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Use of rocuronium during ophthalmic surgery is associated with less in

Shao-Chun Wu,^{1– 3,}^&ast; Jo-Chi Chin,^4,^&ast; Kuo-Chuan Hung,^3,⁵ Chih-Yi Hsu,³ Yung-Fong Tsai,^2,⁶ Amina M Illias^2,⁶

¹Department of Anaesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; ²Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; ³School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan; ⁴Department of Anaesthesiology, Kaohsiung Show Chwan Memorial Hospital, Kaohsiung, Taiwan; ⁵Department of Anaesthesiology, Chi Mei Medical Centre, Tainan, Taiwan; ⁶Department of Anaesthesiology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

Correspondence: Amina M Illias, Department of Anaesthesiology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan, Tel +886-975366367, Email [email protected]

Purpose: Serious complications may arise during the onset and management of intraoperative bradycardia. This study aimed to investigate several factors that may reduce the incidence of intraoperative bradycardia in adult patients undergoing general anaesthesia for various ophthalmic procedures.
Patients and Methods: A total of 947 adult patients who underwent general anaesthesia for different ophthalmic surgeries in 2020 were initially included. Following the exclusion of 104 cases, 843 patients were eligible for analysis. Patients received either cisatracurium with neostigmine (n = 388) or rocuronium with sugammadex (n = 455) as neuromuscular blocking and reversal agents, respectively. Quantitative neuromuscular monitoring was applied in all cases, while depth of anaesthesia was monitored using the bispectral index (BIS) in selected cases. The primary outcome was the incidence of intraoperative bradycardia, defined as a heart rate of fewer than 60 beats per minute.
Results: The group receiving rocuronium and sugammadex demonstrated a significantly lower incidence of intraoperative bradycardia (p < 0.001). This reduction was further supported by logistic regression analysis, both in univariate (OR, 0.07; 95% CI, 0.02– 0.24; p = 0.001) and multivariate models (OR, 0.08; 95% CI, 0.02– 0.94; p = 0.001). Additionally, this group exhibited a significantly higher rate of BIS monitoring during surgery, alongside a significant reduction in total opioid (p = 0.039) and sevoflurane consumption (p < 0.001).
Conclusion: The use of rocuronium is associated with a significant reduction in the incidence of intraoperative bradycardia in adult patients undergoing ophthalmic surgery under general anaesthesia.

Introduction

The typical normal adult resting heart rate (HR) is around 60–100 beats per minute (bpm) and bradycardia is mostly identified as a condition where the HR drops below 60 bpm.^1,2 Intraoperative bradycardia could be induced by many factors including: the stimulation of certain nerves or reflexes and the use of certain medications during anaesthesia.³ Bradycardia during ophthalmic surgery, specifically strabismus surgery, is commonly caused by the oculocardiac reflex. Oculocardiac reflex is triggered by trigeminal nerve stimulation around the orbit or tension on an extraocular muscle tendon.^4,5 Moreover, anaesthesia protocol and intraoperative medications have been reported to have significant influence on oculocardiac reflex.⁶ During general anaesthesia for strabismus surgery, oculocardiac reflex was increased with certain opioids such as remifentanil and hydromorphone, dexmedetomidine, dexamethasone, and hypercapnia. Additionally, when compared between six different muscle relaxants, oculocardiac reflex was increased with rocuronium.⁶

The best way to treat oculocardiac reflex-induced bradycardia is by immediate cessation of the stimulus that triggers the reflex.⁴ This involves releasing the traction on the eyeball or removing the instrument that is causing compression on the eyeball. Once the stimulus is removed, bradycardia or cardiac arrest associated with the reflex should resolve. Anticholinergic drugs such as atropine and glycopyrrolate were equally able to prevent oculocardiac reflex with subsequent increase in HR.⁷ Prompt treatment of significant bradycardia is essential because untreated significant bradycardia leads to the development of cardiac arrest, hypotension and organ dysfunction.^2,8 Nevertheless, potentially life-threatening conditions were reported as a consequence of attempts to treat oculocardiac reflex-induced bradycardia.^9,10

To avoid complications related to oculocardiac reflex and its treatment, it is essential to investigate the association between anaesthesia-related factors and drugs with the risk of developing intraoperative bradycardia. In this study, we compared between 2 groups of patients who received either cisatracurium or rocuronium as the neuromuscular blocking agent during general anaesthesia for different types of ophthalmic surgery. We assessed the increased incidence of intraoperative bradycardia with several anaesthesia factors, including the type of neuromuscular blocking agent, the intraoperative use of bispectral index (BIS) monitoring, along with the amount of intraoperative fluid, opioids, and sevoflurane consumption.

Materials and Methods

Patient Selection

This study was approved by the Kaohsiung Chang Gung institutional review board (IRB No. 202301421B0) and the research registry identifying number can be found at https://www.researchregistry.com/browse-the-registry, Research Registry #9684. The requirement for a written or verbal informed consent was waived due to the retrospective nature of the study. Data were anonymized and maintained with confidentiality to ensure the privacy of all participants. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies have been applied in this retrospective observational study.¹¹

A total of 947 patients received general anaesthesia for different types of ophthalmic surgery throughout 2020. None of the patients had pacemaker implantation or arrhythmia on preoperative evaluation. Patients’ available medical records at our centre from January 2020 to December 2024 were further reviewed and patients other than covid-19 positive or asystole were excluded if HR less than 60 bpm was detected on 12-lead echocardiography (ECG). We did not review what medications the patients were receiving preoperatively. We excluded 104 patients: fifteen with missing data (recorded HR of less than 60 bpm before operation but with no available preoperative 12-lead ECG) and 89 patients were under 18 years of age. Finally, 843 patients were enrolled in the analysis.

Anaesthesia and Intraoperative Monitoring

Patients were divided into two study groups. One group received rocuronium for neuromuscular blockade and was later administered sugammadex to reverse the neuromuscular blocking effect caused by rocuronium (n = 455); and the second group received cisatracurium for neuromuscular blockade and later neostigmine as a reversal agent (n = 388) (Figure 1). In all patients, intravenous fentanyl 2 mcg kg⁻¹ and propofol 2 mg kg⁻¹ were used for induction of general anaesthesia and sevoflurane was used for maintenance. Patients with intraoperative BIS monitoring, BIS value was maintained between 40 and 60 to ensure adequate depth of anaesthesia. Patients did not receive any prophylactic anticholinergics during the induction or maintenance of anaesthesia.

Figure 1 Flow diagram of participants.

Abbreviations: HR, Heart rate; bpm, beat per minute; ECG, echocardiography.

Quantitative neuromuscular monitoring was utilized in all cases (E-NMT Module, GE Healthcare, USA). To facilitate endotracheal intubation, cisatracurium 0.2 mg kg⁻¹ or rocuronium 0.6–1.2 mg kg⁻¹ were used during the induction of anaesthesia. The trachea was intubated after loss of all four twitches and train-of-four (TOF) count dropped to 0. Maintenance of paralysis during anaesthesia was achieved by redosing with an intravenous bolus of 0.03 mg kg⁻¹ cisatracurium or 0.2 mg kg⁻¹ rocuronium each time a TOF count equals or exceeds 2. At the end of anaesthesia, neuromuscular blocking with cisatracurium was reversed with neostigmine 0.05 mg kg⁻¹; while rocuronium was antagonized with sugammadex 2 mg kg⁻¹. Atropine 0.02 mg kg⁻¹ was mixed with neostigmine to minimize the cholinergic side effects of neostigmine. Tracheal extubation was attempted only after the TOF ratio reached > 0.9.

Objectives and Outcomes

Some ophthalmic surgeries tend to have higher risk of developing bradycardia as reported in previous literatures.⁴ In this study, based on our experience and the degree of intraoperative extraocular muscle tension and stretch, we classified: eyeball surgery, keratoplasty, nasolacrimal duct surgery and orbital surgery as ophthalmic surgeries associated with less incidence of bradycardia (n = 172). Whereas pars plana vitrectomy, scleral buckling and strabismus surgery were considered as ophthalmic surgeries associated with more incidence of bradycardia (n = 671).

The primary outcome was the incidence of bradycardia during surgical manipulation over eye area. Heart rate less than 60 bpm was considered as bradycardia in this study. Once an HR under 60 bpm was detected, surgeons were asked to stop all surgical manipulation immediately and intraoperative ECG was monitored for at least 1 minute before resuming the surgery. Atropine 1 mg was prepared as a rescue drug for any sustained or worsening significant bradycardia with HR of 40 bpm or less that lasts even after cessation of surgical manipulation.

Statistical Analyses

Categorical variables are presented as raw numbers or percentages. Chi-squared or Fisher’s exact test was used to compare the groups. The normality of the distribution of data was tested with the Kolmogorov–Smirnov test. Data within normal distribution were analysed with Student’s t-test and presented as mean (± standard deviation). For not normally distributed data, Mann–Whitney U-test was used for analysis and the results were presented as median (± interquartile range).

