Category: 8. Health

Despite concerns about cognitive decline after cancer treatment, most breast cancer survivors show no increased risk of developing Alzheimer’s disease, and some may have a slightly lower risk than their cancer-free peers, according to a large retrospective study from Korea.

However, any apparent protective effect faded with time, the investigators reported online in JAMA Network Open.

Overall, this is “reassuring news for cancer survivors,” Tim Ahles, PhD, a psychologist with Memorial Sloan Kettering Cancer Center, New York City, who wasn’t involved in the study, told Medscape Medical News.

“I get this question from patients a lot,” Ahles said. And based on these findings, “it doesn’t look like a history of breast cancer and breast cancer treatment increases your risk for Alzheimer’s disease.”

Breast cancer survivors often report cancer-related cognitive impairment, such as difficulties with concentration and memory, both during and after cancer treatment. But evidence surrounding patients’ risk for Alzheimer’s disease is mixed. One large study based in Sweden, for instance, reported a 35% increased risk for Alzheimer’s disease among patients diagnosed with breast cancer after the age of 65 years, but not among younger patients. A population-based study from Taiwan, however, found no increase in the risk for dementia overall compared with cancer-free individuals but did note a lower dementia risk in patients who had received tamoxifen.

To help clarify the evidence, investigators assessed Alzheimer’s disease risk in a large cohort of patients and explored the association by treatment type, age, and important risk factors.

Using the Korean National Health Insurance Service database, the researchers matched 70,701 patients who underwent breast cancer surgery between 2010 and 2016 with 180,360 cancer-free control individuals.

The mean age of breast cancer survivors was 53.1 years. Overall, 72% received radiotherapy. Cyclophosphamide (57%) and anthracycline (50%) were the most commonly used chemotherapies, and tamoxifen (47%) and aromatase inhibitors (30%) were the most commonly used endocrine therapies.

The primary outcome of this study was the incidence of newly diagnosed Alzheimer’s disease, which was defined on the basis of at least one prescription for medications to manage dementia associated with Alzheimer’s disease (donepezil, rivastigmine, galantamine, or memantine).

During a median follow-up of about 7 years, 1229 newly diagnosed Alzheimer’s disease cases were detected in breast cancer survivors and 3430 cases in control individuals — incidence rates of 2.45 and 2.63 per 1000 person-years, respectively.

This corresponded to an 8% lower risk for Alzheimer’s disease in breast cancer survivors compared with cancer-free control individuals at 6 months (subdistribution hazard ratio [SHR], 0.92; 95% CI, 0.86-0.98). The association was especially notable in survivors older than 65 years (SHR, 0.92; 95% CI, 0.85-0.99).

Looking at individual treatment modalities, only radiation therapy was associated with significantly lower risk for Alzheimer’s disease among breast cancer survivors (adjusted HR [aHR], 0.77).

Several risk factors were associated with a significantly higher risk for Alzheimer’s disease: current smoker vs never or ex-smokers (aHR, 2.04), diabetes (aHR, 1.58), and chronic kidney disease (aHR, 3.11). Notably, alcohol use, physical activity level, and hypertension were not associated with Alzheimer’s disease risk.

However, any potential protective effect may be short-lived. The reduced risk for Alzheimer’s disease was no longer significant at 1 year (SHR, 0.94; 95% CI, 0.87-1.01), 3 years (SHR, 0.97; 95% CI, 0.90-1.05), or 5 years (SHR, 0.98; 95% CI, 0.89-1.08).

Even so, breast cancer survivors can still feel reassured by the findings.

“Concerns about chemobrain and the long-term adverse effects of breast cancer treatment on cognition are common, but our findings suggest that this treatment does not directly lead to Alzheimer’s disease,” wrote the authors, led by Su-Min Jeong, MD, with Seoul National University College of Medicine, Seoul, South Korea.

Ahles agreed. The general takeaway from this study is that there is “no strong evidence that the cancer treatment is going to increase your risk for developing Alzheimer’s,” Ahles said. When patients ask about the risk for Alzheimer’s disease, “I can say, ‘Here’s yet another new study that supports the idea that there’s no increased risk.’”

He cautioned, however, that the study doesn’t address whether people with a genetic predisposition to Alzheimer’s might develop it sooner due to cancer treatment.

“Does the cancer treatment increase your probability or nudge you along? The study doesn’t answer that question,” Ahles said.

The study reported having no commercial funding. Jeong and Ahles reported having no relevant disclosures.

This cross-sectional study reports the prevalence and genotype distribution of human papillomavirus infection among women in Yangpu District, Shanghai, China from 2020 to 2024. The overall HPV infection rate detected in this study was 23.10%. Compared with similar studies in China, this infection rate is higher than the 21.0% reported in Beijing [11], 21.97% in Jinshan District Shanghai [12], 22.82% in Luoyang Henan Province [13], and 17.92% in Zhoupu District Shanghai [14], but lower than the 41.04% in Hangzhou Zhejiang Province and 50.64% in Tianjin [15, 16]. This discrepancy may be associated with variations in regional epidemiological characteristics or demographic composition of study populations [17]. Previous studies have reported substantial heterogeneity in HPV prevalence across China, ranging from 6.2–50.64% [16, 18]. Prevalence rates in clinical populations significantly exceed those in community-based screening cohorts, likely reflecting health-seeking behaviors related to symptomatic presentation that differ fundamentally from asymptomatic screening populations [19]. In the present study, an HPV prevalence of 10.5% was observed among general screening populations, lower than the 13.6% rate reported in routine screening cohorts from Zhejiang Province [20].

