomarkers implicated in EC (eg, HE4, CA-125); and (3) relevant frontier guidelines research and literature (eg, NLR).

    The clinical pathological data of patients were obtained through the hospital electronic medical record database:

    1. Basic information: including age, height, weight, comorbidities, etc.; Body mass index (BMI) is calculated as the patient’s weight (kg) divided by the square of the height (m).

    2. Preoperative serum examinations including WBC, neutrophil count, lymphocyte count, monocyte count, platelet count;

    3. Preoperative tumor markers including Serum carbohydrate antigen 125 (CA-125) and human epididymis protein 4(HE4).

    Neutrophil-to-lymphocyte ratio (NLR) is calculated as: neutrophil count/lymphocyte count; Monocyte-to-lymphocyte ratio (MLR) is calculated as: monocyte count/lymphocyte count; Platelet-to-lymphocyte ratio (PLR) is calculated as: platelet count/lymphocyte count; Systemic immune-inflammation index (SII) is calculated as: platelet count × neutrophil count/lymphocyte count; Systemic inflammatory response index (SIRI) is calculated as: neutrophil count × monocyte count/lymphocyte count.

    Pre-Processing and Model Development, Evaluation

    To mitigate the issue of class imbalance between two groups, we implemented a comprehensive data preprocessing strategy combining the Synthetic Minority Oversampling Technique (SMOTE) with random under sampling. Subsequently, all features were standardized using Standard Scaler to prevent potential bias from features with larger numerical ranges.

    The dataset was strategically partitioned through random stratified sampling into a training set (80%, n = 686) and a validation set (20%, n = 171). The training set was exclusively used for model development, while the validation set served as an independent cohort for performance evaluation. Six machine learning algorithms including Random Forest (RF), Extreme Gradient Boosting (XGBoost), Support Vector Mac (SVM), Gradient Boosting Machine Model (GBDT), Logistic Regression (LR) and Multilayer Perceptron (MLP) were used to construct the prediction model of EC. Among them, the RF classifier is a popular machine learning algorithm implemented in the Python package RF. The RF classification algorithm can be run without tuning the parameters and can give an approximate estimate of the importance of the features. Boosting refers to the use of a series of linear combinations of models to complete model tasks. It includes gradient boosting, there is a technique called GBDT. MLP is one of the simplest artificial neural networks, which consists of three layers—an input layer, an output layer, and a hidden layer.22 LR is a member of the general linear model family.23 Model performance was comprehensively evaluated using multiple metrics, with particular emphasis on the area under the receiver operating characteristic curve (AUC)as the primary indicator of discriminative ability. Brier score is a measure of the degree of deviation between the predicted and actual results, with lower values indicating better alignment between predicted probabilities and actual outcomes. Sensitivity and specificity were analyzed as complementary performance measures.

    To elucidate feature contributions, SHapley Additive exPlanations (SHAP) values were employed to quantify and interpret feature importance in the best predictive performance model. The algorithm provides a measure of feature importance across the model.

    Statistics

    The Shapiro–Wilk normality test was performed to assess the data normality. Continuous variables are reported as mean (SD) or medians with interquartile ranges (IQRs) for skewed distributed variables and were compared using an unpaired, Mann–Whitney U-test. Categorical variables are reported as whole numbers and proportions (n [%]) and were compared using the χ2 test. Statistical significance was defined as a p-value <0.05. The strength of associations among modeling variables was assessed using Spearman correlation analysis.

    All statistical analyses were performed using IBM SPSS Statistics 22 (SPSS Inc., Chicago, IL, USA). The predictive model construction and graphical representations were implemented using Python V3.7 (Python Software Foundation) and Prism 10.0 (GraphPad Software, San Diego, CA, USA), respectively.

    Ethics

    The study reporting adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and has obtained informed consent from all participants. This study was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University (No. II2023-008-02). Our research strictly adheres to the principles of the Declaration of Helsinki.

    Results

    A retrospective cohort of 948 patients diagnosed with endometrial lesions was identified from the electronic medical records of the Third Affiliated Hospital of Sun Yat-sen University between January 1, 2014 and August 31, 2024.According to the inclusion and exclusion criteria,857 patients were included in the final analysis (Figure 1).

    Figure 1 Flowchart of the study population.