Ten variables were used for univariate and multivariate logistic regression analysis, including gender, age, body weight, ASA, along with the use of BIS and rocuronium, the amount of intraoperative fluid, sevoflurane, and opioids, as well as the type of ophthalmic surgery according to risk of developing bradycardia. We estimated the total sample size using G*Power,¹² version 3.1.9.7: with multiple linear regression analysis of the previously mentioned 10 variables used for logistic regression analysis, effect size = 0.15, α = 0.05, power = 0.95, resulting in a total sample size of 172. A total of 843 patients were enrolled in the study and assigned to 2 comparison groups comprising 388 and 455 patients, respectively. Therefore, the total number of patients in this study is far beyond the estimated total sample size.

Results

Study Population and Patient Characteristics

After excluding 104 patients from a total of 947 patients, the number of patients enrolled in this study was 843. The cisatracurium and neostigmine group had 388 patients, while 455 patients were in the rocuronium and sugammadex group (Figure 1). Patient characteristics including sex, body weight, American Society of Anaesthesiologists physical status classification (ASA), comorbidity index, Apfel score, hypertension, diabetes mellitus, and cerebrovascular accident, all had no significant differences between the 2 study groups (Table 1). The median age of 60 years (52–67) for patients in the rocuronium and sugammadex group was higher than the median age of 55years (43–66) in the cisatracurium and neostigmine group.

Table 1 Patient Characteristics

In both groups, a significantly higher number of cases underwent ophthalmic surgeries that had relatively increased risk of bradycardia.

Incidence of Intraoperative Bradycardia

Several variables during anaesthesia and perioperative care are listed in Table 2. There were no significant differences in the: duration of anaesthesia, intraoperative amount of fluid infused, tracheal extubation time, the incidence of postoperative nausea and vomiting (PONV) and the total days of hospitalisation between the cisatracurium with neostigmine group and the rocuronium with sugammadex group (Table 2). When compared to the cisatracurium and neostigmine group, the rocuronium and sugammadex group had significantly lower incidence of intraoperative bradycardia. The total amount of opioid consumption (converted into morphine milligram equivalents (MME)), and the amount of sevoflurane consumption were significantly reduced in the rocuronium and sugammadex group. The intraoperative use of BIS monitoring was significantly higher in the rocuronium and sugammadex group. Interestingly, there was no significant difference in the incidence of bradycardia during ophthalmic surgeries with higher risk of developing bradycardia and those with lower risk of developing bradycardia (Table 3).

Table 2 Anaesthesia and Perioperative Care

Table 3 Comparison of Incidence of Bradycardia in Different Ophthalmic Surgeries

Univariate and multivariate logistic regression model was built to analyse the association of risk variables with the incidence of intraoperative bradycardia (Table 4). In univariate analysis, the use of BIS monitoring was associated with a significant reduction in development of bradycardia. (OR 0.27; 95% CI: 0.13–0.55; p< 0.001). However, in multivariate analysis using BIS had no direct impact on the incidence of intraoperative bradycardia (p = 0.554). The rocuronium and sugammadex group had significantly lower risk of bradycardia on univariate analysis (OR 0.07; 95% CI: 0.02–0.24; p <0.001). This significant decrease in the incidence of intraoperative bradycardia with the use of rocuronium was also confirmed by multivariate analysis (OR 0.08; 95% CI: 0.02–0.94; p <0.001). Sex, age, body weight and ASA physical status, and the amount of intraoperative fluid, sevoflurane and opioids had no significant influence on the incidence of bradycardia.

Table 4 Univariate and Multivariate Logistic Regression to Evaluate the Risk of Bradycardia (n = 843)

Discussion

In this retrospective single-centre study, we analysed the association between several variables and the incidence of bradycardia during surgical manipulation in various types of ophthalmic surgeries. The use of rocuronium was associated with a significant reduction in the incidence of intraoperative oculocardiac reflex-induced bradycardia.

Researchers have defined oculocardiac reflex and bradycardia in many different ways.^5,13 In this study we defined bradycardia as HR less than 60 bpm.¹ Bradycardia during oculocardiac reflex could be associated with severe and possibly fatal complications.^2,8,14,15 It is also important to note that while most cases of oculocardiac reflex are self-limited; the condition can potentially lead to significant morbidity and mortality, particularly during eye muscle surgery.^16–18 Bradycardia can be prevented by the administration of adequate doses of anticholinergic drugs such as atropine and glycopyrrolate.⁷ However, treatment with anticholinergics like atropine is warranted; especially in patients who are susceptible to myocardial ischemia as a result of tachycardia and increased myocardial oxygen demand.^{4,9,10,16,18,19} Consequently, it is important to search for anaesthetic agents or strategies that could be associated with reduced incidence of bradycardia during ophthalmic surgeries without relying on perioperative use of anticholinergics.

Previous studies have addressed that anaesthesia protocol and anaesthetic agents have a significant influence on oculocardiac reflex.⁶ Intraoperative use of certain opioids, dexmedetomidine and dexamethasone were associated with augmented oculocardiac reflex;^5,6,20–22 whereas ketamine infusion was reported to decrease oculocardiac reflex.²³

Rocuronium has mild vagolytic effects that could increase HR specially when administered in large doses.^24,25 It has been reported that the administration of rocuronium during ophthalmic surgery did not reduce the incidence of bradycardia; however, it was associated with less occurrence of intraoperative arrhythmias such as: supraventricular and ventricular premature beats.²⁶ In a recent observational study, when compared to several other muscle relaxants, rocuronium was associated with more incidence of oculocardiac reflex.⁶ However in our study, patients who received rocuronium had significantly lower incidence of intraoperative bradycardia than patients in the cisatracurium and neostigmine group. We could think of 2 possible explanations for the reason why rocuronium was associated with decreased incidence of bradycardia in our current study while it was found to have no effect on the reduction of bradycardia in the previous 2 studies by Arnold et al⁶ and Karanovic et al.²⁶ Firstly, the definition of bradycardia in different studies was not the same. Bradycardia was defined as the percentile reduction of HR in the previous two studies; while in our current study bradycardia was considered a constant, as an HR less than 60 bpm during surgical manipulation over the eyes. Patients with HR less than 60 bpm were excluded from this study. We did not investigate if patients with basic lower heart rate are subject to bradycardia after surgical manipulation. Therefore, further studies are needed to clarify this last concern. Secondly, the variation in anaesthesia condition and agents could also contribute to the difference in result between the previous 2 studies and our study. Most elective surgeries were restricted in 2021 and 2022 due to the increased number of COVID 19 cases in Taiwan during this period. To limit any bias caused by staff adjustments, lack of training and decreased number of patients; we only included ophthalmic surgeries in adult patients during 2020 in this study. We aimed to compare between 2 groups of patients who received either cisatracurium and neostigmine or rocuronium and sugammadex as the neuromuscular blocking and reversal agents, respectively. All other factors such as the kind of anaesthetic agents administered and anaesthesia conditions were held as constant as possible. It is worth to mention that in this study rocuronium was never reversed with neostigmine and patients were divided into only two groups based on the type of neuromuscular blocking and reversal agents because rocuronium was administered along with sugammadex and BIS monitoring in a set of anaesthesia package that requires self-pay. This may also explain why significantly more patients in the rocuronium and sugammadex group used BIS monitoring.

Interestingly, in this study and in a previous study done by our group,²⁷ the combination of rocuronium and sugammadex was associated with less consumption of volatile agents and opioids. Here, it is not clear if rocuronium itself has any potential analgesic and anaesthetic properties that could attribute to the decreased amount of opioids and sevoflurane, leading to less bradycardia with the use of rocuronium. More importantly, the reduced incidence of intraoperative bradycardia may not be attributed to a single factor such as the use of rocuronium and sugammadex. The collective effect of multiple factors should be considered as an important determinant of the incidence of intraoperative bradycardia.

In this study, monitoring the depth of anaesthesia with a target range for BIS value between 40 and 60 – allowed consultant anaesthetists to administer sevoflurane and opioids accordingly. Intentional deep inhalational anaesthesia was never attempted, and the total amount of sevoflurane used was not inversely proportional to the incidence of bradycardia. In previous studies, the depth of anaesthesia was influenced by many factors including patient’s age, neuromuscular blocking and the use of several other medications such as: ketamine, nitrous oxide, inhalation agents and opioids.^28,29 Although BIS monitoring cannot entirely prevent intraoperative awareness,^30–32 yet many other potential benefits were reported when BIS monitoring was utilized during general anaesthesia; specifically, the significant reduction in anaesthetic drug consumption and optimal enhanced recovery after surgery (ERAS).^33,34 Despite the difference in anaesthesia agents and conditions such as: the use of neuromuscular blocking in some cases, the use of laryngeal mask instead of endotracheal tube, and the difference in the definition of bradycardia in each study; all previous evidence suggested that deeper anaesthesia could protect against oculocardiac reflex.^13,35 However, in an era where we cannot emphasize enough on the importance of precision medicine, it would be inappropriate to increase the amount of anaesthesia agents and hence increasing the depth of anaesthesia just to prevent oculocardiac reflex without actual/digital evidence that the depth of anaesthesia is not enough for a certain surgical stimulation. Not to mention the serious consequences of unnecessary increased amount of anaesthetic agents which could lead to hemodynamic instability and burst suppression of electroencephalography (EEG).^36–39 Lastly, the decrease in the total amount of opioids in the rocuronium and sugammadex group is beneficial in terms of reducing the augmentation of oculocardiac reflex by excessive use of opioids.²¹

Regardless of the type of neuromuscular blocking or reversal agent used during general anaesthesia, the routine use of perioperative quantitative neuromuscular monitoring was suggested by many investigators in several publications. The use of quantitative neuromuscular monitoring could ensure sufficient neuromuscular blocking effect during the surgery and complete reversal before tracheal extubating.^40–42 However it is not clear if the TOF ratio and hence the depth of neuromuscular blocking, has anything to do with the incidence of oculocardiac reflex during ophthalmic surgery.