This regional analysis identified HPV-52 as the predominant high-risk genotype, followed by HPV-53, -58, -51, -39, and − 68, aligning with patterns reported in other Chinese studies. HPV-52, -16, -58, -51, and − 66 represent predominant subtypes in Beijing [11], while HPV-52, -16, -58, -51, and − 53 dominate in Jinshan District, Shanghai [12]. Similarly, HPV-52, -58, -16, -53, and − 51 constitute major subtypes in the Golden Triangle region of Fujian, China [3]. Substantial evidence confirms that beyond HPV-16 and − 18, genotypes including HPV-52, -58, -51, and − 53 significantly contribute to cervical carcinogenesis [21]. This study’s findings exhibit discrepancies in subtype prevalence rankings compared with certain Chinese regions [22], indicating significant geographical heterogeneity in high-risk HPV genotype distributions. This epidemiological variation likely originates from multifactorial mechanisms: Firstly, socio-behavioral patterns—including number of sexual partners, marital/reproductive history, and sexual health literacy—fundamentally shape subtype distributions by modulating viral transmission routes and exposure frequency. Secondly, molecular interactions between HPV genotypes and region-specific host immunogenetic backgrounds may establish distinct infection profiles in defined populations [23].

From the perspective of infection patterns, HPV infections exhibit a phenomenon of multi-subtype coexistence. Beyond single-subtype infections, mixed-infection modes are particularly prominent, with dual infections being the predominant form. It remains unclear whether co-infection with multiple HPV genotypes involves competitive or synergistic relationships. However, existing studies indicate that mixed infections with multiple types increase the risk of cervical cancer more significantly than single-genotype infections [24, 25]. A study conducted in Mexico observed a correlation between multiple HPV infections and high viral load as well as infection persistence [26]. Research from South Korea demonstrated that patients with multiple HPV infections had longer viral clearance cycles compared to those with single-type infections [27]. The mechanisms and potential carcinogenic effects of multiple infecting genotypes require further investigation.​​ Fig. 2 results revealed that HPV-52, HPV-53, and HPV-58 were the most common genotypes in co-infections among women in this study, with HPV-52 + HPV-53 and HPV-52 + HPV-58 co-infections being the most frequent combinations. In Shanghai, China, HPV vaccination began in 2017, and Yangpu District started the program in 2018. Initially, the bivalent vaccine targeting HPV-16 and − 18 and the quadrivalent vaccine covering HPV − 6, -11, -16, and − 18 were mainly provided. In October of the same year, the nine-valent HPV vaccine, which covers more high-risk types including HPV − 6, -11, -16, -18, -31, -33, -45, -52, and − 58, was officially made available for vaccination. Vaccination mainly relies on the principle of self-payment and voluntary participation, and the overall vaccination rate remains relatively low. Among the HPV vaccines available on the market, only the nine-valent vaccine covers HPV-52 and HPV-58, making it more suitable for women in Yangpu District, Shanghai.

Given that the HPV-53 vaccine is still in the preclinical research stage, its high prevalence in certain regions further highlights the insufficiency of the existing vaccine’s coverage. Currently available vaccines are all based on HPV L1 self-assembled virus-like particles (VLPs), which can prevent HPV infection by inducing the production of specific neutralizing antibodies in the body [28]. Although these vaccines have shown significant efficacy, they still have several limitations, including a limited coverage of HPV types, the need to produce VLPs of different types separately before mixing them, and a high dependence on cold chain transportation and storage. The high prevalence of HPV-53 indicates the insufficiency of the current vaccine strategy in terms of protection spectrum. Therefore, in the future, it is urgent to expand the vaccine coverage through technological innovation, such as developing cross-protective vaccines based on L2 protein or constructing new multivalent vaccine systems using DNA and mRNA platforms. Although these emerging technologies face challenges in terms of research and development difficulty and cost control, they have significant potential in improving the broad-spectrum and accessibility of vaccines. The development of vaccines targeting HPV-53 is expected to provide more targeted prevention measures for regions with high prevalence.

Multiple studies have confirmed that HPV infection rates in China exhibit a U-shaped curve distribution with age, characterized by two distinct peaks [11, 24]. In this study, the first peak occurred in the under-20 age group, which may be associated with evolving sexual attitudes among youth in the current social context. A large-scale cross-sectional survey of Chinese women aged 15–24 revealed that the median age of first sexual intercourse in this cohort was 17 years [29]. Another epidemiological study demonstrated that within two to three years after initial sexual activity, HPV infection rates among adolescents can reach 50–80%, with a corresponding 2.41-fold increase in infection risk [30]. Although the sample size of the under-20 population in this study was limited, their significant disease risk profile indicates the necessity of HPV screening for this age group.​​ The second peak emerged in the 61–70 age group, likely attributed to age-related declines in immune function and hormonal changes, which increase HPV susceptibility and reduce viral clearance capacity [31, 32]. The differential infection patterns across age groups underscore age as a critical influencing factor for HPV infection, necessitating age-specific screening strategies. Particularly in the 61–70 cohort, the marked elevation in HPV infection rates suggests these individuals should be prioritized as key surveillance targets.​.

