Category: 8. Health

Background

Traumatic events, especially large-scale disasters, can have significant and lasting effects on mental health, often resulting in conditions such as post-traumatic stress disorder (PTSD) and sleep is frequently affected. For many who experience trauma, insomnia can become persistent long after the initial event.¹ The Beirut Explosion which occurred on the fourth of August 2020 resulted in significant destruction and loss of life. Beirut is the capital and largest city of Lebanon; a small country in the eastern Mediterranean. The explosion was caused by the detonation of 2750 tons of ammonium nitrate, stored in the port, which caused massive damage to the city and hundreds of lives lost, thousand injured and tens of thousands displaced.² This large-scale catastrophic disaster provides a context to examine the long-term psychological impact of such traumatic events. Research has consistently shown that trauma-exposed populations exhibit a high prevalence of sleep disturbances, including disruptions in sleep continuity, duration, and quality, which are also core features of PTSD.^3–5 More severe PTSD symptoms have been strongly correlated with both shorter sleep duration⁶ and lower sleep quality.⁴ Prior research indicates that insomnia is not only a common symptom following traumatic experiences but can also become a chronic condition that affects overall health and quality of life: sleep disturbances not only persist as symptoms but are significant predictors of PTSD development. For example, pre-deployment insomnia among soldiers, was linked to an increased risk of PTSD onset and suicidal ideation following deployment.⁵ Sleep disturbances have also been found to predict harmful health-related behaviors, such as aggression, substance abuse, and increased alcohol consumption, in trauma-affected populations.⁴

Trauma exposure can cause long-lasting disruptions in sleep by dysregulating the hypothalamic-pituitary-adrenal (HPA) axis and activating the sympathetic nervous system, resulting in chronic hyperarousal and impaired sleep regulation. Stress-induced activation of the HPA axis increases secretion of CRH, ACTH, and cortisol, contributing to persistent insomnia symptoms.^7,8

Similar long-term sleep disturbances have been documented following other catastrophic events. For example, in Japan after the Great East Japan Earthquake, researchers found a sharp increase in insomnia prevalence (21.2% four months post-disaster compared to 11.7% pre-disaster) and associations with persistent psychological distress.⁹ Among survivors of the 2011 Great East Japan earthquake and tsunami, material damage and financial hardship were linked to long-term sleep disturbances, while other forms of loss had less impact. Effective disaster response helped mitigate sleep problems.³

Lebanon faces compounding challenges, including political instability, economic crisis, and under-resourced mental health systems, all of which amplify psychological vulnerability. Stigma, lack of policy, and limited access further restrict the use of mental health services, hindering help-seeking behaviors.¹⁰ Within this context, evidence on sleep behaviors in the Lebanese population remains scarce, highlighting the need for further research. In a cross-sectional study in Lebanon by Chami et al (2019), 44.5% of participants reported experiencing insomnia symptoms regularly, and 34.5% met the criteria for insomnia disorder. These symptoms were found to be more prevalent in women, socioeconomically disadvantaged individuals, and those with medical comorbidities.¹¹ A more recent study found an insomnia prevalence of 47.1%.¹²

On August 4, 2020, the Beirut port explosion devastated Lebanon’s capital, causing widespread destruction from the port, injuring over 6,000 people, and displacing approximately 300,000 individuals from their homes.^13,14 In the immediate aftermath of the explosion, those seeking mental health support predominantly reported trauma-related symptoms, insomnia, depression, and anxiety.¹⁵ Several short-term studies have documented this acute psychological impact: among survivors presenting to the emergency department at the American University of Beirut Medical Center, nearly half exhibited symptoms of depression and two-thirds showed signs of PTSD.¹⁶ Within the first months following the blast, psychological distress remained high: two months after the explosion, 37% met criteria for PTSD and 80% screened positive for depression, with one-fourth categorized as moderately-to-severely depressed.¹⁷ At four months, 75–80% of participants in a cross-sectional internet-based study reported high levels of emotional distress.¹⁸ By six months, 75.8% still met criteria for PTSD, nearly half with severe symptoms, with predictors including unemployment, injury, and bereavement.¹⁹ A visual timeline of prior Lebanese studies on mental health outcomes following the Beirut explosion is provided in Supplementary Figure 1. While these findings highlight the acute burden of trauma in the short term, none of these studies specifically assessed sleep outcomes. Importantly, no studies to date have examined the long-term impact of the Beirut explosion on mental health and sleep quality, which is the gap addressed by the present study.

This investigation is relevant as long-term sleep disturbances may reinforce the persistence of PTSD by disrupting memory, emotional stability, and trauma processing.²⁰ This study aims to assess the long-term psychological impact of the Beirut explosion, focusing primarily on sleep disturbances and trauma. It also examines the relationship between proximity to the explosion site, social consequences, personal injury, and demographic factors with insomnia severity. Additionally, the study explores substance use changes related to proximity to the explosion site and their potential association with insomnia.