The primary outcome in this study was the incidence of bradycardia during surgical manipulation of the eyes. No persistent or worsening significant bradycardia was recorded after cessation of surgical manipulation. Therefore, no atropine was required to treat sustained bradycardia or cardiac arrest. Several factors were attributed to the limited incidence of persistent bradycardia and hemodynamic instability in this study, including careful selection of patients, proper monitoring of the depth of anaesthesia and neuromuscular blockade, as well as avoiding the administration of excessive anaesthetic agents and opioids. Nevertheless, vigilant consultant anaesthetists played a major role in early termination of intraoperative bradycardia by immediately warning the surgeons who in return stopped all surgical manipulation at once. This highlights the importance of continuous communication and discussion between the anaesthesia and surgical teams during surgery.^13,43

In both study groups, more surgeries with relatively increased risk of bradycardia were performed. Interestingly, when compared to ophthalmic surgeries with low risk of developing bradycardia, no significant difference was discovered in the incidence of bradycardia in ophthalmic surgeries with higher risk of developing bradycardia. This probably indicates that our surgeons have a matured skill with limited surgical stimulation that largely reduce the incidence of oculocardiac reflex.⁴

Finally, we must address the potential bias inherent to retrospective studies that could interfere with the findings of this study. The generalizability of the result from this study in paediatrics and different races should be tested in a large randomized prospective trial. Indeed, it is the less likely for a single factor or a drug to be the sole determinant of decreased intraoperative bradycardia unless all variables are held constant throughout the anaesthesia and surgery. Consequently, the more factors associated with decreased oculocardiac reflex are available during anaesthesia, the less likely for an intraoperative bradycardia to occur. However, large randomized controlled clinical trials are needed to determine if one factor has a greater effect on suppressing oculocardiac reflex than another one.

In conclusion, both consultant anaesthetist and surgeon have an influence on the incidence of bradycardia during ophthalmic surgery. The use of rocuronium was associated with a significant reduction in the incidence of bradycardia during ophthalmic surgery in adult patients. Regardless of the cause of intraoperative bradycardia, oculocardiac reflex related or not, it is important to note that the management of bradycardia and the administration of anaesthesia agents should be individualized based on each patient’s specific condition and proper clinical monitoring and evaluation. Further, randomized controlled clinical trials are essential to establish a clear connection between any suggested risk factor and the incidence of bradycardia during ophthalmic surgeries.

Abbreviations

ASA, American Society of Anaesthesiologists physical status classification; bpm, beats per minute; BIS, bispectral index; CI, confidence interval; ECG, echocardiography; EEG, electroencephalography; HR, heart rate; IQR, interquartile range; OR, odds ratio; TOF, train-of-four.

Data Sharing Statement

The data presented in this study are available from the corresponding author upon reasonable request.

Acknowledgments

We appreciate the statistical analyses assistance by the Biostatistics Canter, Kaohsiung Chang Gung Memorial Hospital.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This research received no external funding.

Disclosure

The authors declare that they have no conflicts of interest.

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39. Quan C, Chen J, Luo Y, et al. BIS-guided deep anesthesia decreases short-term postoperative cognitive dysfunction and peripheral inflammation in elderly patients undergoing abdominal surgery. Brain Behav. 2019;9(4):e01238. doi:10.1002/brb3.1238

40. Wu EB, Huang SC, Lu HI, et al. Use of rocuronium and sugammadex during video-assisted thoracoscopic surgery is associated with reduced duration of chest-tube drainage: a propensity score-matched analysis. Br J Anaesth. 2022;130(1):e119–e127. doi:10.1016/j.bja.2022.07.046

41. Viby-Mogensen J. Postoperative residual curarization and evidence-based anaesthesia. Br J Anaesth. 2000;84(3):301–303. doi:10.1093/oxfordjournals.bja.a013428

42. Weigel WA, Williams BL, Hanson NA, et al. Quantitative neuromuscular monitoring in clinical practice: a professional practice change initiative. Anesthesiology. 2022;136(6):901–915. doi:10.1097/ALN.0000000000004174

43. Marshall SD, Touzell A. Human factors and the safety of surgical and anaesthetic care. Anaesthesia. 2020;75 Suppl 1:e34–e38. doi:10.1111/anae.14830

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August 20, 2025
‘I’d never seen anything like it’: Lucinda Childs on the extraordinary worlds of Robert Wilson | Stage

There was a production of Bob’s in New York in 1975, A Letter for Queen Victoria, and some friends told me, “Oh, you should see this, it’s really amazing”. I was a dancer and choreographer and I had worked with the Judson Dance Theatre – it was all about no music, pedestrian movement, performing in alternative spaces, avoiding all the traditional trappings. Here was Bob, though, in a theatre, with a composer and lighting … it was such a contemporary sensibility. I’d never seen anything like it.

I met Bob shortly thereafter at a festival, and he talked right away about working together on Einstein on the Beach [with composer Philip Glass]. We worked in his studio in lower Manhattan. Bob worked in a kind of improvisatory fashion. Day to day we were never sure if he was going to review what we had done or start again. You just would come up with something and run with it and see what happened. We would improvise day after day and narrow it down and see what worked. He was never entirely specific about what he wanted, but somehow he got exactly what he wanted. There was a lot of trust and he supported me in my work in such a strong way. It gave me a sense of freedom.

The next thing we worked on was Patio [full title: I Was Sitting on My Patio This Guy Appeared I Thought I Was Hallucinating]. Right after Einstein, he gave me a 38-page script and said, “Tell me what you think”. And, of course, I loved it. He thought of text in different ways. Not necessarily the meaning or the narrative aspect, but the music of it, the timing and the rhythm.

He just had a unique way of thinking. A lot of the notes that I got from Bob when he was directing were in the form of pictures. From Einstein I have several pages of little drawings he did for every single scene. He was always thinking visually. Watching him do the lighting for Einstein in the theatre in Avignon – to appreciate what he could see, the time and consideration it takes to develop exactly what he wanted – this is something so special and, in a way, difficult about Bob’s career. It all happens in three dimensions – it doesn’t translate anywhere else.

‘He was always thinking visually’ … Einstein on the Beach performed in Avignon, France, 1976. Photograph: Philippe Gras/Alamy

There were a lot of difficulties getting work made in the US. Luckily, he had so much support in Europe. He was appreciated and given opportunities. But there was disappointment, and certainly some anger, because it was difficult for any of us in the downtown crowd in New York. The attitude was: why don’t you just stay downtown! But it didn’t stop him. Bob wanted to do Einstein at the Met – and he did.

I have to mention the Watermill [a centre for alternative arts education in New York]. He managed to bring this wonderful place to America and bring these students in year after year. Every morning he would talk to the entire group, and he’d get round to every single student. He created this place that’s so special.

‘He gave me a sense of freedom’ … Lucinda Childs in La Maladie de la Mort, directed by Robert Wilson at the Peacock theatre, London, in 1997. Photograph: Tristram Kenton/The Guardian

As a friend, he offered enormous support. He never forgot a birthday, always sent a message. Never forgot after a performance to write a lovely note to thank you, and he would mean what he said. He was incredibly thoughtful. There was so much support, and anybody I run into says exactly the same thing. There must be hundreds of people with these memos and mementoes.

It was 50 years on and off working together. From the very beginning, Bob said, “I think we think in the same way”. I was working in Hamburg with him on the production H–100 Seconds to Midnight and we all were assembled together, he was introducing all the actors and dancers. And when he got to me he said: “Lucinda and I don’t really talk very much, because we don’t need to. We understand each other.” And there was something very touching about that.

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August 20, 2025
I Went to an AI Film Festival Screening and Left With More Questions Than Answers

Last year, filmmaker Paul Schrader—the director of Blue Collar, American Gigolo, and First Reformed, and writer of Martin Scorsese’s Taxi Driver—issued what seemed like the last word on artificial intelligence in Hollywood filmmaking. A few days after the release of Denis Villeneuve’s sci-fi blockbuster Dune: Part Two, Schrader asked his Facebook followers: “Will Dune 3 be made by AI? And, if it is, how will we know?”