Figure 3 results show that HPV-52, HPV-53, and HPV-58 were the predominant subtypes, with their infection rates maintaining high levels across all age groups. The peak infection rates occurred in the ≤ 20 years and 61–70 years age groups, but positive infections for various HPV types were primarily concentrated in the 31–40 years, 51–60 years, and 61–70 years age groups. This indicates that the population actively undergoing gynecological examinations is mainly composed of middle-aged and elderly women, which is associated with increased awareness of HPV infection among this demographic due to the introduction and promotion of HPV vaccines in recent years [22].​​ From a prevention and control strategy perspective, HPV vaccination and screening are core measures to reduce cervical cancer risk. Data demonstrate that the earlier young women receive the HPV vaccine, the higher the antibody titer and the better the protective effect of the vaccine [33]. However, HPV vaccination coverage in China remains critically low at approximately 2.64–11.0%, significantly below immunization rates observed in most other countries [8, 34, 35]. Multiple obstacles have led to this low vaccination rate. Among female college students, insufficient awareness of the risk of HPV infection and concerns about the safety and efficacy of the vaccine are the main obstacles [36]. Concurrently, current vaccine shortages and exclusion from the national immunization program likely impede or delay individual vaccination decisions [37]. Consequently, stratified immunization and screening strategies informed by age-specific prevalence patterns should be implemented to address differential HPV exposure across age cohorts.

This study constitutes a cross-sectional analysis based on HPV testing data from 2020 to 2024 at Shanghai Yangpu District Shidong Hospital, systematically elucidating the epidemiological characteristics of HPV in Yangpu area. It supplements the multi-center epidemiological database of Shanghai and provides scientific evidence for regional prevention policies. However, the following limitations exist: Firstly, the study cohort solely comprised hospital patients within this five-year timeframe, which is not representative of the typical local population. Secondly, HPV vaccination history was not incorporated into the dataset, whereas existing evidence indicates that vaccination status significantly influences the infection spectrum distribution of high-risk HPV subtypes. Finally, the absence of synchronized collection of cervical cytology or histopathological diagnosis results restricted the analysis of associations between HPV genotype distribution patterns and cervical lesion severity. As a retrospective single-center study, our research sample included only patients seeking hospital care. This design excludes potentially infected individuals within the community who did not present for medical attention. This may limit the generalizability of our findings to the broader community population. Therefore, caution is warranted when extrapolating these conclusions to wider populations. Future investigations should expand sample size, enhance data dimensionality, and adopt multi-center collaborative models to systematically explore the association mechanisms between HPV infection and cervical lesions in Yangpu area.​.

Study design

We are planning a monocentric, double-blind, sham-controlled, randomized clinical trial to evaluate the efficacy and safety of rTMS in in children and adolescents diagnosed with ASD. The study will involve 40 patients randomized into active rTMS and sham stimulation groups. The duration of the study will be 36 months. Participants will be assessed before rTMS (T0), immediately post-treatment (T1), and at a 1-month follow-up (T2) (Fig. 1). Assessments will evaluate neuropsychological function, mainly executive functions; the severity of ASD clinical symptoms; and safety and tolerability. Additionally, biological samples, including urine and blood, will be collected at each assessment to measure biomarker changes.

Ethical issues

A participant information sheet will be provided, and informed consent will be obtained from the parents or caregivers of study participants (see Supplementary File 1). The study protocol has been reviewed and approved by the Independent Ethics Committee of Policlinico “Riuniti” of Foggia (reference number 50/CE/2023). The trial has been registered with ClinicalTrials.gov under the identifier NCT06069323. The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and applicable regulatory requirements. To ensure appropriate oversight, key study staff will meet monthly to review trial conduct, participant recruitment, protocol adherence, data quality, and any adverse events. Given the low-risk nature of the rTMS intervention, a formal independent Data Monitoring Committee was not established. Instead, trial oversight, including safety and data integrity, will be managed internally by the study team. Any serious adverse events or protocol deviations will be reported to the Ethics Committee in accordance with regulatory requirements. No formal interim analyses or independent audits are planned. Any significant amendments to the protocol will be reviewed by the Principal Investigator and submitted to the Ethics Committee for approval. Once approved, all relevant members of the study team will be informed, and the revised protocol will be stored with the local study documentation. Any deviations from the approved protocol will be documented using a breach report form, and the Clinical Trial Registry will be updated as required.

Study setting

Participants will be recruited through the Child and Adolescent Neuropsychiatry Unit at the General Hospital “Riuniti of Foggia”, community health clinics, and family associations supporting individuals with neurodevelopmental disorders. Initially, interested participants will receive detailed study information and undergo preliminary screening to assess eligibility based on age, confirmed ASD diagnosis, and absence of a personal history of seizures. Following this initial screening, eligible participants will be invited for an in-person assessment to further verify inclusion criteria. Those meeting the criteria will subsequently receive neurostimulation treatments as outpatients at the Department of Clinical and Experimental Medicine, University of Foggia. A detailed timeline of data collection is shown in Table 1. We used the SPIRIT checklist when writing our protocol (see Supplementary File 2) [27].

Eligibility criteria, sample size, and data collection

Participants will be eligible for inclusion in the study if they are between 7 and 18 years old and have a confirmed diagnosis of ASD based on DSM-5 criteria. Exclusion criteria for this study include any history of seizures, epilepsy, or repeated febrile seizures, as well as any severe or traumatic brain injury. Participants with comorbid neurological or genetic conditions that impact brain function or structure, such as brain tumors, fragile X syndrome, or tuberous sclerosis, will also be excluded. Additionally, those with known endocrine, cardiovascular, pulmonary, liver, kidney, or other significant medical diseases, or with any unstable medical condition, will not be eligible to participate. Participants will also be excluded if they are on an unstable medication regimen or using medications contraindicated for TMS. Vision or auditory impairments that could interfere with study participation will preclude eligibility. Participants will also be excluded if they demonstrate significant epileptiform activity on electroencephalogram (EEG), such as seizures or continuous epileptiform discharges. Furthermore, individuals with psychosis disorder and diagnosed chronic or acute inflammation or infection, or those unable to provide informed consent, will not be eligible for the study. To detect significant differences in outcomes between the active and sham groups with 80% statistical power and a significance level (α) of 0.05, the sample size calculation indicated that 20 participants per group (n = 40 total) would be required. We will use REDCap (Research Electronic Data Capture) as our clinical data management system. Personal information will be stored separately from study data, secured on password-protected systems, and pseudo-anonymized with unique numeric codes accessible only to authorized personnel.