Methods

Study Design and Sampling

This cross-sectional study targeted adults (18+) residing in Lebanon during the Beirut explosion, regardless of their proximity to the capital. Data were collected from December 2023 to September 2024, including participants from Beirut, nearby areas, other Lebanese governorates, and those abroad but present during the explosion. Data collection was halted in September 2024 due to the intensification of the war on Lebanon, which introduced new traumatic exposures that could have acted as confounding factors.

A sample size calculation was conducted using the proportions of individuals expected to report insomnia symptoms in the two study groups: 70% among those residing within 6 km of the Beirut blast and 51% among those residing beyond this distance. Using a significance level (α) of 0.05 and a power (1−β) of 80%, and assuming equal group sizes, the minimum required sample size per group was calculated using the following formula for two independent proportions:

Where:

p₁ = 0.51

q₁ = 1 − p₁ = 0.49

p₂ = 0.70

q₂ = 1 − p₂ = 0.30

Δ = |p₂ − p₁| = 0.19

K = 1 (equal sample sizes)

Z₁ − α/2 = 1.96

Z₁ − β = 0.84

Calculating using our values:

N₁ = { [1.96 × √(0.605 × 0.395 × (1 + 1/1))] + [0.84 × √(0.51 × 0.49 + (0.70 × 0.30)/1)] }²/ (0.19)²

N₁ ≈ 103

N₂ = K × N₁ = 103

Therefore, the total sample size required is 206 participants, with 103 in each group. A total of 248 participants were included.

Procedure

Participants were recruited through flyers and social media posts with our contact details and a link or QR code to the consent page. After consent, they completed the survey. Eligibility was based on age, location, and presence in Lebanon during the Beirut explosion. Participants were divided into two groups: those within 6 km of Beirut and those from areas further away. The 6 km cutoff was selected based on reports of major damage within this radius, corresponding to a 3.3 magnitude earthquake.²¹

Protocol Instruments

The questionnaire was available in both English and Arabic. The questionnaire included:

1. Demographics and personal data: Gender, age, marital status, employment status, medical history, mental health history, substance use, sedative or hypnotic use, personal injury, injury or loss of a family member or friend, and property damage.
2. Insomnia Severity Index (ISI): A widely used, validated 7-item questionnaire that is designed to assess the nature, severity, and impact of insomnia, with responses rated on a 5-point Likert scale. Scores range from 0 to 28, with the following cut offs: 0–7 = no clinically significant insomnia, 8–14 = subthreshold insomnia, 15–21 = moderate clinical insomnia, and 22–28 = severe clinical insomnia. To categorize insomnia as a binary variable in our data analysis, we adopted a cutoff score of 14, which enhanced our ability to accurately detect clinical insomnia in a community sample, achieving high specificity at 98.3%.²² The scale is validated in Arabic.²³ The scale demonstrated excellent internal consistency in this study (Cronbach’s alpha = 0.90).
3. Patient Health Questionnaire for Anxiety and Depression (PHQ-4): A 4-item scale to screen for anxiety and depression, with scores categorized as normal (0–2), mild (3–5), moderate (6–8), and severe (9–12). A total score ≥3 for the first two questions indicates anxiety, and ≥3 for the last two indicates depression.²⁴ The scale is validated in Arabic.²⁵ In this study, the PHQ-4 showed high internal reliability (Cronbach’s alpha = 0.936).
4. Impact of Events Scale-Revised (IES-R): A 22-item self-report measure (DSM-IV) assessing distress from traumatic events. Items are rated on a 5-point scale (0 = “not at all” to 4 = “extremely”). It provides a total score (0–88) and subscale scores for intrusion, avoidance, and hyperarousal.²⁶ This scale is also validated in Arabic.²⁷ The scale displayed excellent reliability with a Cronbach’s alpha of 0.959.

Statistical Analysis

Data normality was assessed using Shapiro–Wilk tests; non-normal distributions (eg, ISI, IES-R scores) prompted non-parametric tests. Descriptive statistics summarized demographic characteristics and prevalence rates of insomnia and PTSD. Insomnia, depression, anxiety, and PTSD were treated as dichotomous variables based on ISI, PHQ-4, and IES-R cutoff scores. Chi-square tests examined associations between explosion proximity and these conditions. Logistic regression assessed predictors (eg, proximity, gender, age, substance use) of insomnia (ISI > 14), calculating odds ratios while controlling for confounders. Before regression, chi-square tests identified significant demographic and lifestyle influencing factors. Clinically relevant factors were included to adjust for confounding. Spearman correlation analyzed relationships between insomnia severity (ISI scores) and PTSD symptoms (IES-R scores). Mann–Whitney U-tests compared ISI scores by PHQ-4 depression/anxiety status. Chi-square tests also examined proximity-related substance use changes. Cronbach’s alpha assessed scale reliability. Significance was set at p < 0.05. The data analysis was performed using Python 3 (Python Software Foundation, https://www.python.org/), with the help of relevant statistical libraries such as Pandas, NumPy, and SciPy for data manipulation and statistical tests.