Schrader is well regarded not only as a director, but one of cinema’s top-shelf curmudgeons, quick with a wry burn or baiting shit-post. But his Dune tweet seemed like more than another provocation. It spoke to a mounting feeling among many filmgoers, myself included: that Hollywood had stooped to producing sleek, antiseptic images so devoid of personality that they might as well have been made not by a living, breathing, thinking, feeling artist, but by a computer.

Most generative AIs “train” on existing troves of man-made images. With Dune, the opposite seemed true. It appeared as if Villeneuve was training on AI conjurations, screensavers, and glossy desktop wallpapers. (In fact, the film used “machine learning” models to relatively modest ends.) Still, it got me thinking: Is there an actual AI aesthetic? Do video generators powered by AI share a set of artistic ideas, or values, common among their output? Or, even more basically, can AI video generators have ideas, or values, at all?

My initial hunches here were … a) no; b) no; and c); no, of course an AI could not have “ideas” or “values,” which are the exclusive province of human artists, and human beings more generally. A toaster does not get a notion to warm up your bread or bagel, and then follow through with it. Nor does it care about how it does so. It merely executes a set of routinized, mechanized functions related to the warming (and eventual jettisoning) of breads, bagels, and other toastables. Why should generative AI be any different?

To test these premises (and my own rather dismissive conclusions) I trekked to a theater in New York to take in a program of 10 short films from the 2025 AI Film Festival.

The AI Film Festival is backed by Runway, a New York–based AI company offering “tools for human imagination.” Among those tools are image and video generators allowing users to create characters, sets, lighting schemes, and whole immersive scenes. With its Gen-4 software, users can theoretically create a whole movie—or something vaguely approximating one, anyway.

“We were all frustrated filmmakers,” says Runway’s cofounder, Alejandro Matamala Ortiz, of he and his partners, who met as grad students enrolled in the Interactive Telecommunications Program (ITP) at NYU’s Tisch School for the Arts. “We wanted to build the tools that we wanted to use.”

The film festival was born of a further desire to help legitimize those same AI tools. A gala screening held earlier this summer at New York’s prestigious Alice Tully Hall at the Lincoln Center (home to the New York Film Festival and year-round programming) saw filmmakers and technologists gather to watch the crème de la crème of a technology typically written off for producing mere “slop.” The festival format, Ortiz says, serves to “bring people together.” Now, that same gala program is touring Imax cinemas around the country, for a limited engagement.

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August 20, 2025
Lasers can eavesdrop on microbes, including viruses

bacteria: (singular: bacterium) A type of single-celled organism. These dwell nearly everywhere, from the bottom of the sea to inside other living organisms (such as plants and animals). Bacteria are one of the three domains of life on Earth.

chemistry: The field of science that deals with the composition, structure and properties of substances and how they interact. Scientists use this knowledge to study unfamiliar substances, to reproduce large quantities of useful substances or to design and create new and useful substances.

E. coli: (short for Escherichia coli) A common bacterium that researchers often harness to study genetics. Some naturally occurring strains of this microbe cause disease, but many others do not.

environment: The sum of all of the things that exist around an organism or the process and the condition those things create. Environment may refer to the weather and ecosystem in which an animal lives, or, perhaps, the temperature and humidity (or even the placement of things in the vicinity of an item of interest).

fungi: (sing: fungus) Organisms with one or more cells that reproduce via spores and feed on living or decaying organic matter. Examples include mold, yeasts and mushrooms.

germ: Any one-celled microorganism (microbe), such as a bacterium or fungal species, or a virus particle. Some germs cause disease. Others can promote the health of more complex organisms, including birds and mammals. Most live in the environment and have no known effects on human health.

infect: To spread a disease from one organism to another. This usually involves introducing some sort of disease-causing germ to an individual.

laser: A device that generates an intense beam of coherent light of a single color. Lasers are used in drilling and cutting, alignment and guidance, in data storage and in surgery.

microbiologist: A scientist who studies microorganisms, the infections they might cause or ways that they can interact with their environment.

microscope: An instrument used to view objects — such as bacteria or the single cells of plants or animals — that are too small to be visible to the unaided eye.

molecule: An group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O₂), but water is made of two hydrogen atoms and one oxygen atom (H₂O).

organism: Any living thing, from elephants and plants to bacteria and other types of single-celled life.

Proceedings of the National Academy of Sciences: A prestigious journal publishing original scientific research, begun in 1914. The journal’s content spans the biological, physical and social sciences. Each of the more than 3,000 papers it publishes each year are not only peer-reviewed but also approved by a member of the U.S. National Academy of Sciences.

protein: A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of cells and do the work inside of cells and throughout the body. Antibodies, hemoglobin and enzymes are all examples of proteins. Medicines frequently work by latching onto proteins.

sensor: A device that picks up information on physical or chemical conditions — such as temperature, barometric pressure, salinity, humidity, pH, light intensity or radiation — and stores or broadcasts that information. Scientists and engineers often rely on sensors to inform them of conditions that may change over time or that exist far from where a researcher can measure them directly.

sound wave: A wave that transmits sound. Sound waves have alternating swaths of high and low pressure.

species: A group of similar organisms capable of producing offspring that can survive and reproduce.

strain: (in biology) Organisms that belong to the same species and share some small but definable characteristics. For example, biologists breed certain strains of mice that may have a particular susceptibility to disease. Species of bacteria or viruses may develop strains when some members of the species gain mutations. Sometimes, specific strains are immune to drugs that would usually kill that species of microbe.

technology: The application of scientific knowledge for practical purposes, or the devices, processes and systems that result from those efforts.

unique: Something that is unlike anything else; the only one of its kind.

virus: Tiny infectious particles consisting of genetic material (RNA or DNA) surrounded by protein. Viruses can reproduce only by injecting their genetic material into the cells of living creatures. Although scientists frequently refer to viruses as alive or dead, in fact many scientists agree that viruses are not truly alive. They don’t eat as animals do or make their own food as most plants do. A virus must hijack the cellular machinery of a living cell to survive.

wave: A disturbance or variation that travels through space and matter in a regular, oscillating fashion.

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August 20, 2025
MacOS Tahoe vs. Sequoia: Here’s How Liquid Glass Redesigns Your Mac’s Icons

Apple’s Liquid Glass software design language is bringing a new look to your Mac. Some of it you’ll likely spot right away — like the revamped menu bar, which will have a completely clear background. But other design changes coming in MacOS 26 Tahoe will be more subtle, to the point where you might almost miss them entirely. But they’re worth hunting down.

MacOS Tahoe is more than a design update. Functional changes include a smarter Spotlight search, new continuity features, live translation and a new Games app. MacOS even picked up the Phone app in this release.

But I’m here to talk to you about the Mac OS icons, many of which — until now — have barely changed in decades. There are cool new things you can do, like change the default color of an icon folder without replacing it entirely, along with additional customization options that previously were never available (you can now tint icons or make them completely clear like you can on the iPhone). Other icons are seeing a tweaked return to their former designs, but the updated versions are shiny and sophisticated.

What I find fascinating is the way Tahoe’s icons tell the same story while saying less in their imagery.

Below, I’ve detailed some of the updated icons you’ll find on MacOS 26, keeping in mind that the final designs may change by the time the OS exits beta and the final build is released. I’ll compare the new icons to the current version of the OS, Sequoia, much like I did when comparing the Liquid Glass effect in iOS 26 to the not-long-for-this-world look of iOS 18.

Everyday Mac users may choose to overlook some of the updates to the icons, and that’s fine — they’re just doors to a destination. But if you appreciate the subtleties Apple put into the details of its latest OS, follow along.

For more, don’t miss our iPhone 17 rumor roundup.

Tucked in, flattened down and rounded out

Icons on the Mac now feel more like that of those on iOS, with a more rounded, squircle design. Compared to Sequoia, Tahoe’s icons become flatter in the details and sometimes that texture found in the former OS version’s icons is replaced with a subtle translucent effect. Sequoia’s sometimes concave or indented style has been pushed outwards, allowing for Liquid Glass to add a little shine on the corners of elements within the icon’s design. Apple has also pulled in all icon elements that had previously hung off the edges — now everything is tucked within the icon shape.

Books

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

The Apple Books icon updates are simple, but do a lot for the overall design. The pages show gradients to inform depth and the edges add a touch of the signature Liquid Glass shine. Additionally, a book cover has been added behind the pages, showing off a layered glass look.

Contacts

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

The Contacts app icon largely looks the same as far as the elements within it are concerned, but otherwise — wow, what a difference. The cardboard-box brown of the “contact book” is replaced with a gradient and translucent off-white surface with a contrasting standard profile image. There’s one less colored tab to the right of the icon, and the remaining three are now flat in design and span the entire height of the icon.

Digital Color Meter

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

Another good example of Apple turning down the detail without sacrificing impact is the Digital Color Meter app. The dropper no longer hangs off the edge, the background is a simple white instead of stark red, the shapes have been simplified to circles and the colors take on more pastel shades.