Blinding and randomization

Participants, care providers, and clinical raters will be blinded to treatment assignment. Only the clinician who generates the treatment allocation and delivers the pulses will remain unblinded, without participating in any other study activities. Data analysis will be conducted independently by two statisticians who are not otherwise involved in the trial procedures. A stratified randomization approach with permuted blocks will be used. Clinical severity will be classified based on scores from the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Childhood Autism Rating Scale Second Edition (CARS-2). Participants will be stratified into mild-to-moderate and severe groups before randomization to ensure balanced allocation between treatment arms. This approach is intended to minimize baseline differences in symptom severity across groups. Randomization will be performed using a computer-generated allocation sequence (a function available in SAS software), with permuted blocks employed to prevent predictability of group assignments and maintain balance within each stratum.

Neuropsychological assessment and primary outcomes

A comprehensive neuropsychological assessment will be conducted using a battery of tests to confirm the ASD diagnosis and evaluate clinical severity. These assessments will be performed at baseline, post-treatment, and at a 1-month follow-up, representing the primary outcomes of the study. The ADOS-2 and Autism Diagnostic Interview-Revised (ADI-R) will be administered to evaluate social interaction, communication, play, and the imaginative use of materials across different age groups [28, 29]. The Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) will be used to evaluate intellectual functioning in verbal children, whereas non-verbal children will be assessed with the Leiter International Performance Scale-Revised (Leiter-R) [30, 31]. To measure neuropsychological functions, particularly executive functions, the NEPSY Second Edition (NEPSY-II) will be used. The Movement Assessment Battery for Children Second Edition (MABC-2) will assess motor skills in everyday activities [32]. The CARS2 will be administered to evaluate autistic symptoms, and the Vineland Adaptive Behavior Scales Second Edition (Vineland-II) will assess a range of adaptive behaviors [33,34,35]. Additionally, parents will complete the Conners Third Edition (Conners 3) to report attention-deficit/hyperactivity disorder (ADHD) symptoms in their children, the Child Behavior Checklist for Ages 6–18 (CBCL/6–18) to identify behavioral and emotional problems, and the Social Communication Questionnaire (SCQ), a tool used to evaluate communication skills and social functioning [36,37,38]. The Children’s Depression Inventory 2 for parents (CDI-2) and the Multidimensional Anxiety Scale for Children (MASC) will also be used to assess depressive and anxiety symptoms [39, 40]. A detailed patient and medication history will be collected to assess any potential impact on the efficacy of rTMS.

Electroencephalogram recording

A standard EEG, following the international 10–20 system, will be recorded at each study time point: at baseline (T0), after rTMS treatment completion (T1), and at a 1-month post-treatment follow-up (T2). This procedure will identify pre-neurostimulation epileptic discharges that may exclude participants from the study and monitor any electrical changes induced by rTMS.

Intervention and adherence to protocol

The intervention will consist of 18 sessions of 2 Hz rTMS over 9 weeks, targeting the DLPFC. Stimulation intensity will be set at 90% of the motor threshold, delivering 180 pulses per session consisting of 9 trains of 20 pulses each, with a 20-s inter-train interval. The selection of 2 Hz frequency and 180 pulses per session was based on prior studies demonstrating that low-frequency stimulation over the DLPFC can reduce gamma activity and enhance executive function in individuals with ASD [4, 5, 19]. These parameters were selected to ensure both safety and potential clinical benefit in a pediatric population, consistent with previous trials that reported good tolerability and modulation of cortical excitability using low-frequency, low-dose protocols [4, 18]. The first six sessions will target the left DLPFC, the next six the right DLPFC, and the final six both hemispheres. rTMS will be administered using a Magstim R2 stimulator (Magstim, Whitland, UK) with a 70-mm figure-eight coil positioned at a 45° angle from the midline. Anatomical landmarks corresponding to EEG sites F3 and F4 (10–20 system) will be used to accurately target the DLPFC and to minimize discomfort in pediatric patients with ASD. Motor thresholds for each hemisphere will be established by incrementally raising machine output by 5% until a visible twitch in the first dorsal interosseous (FDI) muscle is observed in 2 out of 3 trials [41]. A sham group will undergo identical procedures without magnetic field application. The sham stimulation will replicate the auditory and tactile sensations of active rTMS by using the same coil orientation and clicking sounds. The coil will be positioned against the scalp at the same angle and location, and the stimulator will be activated to produce the characteristic clicking noise and slight vibration. This is to ensure that the sensory experience remains comparable between active and sham conditions, thereby supporting effective blinding. Throughout and immediately after each session, participants will be monitored for well-being, with any reported side effects documented and reviewed post-study. All sessions will be conducted under standardized conditions, with participants seated comfortably in an armchair in a quiet room, and their elbows positioned at a 90° flexion angle.

All rTMS sessions will be scheduled at consistent times and on the same days to establish a routine for participants and their parents or caregivers. Reminders via phone calls or text messages will be sent to parents or caregivers before each session. Missed sessions will be promptly rescheduled within the same week whenever possible. Study staff will educate families on the importance of session attendance and protocol compliance. Reasons for missed sessions will be documented, and efforts will be made to re-engage participants. The rTMS clinician will complete a checklist at each session to confirm that all protocol steps (e.g., stimulation parameters, coil positioning) are followed.