    Characteristics of the Participants

    The study cohort included 857 patients, stratified into two groups based on histopathological diagnosis: 208 patients in EH group and 649 patients in EC group (Table 1). Demographic analysis revealed significant between-group differences in median age (EH group: 46 years [IQR 41.3–50] vs EC group: 53 years [IQR 47–59]; p<0.001). Furthermore, statistically significant differences were observed in menopausal status, hypertension, diabetes mellitus and endometrial thickness between the two groups. Among EC patients: Stage I (n=524, 80.7%), Stage II (n=44, 6.8%), Stage III (n=68, 10.5%), and Stage IV (n=13, 2.0%).

    Table 1 Baseline Characteristics and Serum Inflammatory Markers of the Participants

    Performed Spearman’s rank correlation analysis to quantify the strength of associations among these differential variables, with the results visualized in a heatmap (Figure 2). These variables may play important roles in cancer pathogenesis and progression.

    Figure 2 The overall correlation between parameters in EC patients.

    Construction and Evaluation of Prediction Model

    The predictive performance of these selected features was evaluated using six ML model: Random Forest (RF), Extreme Gradient Boosting (XGBoost), Support Vector Machine (SVM), Gradient Boosting Decision Tree (GBDT), Logistic Regression (LR), and Multilayer Perceptron (MLP). As detailed in Table 2, the GBDT model demonstrated superior discriminative performance, achieving an AUC of 0.95 (95% CI: 0.93–0.97), with specificity of 0.90, and F1-score of 0.90. Subsequent validation in an independent cohort confirmed the model’s performance. With the lowest integrated Brier score (0.06), the GBDT model demonstrated significant advantages in predicting EC compared to other models. The ROC curves for all six models are presented in Figure 3A and B, providing a comprehensive comparison of their predictive capabilities across different models.

    Table 2 Predictive Performances of the Six ML Models for EC

    Figure 3 Receiver operating characteristic curves for the 6 machine learning models. (A). Comparison of area under the curve. (B). Receiver operating characteristic curves.

    Importance of Features Interpreted by SHAP Value

    To elucidate feature contributions and interpret model predictions, we implemented SHAP analysis, a robust game-theoretic approach that quantifies the relative importance of each predictive feature (Figure 4A and B). The higher the SHAP value of a feature, the higher your log odds of risk. Red to blue represents the eigenvalue from large to small. The thickness of the line represents the sample distribution. In the optimal performing GBDT model, the top three predictive features for EC identification were HE4 (0.03), CA-125 (0.02) and SIRI (0.02).

    Figure 4 SHAP interpretation of the GBDT model. (A). Importance score ranking of the model prediction characteristics. (B). Every feature’s impact on the model’s output.

    Discussion

    This study represents an advancement in EC prediction by developing and validating a machine learning (ML) model that integrates baseline characteristics with non-invasive biomarkers. Among six ML models, the GBDT model demonstrated superior predictive performance, achieving an AUC of 0.95, Brier score of 0.06. SHAP interpretability analysis identified HE4, CA-125 and SIRI as key contributors to the model’s predictions. These findings provide a novel technical pathway for EC risk prediction.

    EC has emerged as the most prevalent gynecological malignancy globally, surpassing cervical cancer in disease burden. Late-stage diagnosis is associated with poor clinical outcomes. Among gynecologic tumors, cervical and ovarian cancers can be screened early and non-invasively. The significant reduction in cervical cancer incidence and mortality rates has been largely attributed to the implementation of population-based screening programs and the development of robust risk-prediction algorithms.,24,25 EC lacks effective early detection tools. Early identification and management of high-risk precancerous lesions remain the most cost-effective strategy for reducing cancer-related morbidity and mortality.

    The management of EH, particularly atypical hyperplasia, presents significant clinical challenges. That may progressively evolve into EC if left undetected or untreated. While current clinical guidelines recommend periodic endometrial surveillance via diagnostic curettage or hysteroscopic sampling,26,27 these invasive procedures carry inherent risks of iatrogenic endometrial damage, including irreversible basal layer injury and intrauterine adhesions—complications particularly detrimental to young patients with fertility preservation requirements. Therefore, developing cost-effective, non-invasive methods for EC prediction is crucial for improving risk stratification and guiding conservative management strategies.