Disk Utility

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

MacOS Tahoe shows Apple pulling back and toning down details of its icons while communicating the same thing. The Disk Utility app is one of the better examples of this — compare the new version to Sequoia and previous versions.

Folders

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

For years and years, the default folder on a Mac has been a turquoise blue, without much customization at your disposal. And maybe the folder color on your Mac isn’t something you’ve cared to spend time on thinking about, but if who’ve wished that they could change their folder color, you’ll be able to with Tahoe.

Tucked into the Appearance menu in system settings is a new default folder color option, allowing you to switch between red, orange, yellow, green, blue, purple, pink and graphite. In addition, the icon in Tahoe shows a document in it, as opposed to Sequoia’s empty folder.

iPhone Mirroring

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

The updated iPhone Mirroring icon is now more representative of what the app does. It may not say much about the app’s functionality, but it’s a step up from Sequoia’s icon with a single iPhone.

Photos

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

Another subtle Liquid Glass icon tweak is found in the Photos app. In essence, it’s the same design, but the overlapping, oblong color panels look to have a slight decrease in overall width and Apple has added shiny glass edges to them.

Settings

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

The updates to the Settings icon in Tahoe are minor, but it’s a good example of Liquid Glass’ subtlety. That inward depth the icon has maintained for over a decade has shifted, colors are changed, and the teeth of the gears are both widened and softened. Liquid Glass is most notable in the smaller gear, which is slightly more transparent, as if it has a piece of layered glass on top of it.

Stickies

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

The Stickies app redesign is a return to how its icon appeared from 2000 to 2020, according to Basic Apple Guy’s MacOS icon history chart. Instead of what looks like a Post-It notepad, the latest icon returns to a stack of three notes lying on top of each other.

Text Edit

Left: MacOS Sequoia. Right: MacOS Tahoe.

Apple/Screenshots by Matthew Elliott and Blake Stimac

Tahoe’s update to the Text Edit app might almost be too reductive from Sequoia’s, removing the pen entirely, leaving only a segment of a piece of notebook paper. It’s most certainly simplified, but Mac users that may not be so intimately familiar with each individual icon may easily mistake Text Edit for something else.

For more, don’t miss how Apple’s iPhone release schedule might change.

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August 20, 2025
Samsung unveils ‘Galaxy Flexival’ activation in SG, to highlight everyday life with Galaxy devices

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August 20, 2025

Safety Profile and Influence Factors of Incadronate Disodium Treatment

Introduction

Breast cancer is one of the most common malignant tumors among women worldwide. According to the 2020 GLOBOCAN statistics, breast cancer has overtaken lung cancer to become the most common cancer in women, with approximately 2.3 million new cases globally, accounting for 24.5% of all malignant tumors in women.¹ With the widespread use of early screening and continuous improvements in treatment methods, the survival rate of breast cancer patients has increased significantly. However, among newly diagnosed breast cancer patients each year, approximately 3% to 10% have distant metastasis at the time of diagnosis.² About 30% of early-stage patients may progress to advanced breast cancer. Compared to early-stage breast cancer, the prognosis of advanced breast cancer is worse, with a 5-year survival rate of only 20% and a median overall survival time of 2 to 3 years.^3,4 Bone metastasis (BM) remains a serious clinical problem in the advanced breast cancer. The mechanism of bone metastasis is complex and mainly involves the interaction between tumor cells and the bone microenvironment, which ultimately leads to the alteration of the bone microenvironment and activation of osteoclasts, promoting bone resorption and destruction.⁵ Studies have shown that approximately 70% of patients with advanced breast cancer will develop bone metastasis, which can further lead to skeletal-related events such as bone pain, fractures, spinal cord compression, and hypercalcemia, significantly affecting the patient’s quality of life and survival prognosis.⁶

The use of bone-modifying agents (BMAs) to prevent bone resorption is clinically significant in many aspects of breast cancer treatment, including treating osteoporosis caused by endocrine therapy, managing bone metastasis, and potentially preventing bone metastasis. Best established agents include the bisphosphonate zoledronic acid and the receptor activator of NF-κB ligand (RANKL) antibody denosumab.⁷ Bisphosphonates inhibit osteoclast activation mainly by inhibiting bone mineralization or bone resorption, thus reducing bone destruction caused by malignant tumor bone metastasis, alleviating bone pain, and decreasing the incidence of fractures.⁸ They are recommended upon diagnosis of bone metastases and have been shown to alleviate bone pain and reduce fracture risk. Furthermore, the addition of bisphosphonates to standard adjuvant therapy for early-stage breast cancer can decrease bone recurrence and enhance survival rates. A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) and trials such as ABCSG-12 demonstrated that adjuvant bisphosphonate use reduces recurrence and mortality in early-stage breast cancer. However, the occurrence of side effects remains an undeniable part of the clinical application of bisphosphonates. These adverse effects can affect various systems of the body, with common manifestations including acute-phase reactions, hypocalcemia, renal toxicity, osteonecrosis of the jaw, and gastrointestinal issues.^9,10 Undoubtedly, in most cases, the benefits of anti-resorptive therapy outweigh the potential adverse events. However, the long-term use of these medications may increase the cumulative risk of adverse events. A 20-year follow-up study on breast cancer patients with bone metastases found that 2.8% of patients in the bisphosphonate group were diagnosed with medication-related osteonecrosis of the jaw (MRONJ), with a median time to diagnosis of 5.1 years.¹¹ Additionally, switching from zoledronic acid to denosumab increased the risk of MRONJ in patients with bone metastasis.¹²

Incadronate disodium is a third-generation bisphosphonate, which is superior to the first- and second-generation bisphosphonates for the treatment of osteoporosis, pain, fractures, and other symptoms associated with metastasis of malignant tumors. An in vitro study demonstrated that its anti-resorptive ability is 1000 times that of clodronate and 100 times that of pamidronate.¹³ And it can also regulate the proliferation and apoptosis of tumor cells.^14,15 Meanwhile, it has been shown that incadronate disodium can inhibit the increase in DNA synthesis as well as tube formation of human microvascular endothelial cells, thereby exerting certain anti-angiogenic effects.¹⁶ Although previous studies have suggested that incadronate disodium may cause fewer adverse reactions than zoledronic acid, the evidence remains limited due to small sample sizes, short follow-up periods, and incomplete event reporting. Although the efficacy of incadronate disodium has been widely recognized in clinical practice, there remains uncertainty about its safety, particularly due to the limited safety data available for long-term use and in specific patient populations, as well as the lack of systematic studies. In breast cancer patients, there are currently no detailed reports on the efficacy and related adverse events of incadronate disodium.

These issues above have raised our further concerns about the safety of incadronate disodium. Therefore, we conducted this retrospective study to evaluate the safety of incadronate disodium treatment in breast cancer patients with bone metastases, focusing on common adverse events such as dental-related problems and acute-phase reactions. Additionally, we aim to explore the associated risk factors for these adverse events to provide scientific evidence for safe clinical drug use.

Materials and Methods

Study Design

This was a single-arm, single-center retrospective study that included 106 patients with breast cancer bone metastases who received incadronate disodium treatment at the Cancer Hospital Chinese Academy of Medical Science between February 2022 and August 2024. Eligible patients had received at least two consecutive infusions of incadronate disodium and were ≥18 years old with histologically confirmed breast cancer. All patients had at least one bone metastasis lesion confirmed by imaging (ie, X-ray, computed tomography, or bone scintigraphy) or pathology. Patients who received treatment for bone metastases from other cancers (n = 10), had fewer than two consecutive administrations of the medication (n = 6), or had no available follow-up information (n = 6) were excluded from the study. Patients with bone metastases originating from cancers other than breast cancer were excluded. Breast cancer patients with bone metastases, regardless of the presence of additional metastases to visceral organs (eg, liver, lung), were eligible for inclusion. Ultimately, a total of 84 patients met the inclusion criteria for the study (Figure 1). Incadronate disodium was administered intravenously once every 3–4 weeks at a dose of 10 mg per infusion, with each infusion lasting at least 2 hours. Physicians were allowed to adjust the dosage and infusion interval based on the patient’s individual condition. Dose adjustment was primarily based on renal function, general condition, and tolerance. Specifically, patients with eGFR <60 mL/min/1.73m², ECOG performance status ≥2, or clinical frailty typically received a reduced dose of 5 mg per infusion. In principle, the discontinuation criteria for incadronate disodium are the occurrence of intolerable adverse reactions or a deterioration in the patient’s physical condition assessed by the physician, making further treatment unadvisable.

Figure 1 Study schematic.