Biochemical measures and secondary outcomes

Biochemical measures will be assessed as secondary outcomes to provide a more comprehensive understanding of the effects of rTMS on ASD. Tryptophan metabolites, including 3-hydroxykynurenine (3-HKYN), KYNA, and QUIN, will be measured in urine using

high-performance liquid chromatography with electrochemical detection (HPLC-ECD) (Ultimate ECD, Dionex Scientific, Milan, Italy) [42]. HPLC-ECD will be also used to measure systemic levels of neurotransmitters, such as glutamate, GABA, serotonin, and dopamine, in urine samples [43]. To measure circulating BDNF, serum samples will be collected, and an enzyme-linked immunosorbent assay (ELISA) (DBA Italia, Segrate, Italy) will be performed [44]. Additionally, BDNF gene polymorphism (Val66Met) will be genotyped using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR–RFLP). This approach amplifies the BDNF gene region containing the Val66Met variant, followed by restriction enzyme digestion to distinguish the Val and Met alleles based on fragment length analysis [45]. Inflammatory mediators, including IL-6, IL-10, IL-1β, TNF-α, and CRP, will be measured in serum using ELISA [46].

Follow-up

A follow-up visit will be scheduled 1 month after the final rTMS session to evaluate the persistence of rTMS effects and the need for possible booster sessions. Accordingly, neuropsychological assessments and biochemical sampling will be performed again at the follow-up visit. To enhance the response rate, the study coordinator will request contact information from both parents.

Safety

Before the enrollment, participants will undergo comprehensive screening to confirm they meet eligibility and rTMS safety criteria. Additionally, a qualified physician will review medical history and perform a general physical examination to confirm the absence of risk factors. After enrollment, a standard clinical EEG, reviewed by a neurologist, will be conducted to exclude participants with epileptiform discharges. To ensure safety, rTMS will be administered by a trained neuropsychiatrist equipped to promptly manage any seizures or adverse events. A stimulation intensity of 90% of the motor threshold will be used for ASD participants to minimize seizure risk. Before each rTMS session, participants will be asked about their current health status and any adverse events experienced since the previous session. All adverse events will be documented and reported. In the case of a serious adverse event, treatment will be suspended.

Statistical methods

Statistical analyses will be performed using SPSS (IBM Corp., Armonk, NY). Primary analyses will focus on evaluating differences between the active and sham rTMS groups across three time points: baseline (T0), immediately post-treatment (T1), and 1-month follow-up (T2). Changes in neuropsychological and clinical measures across time points will be assessed using repeated-measures analysis of variance (ANOVA), with group (active vs. sham) as the between-subjects factor. If assumptions of normality are not met, the Wilcoxon signed-rank test will be applied to evaluate within-group differences over time, while the Mann–Whitney U test will be used to compare between-group differences at each time point. Biomarker levels will be compared using generalized linear models to account for potential covariates, including age and baseline severity. Chi-square tests will evaluate categorical variables, and t-tests will be applied for continuous variables where applicable. Spearman’s rank or Pearson correlation coefficients, depending on data distribution, will be employed to examine relationships between neuropsychological scores and biochemical measures. All statistical tests will be two-sided, with p-values below 0.05 considered statistically significant.

This multicenter study investigates the association between hydroxychloroquine (HCQ) dosage and COVID-19 mortality among hospitalized patients in China, aiming to clarify conflicting evidence from prior research. Leveraging data from multiple medical centers, the analysis focuses on determining whether low-dose HCQ confers mortality benefits with acceptable safety, contrasting with potential risks of higher doses. By systematically evaluating clinical outcomes across different HCQ dosage groups, the research seeks to provide evidence-informed guidance for antiviral therapy in COVID-19 management, particularly in resource-constrained settings.

The retrospective cohort includes 2,387 COVID-19 patients admitted to 12 hospitals in Hubei Province between January and June 2020. Patients are categorized into three groups: non-HCQ use (n=1,124), low-dose HCQ (≤600 mg/day, n=893), and high-dose HCQ (>600 mg/day, n=370). Baseline characteristics are compared across groups, with adjustments for age, sex, comorbidities (hypertension, diabetes, cardiovascular disease), disease severity (mild, severe, critical), and concurrent medications (antibiotics, glucocorticoids). The primary endpoint is all-cause mortality, while secondary endpoints include treatment-related adverse events (AEs), such as QT interval prolongation and ventricular arrhythmias.

Descriptive statistics show that high-dose HCQ users are more likely to be male, older, and have preexisting conditions, reflecting clinical decisions to escalate therapy in severe cases. Univariate analysis reveals significantly lower mortality in the low-dose HCQ group (15.2%) compared to non-HCQ (22.8%) and high-dose HCQ (28.9%) groups (p<0.001 for both comparisons). After propensity score matching (1:1:1 matching), the low-dose group maintains a survival advantage (adjusted HR=0.68, 95% CI: 0.51-0.90, p=0.008), while the high-dose group exhibits higher mortality (HR=1.32, 95% CI: 1.05-1.67, p=0.018). Subgroup analyses by disease severity show consistent benefits of low-dose HCQ in severe (HR=0.72, p=0.023) and critical (HR=0.65, p=0.011) patients, but no significant effect in mild cases.

Safety data indicate a dose-dependent increase in AEs: low-dose HCQ has an AE rate of 12.7%, comparable to non-HCQ (10.9%, p=0.21), while high-dose HCQ shows a significantly higher rate (22.4%, p<0.001). The most common AEs are gastrointestinal symptoms (nausea, diarrhea) and electrolyte imbalances, with rare but serious ventricular arrhythmias (2.1% in high-dose vs. 0.8% in low-dose, p=0.03). Multivariate Cox regression identifies high-dose HCQ (HR=1.45, 95% CI: 1.12-1.87, p=0.005) and older age (HR=1.08 per year, p<0.001) as independent risk factors for mortality, while low-dose HCQ (HR=0.79, 95% CI: 0.63-0.99, p=0.04) and early treatment initiation (within 5 days of symptom onset, HR=0.64, p=0.002) are protective.

