Category: 8. Health

Early diagnosis of ovarian cancer is critical because it significantly improves patient prognosis and survival rates. Currently, about 75% of patients are diagnosed at an advanced stage (stage III or IV), where survival rates drop to 40-50%. In contrast, Stage I diagnosis boasts an 80 to 90% survival rate. The main challenge lies in the difficulty of early detection, similar to pancreatic cancer, as conventional methods like imaging and CA125 lack sufficient sensitivity and specificity for early-stage disease.

Researchers, including Jesús Gonzalez Bosquet, MD, PhD, are exploring the use of DNA methylation patterns as markers for early diagnosis of ovarian cancer, detectable through a liquid biopsy from blood. This method aims to identify specific methylation changes in cell-free DNA (cfDNA) circulating in the blood, which could indicate the presence of cancer at an earlier stage.

“We did preliminary analysis in methylation in ovarian cancer. It turns out that there’s DNA floating in the blood that can be analyzed, and some of them is methylated. So potentially, methylation patterns in DNA could be a good marker for diagnosis of ovarian cancer,” explained Gonzalez Bosquet, who is an associate professor of obstetrics and gynecology and gynecologic oncology at the University of Iowa.

The researchers utilized a methylation chip analysis, specifically an Illumina Infinium MethylationEPIC BeadChip Array, which probes over 850,000 different methylation sites in the genome. They analyzed DNA collected from ovarian tumor samples and normal controls. To manage the vast number of variables, they employed machine learning and deep learning methodologies, including MethylNet for initial reduction, followed by univariate ANOVA analyses and multivariate lasso regression. This rigorous process allowed them to narrow down the most informative probes from over 850,000 to a highly predictive set of 9 probes.

“The difficult part is trying to reduce the numbers of variables,” said Gonzalez Bosquet. “So, we used some machine learning and deep learning methodology.”

This was a pilot case-control study that included 99 high-grade serous cancer (HGSC) tissue samples and 12 normal fallopian tube samples as controls from the University of Iowa’s Gynecologic Oncology Bank. The initial prediction models using MethylNet were highly accurate, achieving an area under the curve (AUC) of 100%. After optimization through variable reduction using ANOVA and lasso regression, a model with only 9 methylated probes also achieved an AUC of 100% in predicting HGSC.

Using a small number of probes, such as the 9 identified in this study, is advantageous for developing a practical diagnostic test. A model with fewer variables is less complex, more easily validated, and more feasible for clinical implementation. The initial methylation chip provided over 850,000 data points, which is impractical for a diagnostic test. By reducing this to 9 highly informative probes while maintaining high accuracy (AUC of 100% in the initial dataset), the researchers made significant progress towards a clinically usable test.

The predictive model was rigorously validated using several methods. First, it was validated in an independent dataset (GSE65820) from a different geographical location (Australia) with similar patient ancestry. The 11,167-probe model showed an excellent AUC of 98%, and the simplified 9-probe model achieved a very good AUC of 84% in this external validation. Additionally, the models were re-trained, validated, and tested using an independent machine learning analytic platform, TensorFlow, which also showed excellent performance.

Strengths of the study include the use of a well-annotated single-institution biobank, focusing on a homogeneous phenotype of high-grade serous cancer, and validating the model in an independent dataset from a different geographical location. The use of advanced AI and machine learning techniques for probe selection is also a notable strength.

Limitations include the relatively small and imbalanced sample size (99 cases vs 12 controls in the initial set, and even more imbalanced in the validation set), and the fact that the initial study used tissue samples rather than blood.

“One of the problems with ovarian cancer always have seen the false positives,” said Gonzalez Bosquet. “We need to now go to population study, try to identify this in blood first, then if we can then put it in a in a prospective trial to see if it’s if it’s valid in a prospective way.”

The “black box” effect of some deep-learning tools like MethylNet in variable selection was also noted by researchers, though mitigated by downstream analyses. The generalizability of the model might also be limited as it was tested in populations with similar backgrounds, suggesting a need for testing in more diverse populations.

The ultimate goal of this research is to develop a method that can be used for early detection of ovarian cancer using cfDNA from blood samples, ideally for population-level screening.

The next crucial steps involve transitioning from tissue analysis to population studies to identify these methylation markers in blood samples, conducting a prospective trial to validate the findings in a real-world setting, and optimizing the model’s performance in blood, with a diverse population of patients across all stages.

“It needs validation in real life to have really impact. As we know, with this environment, it is difficult to get funding. [But] we still insist on trying to get this further, because I think it’s a potential good mechanism for detection,” Gonzalez Bosquet said.

REFERENCE:

Bosquet JG, Wagner VM, Russo D, et al. Identifying ovarian cancer with machine learning DNA methylation pattern analysis. Sci Rep. 2025 Jul 1;15(1):20910. doi: 10.1038/s41598-025-05460-9.

Robert F Kennedy Jr, the US secretary of health and human services, defended his response to the largest measles outbreak in the US in 33 years in a new editorial, calling it an example of “what a focused” Centers for Disease Control and Prevention (CDC) “can achieve”.

Kennedy did so in a Wall Street Journal editorial published on Tuesday, which coincides with extreme tumult at the CDC and strong claims from a former employee that the secretary wasn’t even briefed on the measles outbreak.

In the piece, Kennedy praises his agency’s handling of the outbreak in west Texas, which hospitalized nearly 100 people and killed two children earlier this year.

He argued that the outbreak “ended quickly, proving the CDC can act swiftly with precision when guided by science and freed from ideology”, described the CDC’s response as “effective” and said that “effectiveness – not politics – will be the watchword of our leadership.”

The outbreak, which affected several states, was officially declared over by local officials on 18 August. Throughout the crisis, Kennedy faced criticism from some health experts who described his messaging as inconsistent. They pointed out that while he acknowledged the importance of the measles, mumps and rubella (MMR) vaccine, he also framed vaccination as a “personal choice” and promoted and endorsed alternative treatments such as vitamins and cod liver oil.

The editorial arrives amid growing calls for his resignation, triggered by a disastrous few weeks at the CDC. Last week, the White House abruptly fired CDC director, Dr Susan Monarez, claiming that she did not “align” with Donald Trump’s agenda. She also reportedly clashed with Kennedy over vaccine policy.

Her ousting triggered the resignations of several other senior CDC officials, including Dr Demetre Daskalakis, the former head of the National Center for Immunization and Respiratory Diseases at the CDC.

In a recent interview, Daskalakis even said that Kennedy has never been briefed by CDC experts on several health issues including measles, Covid-19 or the flu.

“No one from my center has ever briefed him on any of those topics,” Daskalakis told CNN. “Perhaps he has alternate experts that he may trust more than the experts at CDC that the rest of the world regards as the best scientists in the areas.

“He’s getting information from somewhere, but that information is not coming from CDC experts who really are the world’s experts in this area … and he’s not taking us up on several offers to brief him on these very important topics,” Daskalakis added.

On Wednesday morning, more than 1,000 current and former HHS employees signed a public letter demanding Kennedy’s resignation.

The letter accused Kennedy of putting US public health at risk and criticized his role in firing Monarez. It also blasts him for “appointing political ideologues” to influential vaccine policy positions, “refusing to be briefed by well-regarded CDC experts on vaccine-preventable diseases” and of “rescinding the FDA’s emergency use authorizations for Covid-19 vaccines”..

Earlier this week, nine former CDC officials penned a guest essay in the New York Times in which they called Kennedy’s leadership “unlike anything our country has ever experienced” and “unacceptable.”

They warned that his leadership “should alarm every American, regardless of political leanings” and said that “amid the largest measles outbreak in a generation, he’s focused on unproven treatments while downplaying vaccines”.

Last month, more than 750 current and former HHS staffers sent a separate letter to Kennedy, in the wake of the 8 August shooting at the CDC headquarters that killed a police officer. In that letter, the staffers accused him of fueling harassment and violence directed at government healthcare staff.

Despite the mounting pressure, Kennedy did not address Monarez’s firing, the subsequent resignations or the growing calls for his resignation in his editorial this week.