Data Collection

Based on the inclusion and exclusion criteria, baseline data of eligible patients were retrieved from the hospital’s electronic medical records, including age, body mass index (BMI), tumor pathology characteristics, presence of comorbid diabetes, total duration of medication, dose per administration, dosing interval, sites of metastases, timing of bone metastasis occurrence (primary or secondary), number of bone metastases at initiation (extent of disease [EOD] grade¹⁷), concurrent use of anti-angiogenic drugs, and clinical laboratory data at the first infusion (hemoglobin [Hb], serum albumin [Alb], serum alkaline phosphatase [ALP], serum total cholesterol [TC], serum calcium [Ca], carcinoembryonic antigen [CEA], cancer antigen 125 [CA125], and cancer antigen 15–3 [CA15-3]). Baseline blood tests, including hemoglobin, were collected to explore their potential association with treatment-related adverse events. In our study, primary bone metastases were defined as present at the initial diagnosis of breast cancer and secondary metastases developed during disease progression. Due to the long half-life of the medication, any adverse events occurring within 90 days after discontinuation of treatment were also considered to be potentially related to the medication.

Endpoints

The primary endpoint was the incidence of dental-related issues and acute phase reactions, with an analysis of the associated risk factors. The secondary endpoint was the incidence of other adverse events. Most studies on the adverse effects of bisphosphonate focus on medication-related osteonecrosis of the jaw. However, our primary concern was the occurrence of dental-related issues potentially induced by the medication, defined as newly developed symptoms such as gingival recession or swelling, tooth sensitivity, tooth looseness, or fractures, with osteonecrosis of the jaw (MRONJ) representing the most severe complication. The evaluation of MRONJ was based on both imaging findings and documented dental-related complaints during follow-up. When dental issues were reported or suspected, further imaging examinations, including panoramic dental X-rays or CT scans, were performed to confirm or exclude MRONJ. Acute phase reactions (APRs) were defined as flu-like symptoms (fever, chills, fatigue, and musculoskeletal pain) occurring within the first week of treatment. Renal impairment was defined as an increase in serum creatinine by ≥0.5 mg/dL or 1.0 mg/dL for patients with baseline serum creatinine levels of <1.4 mg/dL or >1.4 mg/dL, respectively, or serum creatinine that increased to at least twice that of the baseline value. Hypocalcemia was defined as a serum calcium level below 2.1 mmol/L after treatment, with baseline serum calcium in the normal range.

Ethics

The study was approved by the Independent Ethics Committee of the National Cancer Center/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College (25/020-4966). Given the retrospective nature of the study and the use of anonymized data, the requirement for written informed consent was formally waived by the ethics committee. This study was conducted in accordance with the principles outlined in the Declaration of Helsinki.

Statistical Analysis

For continuous data with a normal distribution, statistical descriptions were presented as mean ± standard deviation, while for continuous data with a non-normal distribution, they were presented as median and interquartile range. The continuous data between the two groups were compared using the independent samples t-test, provided the data met the assumptions of normality and homogeneity of variance. If these assumptions were not satisfied, the independent samples nonparametric test was applied instead. Categorical data were presented as percentages (%), and comparisons between groups were conducted using the chi-square test or Fisher’s exact test. Binary univariate and multivariate logistic regression analyses were performed to explore the risk factors associated with the occurrence of dental-related issues and acute phase reactions. The odds ratio (OR) and its 95% confidence interval (95% CI) were used to quantify the impact of different factors on the endpoint events. A p-value <0.05 was considered statistically significant. Variables with p <0.05 in the univariate analysis were included in the multivariate analysis. To assess potential multicollinearity among independent variables in the multivariate logistic regression, variance inflation factors (VIFs) were calculated. All variables included had VIF values <2, indicating no significant multicollinearity. SPSS 27.0 and R Studio were used for statistical analyses.

Results

Patient Characteristics

A total of 84 breast cancer patients with bone metastases who met the inclusion criteria were included in our study. The detailed characteristics of patients are shown in Table 1. The mean age of the patients was 55.3 (range 33–82) years, and the average BMI was 24.67 kg/m² with obesity status assessed based on BMI values. In terms of comorbidities, 15 patients had diabetes mellitus. Eight patients received anti-angiogenic therapy simultaneously: seven received bevacizumab, and one received anlotinib. The mean duration of treatment was 7.5 (range 2–32) months, with 17 patients receiving treatment for more than one year. A total of 60 patients received the standard dose of 10 mg per infusion, and 72 patients had an infusion interval of less than one month. Regarding the tumor immunohistochemistry (IHC), 80.95% of the patients were hormone receptor-positive, 30.95% were HER-2 positive, and 11.9% were triple-negative. Thirty-four patients had bone metastases alone, while the remaining patients had metastases in locations other than bone, such as the liver, lungs, or other regions. Twenty-eight patients had bone metastases at the time of their breast cancer diagnosis, while in the others, bone metastases occurred secondarily. According to the EOD grade for evaluating the number of bone metastatic lesions, 64 patients had a stage of ≥2. Bone metastases were observed in 59 patients with axial skeletal involvement and in 25 patients with appendicular skeletal involvement. In terms of adverse events, our study found that dental-related issues were the most frequent complications, occurring in 28 patients (33.3%), followed by acute phase reactions (APRs) in 22 patients (26.2%). Other reported AEs included hypocalcemia in 4 patients (4.8%) and renal dysfunction in 1 patient (1.2%) (Figure 2).

Table 1 Patients’ Baseline Characteristics

Figure 2 Distribution of adverse events (AEs) among patients treated with Incadronate Disodium. The most common AEs were dental-related issues and acute phase reactions (APRs), followed by hypocalcemia and renal dysfunction.

Incidence and Risk Factors of Dental-Related Issues

In our follow-up, a total of 28 patients developed dental-related issues, with an incidence rate of 33.3%. The most common symptoms included gingival recession or swelling, tooth sensitivity, fractures, and jaw pain. Notably, only one patient (1.2%) was definitively diagnosed with osteonecrosis, and the medication was discontinued in this case. A comparison of baseline characteristics between patients with and without dental-related issues is presented in Table 2. The total duration of treatment, the time of bone metastasis onset, concurrent use of anti-angiogenesis therapy, and hemoglobin levels were found to be associated with the occurrence of dental-related issues (p < 0.05). Table 3 presents the results of the analysis of factors associated with dental-related issues. In the univariate analysis, a treatment duration exceeding one year was identified as a significant risk factor for the occurrence of dental-related issues (OR = 3.89, 95% CI:1.30–12.24, p = 0.016). Compared to primary bone metastases, secondary bone metastases were more likely to cause dental-related issues (OR = 4.5, 95% CI:1.50–16.84, p = 0.013). Patients using anti-angiogenic drugs (OR = 7.36, 95% CI:1.56–52.98, p = 0.02) and those with lower hemoglobin levels (OR = 3.33, 95% CI:1.31–8.79, p = 0.013) were also more likely to have dental problems. In multivariate analysis, secondary bone metastases were a significant predictor of dental issues (OR = 6.3, 95% CI:1.58–25.00, p = 0.009). A total treatment duration of more than 1 year (OR = 4.33, 95% CI:1.21–15.50, p = 0.024) and hemoglobin levels below 120 g/L (OR = 4.16, 95% CI:1.31–13.2, p=0.016) also increased the likelihood of dental issues.

Table 2 Characteristics of Patients with and Without Dental-Related Issues at Induction

Table 3 Risk Factors for Dental-Related Issues (Univariate and Multivariate Analyses)

Incidence and Risk Factors of Acute Phase Reactions

Acute phase reactions were observed in 22 patients (26.2%), characterized by flu-like symptoms such as mild fever, fatigue, and joint and muscle pain, which occurred 2–3 days after infusion. Most patients recovered spontaneously within a week. Table 4 describes the baseline data of patients with or without acute phase reactions. The dose of each infusion, the site of metastases, and hemoglobin levels were all associated with the occurrence of acute phase reactions (p < 0.05). Table 5 outlines the results of analyzing the factors associated with acute phase reactions. In univariate analysis, 10mg per dose increased the risk of acute phase reactions compared to 5mg (OR = 1.41, 95% CI:1.07–2.05, p = 0.030). Multiple metastatic sites (OR = 4.22, 95% CI:1.39–15.89, p = 0.018) and lower hemoglobin levels (OR = 3.27, 95% CI:1.21–9.22, p=0.021) were also significant risk factors for acute phase reactions. Variables with p<0.05 in the univariate analysis were included in the multivariate analysis. No significant variables were found to be associated with acute phase reactions, but patients with bone and other site of metastases were considered at higher risk due to the p-value being close to 0.05.

Table 4 Characteristics of Patients with and Without Acute Phase Reactions at Induction

Table 5 Risk Factors for Acute Phase Reactions (Univariate and Multivariate Analyses)

Other Adverse Effect

One patient (1.2%) developed renal dysfunction after treatment, with a baseline creatinine level of 0.63mg/dL, which increased to 1.17mg/dL after treatment. Four patients (4.76%) had a decrease in serum calcium to below 2.1mmol/L after treatment and experienced symptoms such as numbness in the hands and feet, and muscle cramps. Other adverse reactions associated with bisphosphonate use, such as atrial fibrillation and conjunctivitis, were not observed in this study.