The findings align with prior studies suggesting HCQ’s immunomodulatory effects at low doses may reduce cytokine storm and viral replication, whereas high doses increase toxicity without additional benefit. Mechanistically, HCQ’s inhibition of Toll-like receptor signaling and enhancement of autophagic antiviral responses are hypothesized to be dose-dependent, with therapeutic windows narrow enough to distinguish protective vs. toxic effects. The study’s real-world data contrast with the negative results of the RECOVERY trial, potentially due to RECOVERY’s inclusion of higher-dose and later-treatment patients, highlighting the importance of dosing strategy and timing in HCQ therapy.

Limitations include the retrospective design’s susceptibility to residual confounding, lack of randomization, and reliance on administrative data for dosing accuracy. Additionally, the study’s focus on hospitalized patients limits generalizability to outpatient settings or other populations. However, the large sample size, multi-center design, and rigorous statistical adjustments strengthen the validity of dose-response conclusions.

Clinically, the results support cautious use of low-dose HCQ (≤600 mg/day) in severe COVID-19 cases, particularly when initiated early, while advising against high-dose regimens due to increased toxicity. This aligns with emerging guidelines emphasizing personalized dosing based on patient characteristics and close monitoring of cardiac biomarkers. Future randomized controlled trials are needed to confirm these findings and explore HCQ’s role in combination with other antiviral agents, such as remdesivir or nirmatrelvir.

In summary, this study provides observational evidence that low-dose hydroxychloroquine is associated with reduced COVID-19 mortality in hospitalized patients, particularly those with severe illness, when administered within the first week of symptoms. The findings highlight the critical role of dosing precision in antiviral therapy, balancing therapeutic benefits with safety profiles. As COVID-19 continues to evolve, such real-world data contribute to the dynamic optimization of treatment protocols, especially in regions where access to novel antivirals is limited.

In the last years of her life, my mother began to have nightmares. One recurred from time to time and became a metaphor for the dementia that, in the end, took her life. In it, she was trapped on a ship and could not get off.

Once, while staying with my sister, mum began to crash around her room in the night. When my sister went to investigate, she found our mother trying to get off her ship. On another occasion, while with me, she clambered on top of the toilet, again to get off the ship. She fell backwards, cracking her head on the floor, and required stitches.

My mother’s nightmares could have been linked to Alzheimer’s disease, according to a 2024 study by a team at Boston University in the US state of Massachusetts. It found that cognitive impairment had a correlation with higher nightmare frequency and distress in the elderly.

However, Dr Abidemi Otaiku, a neuroscientist at Imperial College London, says that nightmares can be a marker of earlier dementia – and even a driver of it.

His findings have shown that frequent or persistent nightmares may be an easily identifiable marker of dementia risk, one that can be detected even in the first decade of life. Other risk factors for dementia, such as diabetes and hypertension, typically only surface from middle age, he says.

In the last years of her life, my mother began to have nightmares. One recurred from time to time and became a metaphor for the dementia that, in the end, took her life. In it, she was trapped on a ship and could not get off.

Once, while staying with my sister, mum began to crash around her room in the night. When my sister went to investigate, she found our mother trying to get off her ship. On another occasion, while with me, she clambered on top of the toilet, again to get off the ship. She fell backwards, cracking her head on the floor, and required stitches.

My mother’s nightmares could have been linked to Alzheimer’s disease, according to a 2024 study by a team at Boston University in the US state of Massachusetts. It found that cognitive impairment had a correlation with higher nightmare frequency and distress in the elderly.

However, Dr Abidemi Otaiku, a neuroscientist at Imperial College London, says that nightmares can be a marker of earlier dementia – and even a driver of it.

His findings have shown that frequent or persistent nightmares may be an easily identifiable marker of dementia risk, one that can be detected even in the first decade of life. Other risk factors for dementia, such as diabetes and hypertension, typically only surface from middle age, he says.

Scientists reveal that children exposed to certain plastic-derived chemicals before age five face higher risks of asthma and wheeze, underscoring growing concerns over everyday environmental exposures.

Study: Phthalates and bisphenols early-life exposure, and childhood allergic conditions: a pooled analysis of cohort studies. Image Credit: antoniodiaz / Shutterstock

In a recent study published in the Journal of Exposure Science & Environmental Epidemiology, researchers utilized an extensive (n = 5,306) pooled Australian, United States (US), and Canadian cohort to investigate the clinical outcomes of childhood and early life (before the age of 5) exposure to harmful plastic-derived chemicals.

Their findings reveal that increased prenatal and early-life exposure to phthalates and bisphenols, chemicals found in many everyday products such as shampoos and food packaging, was associated with a modestly increased risk of developing asthma and other allergic conditions by preschool age. The findings contribute to a growing body of evidence on how we address invisible pollutants that surround us and our children from birth.

Background

Phthalates and bisphenols, ubiquitous chemicals found in plastics, packaging, toys, grooming, and personal-care products, are increasingly scrutinized for their potentially harmful effects on child health. A growing body of evidence suggests that these persistent environmental contaminants act as endocrine-disrupting chemicals (EDCs), altering metabolic and neurodevelopmental pathways and having potentially lifelong consequences.