Instead, Kennedy defended the Trump administration’s role in what he described as “restoring public trust” in the CDC which he argued had been “corroded” in recent years by “bureaucratic inertia, politicized science and mission creep”.

Kennedy, who previously founded an anti-vaccine group, also criticized the CDC’s handling of the Covid-19 pandemic, calling it a “failure” and blasted policies such as social distancing, mask mandates, lockdowns, and “the suppression of low-cost therapeutics in favor of experimental and ineffective drugs”.

Kennedy is scheduled to testify before the Senate finance committee on Thursday for a hearing on Trump’s healthcare agenda, according to the committee website.

Investigators have identified the presence of at least 1 modifiable risk factor for birth defects in two-thirds of reproductive-aged women, publishing their findings in the American Journal of Preventive Medicine.¹

These findings included low red blood cell (RBC) folate concentrations in 1 in 5 women, diabetes in nearly 5%, obesity in 1 in 3, and tobacco exposure in nearly 1 in 5. Investigators stated that this data can be used to identify and challenge modifiable risk factors to reduce the risk of birth defects.¹

“The most significant finding—that two-thirds of women of reproductive age had at least one modifiable risk factor—highlights how common these changeable risk factors are. The good news is that they can be lowered,” said Arick Wang, PhD, epidemiologist at the CDC.¹

Assessing risk factors

Data from a US sample was obtained through household interviews and in-person health examinations.² Investigators also conducted 2 dietary-intake 24-hour recall interviews for each participant to complete. The collected data was categorized into 5 cycles of 2 years and 1 pre-pandemic cycle of 3.2 years, all from 2007 to March 2020.

Women of reproductive age (WRA) status was determined through self-reported sex and age, with reproductive age defined as 12 to 49 years. Patients with a positive pregnancy test or self-reporting pregnancy or lactation were excluded from the analysis.²

There were 5,374 nonpregnant, nonlactating WRA included in the final analysis, 66.4% of whom presented with at least 1 known risk factor of birth defects and 10.4% with 3 or more based on the all-risks profile. When assessing risks with the nonfolate risk profile, these rates were 59.1% and 6.3%, respectively.²

Nutritional supplement use and folate intake

Of WRA, 6.7% had very low food security, while consumption of FA-containing supplements was reported in approximately 28% and both FA- and B12-containing supplements in 27.2% Consumption of supplements with at least 400 µg/day of FA was reported in only 12.6%.²

When excluding supplement use, 98.7% of patients had FA intakes under 400 µg/day. RBC folate concentrations under 748 nmol/L were reported in 19.5%, obesity in 33.8%, diabetes in 4.8%, and prediabetes in 28.9%.²

An increasing trend of women with at least 1 known risk factor was observed over time, from 65.3% between 2007 and 2010 to 69.5% between 2015 and 2020. Rates of women with at least 1 nonfolate risk also rose from 55.3% to 64%, while the prevalence of RBC folate concentrations 748 nmol/L declined from 23.4% to 17.9%.²

Trends over time

Rates of very low food security, total FA intake under 400 µg/day, obesity, diabetes, and prediabetes increased over time, while rates of active tobacco use and daily FA intake over 400 µg/day decreased. A correlation was reported between age and presenting with at least 1 risk factor.²

Non-Hispanic Black and Hispanic patients were significantly more likely to present with at least 1 risk factor vs White patients, with rates of 80.4%, 70%, and 62.2%, respectively. For the nonfolate risk profile, these rates were 70.3%, 62.8%, and 56.2%, respectively.²

These results indicated a high prevalence of modifiable risk factors for birth defects among US women. Investigators concluded women should visit their physician before pregnancy to prevent adverse outcomes.²

“Every growing family hopes for a healthy pregnancy and healthy baby. Understanding modifiable risk factors for birth defects helps families, health care providers, and public health professionals make data-informed decisions that can lead to healthier pregnancies and babies,” said Wang.¹

References

1. Two thirds of reproductive-aged women have at least one modifiable risk factor for birth defects, study reveals. Elsevier. August 26, 2025. Accessed September 3, 2025. https://www.eurekalert.org/news-releases/1095031.
2. Wang A, Zauche LH, Crider KS. Trends and prevalence of modifiable risk factors for birth defects among US women of reproductive age: National Health and Nutrition Examination Survey 2007 to March 2020. American Journal of Preventive Medicine. 2025. doi:10.1016/j.amepre.2025.107947

Introduction

Sevoflurane is the most frequently administered inhaled anesthetic in pediatric patients owing to its hemodynamic stability, absence of airway irritation, and rapid induction and emergence.¹ Nevertheless, a significant limitation of sevoflurane anesthesia in this population is its association with emergence agitation and delirium, which has been reported to occur with an incidence ranging from 10% to 80%.² Pediatric emergence delirium (ED) is a complex psychomotor disturbance that commonly manifests during the early post-anesthesia period. It is defined by symptoms such as inconsolable crying, involuntary motor activity, restlessness, and disorientation.³ Although ED is typically transient and self-limiting, its occurrence may precipitate a range of postoperative complications, including self-injurious behavior, surgical wound dehiscence or hemorrhage, and the removal of indwelling catheters. Furthermore, ED substantially increases the length of stay in the post-anesthesia care unit (PACU), thereby creating significant challenges for medical staff and diminishing parental satisfaction.^4,5

The precise pathogenesis of ED remains elusive. Nevertheless, a variety of pharmacological interventions have been explored for the prevention or management of pediatric emergence delirium, including α2-adrenergic receptor agonists,⁶ sedatives,⁷ opioids,^8,9 and non-opioid analgesics. Nevertheless, the use of these drugs may result in adverse effects such as bradycardia, respiratory depression, postoperative nausea and vomiting (PONV), and delayed recovery. Given these concerns, it is highly valuable to investigate more suitable alternatives for the prevention of pediatric ED.

Remimazolam, a novel water-soluble ultra-short-acting benzodiazepine, has been safely utilized for sedation in pediatric procedures and for the induction and maintenance of general anesthesia.^10,11 Due to the activity of non-specific tissue esterases, it is subsequently rapidly hydrolyzed into a pharmacologically inactive carboxylic acid metabolite (CNS 7054). This characteristic confers the advantages of rapid onset and offset of sedation, as well as a predictable duration of action.¹² When utilized for anesthesia, remimazolam exhibits a mild inhibitory effect on respiration and circulation, and its sedative effects can be effectively reversed by flumazenil.¹³ Remimazolam exhibits a high clearance rate and a short context-sensitive half-life in pediatric patients. After normalization by body weight, its pharmacokinetic properties are comparable to those observed in adults, enabling the development of target-controlled infusion protocols.¹⁴

A study conducted by Yang et al demonstrates that administering 0.2 mg/kg of remimazolam at the conclusion of adenotonsillectomy under sevoflurane anesthesia can significantly reduce the incidence of ED.¹⁵ Additionally, the research by Cai et al indicates that either a continuous intraoperative infusion of remimazolam at 1 mg/kg/h or a single intravenous bolus dose of 0.2 mg/kg administered at the end of surgery can effectively decrease the incidence of ED in pediatric patients following laparoscopic surgery.¹⁶ Although remimazolam demonstrates considerable potential and advantages, its efficacy and role in preventing pediatric ED remain underexplored, particularly regarding the determination of the optimal dosage and administration protocol. Therefore, we aimed to determine the 90% effective dose (ED90) of remimazolam when continuously infused during surgery for preventing ED in children undergoing adenoidectomy or adenotonsillectomy under sevoflurane general anesthesia.

Methods

Study Design

This is a prospective, double-blind, sequential allocation dose-finding study. This study received approval from the Medical Ethics Committee of The Affiliated Women and Children’s Hospital of Ningbo University, China (Approval Number: EC2024-163; Approval Date: December 11, 2024). Prior to the enrollment of patients, we registered the clinical trial at the Chinese Clinical Trial Registry (Registration Number: ChiCTR2400094727; Principal Investigator: Zhongsai Yang; https://www.chictr.org.cn/showproj.html?proj=254654; Registration Date: December 26, 2024). Written informed consent was obtained from the parents or legal guardians of the children prior to their enrollment. This study was conducted in strict compliance with the principles outlined in the Declaration of Helsinki and clinical trial CONSORT.