Discussion

Bone is the most common site of metastasis in breast cancer, and therefore, the clinical management of bone metastasis is an important aspect of treatment for advanced tumors.¹⁸ Bisphosphonates are widely used in clinical practice for their ability to inhibit osteoclast activation and thereby reduce bone destruction, and their efficacy has been significantly recognized. However, the occurrence of side effects remains an unavoidable part of clinical applications, especially those that may be associated with long-term use. Bisphosphonates have now progressed to the third generation. The first-generation non-nitrogen-containing bisphosphonates are represented by clodronate; the second-generation nitrogen-containing bisphosphonates are exemplified by pamidronate; the third-generation bisphosphonates feature extended side chains, leading to further enhanced pharmacological activity, such as incadronate disodium, which is derived from cycloheptylamine.¹⁹ Incadronate disodium, as a new drug, there is limited knowledge about its safety. Previous retrospective studies have suggested that incadronate disodium provides effective protection against bone metastases with a favorable safety profile. Reported adverse events include fever (9.4%) and fatigue (25%), indicating acceptable tolerability in clinical practice. Although some studies have compared incadronate disodium with other bisphosphonates such as zoledronic acid, robust head-to-head evidence remains limited, and our study primarily focused on the safety assessment of incadronate disodium itself in breast cancer patients with bone metastases and revealed some risk factors. Our findings showed that dental-related issues and acute phase reactions were common adverse effects. Among the patients, 28 (33.3%) experienced dental-related issues, but only 1 (1.2%) developed osteonecrosis of the jaw. This rate is within the lower range of incidence reported in prior studies on bisphosphonates. Literature data on MRONJ incidence are variable. A single-center retrospective study involving 179 prostate cancer patients with bone metastasis reported that 13% of those treated with zoledronic acid developed MRONJ.²⁰ Other studies on real-world data have reported incidences as high as 24% and 6.7%.^21,22 A 20-year multicenter retrospective study also reported that 2.8% of breast cancer patients treated exclusively with zoledronic acid developed MRONJ, while the incidence increased to 16.3% in patients who were sequentially treated with denosumab after bisphosphonates.²³ The above studies have reported the incidence of MRONJ, but none have focused on dental-related issues prior to the occurrence of necrosis. Prior to the appearance of clinically detectable bone necrosis, potential signs and symptoms may include chronic dull jaw pain, toothache, looseness of teeth, and gum swelling.²⁴ Our study mainly followed up on the early dental symptoms in patients, which allows for early recognition when such symptoms occur, enabling preventive measures to avoid progression to MRONJ, and provides some guidance for future treatments.

In the univariate analysis, our study showed that total medication duration (p=0.016), time of bone metastasis occurrence (p=0.013), concurrent anti-angiogenesis treatment (p=0.02), and hemoglobin levels (p=0.013) were associated with the occurrence of dental-related issues. Like previous studies on zoledronic acid, our further multivariate analysis found that a total medication duration of over 1 year with incadronate disodium was significantly associated with the occurrence of dental-related issues (p=0.024). A prospective observational cohort study, the SWOG S0702 trial, which included 3491 patients treated with zoledronic acid for bone metastases, found that those treated for longer duration were at a higher risk, with cumulative MRONJ incidence rates of 0.8%, 1.2%, and 2.8% at 1, 2, and 3 years, respectively.²⁵ Therefore, it might be considered to extend the dosing interval in long-term medication patients to reduce adverse events. A systematic review of three randomized trials showed that compared with dosing every 4 weeks, administering zoledronic acid every 12 weeks reduced the incidence of MRONJ.²⁶ In breast cancer, both dosing intervals of every 3 to 4 weeks and every 12 weeks for zoledronic acid are recommended as the preferred options.²⁷ There were also 12 patients in our study with dosing intervals longer than 1 month, but no clear correlation was found between dental-related issues and the dosing interval, possibly due to the small sample size. Thus, in the future use of incadronate disodium, the total medication duration and dosing interval should be carefully monitored.

In the multivariate analysis of our study, lower hemoglobin levels (p=0.016) and secondary bone metastases (p=0.009) were also identified as significant factors related to dental issues. The pathophysiological mechanisms of osteonecrosis of the jaws are not yet fully understood, and the main hypotheses include excessive suppression of bone conversion or bone remodeling, inhibition of blood supply, persistent microtrauma, and infection or inflammation.²⁸ Our study found that patients with hemoglobin levels below 120 g/L are more likely to have dental-related issues. The association between low hemoglobin levels and dental-related adverse events may be partially explained by tissue hypoxia. Anemia can impair oxygen delivery to oral and maxillofacial tissues, compromising mucosal integrity and impairing wound healing. Additionally, hypoxic conditions may alter immune responses, increasing susceptibility to chronic inflammation and infection, which are known contributors to the development of MRONJ. These mechanisms, although plausible, require further validation in experimental and clinical studies. Currently, no other studies have observed a correlation between the timing of bone metastasis occurrence and dental-related issues. However, factors such as immunosuppression and inflammation can promote tumor cell colonization and metastasis,²⁹ and we speculate that patients with secondary metastases are more immunosuppressed, and that immunosuppressed patients will be more susceptible to infections and inflammation, which are important risk factors for bisphosphonate-related dental and jaw complications. Therefore, further large sample studies are necessary to confirm our hypothesis.

Although no significant association was found between the use of anti-angiogenic drugs and dental issues in our multivariate analysis, the number of patients with dental adverse reactions was three times higher in those treated with anti-angiogenic drugs than in those without. Previous evidence suggests that anti-angiogenic drugs play a role in the development of osteonecrosis, especially when combined with osteoclast inhibitors.^30,31 These drugs inhibit the development of new blood vessels, which can lead to osteonecrosis of the jaw through ischemia. In summary, these findings indicate the potential role of anti-angiogenic drugs in the risk of MRONJ, which deserves further study.

The other major adverse reaction found in our study was acute phase reaction with an incidence of 26.2%, which mainly manifested as mild fever, fatigue, joint and muscle pain, occurring in most patients within 3 days after the first dose and resolving spontaneously within a week. A previous multicenter, randomized, double-blind study on breast cancer patients with bone metastasis found that 27.3% of patients receiving zoledronic acid infusion experienced acute phase reactions after treatment.³² In cancers other than breast and prostate cancer, a study by David H. Henry also reported that acute phase reaction occurred in 14.5% of patients treated with zoledronic acid.³³ Furthermore, these studies all indicate that the use of denosumab reduces the risk of acute phase reactions. Our data are generally consistent with previous reports. It is speculated that the cause of acute phase reactions may be a transient increase in cytokine production.³⁴ According to univariate analysis, higher medication doses (10mg vs 5mg), multiple metastatic sites, and lower hemoglobin levels were all related to acute phase reactions (p<0.05). While no significant statistical relationship was found in the multivariate analysis, patients with multiple metastatic sites were at higher risk for acute phase reactions. This may be because multiple sites of metastases imply a higher degree of disease progression and the involvement of bones and other organs may lead to excessive immune response activation, resulting in acute phase symptoms. These findings should be interpreted cautiously due to limited statistical power and may serve as the basis for hypothesis generation in future studies. Future studies could further explore personalized dosing regimens for patients at high risk to improve drug tolerance.

Our study also recorded one case of renal dysfunction (1.2%) and four cases of hypocalcemia (4.76%). Although these adverse reactions have a low incidence, they still require special attention. A report that included 120 patients who received a total of 546 infusions of zoledronic acid for multiple myeloma or another malignancy showed that 42 (35%) patients developed hypocalcemia after 55 infusions (10% of the total).³⁵ In terms of renal dysfunction, a study on bone metastases in breast cancer patients showed that 4% of patients developed an increase in serum creatinine after zoledronic acid infusion.³² The probability of all the above adverse events in our study due to incadronate disodium was lower than zoledronic acid. Also, other side effects of bisphosphonates such as atrial fibrillation, diarrhea, atypical fractures, and ocular toxicity have been reported,^9,10,36 but none of these adverse events were observed in our research.

Although our study provided important data for the safety evaluation of incadronate disodium, there were still several limitations. First, the sample size was limited, and all patients were from a single center and were breast cancer patients, which may introduce selection bias. The inclusion of patients with both bone and non-bone metastases introduces potential heterogeneity; however, the primary focus remained on bone-targeted toxicity. Stratified analysis in larger cohorts is warranted. Second, the relatively short follow-up period in this study did not allow assessment of the safety of long-term medication and its impact on patients’ quality of life. Third, due to the limitations of a retrospective study, it was impossible to determine whether participants had new medical conditions or were using other drugs during the follow-up period that might have caused serious adverse reactions, which could have affected the outcomes. Fourth, there was a lack of data on outcomes in patients with dental-related issues, so it remained unclear whether these early lesions improve, remain stable, or progress to osteonecrosis of the jaw. To address these limitations, prospective multicenter cohort studies with standardized dental assessments, longer surveillance, and biomarker profiling should be conducted to further investigate the safety profile of incadronate disodium and validate the risk factors identified in this study.