Results

Socio-Demographic Characteristics

The socio-demographic characteristics of the sample are summarized in Table 1. The median age of participants was 31 years (IQR = 23.25–45.0), with 64.4% identifying as female and 35.6% as male. More than half were single (56.5%), and the majority were employed (66.2%). A larger proportion of participants lived more than 6 km away from the explosion site (57.9%) compared to those within 6 km (42.1%).

Table 1 Socio-Demographic Characteristics of the Sample Population

Mental Health and Substance Use Outcomes by Proximity

Mental health and substance use outcomes by proximity to the explosion are summarized in Table 2. Insomnia (ISI >14) was reported by 28.8% of participants within 6 km, compared to 16.8% living farther away (χ² = 5.13, p = 0.024). Similarly, increased alcohol use was more common among those closer to the blast (32.7% vs 21.7%, χ² = 5.68, p = 0.017), as was recreational drug use (10.6% vs 4.9%, χ² = 4.71, p = 0.030). No significant differences were observed in PTSD, depression, anxiety, nicotine use, or caffeine use based on proximity.

Table 2 Cross-Tabulation of Proximity with Mental Health and Substance Use Outcomes

Insomnia

Descriptive Statistics

When using a cutoff score of 8 on the ISI, which includes subclinical insomnia, the overall prevalence of probable insomnia in our sample was found to be 62.1% after the Beirut explosion (95% CI: 56.06–68.13). Table 3 shows the distribution of insomnia severity levels across the study population. Among participants located less than 6 km from the explosion, 65.4% scored above this threshold, as compared to 60.1% of those located more than 6 km away. This difference did not reach statistical significance (p = 0.401).

Table 3 Insomnia Severity Levels in the Study Population

Bivariate Analysis

A chi-square test indicated a significant association between proximity to the explosion and insomnia (χ² = 5.13, p = 0.024). Additional chi-square tests confirmed significant associations between insomnia and:

Gender

Females had a higher prevalence (26.7%) than males (15.6%), χ² = 4.02, p = 0.045.

Direct Exposure Variables

• Defined as experiencing one or more of the following: personal injury, injury or loss of a friend or family member (social consequences), or property damage/financial loss (material consequences). This measure captures personal consequences of the explosion beyond geographic proximity.
• Significant associations were found between insomnia and all categories of direct exposure: Personal injury (p = 0.010), social loss (p = 0.008), material loss (p = 0.007), and general exposure (p = 0.002) were all significantly associated with insomnia.

No significant association was found between insomnia and age (p = 0.691), marital status (p = 0.089) or employment status (p = 0.194).

A significant association was found between direct exposure and PTSD, χ²(1) = 4.33, p = 0.037, indicating that individuals who were directly exposed were more likely to meet criteria for probable PTSD. No significant associations were found between direct exposure and depression, χ²(1) = 0.00, p = 0.984, or anxiety, χ²(1) = 1.93, p = 0.165.

Relationship with Other Mental Health Scales

A significant association was found between insomnia and PTSD symptoms. The correlation between ISI and IES-R scores was strong (Spearman’s rho = 0.57, p < 0.001). Cross-tabulation showed that 65.9% of participants with probable insomnia (ISI > 14) met the PTSD threshold (IES-R ≥ 33), compared to 21.8% of those without insomnia (χ² = 29.48, p < 0.001), indicating a strong association between the two (see Table 4).

Table 4 Chi-Square Test Results: Associations Between Insomnia and Sociodemographic Factors, Proximity, Exposure, and Mental Health Outcomes

In addition, participants with higher scores for depression and anxiety on the PHQ-4 demonstrated significantly higher insomnia scores, as shown by the Mann–Whitney U-test (Anxiety: U = 2591.5, p < 0.001; Depression: U = 1986.5, p < 0.001; results not shown in a table).

Multivariate Analysis

Prior to conducting multivariate analysis, chi-square tests further demonstrated significant associations between direct exposure to the explosion and adverse mental health outcomes, including PTSD, depression, and anxiety (Table 5). The logistic regression analysis, taking the presence/absence of insomnia (ISI score >14 and <14, respectively) as the dependent variable, and adjusting for age, sex, nicotine use, caffeine use, alcohol use, substance use, psychiatric history, sleep disorder history, and hypnotic (sleep aid) usage, confirmed the association between proximity to the explosion and insomnia (OR = 2.17, p =0.025, 95% CI: 1.10–4.27), indicating that those closer to the explosion were more than twice as likely to report clinical insomnia. The analysis also revealed that females were more than twice as likely to experience insomnia than males (OR = 2.40, p =0.035, 95% CI: 1.06–5.42).