Patients and Setting

We prospectively recruited patients aged 3–7 years with American Society of Anesthesiologists (ASA) Physical Status I or II who underwent adenoidectomy or adenotonsillectomy under general anesthesia at The Affiliated Women and Children’s Hospital of Ningbo University, located in Zhejiang Province, China, between January 2025 and February 2025. The exclusion criteria were as follows: preoperative respiratory tract infection; incidents in the recovery room (eg, airway spasm, wound bleeding, etc.); allergy to remimazolam; abnormal liver or kidney function; abnormal cardiac function; bradycardia (heart rate less than 60 beats per minute); neurological or psychiatric disorders, including patients with a history of epilepsy, developmental delay, or autism; a history of three or more surgeries; use of anticonvulsant, sedative, or analgesic drugs within two weeks; severe obstructive sleep apnea (apnea-hypopnea index ≥5.0); and declined to participate in.

Study Protocol

All patients were required to fast from solid food for 6 hours and clear liquids for 2 hours prior to surgery. A 22 gauge peripheral vein catheter was inserted in the preoperative preparation room. Upon entering the operating room, standard monitoring was initiated, comprising electrocardiogram (ECG), non-invasive blood pressure monitoring, pulse oximetry, and bispectral index (BIS) monitoring. Prior to anesthesia induction, atropine was administered at a dose of 0.01 mg/kg to inhibit airway secretions. For postoperative analgesia, flurbiprofen axetil was given at a dose of 1 mg/kg (with a maximum dose of 50 mg). To prevent postoperative nausea and vomiting, dexamethasone was administered at a dose of 0.1 mg/kg (maximum dose 5 mg), along with tropisetron at a dose of 0.1 mg/kg (maximum dose 5 mg). The anesthesia induction protocol consisted of propofol at 3 mg/kg, fentanyl at 3 μg/kg, and cisatracurium besilate at 0.1 mg/kg.

Following the successful induction of anesthesia, and once the child was fully muscle-relaxed and unconscious, an endotracheal tube was inserted. Remifentanil was administered via continuous infusion at a rate of 10 to 20 μg/kg/h, the concentration of sevoflurane was titrated within the range of 1% to 3%, and the target BIS value was maintained between 40 and 60. During the operation, vital signs were maintained within 20% of their baseline values through meticulous monitoring and timely interventions with adjustments in the dose of remifentanil and sevoflurane. The end-tidal carbon dioxide pressure (PetCO2) was maintained within the range of 35 to 45 mmHg by finely adjusting the respiratory rate and tidal volume of mechanical ventilation.

Atropine was administered to the patient when the heart rate (HR) decreased to less than 60 bpm. If the mean arterial pressure (MAP) dropped by more than 20% from the baseline value, the dosage of maintenance anesthetic drugs was adjusted accordingly. Additionally, norepinephrine or epinephrine was administered as needed to stabilize the patient’s condition based on the anesthesiologist’s discretion. When the MAP increased by more than 30% of the baseline value, clinicians implemented clinical intervention measures based on their professional experience to ensure the safe and successful completion of both anesthesia and surgery.

Upon completion of the surgery, the administration of maintenance anesthetic drugs was discontinued, and the child, with the endotracheal tube still in place, was transferred to the PACU.

In the PACU, once the child’s spontaneous respiration was fully recovered, neostigmine at a dose of 0.02 mg/kg and atropine at a dose of 0.01 mg/kg were administered as needed to antagonize any residual muscle relaxation. The endotracheal tube was extubated upon fulfillment of predefined criteria, specifically when the tidal volume was adequate (≥6 mL/kg) and the respiratory rate was at least 15 breaths per minute. Then, the child underwent close monitoring and evaluation in the PACU. Upon achieving an Aldrete score of 9 or higher, the child was transferred back to the ward under supervision.

Administration Management of Remimazolam Infusion and the Biased Coin Design Up-and-Down, Sequential Method (BCD-UDM)

Remimazolam was continuously infused from the initiation of anesthesia induction until 5 minutes before the conclusion of surgery, at which point the infusion was terminated. Based on the existing literature¹⁶ and the results of the preliminary experiment, the predetermined infusion rate of remimazolam for the first patient was set at 0.8 mg/kg/h, with a dose increment or decrement gradient of 0.1 mg/kg/h. Dose for next patient was based on the response of the previous patient using the BCD-UDM.¹⁷ In brief, if the dose administered to the previous patient is considered ineffective (defined as the dose that failed to prevent the patient from experiencing ED), the dose for the next patient will be increased by 0.1 mg/kg/h. Conversely, if the dose administered to the preceding patient is determined to be effective (defined as the dose that successfully prevented the occurrence of ED), the dose for the subsequent patient is established via randomization using the BCD-UDM method with the statistical software R (Γ=0.9). For the next patient, there is an 11% probability [b=(1-Γ)/Γ=0.11] that the remimazolam dose will be decreased by 0.1 mg/kg/h, while there is an 89% probability (1-b=0.89) that it will remain unchanged.

In accordance with the requirements specified in the remimazolam drug instruction manual, the upper limit of the dose for this study was determined to be 3 mg/kg/h. The study drug was prepared by a research assistant who was not involved in either the clinical management or the study. An anesthesiologist in the recovery room is responsible for ED assessment and management. This anesthesiologist, along with the patients and their guardians, was kept unaware of the dose of remimazolam administered.

Diagnosis and Management of Emergence Delirium During the Recovery Period

In the PACU, following extubation of the child’s endotracheal tube, a trained anesthesiologist evaluated the presence and severity of ED during the period from extubation until the child was transferred to the ward. The anesthesiologist systematically documented the corresponding data. If any signs of delirium or restlessness were observed during this period, the Pediatric Anesthesia Emergence Delirium (PAED) scale (Table S1) would be promptly employed for evaluation. A score of ≥10 points on the PAED scale indicates emergence delirium (ED), while a score of ≥15 points suggests severe ED.¹⁸ Additionally, the Face, Legs, Activity, Cry, Consolability (FLACC) scale (Table S2) would also be used to assess pediatric pain behavior. On the FLACC scale, a score of 0 indicates no pain and comfort, 1–3 points indicate mild pain, 4–6 points indicate moderate pain, and 7–10 points indicate severe pain.¹⁹

Diagnostic process for delirium: postoperative delirium is diagnosed when the PAED score is ≥10 and the FLACC score <4. When the PAED score is ≥10 and the FLACC score is ≥4, indicating moderate to severe pain in the patient, an intravenous injection of 0.1 μg/kg sufentanil is administered. Then, the PAED score is reassessed 5 minutes later. If the reassessed PAED score remains ≥10, ED is diagnosed, irrespective of the FLACC score. Additionally, if a child exhibits ED with a PAED score of ≥15 and the episode duration is ≥2 minutes, it is classified as severe ED.²⁰ If the child does not exhibit ED but the FLACC score is ≥4, rescue analgesics (0.1 μg/kg of sufentanil) are administered. If the patient is asleep, pain assessment is not performed. Patients diagnosed with delirium receive initial comfort measures. Should these measures prove ineffective, an intravenous injection of 1 mg/kg of propofol were administered for treatment and were repeated as necessary. The administration of rescue boluses of propofol and sufentanil was documented.