Conclusion

In conclusion, this retrospective study demonstrated that incadronate disodium was generally well-tolerated in breast cancer patients with bone metastases, with a relatively low incidence of severe adverse events, including osteonecrosis of the jaw. Our findings indicate that patients receiving prolonged treatment or presenting with lower hemoglobin levels may be at increased risk for dental-related complications and require closer monitoring. Routine assessment of hemoglobin levels and regular dental evaluations are recommended, particularly for patients undergoing long-term therapy, to help mitigate the risk of osteonecrosis of the jaw. Further prospective studies are warranted to validate these findings and to better characterize the long-term safety profile of incadronate disodium in this population.

Acknowledgments

We deeply appreciate all authors who were involved in this study and patients who participated in this study. The abstract of this paper was published in ‘Meeting Abstract: 2025 ASCO Annual Meeting’ in Journal of Clinical Oncology: [https://doi.org/10.1200/JCO.2025.43.16_suppl.e13113].

Funding

This work was supported by National Key Research and Development Program of China (2024YFA1107400) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-014, 2022-I2M-2-002).

Disclosure

The authors report no conflicts of interest in this work.

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13. Dunford JE, Thompson K, Coxon FP, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001;296(2):235–242. doi:10.1016/S0022-3565(24)38786-5

14. Kawashima H, Ogose A, Hotta T, et al. Effect of incadronate on proliferation of mesenchymal tumor cells with or without activated ras mutation. J Exp Clin Cancer Res. 2005;24(4):617–624.

15. Tsubaki M, Itoh T, Satou T, et al. Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of ras signaling pathways and bim-mediated activation of the intrinsic apoptotic pathway. Biochem Pharmacol. 2013;85(2):163–172. doi:10.1016/j.bcp.2012.10.009

16. Okamoto T, Yamagishi S, Inagaki Y, et al. Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vitro. Biochem Biophys Res Commun. 2002;297(2):419–424. doi:10.1016/s0006-291x(02)02218-0

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36. Paterson AH, Anderson SJ, Lembersky BC, et al. Oral clodronate for adjuvant treatment of operable breast cancer (national surgical adjuvant breast and bowel project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012;13(7):734–742. doi:10.1016/s1470-2045(12)70226-7

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August 20, 2025

Apple wants to bring Touch ID to its watches starting next year

According to a new report purportedly based on internal Apple developer code, the company is currently busy exploring ways to bring Touch ID (aka a fingerprint scanner if you don’t live in Apple’s world) to its watches.

This will arrive next year at the earliest, so presumably on the Apple Watch Ultra 4. The code in question specifically references “AppleMesa”, which has long been the company’s internal codename for Touch ID.

Since the code is for internal use only, the idea is most likely still in the prototype stage. Hence, none of the watches coming out this year will have the feature.

If you’re wondering just where a fingerprint sensor would even go on a watch, the answer is quite simple when we look at smartphones – basically, it’s either going to be embedded into a button, or into the screen. An optical in-display sensor has been rumored in the past, and of course there’s always the route of putting it in the side button.

A rumor from last week claimed Apple’s watches are due for a big redesign next year, and this might fit right in with that. The 2026 models may also get a new processor.

Source

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August 20, 2025
Dramatic phytoplankton changes identified in Antarctic waters

Phytoplankton in the waters around Antarctica are changing – and the shift could have big consequences for the climate and the entire Southern Ocean ecosystem.

Over the past 25 years, scientists have used satellite data to track changes in the makeup of these microscopic organisms.

Their findings point to a long-term, climate-driven transformation in the region’s marine environment – one that could weaken the ocean’s ability to capture and store carbon.

Detecting shifts in phytoplankton

The study was focused on data from the European Space Agency’s Climate Change Initiative (ESA’s CCI) and more than 14,000 samples collected between 1997 and 2023. The goal was to analyze changes in phytoplankton populations.

Alexander Hayward, Earth System Scientist at the Danish Meteorological Institute and lead-author on the paper, explained how the research team used ESA’s CCI data in the study.

“We built machine-learning models using in-situ samples, which we then combined with data from the European Space Agency, such as sea surface temperature, ocean color and sea ice concentration, to track changes in different phytoplankton groups over time,” Hayward explained.

Decline in diatoms

The team identified key changes in the balance of phytoplankton types across the Southern Ocean.

“We observed major reductions in diatom populations between 1997-2016 – a period where sea ice increased,” noted Hayward.

“From 2016 onwards, the satellite record revealed a slight rebound in Antarctic diatom populations, and a related group of marine algae – cryptophytes – rapidly proliferated.”

The researchers found that diatoms – large, carbon-absorbing phytoplankton – fell sharply during the first two decades of the study.

After sea ice retreated in 2017, diatom numbers began to recover in some regions, while smaller phytoplankton such as cryptophytes and haptophytes continued to grow.

In West Antarctica, however, diatom populations have continued to decline.

Not all phytoplankton are equal

Phytoplankton are the foundation of the Antarctic marine food web. Diatoms, haptophytes, and cryptophytes make up the bulk of the microscopic life in these waters.

Diatoms alone account for nearly half of the phytoplankton here, with haptophytes close behind.

But these organisms don’t all play the same role. Diatoms are heavy hitters when it comes to carbon.

Their hard silica shells trap carbon dioxide, and when diatoms die and sink, they carry that carbon to the ocean floor. They also feed krill – the tiny crustaceans that feed whales, penguins, and seals.

The smaller types, like haptophytes and cryptophytes, don’t store carbon as effectively. So a long-term shift away from diatoms could weaken one of the ocean’s most important carbon storage systems.

“If we observe a decrease in the number of diatoms, it is likely that the biological carbon pump will weaken, resulting in less carbon dioxide being transported to the deep sea,” said Hayward.

“Now more than ever, we need more research and observation to monitor the changes in this sensitive ecosystem. What’s happening at the microscopic level could impact the climate itself and needs our attention.”

Satellites track phytoplankton shifts

You might wonder how a satellite flying 815 kilometers above Earth can tell anything about microscopic plankton. It doesn’t see the organisms directly. Instead, satellites like Copernicus Sentinel-3 measure the light reflected off the ocean’s surface.

Changes in that light – especially in the green and blue parts of the spectrum – signal the presence of chlorophyll and other pigments used in photosynthesis.

Different phytoplankton groups have distinct pigment profiles. When combined with data from water samples, these color signals help scientists map where different phytoplankton are and how their populations are changing over time.

Climate, carbon, and the ocean

Phytoplankton extract carbon from the air, fuel entire ecosystems, and are closely connected to climate change. But long-term records of how these creatures function exist in short supply.

That is why ESA is creating a new project known as Phyto-CCI. It will utilize advanced satellite methods for tracking phytoplankton changes from space, and make it possible for scientists to comprehend their contribution to ocean health and the global climate.

As this research illustrates, the Southern Ocean is already in transition due to climate pressures. What will follow depends not only on ice and temperature – but also on these invisible microorganisms that underpin the entire food chain.

The full study was published in the journal Nature.

Image Credit: NASA Earth Observatory

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August 20, 2025
PM says relations with Japan ‘very important’

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SEOUL, Aug 20 (Yonhap/APP): Prime Minister Kim Min-seok said Wednesday relations with Japan are “very important” with many opportunities for mutual cooperation.

Kim made the remarks during a meeting with Japanese delegates visiting Seoul to attend the Korea-Japan Forum, as President Lee Jae Myung was set to visit Tokyo later this week for summit talks with Prime Minister Shigeru Ishiba.

“With the launch of the new administration, South Korea and Japan are moving forward on a future-oriented path,” Kim said. “The two countries have a very important relationship with many areas of mutual cooperation, and the president’s decision to visit Japan was made in that context.”

The Japanese delegates expressed Tokyo’s commitment to continue efforts in building “a more mature, robust and future-oriented” bilateral relationship.

The delegation included former Japanese Ambassador to South Korea Yasumasa Nagamine, acting chair of the forum, and Japanese lawmakers.

The Korea-Japan Forum is an annual forum launched in 1993 to promote high-level talks between the two countries.

Lee was set to depart for Tokyo for a summit with Ishiba, before traveling to Washington for his first summit with U.S. President Donald Trump on Aug. 25.

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August 20, 2025

Blog

Introduction

Materials and Methods

Patient Selection

Anaesthesia and Intraoperative Monitoring

Objectives and Outcomes

Statistical Analyses

Results

Study Population and Patient Characteristics

Incidence of Intraoperative Bradycardia

Discussion

Abbreviations

Data Sharing Statement

Acknowledgments

Author Contributions

Funding

Disclosure

References

Tucked in, flattened down and rounded out

Books

Contacts

Digital Color Meter

Disk Utility

Folders

iPhone Mirroring

Photos

Settings

Stickies

Text Edit

Introduction

Materials and Methods

Study Design

Data Collection

Endpoints

Ethics

Statistical Analysis

Results

Patient Characteristics

Incidence and Risk Factors of Dental-Related Issues

Incidence and Risk Factors of Acute Phase Reactions

Other Adverse Effect

Discussion

Conclusion

Acknowledgments

Funding

Disclosure

References

Detecting shifts in phytoplankton

Decline in diatoms

Not all phytoplankton are equal

Satellites track phytoplankton shifts

Climate, carbon, and the ocean