    In the non-invasive screening of tumors, tumor markers have emerged as pivotal tools for the early detection of malignancies. While tumor markers like HE4 and CA125 have been evaluated for EC detection,28 our study revealed significant limitations: 72% of EC patients showed CA125 levels below the diagnostic threshold, and 67% had subthreshold HE4 levels, despite significant. These results align with multicenter studies,29,30 emphasizing the insufficiency of single-marker strategies. Using ultrasound alone for prediction also has the problem of low sensitivity.31

    The intricate relationship between inflammation and cancer, initially posited by Virchow in 1863,32 extensive research has elucidated the role of inflammatory cells and cytokines in tumorigenesis and progression. These inflammatory cells are implicated in tumor growth, progression, and metastasis.33 Among inflammatory cells, leukocytes constitute the largest group, with neutrophils contributing to tumor progression through the release of tumor necrosis factor, interleukin-1, and interleukin-6.34 Lymphocytes and Monocytes play a crucial role in tumor-specific immune responses by inducing cytotoxic cell death and inhibiting tumor cell proliferation and migration.35 Platelets influence the metastatic potential of cancer cells via multiple biological pathways.36 A single blood parameter as a marker may not adequately reflect the inflammatory state, composite markers such as NLR, PLR, MLR, SII and SIRI can sometimes provide more information. Markers derived from peripheral blood serum can provide predictive information when evaluated preoperatively, and their analysis is cost-effective and readily accessible.

    Machine learning models have gained significant traction in disease prediction due to their ability to handle complex datasets and uncover intricate patterns. The field of EC detection lacks validated machine learning-based prediction models utilizing real-world clinical data, which is essential to improve the screening and diagnostic precision for EC. Previous studies, such as those by Li, Vetter and Su et al,37–39 utilized traditional statistical logistic regression methods to construct prediction models in postmenopausal populations. Qiu et al40 employed genetic data for predictive modeling, which is less feasible for widespread clinical application. While Erdemoglu et al41 used the artificial intelligence in EC prediction, their model’s performance was suboptimal (F1 score: 0.59), potentially due to only demographic data and ultrasonic endometrial thickness were used for modeling. Our investigation addresses these critical limitations through a comprehensive approach that: (1) including pre- and post-menopausal populations; (2) employs advanced machine learning algorithms to identify complex, nonlinear interactions among multidimensional clinical features; and (3) using clinical data and blood markers thereby enhancing model generalizability. Unlike previous studies that predominantly focused on single-type indicators, our research combines demographic characteristics (age, menopausal status, hypertension, etc), imaging metrics (endometrial thickness), tumor markers (CA-125, HE4), and inflammatory markers (PLR, SIRI, etc) to construct a highly discriminative prediction model. Among the six ML models developed, the GBDT demonstrated the highest predictive performance, with an AUC of 0.95, outperforming the other five models.

    To improve the interpretability and intuitiveness of the ML approach, we applied SHAP values to the model, facilitating a better understanding of the impact of key features. SHAP values are widely recognized in ML, particularly in medical applications, for their ability to quantify the contribution of each feature to the model’s output. SHAP decision plots provide clinicians with an intuitive grasp of the results. Our analysis revealed that HE4, CA-125 and SIRI are the primary influencing factors of EC.

    During the clinical application process, the data characteristics of patients are collected and input into the model for risk prediction, when patients are identified as high-risk for EC, timely invasive procedures such as hysteroscopy and curettage can be performed to confirm the diagnosis and facilitate referral to gynecologic oncologists. Conversely, for patients deemed low-risk, non-invasive screening and predictive methods can be employed for regular monitoring.

    Strengths and Limitations

    Our study has demonstrated a satisfactory predictive capability of the model, indicating that the GBDT model could be utilized in the future to assess the risk of EC, offering a non-invasive approach particularly suitable for the long-term follow-up of younger patients. Secondly, the findings of this study can be applied in clinical settings, assisting physicians in managing patients with endometrial lesions more effectively, especially in resource-limited environments.

    However, our study has several limitations. Firstly, the research was conducted in China, with participant selection primarily based on the local population. Consequently, extrapolating these results to a global population may introduce potential biases.42 Secondly, the retrospective single-center design may inherently introduce selection bias,43 and healthy patients were not included in the development of the current model, which limits the generalization of the model to asymptomatic women. Fortunately, compared to previously published studies, our sample size is relatively large.38,39 Future research should involve multicenter, large-sample, prospective studies to further optimize the model.

    Conclusion

    This study establishes a GBDT model integrating preoperative blood-based indices and endometrial thickness achieves high accuracy in predicting endometrial cancer risk. The SHAP- analysis identified three principal determinants: HE4, CA-125, and SIRI, aligning with their established roles in oncogenesis and inflammation. This non-invasive tool holds promise for preoperative risk stratification, particularly in reducing unnecessary invasive procedures. Future prospective studies are warranted to confirm its generalizability in asymptomatic populations and diverse clinical settings.

    Data Sharing Statement

    The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

    Disclosure

    The authors report no conflicts of interest in this work.