Table 5 Chi-Square Test Results: Associations Between Direct Exposure and Mental Health Outcomes

The logistic regression model confirmed significant predictors of insomnia, including proximity to the explosion (OR = 2.17), female gender (OR = 2.40), and hypnotic usage (OR = 3.19) (Table 6). Other variables did not show significant associations.

Table 6 Logistic Regression Analysis of Factors Associated with Insomnia Symptoms

PTSD

Approximately 31% of participants had an IES-R score of 33 or higher, indicating probable PTSD. A chi-square test revealed no significant association between proximity to the explosion and the proportion of individuals crossing the PTSD threshold on the IES-R scale 4 years following the explosion (p = 0.717): Specifically, 29.5% of individuals within 6 km of the explosion exceeded the PTSD threshold, compared to 31.9% of those more than 6 km away (results not shown in a table).

Direct exposure to the Beirut explosion was significantly associated with PTSD (χ²= 4.33, p=0.037), with 39.7% of affected individuals reporting PTSD compared to 25.6% of those not directly affected (see Table 5).

Depression and Anxiety

The presence of possible depression and anxiety was analyzed using the PHQ-4 questionnaire.

No significant association was found between proximity to the explosion and long-term depression or anxiety symptomatology. The chi-square test also showed no significant difference based on proximity for either depression (p = 0.359) or anxiety (p = 0.537) (results not shown in a table).

No significant association was found between direct exposure and the persistence of depressive symptoms (χ²=.00, p = 0.984) or anxiety symptoms (χ²= 1.93, p = 0.165) 4 years after the explosion, with 33.8% and 48.8% of affected participants reporting these symptoms, respectively, compared to 33.9% and 38.8% among those not directly affected (see Table 5).

Substance Use

The relationship between proximity to the explosion and substance use (nicotine, caffeine, alcohol, and recreational drugs) was explored. A significant association was found for alcohol (p = 0.017) and recreational drugs (p = 0.03), with individuals closer to the explosion more likely to report increased use following the explosion. No significant associations were observed for nicotine (p > 0.05) or caffeine (p > 0.05).

Discussion

This study examines the long-term impact of the Beirut port explosion on mental health, focusing on sleep disturbances, which emerged as the most persistent outcome four years later. When using a cutoff score of 8 on the ISI, which includes mild (subclinical) cases of insomnia, we found the overall prevalence of insomnia to be 62.1% in our sample. This was notably higher than the 47.1% prevalence reported by Karaki et al (2017),¹² and the 44.5% reported by Chami et al (2019).¹¹ Several methodological differences, including the use of different insomnia measures and criteria, may account for these discrepancies.

Beyond methodological differences, the context of our study offers an additional explanation for the higher prevalence of insomnia. Both Karaki et al (2017) and Chami et al (2019) examined insomnia in general populations prior to significant societal stressors. Chami et al collected data between March and May 2014, and Karaki et al between August 2017 and April 2018, both before the onset of Lebanon’s economic crisis, the COVID-19 pandemic, and the Beirut explosion, which may all have partly contributed to the increase in the rates of insomnia observed in our sample. To account for these confounding factors and better isolate the potential impact of the Beirut blast, we introduced an additional level of analysis by examining differences in insomnia rates between individuals residing within the blast radius and those outside of it.

The overall prevalence of insomnia using cutoff on ISI of 8 (subclinical insomnia) was higher among individuals located less than 6 km from the explosion, however, this difference did not reach statistical significance. When applying the stricter insomnia cutoff score of 14 on the ISI (clinically significant insomnia), which we used for the remainder of this study, we observed a significant difference between the two groups. Among individuals located less than 6 km from the explosion the prevalence of clinically significant insomnia was 28.8% as compared to 16.8% among those situated farther away (p = 0.024). The significant difference indicates that, although the overall prevalence of insomnia symptoms was elevated in both populations, the traumatic psychological impact of living in closer proximity to the explosion may be more pronounced. These findings of persistent insomnia are consistent with findings on the aftermath of major disasters, including the the September 11^th attacks,²⁸ the Chernobyl disaster,²⁹ and the Great East Japan Earthquake,³⁰ all of which documented prolonged insomnia among survivors. The observed odds ratio of 2.17, adjusted for confounders, indicates that individuals within the explosion radius are more than twice as likely to experience long-term, clinically significant insomnia.

While the study found a high prevalence of self-reported past or present psychiatric diagnoses, adjusting for this variable in the logistic regression analysis did not reveal any significant influence on the outcomes, particularly insomnia. This suggests that, in our sample, psychiatric history did not substantially contribute to the outcomes in the context of proximity to the explosion.

Direct effects of the explosion, such as personal injury, loss of loved ones, and property damage, were strongly linked to higher insomnia rates, consistent with a previous study.^3,31

Female participants were found to be twice as likely to experience insomnia compared to males (OR= 2.40, p =0.035). This is consistent with previous findings that women are disproportionately affected by sleep disturbances following traumatic events. The additional stressors associated with family obligations, work and gender role expectations most likely contribute significantly to the findings in women.^32–35

It is notable that twice as many females completed the survey than males. This gender disparity in our sample may have influenced our findings, particularly the elevated prevalence of insomnia. Prior research suggests that women are more likely to participate in health-related and online surveys,³⁶ which could result in sampling bias and overrepresentation of female-specific experiences.