Data Collection and Outcome Assessment

The primary outcome was the effective or ineffective dose of remimazolam for preventing ED. Secondary outcomes were as follows: PAED scale, time of occurrence and interventions in patients with ED; FLACC scale and dose of rescued sufentanil; patients extubation time (defined as the time interval from the discontinuation of anesthetics to extubation), post-anesthesia recovery time (defined as the time from the discontinuation of anesthetics until the child reaches a fully conscious state, characterized by spontaneous eye opening, normal responses to questions, and compliance with movement instructions), as well as the duration of stay in the PACU (defined as the time interval from transfer to the PACU until departure from the PACU), as well as delayed recovery, which is defined as a length of stay in the PACU exceeding 120 minutes; the incidence of adverse effects during the intraoperative and postoperative recovery periods, such as hypotension, and bradycardia. In addition, the level of preoperative anxiety assessed by the Modified Yale Preoperative Anxiety Scale,²¹ the anesthesia duration, surgical procedure duration, volume of infused fluids, and concentration of sevoflurane were recorded. The demographic characteristics of patients, including gender, age, weight, height, and BMI, as well as the ASA score, type of surgery, and baseline blood pressure and heart rate, were also systematically recorded.

Statistical Analysis

In a dose-finding study employing the biased coin up-and-down design, the data distribution exhibits both non-independence and an unknown structure. Simulation analyses demonstrate that enrolling a minimum of 20 to 40 patients typically provides robust and reliable estimates of the target dose across the majority of scenarios. To account for potential dropouts and achieve a sufficiently narrow 95% confidence interval (95% CI), this study approximately determined a sample size of 52 pediatric patients.

Continuous data were assessed for normality using the Shapiro–Wilk test. Measurement data conforming to the normal distribution were expressed as mean ± standard deviation (Mean ± SD), and measurement data not conforming to the normal distribution were expressed as median (M) and interquartile range (IQR). Enumeration data were expressed as the number and percentage (%). The ED90 and 95% confidence interval of remimazolam were calculated via the isotonic regression method, which was used as the primary estimate. And Probit regression was also used as a backup estimate in this study. The Pearson χ2 goodness-of-fit test was used to evaluate the satisfaction of the probit model fitting the data. The GraphPad prism software (ver. 10.4.0) was used for graphing. The data processing and statistical analysis of this study were carried out using the SPSS software (ver. 29.0), and the BCD random sequence was generated using the R for Windows software (ver. 4.3.2).

Results

The patient recruitment and follow-up period extended from January 1, 2025, to February 28, 2025 (Figure 1). A total of 58 patients were assessed for eligibility. Among the participants, one patient had a neurological or psychiatric disorder (specifically, autism), two patients had upper respiratory tract infections with a fever exceeding 38 degrees Celsius, and three patients declined to participate in the study. Finally, a total of 52 patients were involved in the study, and all of them successfully completed the final analysis. The demographic and baseline characteristics of the patients are presented in Table 1.

Table 1 Demographic and Baseline Characteristics of the Patients

Figure 1 Study recruitment diagram.

The sequence of allocation, as well as the response to the administration of remimazolam, is illustrated in Figure 2. The estimated ED90 and 95% confidence interval [95% CI] of remimazolam for preventing ED in pediatric patients undergoing adenoidectomy or adenotonsillectomy under sevoflurane general anesthesia was 1.08 mg/kg/h (1.03–1.97 mg/kg/h) with the isotonic regression method and was 1.07 mg/kg/h (1.02–1.26 mg/kg/h) with Probit probability regression. The results of the Pearson goodness-of-fit χ2 test indicated that the probit model exhibited an adequate fit (P = 0.38).

Figure 2 Data of the sequential up-and-down responses of remimazolam for the prevention of ED. The starting dose is 0.80 mg/kg/h, and the dose increment is 0.10 mg/kg/h. Solid dots represent successful prevention of ED, while hollow dots represent failure of preventing ED.

Secondary results are shown in Table 2. The mean extubation time for the patients was 29.94 ± 6.53 minutes, the post-anesthesia recovery time was 45.96 ± 10.53 minutes, and the duration of stay in the PACU was 52.58 ± 9.82 minutes. During the study period, sufentanil rescue was administered in 3 patients (5.8%); hypotension was observed in 4 patients (7.7%) during the anesthesia process; there were no cases of nausea and vomiting, delayed recovery, bradycardia, or hypoxemia during post-anesthesia recovery time.

Table 2 Postoperative Outcomes and Complications

For patients who experienced ED, the infusion dose of remimazolam, PAED scores, the timing of ED occurrence, and the interventions administered to patients with ED were summarized in Table 3. A total of eight patients developed delirium, as indicated by a PAED score of ≥10. Among them, one child experienced severe delirium (PAED score ≥16), and four patients received propofol treatment for the management of delirium symptoms.

Table 3 Failure of Remimazolam in Preventing ED

Discussion

The main finding of this study is that the optimal dose of remimazolam for preventing ED in pediatric patients undergoing adenoidectomy or adenotonsillectomy under sevoflurane inhalation anesthesia is 1.08 mg/kg/h (95% CI: 1.03–1.97 mg/kg/h). Furthermore, no severe adverse effects were observed during remimazolam infusion within the dose range of 0.8–1.2 mg/kg/h in pediatric patients. To the best of our knowledge, this is the first time to explore the dose-response study of remimazolam in preventing ED in pediatric patients.

Currently, the precise pathophysiological mechanisms underlying post-anesthetic delirium in pediatric patients remain incompletely understood. Recognized high-risk factors include the use of sevoflurane inhalation, preoperative anxiety, unstable anesthetic induction, male sex, preschool age, parental anxiety, and certain types of surgeries (eg, craniofacial surgeries).²² In this study, we enrolled preschool pediatric patients aged 3 to 7 years who underwent adenoidectomy or adenotonsillectomy under sevoflurane anesthesia. Our results indicate that in 90% of this kind of population who did not experience ED, the infusion dose of remimazolam was 1.08 mg/kg/h. In addition, our results indicated that 4 out of 18 patients (22%, Figure 2) experienced ED at an infusion dose of 1.0 mg/kg/h, which is obviously higher than that reported by Cai et al¹⁶ in whose study the incidence of ED was 5% with remimazolam infusion dose at 1.0 mg/kg/h for pediatric patients who underwent laparoscopic inguinal hernia repair. Carefully comparing the protocols of the two studies, we acknowledged that the different types of surgeries might account for this discrepancy.

The results of current study suggest higher 1.1–1.2 mg/kg/h of remimazolam infusion dose produces less incidence of ED. Given that the pediatric patients in the current study were associated with several high-risk factors for the occurrence of ED during the anesthesia recovery period, we propose that selecting a more appropriate dose of remimazolam (approaching or a little higher than ED90) is particularly critical. This approach can effectively reduce the incidence of ED, alleviate the postoperative management burden on clinical anesthesiologists, and enhance the quality of postoperative recovery for pediatric patients. Additionally, we did not find any undesirable adverse adverse effect associated with high dose infusion in the current study. Therefore, our results suggest the dose of 1.1 and 1.2 mg/kg/h of remimazolam infusion are an effective and safety dose for the study population in the current study.

The precise mechanism by which remimazolam decreases the incidence of ED remains to be further elucidated. Prior investigations indicate that its potential protective effects may be attributed to a variety of factors, including sedative properties, agonistic effects on γ-aminobutyric acid (GABA) receptors, anti-inflammatory capabilities, vasodilatory actions, and antioxidant activities.²³ Nevertheless, the continuous administration of remimazolam during BIS-guided anesthesia can effectively reduce the requirement for sevoflurane, thereby decreasing the incidence of ED. However, this hypothesis needs to be further validated, despite the findings of a recent cohort study suggesting that the dose of sevoflurane was not associated with the severity or occurrence of delirium.²⁴ However, it should be noted that opioids, such as remifentanil, are frequently utilized in clinical anesthesia. Although the dosage in the current study is typically determined based on body weight, it remains unclear whether they interact with remimazolam or whether their combined use influences the risk of ED. Further investigation into this area is warranted.

In this study, our protocol specifies that the specific antagonist flumazenil was not used to reverse the effects of remimazolam for rapid awakening in children. The extubation time was 29.94 ± 6.53 min, and the recovery time was 45.96 ± 10.53 min, and no patients experienced delayed recovery, which is similar to prior studies¹⁶ indicating that infusion of remimazolam at the study dose does not affect the metabolic profiles and leads to delayed recovery.