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  • Dame Stephanie ‘Steve’ Shirley, technology pioneer, dies aged 91

    Dame Stephanie ‘Steve’ Shirley, technology pioneer, dies aged 91

    BBC Dame Stephanie Shirley poses infront of the sea in a white suit covered in drawings of children and a Star of David necklace at the unveiling of a memorial to Kindertransport on the quayside at Harwich in 2022BBC

    To many women in tech, myself included, Dame Stephanie Shirley was inspirational.

    Her pioneering and controversial decision to hire exclusively women coders and data inputters, working from home, was way ahead of its time and changed many lives.

    She had a difficult life, and it made her tough.

    She was stoic about grief and showed – publicly at least – extraordinary strength in the face of a number of traumatic experiences.

    She was from a generation whose childhoods were shaped by the atrocities of World War 2.

    She died on 9 August aged 91, her family said in an Instagram post on Monday.

    AFP via Getty Images Dame Stephanie Shirley wearing a purple hat, matching purple dress, and a pearl necklace, smiles at the camera while holding a medal outside Buckingham Palace after she was made a member of the Order of the Companions of Honour AFP via Getty Images

    Born Vera Buchthal in the German city of Dortmund in 1933, Dame Stephanie’s Jewish father was a judge.

    He had hoped that being in a position of power would protect his family, but as the Nazi government increased its persecution of German Jews, they fled to the Austrian capital Vienna.

    She was one of thousands of Jewish children fleeing the Nazis and came to Britain aged five as part of the Kindertransport – a British rescue effort in the months preceding World War 2 which brought 10,000 children to the UK – where she was brought up by loving foster parents.

    She went on to become a computer industry and women’s rights pioneer in the 1950s and 1960s.

    She founded the software company Freelance Programmers, which shook up the tech industry by almost exclusively hiring women, and in later life donated almost £70m to help those with autism and to IT projects.

    She was very smart and truly formidable, even adopting the name “Steve” to help her in a male-dominated tech world.

    Dame Stephanie Shirley In a black and white photograph a young Dame Stephanie is pictured to the left of her parents and sister wearing a pale dress while her family also pose with neutral expressions in smart clothesDame Stephanie Shirley

    Dame Stephanie (left) and her sister, pictured with their German father and Austrian mother, who put them on a Kindertransport train to escape Nazi-occupied Austria

    Dame Stephanie was determined not to be defined by her traumatic childhood.

    After starting out as a scientific civil servant, in 1962 she founded Freelance Programmers – later known as FI Group, later still Xansa – something which was almost unheard of for a woman to do in the 1960s.

    She designed the company to provide jobs for women with children.

    It changed the landscape for women working in technology by offering flexible working practices.

    Of the first 300 staff, 297 were female.

    The success of the company left Dame Stephanie with a fortune of about £150m, most of which she donated to good causes.

    Her late son Giles was autistic and she was an early member of the National Autistic Society, with her charity the Shirley Foundation funding many projects particularly related to autism.

    She founded Autism at Kingwood, a service which now supports autistic adults in Berkshire, Oxfordshire and Buckinghamshire.

    She also helped set up Prior’s Court – a school for autistic young people in Thatcham, Berkshire.

    Dame Stephanie Shirley Dame Stephanie is pictured in a black and white photograph looking down and wearing a shirt and blazer with technological equipment in the backgroundDame Stephanie Shirley

    Dame Stephanie was at the forefront of UK computing advances

    “Steve was an absolute legend, and an incredible friend and role model for me over the last 30 years,” Professor Sue Black told the BBC.

    “Before the likes of Steve Jobs and Mark Zuckerberg, Steve Shirley was innovating and solving problems with tech in the UK.”

    And Dame Wendy Hall, one of the world’s leading computer scientists said Dame Shirley was “inspirational”.

    “She was my mentor and my friend and she will be hugely missed,” she said.

    “She did so much for the computer science community to encourage women into that community, and of course, for the world of autism.”

    The last time I saw her, I introduced her at an event on stage. She was frail, but as always extremely glamorous and totally captivating.

    She said she knew she was coming to the end of her life and she reflected candidly on what she felt she had learned.

    She had a strong moral compass and believed in using her wealth for good. And she never stopped standing up to sexism.

    She spent her whole life refusing to conform to society’s many gender stereotypes and clichés.

    Much time has passed since Dame Stephanie started signing letters as Steve in order to get the attention of the male business contacts she was messaging.

    But Tech continues to be a male dominated industry and women still have to shout loud to be heard.

    Steve was one of the first, and she shouted the loudest.

    Additional reporting by Charlotte Edwards

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