Age was not a significant predictor of insomnia within this sample (p = 0.691), which is consistent with existing literature.³⁷ However, it is important to note that the age distribution in our sample might not have fully captured the diversity necessary to test this association effectively. Given the sampling method and the mean and SD for age, it is possible that older adults were under-represented, limiting our ability to observe a potential age-related effect. Regardless of age, the type of trauma that one experiences has been identified as an independent predictor of insomnia.³¹

Insomnia is the most common symptom in individuals with PTSD, affecting 80–90% of patients.³⁸ Our findings show that those directly affected by personal injury, loss of loved ones, or property damage had significantly higher levels of insomnia and PTSD. Our analysis found no significant relationship between distance from the explosion and PTSD symptoms, in contrast to short term findings.¹⁷ PTSD was more prevalent among those closest to the blast initially, but over time, the psychological impact may have spread, evolving into a national trauma affecting individuals regardless of proximity, as seen in other large-scale disasters.³⁹

The increased PTSD and insomnia in individuals affected by the explosion may be attributed to the severity of the disaster, ongoing stressors, media coverage, inadequate government response, and lack of closure due to stalled investigations.

No significant association was found between proximity to the Beirut explosion and depression or anxiety four years later, in contrast to short-term studies,^16,17,40 suggesting that mood outcomes may spread or normalize over time as individuals adapt.

These findings suggest that insomnia symptoms may follow different recovery paths compared to PTSD, depression and anxiety, which may improve or normalize over time. Insomnia may persist longer than other mental health symptoms following trauma due to its strong neurobiological roots. Neurobiological models of trauma-induced insomnia describe how trauma triggers sustained hyperarousal, driven by increased activity in stress-related neural circuits, that maintains insomnia independently of PTSD’s core symptoms.¹ Disruptions in REM sleep, including frequent micro-arousals and fragmented REM, impair emotional memory consolidation and extinction processes, making it harder to “downregulate” trauma responses during sleep.^41,42

Targeting sleep disturbances in PTSD not only alleviates insomnia but also provides broader relief of PTSD symptoms, highlighting the importance of differentiated post-disaster mental health interventions that combine targeted sleep support with comprehensive psychological care tailored to symptom-specific trajectories.⁴³

Recent neuroimaging studies further elucidate the neural underpinnings of sleep disturbances in relation to mood disorders. Patients with major depressive disorder (MDD) show distinct brain changes linked to sleep that predict treatment outcomes. Low sleep efficiency is tied to impaired white matter integrity and disrupted brain synchronization.⁴⁴ REM sleep disturbances correlate with reduced interhemispheric connectivity, greater anxiety severity, and changes that track with symptom improvement over time.⁴⁵ Similarly, baseline REM percentage predicts recovery through its effects on brain activity and blood flow.⁴⁶ Resting-state activity in parietal and frontal regions also forecasts symptom improvement, with sleep efficiency mediating these effects.⁴⁷ Overall, disrupted sleep, especially REM, emerges as a neural marker of disease course in MDD.

The cultural context in Lebanon may also influence the prioritization of sleep and somatic complaints over psychological issues. The mental health stigma that is prevalent in Lebanon often deters individuals from seeking help, leading them to focus on somatic symptoms.⁴⁸ In contrast, sleep issues may be perceived as less stigmatizing, prompting individuals to report these symptoms more readily. Alternatively, the lower depression and anxiety in our cohort may reflect the population’s resilience, supported by strong familial bonds and social networks, influenced by cultural factors in Lebanon during crises.

Emerging evidence indicates that insomnia is a powerful independent risk factor for suicidal ideation and behavior, even in populations beyond depression, such as individuals with first-episode psychosis.⁴⁹ This further highlights the urgent need for integrating sleep-focused interventions into post-disaster care not only to address insomnia itself but also to mitigate downstream risks to life.

Finally, our analysis showed that participants closer to the explosion reported a higher increase in recreational substance use (p = 0.03), and alcohol consumption (p = 0.017) compared to those living further away. This suggests that the traumatic event may have led to maladaptive coping strategies, such as increased substance use. Previous research has demonstrated that exposure to traumatic events is often associated with increased substance use.⁵⁰ The absence of increased caffeine and nicotine use suggests that not all substances are equally prone to misuse following trauma, noting that smoking (cigarettes/waterpipe) and caffeine use are already highly prevalent in Lebanon.⁵¹ Incorporating substance use prevention and treatment into post-disaster mental health services is crucial.

In Lebanon’s low-resource setting, developing integrated, culturally sensitive interventions that address both sleep disturbances and substance use will be crucial for supporting long-term recovery and resilience in affected communities.