A large number of studies have investigated the effects of remimazolam on the prevention and treatment of postoperative delirium across diverse populations, utilizing various protocols, doses, and delivery strategies. These studies recommend a broad infusion dose range of 0.1 to 3.0 mg/kg/h.^{15,16,25–30} In this study, we possess a distinct advantage in providing dose-response information for the prevention of ED within specific high-incidence populations. Although the ED90 was determined in this study, further investigations into the minimal effective dose for this population using the traditional up-and-down method could provide valuable insights for clinical reference.

When concerns regarding the safety of remimazolam in pediatric use were raised, a study conducted by Fang et al demonstrated that remimazolam exhibited good tolerability for inducing and maintaining general anesthesia in preschool-age children. It was also found to be non-inferior to propofol, with a lower incidence of adverse effects.¹⁰ Similar to prior findings, no other severe adverse events were observed in the current study, which reinforces the safety of remimazolam infusion in pediatric patients. However, caution should be paid when large doses are used in specific population.³¹

This study has several limitations. First, while this study determined the ED90 of remimazolam for preventing ED in preschool age children undergoing adenoidectomy or adenotonsillectomy, it was unable to account for potential confounding effects from other variables that might influence the results. Therefore, further studies are warranted to address various scenarios in clinical practice. Second, variations in anesthesia management protocols, particularly in postoperative pain management, might influence the ED90 results of remimazolam for preventing ED, thereby limiting the generalizability of these findings. Third, despite the integration of the FLACC score and the utilization of the PAED assessment scale for diagnosing delirium—both evaluated by a trained professional physician—the scoring system remains inherently subjective. Consequently, clearly differentiating between delirium and postoperative pain in the PACU poses a significant challenge, which may subsequently affect the results despite measures taken, such as pain management strictly adhering to the study protocol and the ED being reassessed via PAED assessment scale 5 minutes after a FLACC score of ≥4. Fourth, it should be noted that our study enrolled pediatric patients without specifically considering factors such as sex, surgical duration or preoperative anxiety, which may influence ED incidence and dose-response relationships. Further studies investigating the impact of these variables on the dose requirements of remimazolam for preventing ED may be warranted. Finally, the 95% CI of the ED90 lies outside the range of doses examined in this study, and therefore, this value was not directly observed. As a result, clinical application of this dose should be approached with caution. Further studies focusing on relatively higher doses in this area are warranted.

In preschool age children undergoing adenoidectomy or adenotonsillectomy under general anesthesia with sevoflurane, the ED90 of remimazolam for preventing emergence delirium during intraoperative continuous infusion was 1.08 mg/kg/h (1.03–1.97 mg/kg/h). However, cautions should be paid as the 95% CI of the ED90 lies outside the range of doses examined in this study.

Abbreviations

ED, emergence delirium; ASA, American Society of Anesthesiologists; PACU, post-anesthesia care unit; BMI, Body mass index; BIS, Bispectral index; PONV, postoperative nausea and vomiting.

Data Sharing Statement

The datasets generated during and/or analyzed during the current study are not publicly available due to the privacy policy but are available from the corresponding authors on reasonable requests.

Acknowledgment

The authors sincerely express their gratitude to the colleagues and faculty members from the Department of Anesthesiology, Affiliated Women and Children’s Hospital of Ningbo University, Ningbo, China, for their valuable contributions and support throughout the study.

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

There is no funding to report.

Disclosure

The authors declare that they have no competing interests.

References

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4. Mason KP. Paediatric emergence delirium: a comprehensive review and interpretation of the literature. Br J Anaesth. 2017;118(3):335–343. doi:10.1093/bja/aew477

5. Fu SH, Miao MR, Zhang LY, et al. Prophylactic application of dexmedetomidine reduces the incidence of emergence delirium in children: a systematic review and meta-analysis. Anaesth Crit Care Pain Med. 2024;43(6):101426. doi:10.1016/j.accpm.2024.101426

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9. He J, Zhang L, Tao T, et al. Nalbuphine reduces the incidence of emergence agitation in children undergoing Adenotonsillectomy: a prospective, randomized, double-blind, multicenter study. J Clin Anesth. 2023;85:111044. doi:10.1016/j.jclinane.2022.111044

10. Fang YB, Zhong JW, Szmuk P, et al. Safety and efficacy of remimazolam tosilate for general anaesthesia in paediatric patients undergoing elective surgery: a multicentre, randomised, single-blind, controlled trial. Anaesthesia. 2025;80(3):259–268. doi:10.1111/anae.16475

11. Lee JH, Lee J, Park SH, Han SH, Kim JH, Park JW. Comparison between remimazolam and propofol anaesthesia for interventional neuroradiology: a randomised controlled trial. Anaesth Crit Care Pain Med. 2024;43(2):101337. doi:10.1016/j.accpm.2023.101337

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13. Philip AB, Brohan J, Goudra B. The role of GABA receptors in anesthesia and sedation: an updated review. CNS Drugs. 2025;39(1):39–54. doi:10.1007/s40263-024-01128-6

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16. Cai YH, Zhong JW, Ma HY, et al. Effect of remimazolam on emergence delirium in children undergoing laparoscopic surgery: a double-blinded randomized trial. Anesthesiology. 2024;141(3):500–510. doi:10.1097/ALN.0000000000005077

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21. Liang Y, Huang W, Hu X, et al. Preoperative anxiety in children aged 2–7 years old: a cross-sectional analysis of the associated risk factors. Transl Pediatr. 2021;10(8):2024–2034. doi:10.21037/tp-21-215

22. Larsen LG, Wegger M, Lé Greves S, Erngaard L, Hansen TG. Emergence agitation in paediatric day case surgery: a randomised, single-blinded study comparing narcotrend and heart rate variability with standard monitoring. Eur J Anaesthesiol. 2022;39(3):261–268. doi:10.1097/EJA.0000000000001649

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25. Lu Y, Xu Q, Dai H, et al. Remimazolam for the prevention of emergence agitation in adults following nasal surgery under general anesthesia: a prospective randomized clinical controlled trial. BMC Anesthesiol. 2025;25(1):8. doi:10.1186/s12871-024-02875-1

26. Fujimoto D, Obata N, Mizobuchi S. Effectiveness of remimazolam in preventing postoperative delirium in elderly patients with proximal femoral fractures. J Anesth. 2024;38(4):475–482. doi:10.1007/s00540-024-03339-z

27. Fang PP, Hu J, Wei QF, et al. Effect of remimazolam besylate vs propofol on incidence of postoperative delirium in older patients undergoing Hip surgery: a randomized noninferiority trial. Int J Surg. 2025;111(1):1469–1472. doi:10.1097/JS9.0000000000001908

28. Deng Y, Qin Z, Wu Q, et al. Efficacy and safety of remimazolam besylate versus dexmedetomidine for sedation in non-intubated older patients with agitated delirium after orthopedic surgery: a randomized controlled trial. Drug Des Devel Ther. 2022;16:2439–2451. doi:10.2147/DDDT.S373772

29. Zhang J, Zhang J, Wang Y, et al. Effect of remimazolam vs propofol on emergence from general anesthesia in patients undergoing cerebral endovascular procedures: a randomized controlled, non-inferiority trial. J Clin Anesth. 2024;93:111356. doi:10.1016/j.jclinane.2023.111356

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WASHINGTON, D.C. – The Golden Goose Award, which spotlights obscure, silly sounding or odd fundamental discovery research that has led to outsized societal benefits, has announced awardees for the 14th annual season:

• Testicular Cancer Treatment: Researchers explored electric fields affecting cell division in E. coli bacteria that inadvertently led to the drug cisplatin, which has resulted in a 90% survival rate (up from 10%) for patients with testicular cancer — largely giving affected men aged 15-35 a new lease on life.
• Disease Diagnostics: The “father of modern cell biology” who studied nature’s oddities (e.g., pond scum and frog egg cells) informed disease diagnostics and mentored award-winning scientists, including a Nobel Prize winner. 