The impacts of phthalates and bisphenols on respiratory outcomes and allergies remain less understood. While a limited number of epidemiological investigations have linked these EDCs with an increased risk of adverse childhood respiratory outcomes (wheezing, eczema, asthma, and rhinitis), recent systematic reviews and meta-analyses have flagged these findings as inconsistent and often confounding, potentially due to a glaring lack of methodological standardization between studies.

Furthermore, even in this understudied field, investigations on the impacts of EDCs on children under the age of five, a period of rapid development and exacerbated chemical sensitivity, are underrepresented. Consequently, clinicians and policymakers have little to no scientific evidence upon which to base their public health and environmental recommendations.

About the study

The present study aims to address this knowledge gap and inform future environmental and public health policy. By pooling major birth cohorts across three countries, it evaluates how urinary levels of phthalates and bisphenols (measured during pregnancy and early childhood) correlate with diagnosed allergic outcomes by age five. The study further aims to elucidate if any identified EDC-allergy risk associations are influenced by exposure timing, dose, or sex.

Study data were obtained and pooled from four established longitudinal cohorts: 1. Australia’s Barwon Infant Study (BIS), 2. Canada’s Canadian Healthy Infant Longitudinal Development Study (CHILD) study, and the United States’ (US’s) 3. Health Outcomes and Measures of the Environment (HOME) Study and 4. Environmental Influences on Child Health Outcomes (ECHO).

Individuals with preserved urinary samples or urinary phthalates and bisphenols data from their first five years of life (postnatal subcohort) or pregnancy time (prenatal), alongside at least one allergy test from the same period, were included as current study participants. EDCs were characterized and quantified using standardized high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS).

Study outcomes (wheezing, asthma, rhinitis, and eczema) were assessed using several cohort-specific questionnaires (e.g., the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire). Where possible, caregiver-reported questionnaires were supplemented with clinical allergy evaluations. Sex-stratified generalized estimating equations (for chemical analysis) and quantile G-computation (to evaluate the cumulative effects of several co-occurring EDCs) were leveraged, accounting for potential sociodemographic confounders.

Study findings

The present study validates a link between plastic-derived EDCs and adverse childhood respiratory outcomes. It leverages a final sample cohort of 5,306 children. It reveals that prenatal exposure to dibutyl phthalates (DBP) and butyl benzyl phthalate (BBzP) is associated with a higher risk of asthma in children under five. A two-fold increase in exposure to these phthalates corresponded to a 6-8% increase in asthma risk (RR = 1.08 for DBP and 1.06 for BBzP).

Multivariate dose‒response relationship between the overall chemical mixture and childhood allergic conditions stratified by sex. Red circles: Females. Blue triangles: Male. Models obtained with quantile G-computation. Prenatal analysis models adjusted for cohort membership, maternal age, ethnicity, parental education, marital status, family history of asthma, prenatal tobacco smoke exposure, and season of birth. Postnatal analysis models were further adjusted for breastfeeding duration, age at outcome assessment, postnatal smoke exposure and gestational age.

Mono-(3-carboxypropyl) phthalate (MCPP), one of the most common phthalate metabolites, was similarly associated with a 5% increased risk of rhinitis (relative risk, RR = 1.05). Postnatal phthalate exposure showed similar trends, with BBzP, DEHP, and MCPP levels all associated with an increased risk of childhood wheezing (5-9%).

Additionally, combined exposure to a mixture of phthalates was associated with a higher risk of wheezing, with mixture models revealing that a one-quartile increase in overall postnatal chemical exposure increased the risk of childhood wheeze by 14%.

The study also investigated other factors, finding only limited evidence that the effects of these chemicals differed between boys and girls. However, the analysis did suggest that the timing of exposure during pregnancy could be important, with stronger associations observed for exposure during the first and second trimesters for certain outcomes. The study also noted that some associations were non-linear, following U-shaped or inverted U-shaped patterns, meaning that risk did not always increase steadily with higher exposure.

While the study found no statistically significant associations for bisphenols like BPA, the authors note that low detection rates for these chemicals may have limited the statistical power to identify minor effects. Curiously, high-molecular-weight phthalates were associated with a lower risk of eczema. The study’s authors suggest that this surprising finding requires further investigation, noting that it could be influenced by factors such as reverse causation, where children with eczema may use more personal care products.

Conclusions

With over 5,000 children from across continents contributing to its dataset, this large-scale, multinational study adds to the growing body of evidence that early-life exposure to phthalates may subtly increase the risk of childhood asthma, wheeze, and rhinitis. Although associations between bisphenols and respiratory conditions could not be observed, these findings suggest a need for reduced exposure to plastic-derived chemicals during pregnancy and early childhood. The authors themselves caution that the observed effects are modest on an individual level and highlight study limitations, such as differences in data collection between cohorts and the potential for unmeasured confounding factors, underscoring the need for further research.

Men who swapped cigarettes for vaping during IVF saw better sperm motility and fewer miscarriages, but experts warn that vaping isn’t risk-free for hopeful parents.

Study: Impact of conventional cigarette and electronic cigarette use on sperm quality and IVF/ICSI outcomes. Image Credit: New Africa / Shutterstock

In a recent study published in the journal Scientific Reports, researchers evaluated whether exclusive Electronic cigarette (e-cigarette) use alters semen quality and live-birth outcomes compared with traditional cigarette smoking in couples undergoing in vitro fertilization (IVF).

The study did not include a non-smoking control group, so results specifically compare E-cigarette users to conventional cigarette smokers, not to non-smokers.

Background

Despite decades of anti-smoking campaigns, about one-third of men of reproductive age still smoke conventional cigarettes. Meanwhile, sleek E-cigarettes that heat flavored nicotine liquids have surged in popularity and are marketed as safer. Traditional smoking is firmly linked to lower sperm count, reduced motility, and higher miscarriage rates, but the reproductive impact of electronic aerosols that are rich in metals and aldehydes remains poorly defined.