Limitations

The reliance on self-reported measures without clinical evaluations may introduce response bias, as some participants could overreport or underreport symptoms due to stigma in Lebanese culture. Additionally, the sample may not fully represent the broader Lebanese population, as those most severely affected may have been less likely to participate. Recruitment through social media platforms may have introduced selection bias, favoring younger, more educated, and tech-savvy participants. This could limit the generalizability of findings to older adults or less digitally connected populations, potentially underrepresenting groups with different exposure or symptom profiles. Furthermore, the overrepresentation of females in the sample could affect the findings and their applicability to the general population, despite adjustments for gender in the analyses. Lastly, although data collection occurred approximately 3 to 4 years after the Beirut explosion, this timeframe may not fully capture the long-term trajectory of psychological effects, which could evolve beyond this window.

Conclusion

The Beirut explosion had lasting mental health effects, with insomnia notably higher among those closer to the blast. Nearly 30% of participants within 6 km reported clinically significant insomnia, often linked to direct exposure. While PTSD symptoms were elevated, depression and anxiety showed no long-term association with proximity. Increased substance use near the site raises important public health concerns.

These findings emphasize the need for early sleep health screening in post-disaster settings, as sleep complaints may serve as a culturally acceptable entry point for mental health interventions in Lebanon. Policymakers should prioritize integrating long-term psychological support, with a focus on sleep disturbances, into disaster response, especially in resource-limited regions. Beyond their immediate burden, chronic sleep disturbances have broader consequences for mental health, including increased risk of suicidal ideation and behavior. Incorporating evidence-based sleep interventions into post-disaster care is therefore not only critical for reducing insomnia itself, but also for mitigating downstream psychiatric morbidity and suicide risk.

Declaration of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this work, the author(s) used QuillBot in order to paraphrase some sentences to enhance the clarity and style of language. After using this tool, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article.

Research Data for This Article

Due to the sensitive nature of the data collected, including participants’ location during the Beirut explosion and other personal details, raw data cannot be shared. Participants were assured of confidentiality, and their data will remain confidential.

Ethics Approval and Consent to Participate

This study was approved by the Institutional Review Board (IRB) at the American University of Beirut (IRB ID: SBS-2021-0218), in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all study participants prior to study commencement. No patient identifiable features are included in this paper.

Consent to Publish

Participants provided informed consent to participate in the study, which included acknowledgment that the results would be published in a peer-reviewed journal. No identifiable personal data is included in this paper.

Funding

This study was funded by a grant from the Faculty of Medicine at the American University of Beirut.

Disclosure

The authors report there are no competing interests to declare.

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Background

Since the beginning of 2025, a total of 73,806 cholera cases and 490 deaths (CFR: 0.66%) have been reported across 22 African Union Member States. In comparison, 2024 saw 169,801 cases and 3,056 deaths, with a fatality rate of 1.8%. Over recent years, several African Union Member States have faced severe and protracted cholera outbreaks, underscoring the vulnerability to the disease. To address this, multifaceted strategies have been recommended for the control and elimination of cholera. These strategies include enhanced surveillance, improved access to clean water, sanitation, and hygiene, social mobilization, effective case management, and the use of oral cholera vaccines. In response to these challenges, Member States and governments have called for strengthened preparedness, increased financing, climate-resilient programs, and strategies to enhance surveillance for early detection, all aimed at control and elimination of cholera in Africa.

The Global Task Force on Cholera Control developed a Roadmap aimed at reducing cholera deaths by 90% and eliminating cholera in at least 20 countries by 2030. This will be achieved through: i) enhanced surveillance, early detection, and rapid response to contain outbreaks; ii) targeted, multi-sectoral interventions in ‘hot spot’ areas, focusing on improving WASH (Water, Sanitation, and Hygiene) and deploying oral cholera vaccines (OCV); and iii) effective coordination for technical support, advocacy, resource mobilization, and fostering partnership at local and global levels.

Since 2023, Africa CDC, through the Africa Pathogen Genomics Initiative (Africa PGI), has collaborated with seven highly affected Member States—Nigeria, Cameroon, DRC, Uganda, Zambia, Malawi, and Mozambique—as well as the African Public Health Foundation; researchers from John Hopkins University and Harvard Medical School; and Gates Foundation. Together, we established the Cholera Genomic Consortium in Africa (CholGEN), aimed at building local capacity and piloting the use of advanced tools such as genomic sequencing to provide crucial insights into the spread and evolution of cholera across the continent. As a major achievement, the initiative successfully provided genomic evidence of co-circulating lineages, antimicrobial resistance profiles, and cross-border transmission of cholera, offering critical data to inform regional public health interventions.

Eyes in the pharma and medtech industries are directed to the European Society of Cardiology (ESC) Congress every year to examine the latest clinical trial data, observational study results, and real-word evidence in the cardiology space.