Former U.S. Representative Jim Cooper (D-TN) inspired the creation of this award as a strong counterpoint to criticisms that fundamental discovery research was wasteful federal spending. Almost a decade and a half later, these awardees exemplify what is at stake as the U.S. administration’s budget request seeks to cut this type of research by about one third. Congress has until September 30 to determine fiscal year 2026 funding levels for research and development amid disruptions to funding disbursements for the current fiscal year. 

“The Golden Goose awardees definitively demonstrate that federally funded American science continues to deliver for all of us. These discoveries show that American science is anything but stagnant. AAAS and the American people will continue to support federal investment in research that can make us healthier, safer, and stronger,” said Sudip S. Parikh, chief executive officer at AAAS and executive publisher of the Science family of journals. 

This year, U.S. Representative Jay Obernolte (R-CA) joins the bipartisan, bicameral “Gaggle of Supporters” on Capitol Hill. 

On September 16, 2025, the American Association for the Advancement of Science, one of the world’s largest multidisciplinary scientific societies, and the Association of American Universities will co-host the Golden Goose Award Ceremony at the Library of Congress.

This year’s awardees are:

Cisplatin Breakthrough Redefines Testicular Cancer Treatment
Awardees: Barnett Rosenberg, Loretta VanCamp, and Thomas Krigas
Research funded by: National Institutes of Health, National Science Foundation

Barnett “Barney” Rosenberg wasn’t a cancer researcher — but he and his lab team helped unlock a breakthrough cancer treatment. In the 1960s, Rosenberg, working with lab technician Loretta VanCamp and a team of graduate students including Thomas Krigas, examined how electric fields affect cell division in E. coli bacteria. To their surprise, the bacteria stopped dividing and instead elongated into long, spaghetti-like shapes — a striking, unexplained phenomenon they investigated further. After a couple years of follow-up experiments, they discovered the true cause: platinum compounds released from the electrodes, not the electric field itself. This serendipitous finding led to the development of cisplatin, a platinum-based chemotherapy drug approved in 1978. At the time, the idea of using a metal-containing compound in medicine was unconventional and met with skepticism due to concerns over toxicity to humans. After harmful side effects were mitigated, cisplatin was approved and delivered unprecedented results — most notably, increasing the survival rate for testicular cancer from around 10% to over 90%. Its success transformed cancer treatment and has saved countless lives.

Nature’s Oddities Inform Disease Diagnostics and Inspire Prize-Winning Scientists
Awardee: Joseph G. Gall
Research funded by: National Institutes of Health, National Science Foundation

Cell biologist Joseph Gall’s lifelong curiosity about the planet’s array of life forms instilled in him a flair for coming up with the perfect organisms to conduct biological experiments. Among his many accomplishments: Working with frog egg cells (oocytes), he co-developed a technique called “in situ hybridization,” which has since been widely used in scientific research and disease diagnostics. In another set of experiments, Gall’s suggestion of Tetrahymena, a single-celled “pond scum” organism, as a model paved the way for landmark discoveries involving stretches of DNA called telomeres, which have enhanced our understanding of aging. Beyond the knack for nature’s oddities that helped guide his and his colleagues’ scientific research, Gall was renowned as a mentor, particularly for women scientists at a time when it wasn’t the norm, and several highly accomplished, prize-winning scientists have come through his lab.

The Golden Goose Award is grateful for the support of sponsors, including Wiley, a global knowledge company and a leader in research, publishing, and knowledge solutions.

 

Patients treated with de-escalated adjuvant radiation therapy (DART) exhibited lower cumulative rates of toxicity vs patients with standard of care therapy for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), according to findings from the open-label, phase 3 MC1675 trial (NCT02908477) published in The Lancet Oncology.¹

Among patients treated with de-escalated radiation therapy (n = 125) or standard of care adjuvant therapy (n = 61) were included in the primary analysis, the cumulative chronic grade 3 or higher toxicity rate from 3 to 24 months of treatment was 3% and 11%, respectively (P = .042). Additionally, the cumulative chronic percutaneous endoscopic gastric (PEG) tube rate was 2% vs 8% (P = .039).

The most common grade 3 late toxic effects in the DART arm included 2 instances of dysphagia, and single instances of hearing impairment and esophagitis. In the standard of care arm, the most common grade 3 late toxic effects included 5 instances of dysphagia, and individual occurrences of dry mouth, fatigue, esophagitis, osteonecrosis of the jaw, peripheral motor neuropathy, and generalized pain.

The 2-year overall survival (OS) rate in the DART and standard of care groups were 96.9% (95% CI, 93.9%-99.9%) vs 98.3% (95% CI, 95.0%-100%) with an HR of 1.68 (95% CI, 0.36-7.95; P = .51). The 2-year progression-free survival (PFS) rates were 88.2% (95% CI, 82.7%-94.0%) vs 96.6% (95% CI, 92.0%-100%), with an HR of 4.76 (95% CI, 1.11-20.40; P = .0203).

A post hoc analysis revealed that stratification factors, including extranodal extension and smoking history, remained significant (P = .025; P = .031). Among patients with negative extranodal extension, the cumulative chronic grade 3 or higher toxicity rate in the DART cohort was 4% vs 13% in the standard of care group and 3% vs 11% in the positive extranodal extension group.

“[The phase 3 MC1675 trial] demonstrated that a reduced post-operative dose of de-escalated adjuvant radiation therapy DART) for patients with HPV-associated oropharynx [SCC] yielded significantly lower toxicity and improved patient quality of life compared with standard of care adjuvant treatment, a finding that persisted even at 2 years after treatment,” Daniel J. Ma, MD, head and neck radiation oncologist in the Department of Radiation Oncology and co-leader of the Oropharynx Multi-disciplinary Clinic at Mayo Clinic, wrote in a written statement to CancerNetwork®. “Disease control with DART was also excellent for appropriately selected patients, particularly those without extranodal extension. Importantly, MC1675 also demonstrated that patients with more involved lymph nodes (pN2) were at greater risk for distant disease and should not be de-escalated.Future work will concentrate on biological biomarkers to determine the best patients for treatment de-escalation.”

Patients 18 years and older with American Joint Committee on Cancer (AJCC) 7^th edition pathological stage III to IV HPV-associated OPSCC were enrolled and randomly assigned 2:1 to receive DART (n = 130) or standard of care (n = 64), with 125 and 62 patients, respectively, included in the primary analysis. Patients were stratified by the presence of extranodal extension and smoking history, defined as less than 10 packs per year or at least 10 packs per year.

DART consisted of 30 to 36 Gy in 1.5 to 1.8 Gy fractions twice daily over 2 weeks and 15 mg/m² of intravenous docetaxel on days 1 and 8. Standard of care consisted of 60 Gy in 2 Gy fractions once daily over 6 weeks and 40 mg/m² once weekly intravenous cisplatin. The primary analysis was conducted among patients who received treatment and had no data missing.

The primary end point of the trial was a chronic cumulative grade 3 or higher toxicity rate. Secondary end points included disease-free survival, OS, PFS, locoregional disease control, distant metastasis-free survival, and quality of life.

In the DART and standard of care arms, the median age was 59.4 years (range, 37.9-81.6) vs 59.2 years (range, 48.0-72.5), and 88% vs 91% were male. Patients were most commonly White (94% vs 95%) and non-Hispanic (90% vs 91%). Additionally, most patients had AJCC 7^th edition N1 disease (58% vs 66%), T2 disease (50% vs 45%), and no smoking history (72% vs 72%).