Couples investing in costly IVF worry whether switching from smoke to vapor truly protects fertility or merely changes the risk profile. Comparative evidence, particularly within assisted reproductive technology, is limited, and further research is needed to clarify these uncertainties.

About the study

Medical records from one infertility clinic were reviewed for 296 couples who underwent IVF or intracytoplasmic sperm injection between May 2022 and January 2024. Male partners had exclusively smoked either conventional cigarettes or E-cigarettes for at least six months and provided semen after two to seven days of abstinence.

The study enrolled couples in which the woman’s infertility was attributed to tubal disease, polycystic ovary syndrome, thyroid dysfunction, hyperprolactinemia, or a prior failed intrauterine insemination. Every female participant was a confirmed nonsmoker.

Researchers excluded participants with advanced maternal age, endometriosis, adenomyosis, poor ovarian response, recurrent pregnancy loss, congenital genitourinary anomalies, severe male-factor infertility, or any history of switching between cigarette types. Only the first or second embryo transfer cycles were included to avoid confounding from recurrent implantation failure.

They then performed standard semen analysis, calculated body mass index, assayed serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, prolactin, anti-Müllerian hormone (AMH), and sex hormone-binding globulin (SHBG), and proceeded with controlled ovarian stimulation under a gonadotropin-releasing hormone (GnRH) antagonist protocol, retrieving oocytes 36 hours after a recombinant human chorionic gonadotropin (rhCG) trigger.

All embryos were cryopreserved as blastocysts and transferred in frozen-thawed cycles. Outcomes included categories of pregnancy, miscarriage, and live birth, plus semen parameters. Chi-square and independent t-tests were used to compare groups, and logistic regression identified live-birth predictors at a p-value of ≤ 0.05.

Study results

Male partners in the conventional-cigarette (n = 151) and E-cigarette (n = 145) cohorts shared comparable body metrics and most hormonal parameters, but three laboratory values diverged. Traditional smokers exhibited higher serum prolactin (13.84 ± 5.97 ng/mL vs 13.02 ± 4.80 ng/mL; p = 0.029) and greater sperm concentration (81.55 ± 57.19 × 10⁶/mL vs 71.78 ± 44.40 × 10⁶/mL; p = 0.007), whereas progressive motility was higher among vapers (48.91 ± 11.75 % vs 48.15 ± 13.29 %; p = 0.014); semen volume, leukocyte count, and strict morphology did not differ (p > 0.10).

Female partners in both cohorts were similar in age and ovarian-reserve indices. Their body mass index, however, was modestly higher when the male partner smoked conventional cigarettes (23.38 ± 4.29 kg/m²) compared to vaping (22.16 ± 3.47 kg/m²; p = 0.017). Controlled ovarian stimulation proceeded uniformly: stimulation lasted 9.6 ± 1.5 days with a total gonadotropin dose of 2,385.68 ± 1,047.71 IU in smokers and 2,338.45 ± 898.18 IU in vapers, producing comparable oocytes retrieved (19.19 ± 10.29 vs 19.76 ± 10.67) and two-pronuclear embryos (11.23 ± 7.00 vs 11.28 ± 6.75; all p > 0.38).

Pregnancy endpoints diverged only after ultrasound confirmation. Biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and biochemical miscarriage rates were statistically indistinguishable (p ≥ 0.16). Male partners who vaped rather than smoked were associated with a drop in ultrasound-confirmed miscarriages from 36.3% to 12%, a roughly two-thirds relative reduction (p < 0.001). Concurrently, live-birth rates increased from 41.1% to 55.9%, representing a 15-percentage-point absolute rise (p = 0.011).

Multivariable logistic regression for all 296 couples revealed two independent live-birth predictors: every 1 mIU/mL increase in male serum FSH raised the odds by 19% (adjusted odds ratio 1.19, 95% confidence interval 1.06-1.34; p = 0.004), whereas each additional two-pronuclear embryo reduced the odds (adjusted odds ratio 0.19, 95% confidence interval 0.05-0.71; p = 0.013). However, this latter result is biologically counterintuitive and contradicts the direction seen in univariate analysis; it likely reflects either a statistical artifact or residual confounding and should be interpreted with caution.

Smoking modality, sperm motility, and paternal or maternal body mass index did not retain independent significance once these laboratory factors were taken into account.

The authors note that, although differences in semen parameters and live birth outcomes were observed between cigarette types, key predictors of live birth (such as FSH and 2PN embryo count) did not differ significantly between groups.

Conclusions

To summarize, E-cigarette use by male partners undergoing IVF appears less detrimental to reproductive success than continued conventional smoking. Although semen concentration was marginally lower, progressive motility was higher and prolactin lower among vapers, translating into fewer clinical miscarriages and a fifteen-point gain in live-birth rate.

Importantly, cigarette type did not override established predictors such as FSH level or embryo count, underscoring that vaping is no guarantee of success.

Crucially, the authors emphasize that these findings should not be interpreted as an endorsement of E-cigarette use, since E-cigarettes still pose potential health risks and their long-term impact on reproductive health is not fully understood.

The retrospective design, reliance on self-reported data, lack of information on dietary factors, unmeasured heavy metal exposure, and unaccounted variability in E-cigarette devices all limit causal conclusions and generalizability. Further research, including direct comparisons with non-smokers and more detailed toxicological assessment, is needed to clarify the reproductive risks of E-cigarettes and guide fertility counseling.

These findings highlight how lifestyle choices can still influence assisted reproduction outcomes and support counseling men to abandon combustible tobacco while pursuing parenthood more safely.