On this episode, the healthcare editorial team unpicks several key trials and trends from this year’s event, held from 29 August to 1 September in Madrid.

Data at ESC is from studies evaluating investigational drug or medical device candidates, but also from trials analysing approved therapies.

Pharmaceutical Technology editor Robert Barrie sat down with Abigail Beaney, editor of Clinical Trials Arena, and Ross Law, reporter for Medical Device Network, who both covered the congress, to discuss data presented.

• GAL-101 was well tolerated; excellent safety and pharmacokinetic profile strongly support oral administration
• GAL-101 effectively crosses the blood-brain barrier, supporting further development in Alzheimer’s disease
• A Phase 2 trial in Alzheimer’s disease is planned as the next step, fundraising has been initiated

KENSINGTON, Md. and MUNICH and MARTINSRIED, Germany, Sept. 12, 2025 (GLOBE NEWSWIRE) — Galimedix Therapeutics, Inc. (“Galimedix”), a Phase 2 clinical-stage biotechnology company developing novel oral and topical neuroprotective therapies with the potential to revolutionize the treatment of serious brain and retinal diseases, today announced the completion of its Phase 1 study with orally administered GAL-101, a small molecule specifically designed to target misfolded amyloid beta (Aβ) monomers. In the trial, GAL-101 was shown to be well tolerated and clinically safe, with no serious adverse events (SAEs) observed. Consistent with pre-clinical findings, GAL-101 was shown to effectively cross the blood-brain barrier, and its pharmacokinetic (PK) profile strongly supports advancing the oral formulation in Phase 2 development in Alzheimer’s disease. The full study results are expected to be presented at a future scientific conference.

“Completing our first clinical trial with the oral formulation of GAL-101 is an important milestone for Galimedix,” said Alexander Gebauer, MD, PhD, Co-founder and Executive Chairman of Galimedix. “We are pleased that the results showed that oral GAL-101 was well tolerated with a highly favorable safety profile. Additionally, the pharmacokinetic profile strongly supports the planned administration route, as well as continued development for the treatment of Alzheimer’s disease. We are planning a Phase 2 trial in Alzheimer’s disease, an indication for which patients today have very limited treatment options. GAL-101 is expected to be first-in-class and has the potential to become the future standard of care for all stages of Alzheimer’s, including mild cognitive impairment.”

The Phase 1 trial enrolled a total of over 100 healthy volunteers and evaluated the safety, tolerability and pharmacokinetics of single (SAD) and multiple (MAD) ascending oral doses of GAL-101. The study also evaluated GAL-101’s ability to cross the blood-brain barrier, as well as a variety of other parameters, including the effects of food, age and gender, all of the relevant aspects required to initiate Galimedix’s planned Phase 2 study in Alzheimer’s disease.

Galimedix is also conducting a Phase 2 clinical trial with GAL-101 eyedrops for dry age-related macular degeneration (dAMD); recruitment in the eDREAM study is ongoing in the US, Europe, and other regions. The development in dAMD/geographic atrophy (GA) is partner funded, mitigating the financial exposure of Galimedix.

Galimedix is prepared to discuss the available data and investment and partnering opportunities with interested parties.

Connect with Galimedix
To learn more, investors and partners are invited to connect with Galimedix management, who will attend the following fall conferences:

• LSX World Congress USA, Boston, MA, September 15-17
• 25^th Annual Biotech in Europe Forum, Basel, Switzerland, October 8-9
• BIO-Europe, Vienna, Austria, November 3-5
• LSX Inv€$tival, London, UK, November 17

To schedule a meeting or call, please reach out to info@galimedix.com.

About GAL-101
GAL-101 is a small molecule targeting misfolded Aβ monomers and thus preventing the formation of toxic Aβ oligomers and protofibrils. It is being developed in both oral and topical (eyedrops) formulations. Many studies have indicated that these Aβ aggregates are a major underlying cause of neurodegenerative diseases of the brain and retina, and recent approvals of anti-Aβ drugs have also validated them as a key target in Alzheimer’s disease. GAL-101 is being developed for the treatment of dAMD, glaucoma and Alzheimer’s disease.

In pre-clinical testing, the compound has been shown to prevent and eliminate all forms of toxic Aβ species while leaving healthy Aβ forms intact. GAL-101 has also demonstrated the potential for neuroprotection and for symptomatic alleviation in pre-clinical models of Alzheimer’s disease. Additionally, orally available GAL-101 has shown no antibody-specific immunological side effects (e.g., ARIA), very low systemic toxicity, robust storage stability, and easy and inexpensive manufacturing. Strong efficacy has also been demonstrated in relevant ophthalmic pre-clinical models, protecting neuronal retinal cells from toxic damage. In a previous Phase 1 study, GAL-101 eyedrops demonstrated an excellent safety and tolerability profile. The eDREAM Phase 2 study (NCT06659549) in dAMD/GA with GAL-101 eyedrops is ongoing.