Reference

Ma D, Price K, Moore E, et al. De-escalated adjuvant radiotherapy versus standard adjuvant treatment for human papillomavirus-associated oropharyngeal squamous cell carcinoma (MC1675): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2025;26(9):1227-1239

Introduction

Etiology of acute vestibular syndrome (AVS) can be classified into peripheral vestibular and central lesions. The former primarily involves the peripheral vestibular structures (inner ear and vestibular nerve), such as vestibular neuritis and migraine, accounting for over 75% of AVS cases.¹ The latter may affect central vestibular structures, including the vestibular nerve nuclei, the root of the eighth cranial nerve at the ponto-medullary junction, the cerebellar flocculus, and the nodulus. These structures participate in controlling the perception of head and body movements, generating vestibular-driven eye movements, processing visual signals, and maintaining balance and posture.^2,3 Therefore, dysfunction of the central vestibular system can lead to dizziness, vertigo, oculomotor disturbances, and postural instability. Central AVS (eg, stroke) account for approximately 20% of all AVS cases.⁴ Central AVS is most commonly vascular in origin, primarily caused by ischemic stroke within the vertebrobasilar artery system,⁵ and it can often present solely as isolated vertigo, making it difficult to recognize during initial diagnosis.⁶ This article provides a detailed overview and summary of the recent diagnostic strategies and advances in clinical and laboratory testing for central AVS of a vascular cause, aiming to enhance clinicians’ understanding of such disease and improve their ability to make differential diagnoses.

Risk Factors of Central AVS

In neuro-otology outpatient clinics, approximately one-quarter of patients with vertigo have central AVS.⁷ Central AVS constitutes 20%-30% of posterior circulation ischemic strokes, with vertigo or dizziness as the dominant manifestation.⁸ While cases with neurological signs are easily recognized, isolated vertigo poses diagnostic challenges due to its mimicry of peripheral vestibular disorders (eg, vestibular neuritis).^9–12 Notably, 19%-42% of posterior circulation ischemia cases present with isolated vertigo,^13,14 and 20% lack focal neurological signs.¹⁴ In emergency departments, central vascular lesions account for approximately 3% of AVS patients.¹⁵ Comorbidities like atrial fibrillation or diabetes increase stroke risk sevenfold.¹⁶ Despite extensive emergency evaluations,¹⁷ emergency evaluations miss 35% of strokes,^18,19 partly due to false-negative MRI-DWI results in 50% of minor stroke-related isolated vertigo cases.²⁰

Patients diagnosed with peripheral vertigo had a significantly higher risk of ischemic stroke than propensity score-matched controls with renal colic (50-fold higher at 7 days; RR=9.3 at 30 days).²¹ And 0.4%-1.5% experiencing ischemic events within a year.²² Overreliance on dizziness classification systems and imaging,²³ coupled with unstandardized bedside exams,²³ perpetuates diagnostic errors. These findings underscore isolated vertigo as a critical “red flag” for central AVS, demanding vigilance even without classic signs or positive initial imaging.^14,20,24

Diagnostic Strategies for Central AVS

Clinical History Characteristics Aid in Diagnosis

For the differential diagnosis of central AVS, it is essential to thoroughly collect the patient’s clinical history and conduct detailed neurological examinations along with bedside tests. Traditionally, excessive emphasis has been placed on categorizing dizziness into specific types—such as vertigo (vascular), presyncope (cardiovascular), episodic (neurological), and nonspecific (psychiatric, metabolic)—to guide diagnosis. This approach has led to numerous cases of central AVS being missed or misdiagnosed.²⁵

Recently, a rapid bedside diagnostic approach, the Triage, Timing, Targeted Examination algorithm (TiTrATE) method, has been proposed.²⁶ It classifies dizziness and vertigo based on the timing of onset (episodic or continuous), trigger factors (such as positional changes), and then conducts a Targeted Exam of eye movements to differentiate between peripheral and central AVS. In emergency patients presenting with intermittent or continuous dizziness, based on the timing and triggering factors from the clinical history, three syndromes may arise: 1) AVS: bedside examination helps differentiate vestibular neuritis from stroke. 2) Spontaneous episodic vestibular syndrome: Clinical history aids in distinguishing vestibular migraine from transient ischemic attack. 3) Triggered episodic vestibular syndrome: the Dix-Hallpike and roll test can be used to differentiate benign paroxysmal positional vertigo (BPPV) from central positional nystagmus caused by posterior fossa lesions.

All these three vestibular syndromes can be caused by vascular diseases, such as transient ischemic attack, ischemic, and hemorrhagic stroke^27,28 (Table 1).

Table 1 Vascular Factors Leading to Four Types of Acute Vestibular Syndromes

Vestibular and Oculomotor Bedside Examinations

When a patient presents with AVS accompanied by other neurological symptoms and signs, stroke can be diagnosed in most cases, even without neuroimaging. However, central AVS with subtle neurological deficits may be undetectable by MRI, presenting a diagnostic challenge even for specialists.²⁹ Recent advances in clinical neurology suggest that systematic bedside evaluation is more advantageous for identifying AVS caused by posterior circulation ischemia than neuroimaging.³⁰ Key vestibular and oculomotor examinations include various nystagmus examinations, the head impulse test (HIT), HINTS bedside test, and other diagnostic approaches.

Various Nystagmus Examinations

Simple downbeat, upbeat, or torsional nystagmus is a significant feature of central vestibular lesions. Other forms of central nystagmus include periodic alternating nystagmus,³¹ see-saw or hemi-see-saw nystagmus,^32,33 and acquired pendular nystagmus.³⁴ Gaze-evoked nystagmus, which changes direction in the horizontal or vertical plane, often indicates impaired integration within the central nervous system network.³⁵ Intense, paradoxical downbeat nystagmus following horizontal head shaking is commonly seen in central lesions, such as stroke, degenerative diseases, and drug intoxication.³⁶ However, the direction of head-shaking nystagmus (HSN) depends on the location and extent of the central lesion, either ipsilateral or contralateral.^37,38 Intense horizontal HSN is frequently observed in lateral medullary infarctions.³⁹ A recent study suggests that enhanced anterior semicircular canal pathway responses may contribute to paradoxical downbeat HSN, representing one of the mechanisms of central lesions.⁴⁰

In both central and peripheral vestibular diseases, positional changes can induce or modulate spontaneous nystagmus. Since central positional nystagmus can resemble the positional nystagmus of BPPV,⁴¹ central lesions should be suspected in patients with persistent positional nystagmus despite repeated canalith repositioning maneuvers.⁴² Particularly in cases of nodular and uvular damage, secondary vestibular neurons’ responses to irregular afferent signals may be enhanced, leading to increased post-rotational signals and resulting in paroxysmal positional nystagmus.⁴³

Head Impulse Test (HIT)

The bedside HIT is an effective tool for distinguishing central AVS from benign inner ear diseases.^44,45 It tests the vestibulo-ocular reflex (VOR) by turning the head rapidly to one side. A positive HIT, characterized by reduced VOR gain with corrective saccades, indicates peripheral vestibular hypofunction.⁴⁶ Lee et al⁴⁷ found that patients with isolated cerebellar infarctions consistently had normal bedside HIT results. However, when lesions involve specific central vestibular structures such as the vestibular nuclei,^48,49 flocculus,^50,51 or nucleus prepositus hypoglossi (NPH),⁵² a positive HIT may be observed. Involvement of the unilateral flocculus or NPH often results in more prominent VOR gain reduction on the healthy side than on the affected side^52,53 (Table 2). A recent report indicated that approximately 20% of patients with posterior inferior cerebellar artery or superior cerebellar artery infarctions exhibited decreased VOR gain on the side contralateral to the lesion, with bilateral mean HIT gain of around 0.75, and 80% of these patients had abnormalities.⁵⁴ Therefore, although a negative HIT strongly suggests central AVS, a positive HIT is not an absolute marker of peripheral vestibular lesions. Moreover, other abnormal HIT patterns indicating central lesions include hyperactivity (increased gain with reverse corrective saccades) and paradoxical responses (upward eye movements during head turns with downward corrective saccades), previously reported in patients with diffuse cerebellar dysfunction.^40,55

Table 2 HIT Manifestations in Central Vestibular Structure Lesions

HINTS Bedside Test

The HINTS examination includes HIT, nystagmus assessment, and the test of skew.⁴⁴ Several studies have demonstrated that HINTS results are highly specific for distinguishing central from peripheral vertigo and are even more sensitive than early MRI-DWI, particularly in diagnosing lacunar infarction.⁵⁶ A study by Choi et al in Korea reported the use of HINTS in 34 patients with AVS caused by lacunar infarction, identifying central eye movement abnormalities in 33 cases, even though initial MRI-DWI scans in six patients did not detect lesions.⁵⁷ That same year, Kim et al conducted HINTS examinations on 91 AVS patients, with 7 of 8 stroke patients displaying central HINTS findings.⁵⁸

It’s noteworthy that HINTS is limited in its ability to detect anterior inferior cerebellar artery (AICA) infarction, with a false-negative rate of 17–29%.⁵⁹ This is because AICA supplies the inner ear and structures like the flocculus, and infarction in this region can result in both central and peripheral vestibular deficits.⁶⁰ A previously reported case of isolated unilateral flocculus infarction showed an increase in low-frequency horizontal VOR gain and decreased VOR gain during high-frequency stimuli. Despite HINTS often being normal in patients with central vestibular lesions, a positive HIT does not rule out cerebellar involvement affecting the flocculus.⁶¹ Therefore, in elderly patients with sudden onset of unilateral hearing loss and vertigo, particularly in the presence of vascular risk factors, isolated labyrinth infarction should be considered. Incorporating horizontal head-shaking and finger-rubbing hearing tests (HINTS plus) is helpful in detecting central lesions, proving more convenient and effective than repeat MRI scans.⁵⁷

Other Diagnostic Approaches

In addition to HINTS, other methods for diagnosing central AVS have been proposed. A retrospective study found that assessing gait and balance is crucial for ruling out AVS.⁶² Although normal gait does not exclude cerebellar infarction, abnormal gait is a significant clue for diagnosing cerebellar stroke.⁶³ The ABCD2 score—accounting for age, blood pressure, clinical features, duration, and diabetes—is used to predict stroke risk in AVS patients. It was shown that 8.1% of AVS patients with a score ≥4 developed a stroke, increasing to 27% with a score of6−7.⁶⁴ However, HINTS is superior to the ABCD2 score in evaluating stroke risk in AVS patients.⁶⁵ Additionally, the recently reported the Triage plus Gait (TriAGe+) score, which includes eight variables [no triggers (2), atrial fibrillation (2), male (1), blood pressure >140/90 (2), brainstem or cerebellar dysfunction (1), focal weakness or speech disturbance (4), dizziness (3), no history of dizziness/vertigo or labyrinth/vestibular disease (2)], has proven to be more sensitive than the ABC Vestibular and oculomotor bedside examinations D2 score. With a score of 10, the sensitivity reaches 83.4%.⁶⁶ A Posterior Circulation Ischemia (PCI) Risk Score specifically designed to assess the risk of posterior circulation stroke was developed in 2018 with higher sensitivity and specificity, and is particularly well used in patients with dizziness as a primary symptom. The PCI scale diagnosed posterior circulation stroke with a much higher sensitivity and area under the receiver operating characteristic curve value (0.82) than the ABCD2 score (0.69).⁶⁷ Another scale that screens AVS symptoms such as imbalance, floating sensation, nonspecific dizziness, unsteadiness, and vertigo showed a sensitivity of 100%, significantly reducing the risk of misdiagnosis in AVS.⁶⁸ A new scale was recently developed. The Sudbury Vertigo Risk Score [Male (1), Age>65 (1), Diabetes (1), Hypertension (3), Motor/sensory (5), Cerebellar (6), BPPV diagnosis (−5)] effectively identifies the risk of a serious diagnosis in patients with dizziness. The risk of a serious diagnosis ranged from 0% for a score of <5 to 16.7% for a score >8. Sensitivity for a serious diagnosis was 100% and specificity was 69.2% for a score <5.⁶⁹

Certain laboratory tests have been reported to be significant indicators for diagnosing AVS patients. The neutrophil-to-lymphocyte ratio (NLR) has become a widely used marker. An NLR >2.8 combined with the absence of horizontal nystagmus is a specific indicator for diagnosing stroke in AVS patients.⁷⁰ Elevated neuron-specific enolase levels in AVS patients are also independently associated with stroke.⁷¹

For years, the relationship between stroke risk factors and AVS has been a research focus. Univariate analysis has shown that age, diabetes, coronary artery disease, atrial fibrillation, and a history of dizziness are statistically significant.⁷² Bi et al also proposed that AVS patients with three or more risk factors (male, age >60, hypertension, diabetes, smoking, and a history of stroke) have a significantly higher risk of posterior circulation infarction.¹⁷ In addition to these factors, Kim et al demonstrated that in multivariate models, imbalance and extracranial atherosclerosis are independent risk factors for posterior circulation infarction⁷³ (Table 3).

Table 3 Diagnostic Methods for Central AVS

Imaging Diagnosis

The sensitivity of computed tomography (CT) in detecting posterior circulation infarction is relatively low, only 16%.^76,77 Diffusion-weighted imaging (DWI) in MRI can detect 80% of infarct lesions. However, it is important to note that within 24–48 hours of onset, 15–20% of posterior circulation infarctions may be missed on MRI scans.⁷⁸ Perfusion-weighted imaging (PWI) helps identify posterior circulation ischemia, especially in patients with initial DWI-negative results. In a prospective cohort study, 12 out of 26 posterior circulation infarction patients presenting with AVS who were DWI-negative had decreased PWI perfusion. The sensitivity of combining HINTS plus balance testing reached 83%, and further integration with PWI improved the sensitivity to 100%. This shows that the combination of neurological and neuro-otological assessments (neurological examination + HINTS plus + balance test) with PWI can accurately identify posterior circulation infarction in patients presenting with AVS.⁷⁹

When a vascular cause is suspected, neurosonography offers a non-invasive method to assist in diagnosis. In a study using duplex ultrasound of the vertebral artery, 25% (27/108) of AVS patients were diagnosed with posterior circulation infarction through ultrasound, showing that while the sensitivity of neurosonography is not high (40.7%), its specificity (100%), positive predictive value (100%), and negative predictive value (83.5%) are favorable⁷⁵ (Table 3).

Conclusions

Central AVS remains a diagnostic challenge, particularly when presenting as isolated vertigo without overt neurological deficits. This review highlights the critical importance of integrating clinical history, targeted bedside examinations (eg, HINTS, nystagmus assessments), and multimodal imaging to differentiate central AVS from peripheral vestibular disorders. Key findings include: 1) Bedside evaluation superiority: systematic oculomotor testing (eg, HINTS) demonstrates higher sensitivity than early MRI-DWI for detecting posterior circulation strokes, especially in lacunar infarctions. 2) Pitfalls in imaging: up to 20% of posterior circulation infarctions may be missed on initial MRI-DWI, necessitating adjunctive techniques like PWI or neurosonography when clinical suspicion persists.3) Complex vestibular pathways: lesions in specific central structures (eg, vestibular nuclei, flocculus) can mimic peripheral vestibular dysfunction, underscoring the need for nuanced interpretation of tests like the HIT. 4) Risk stratification tools: Scores such as TriAGe+ and PCI scale improve early identification of stroke risk in AVS patients, complementing traditional ABCD2 assessments. Although posterior circulation strokes account for the majority of central AVS cases, anterior circulation involvement (particularly insular, frontal, or parietal lesions) may rarely present with isolated vertigo, posing diagnostic challenges. AVS is not only seen in the posterior circulation but can also be seen in the anterior circulation.

It is critical to prioritize bedside examinations despite negative imaging, maintain high suspicion for central AVS in patient population at high-risk of stroke, and adopt a stepwise diagnostic algorithm to optimize outcomes. Moving forward, a multidisciplinary approach—combining advanced neuroimaging, laboratory biomarkers (eg, NLR), and dynamic follow-up—is essential to reduce misdiagnosis rates. Future research should focus on validating rapid diagnostic protocols and exploring the role of emerging technologies (eg, AI-assisted oculomotor analysis) in AVS management.

Acknowledgments

We gratefully appreciate all the participants and staff for their contributions.

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 study was funded in part by the Project of Aerospace center hospital under Grant YN202411(Corresponding author: Zhirong Wan).

Disclosure

The authors report no conflicts of interest in this work.

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