About Galimedix Therapeutics, Inc. 
Galimedix is a Phase 2 clinical-stage private company developing novel oral and topical neuroprotective therapies with the potential to revolutionize the treatment of serious brain and retinal diseases. Founded by a seasoned and highly dedicated team of bio-entrepreneurs, pharmaceutical executives and scientists, Galimedix’s groundbreaking small molecules offer the hope of changing the course of disease where amyloid beta (Aβ) plays a role, such as in Alzheimer’s disease, dry age-related macular degeneration (dAMD) and glaucoma – Galimedix’s initial areas of focus.

Contact 
Alexander Gebauer, MD, PhD 
Galimedix Therapeutics, Inc.
Co-founder and Executive Chairman
info@galimedix.com

Media inquiries: 

Anne Hennecke	U.S.
MC Services AG	Laurie Doyle
Tel: +49 (0)170 7134018	Tel: +1-339-832-0752
galimedix@mc-services.eu

Background

The SWItch/Sucrose NonFermentable (SWI/SNF) chromatin-remodeling complex is an evolutionarily conserved, ATP-dependent multi-subunit assembly, plays a critical role in fundamental cellular processes such as cell proliferation, lineage-specific differentiation, and DNA repair.¹ Inactivation of subunits within this complex has emerged as a key molecular driver in the development and progression of both benign and malignant tumors.² Mutations in one or more subunits and the corresponding loss of protein expression have been observed in approximately 20% of cancer cases.³ Notably, core subunits of the SWI/SNF complex, including SMARCA2 (BRM), SMARCA4 (BRG1), and SMARCB1 (INI1), have been found to be lost in various malignancies characterized by rhabdoid or undifferentiated morphology. Specifically, alterations in nasal and paranasal tumors predominantly involve SMARCB1 and SMARCA4,⁴ while soft tissue tumors are primarily associated with SMARCB1 mutations,⁵ and thoracic tumors exhibit mainly SMARCA2 and SMARCA4 deletions.⁶ Thoracic SMARCA4-deficient undifferentiated tumor was included in the 5th edition of the WHO Classification of Thoracic Tumors, exhibiting undifferentiated histological features and highly aggressive biological behavior.⁷ Recently, three cases of undifferentiated thoracic tumor have been documented, each characterized by a deletion of SMARCA2 while retaining SMARCA4 and SMARCB1 expression.⁸ This suggests that a more precise classification of tumors with deficiencies in the SWI/SNF complex within the thoracic region could significantly enhance clinical management strategies.

In addition, the deletion of the SWI/SNF complex subunit was observed in 5.4% of non-small cell lung cancer cases.⁹ SWI/SNF complex-deficient non-small cell lung cancer (NSCLC) exhibit aggressive clinicopathological characteristics, PD-L1 positivity, high tumor mutation burden (TMB), and exhibit favorable responses to both immunotherapy and platinum-based chemotherapy.¹⁰ SMARCA2 deficiency was identified in 6.4% of lung adenocarcinomas and 1.7% of squamous cell carcinomas within a large cohort study, indicating a potential role for SMARCA2 in the dedifferentiation process of NSCLC.⁹ However, the expression status of SMARCA2 is not routinely assessed in the pathological diagnosis of poorly differentiated lung adenocarcinoma, and the subtype of lung adenocarcinoma characterized by isolated SMARCA2 deficiency remains underrecognized. Studies have indicated that the Wnt/β-catenin signaling pathway is dysregulated in various solid tumors and plays a role in the process of tumor dedifferentiation, which is characterized by the abnormal accumulation of β-catenin protein within the cell nucleus.¹¹ This study aims to characterize the clinicopathological, immunohistochemical, and molecular features of SMARCA2-deficient lung adenocarcinoma with preserved SMARCA4 expression, as well as to explore its potential correlation with abnormal expression of β-catenin.

Methods

Cases

The study was performed with the approval of Institutional Review Board of Zhejiang Hospital, and informed consent of the subjects has been waived. Inclusion criteria for the patient cohort were pathologic diagnosis of lung adenocarcinoma characterized by SMARCA2-deficient and SMARCA4-preserved between 2019 and 2024 for which the patients have consented to molecular testing. The specific diagnostic criteria were defined as follows: a diagnosis of lung adenocarcinoma in accordance with the 5th edition of the World Health Organization classification criteria, the absence of SMARCA4 and SMARCA2 is defined as either a complete and unequivocal absence or a diffuse and markedly reduced expression within the tumor cell nuclei. These cases included fine needle aspiration, bronchial biopsy specimens, and surgical resections. Additionally, we reviewed the electronic medical records of the study patients to document their clinical characteristics.

Histopathologic Analysis

The tissue samples were fixed in 3.7% neutral formaldehyde solution, subjected to routine dehydration, paraffin embedding, and sectioned at a thickness of 4 μm for hematoxylin and eosin (H&E) staining and subsequent light microscopic examination. Immunohistochemical staining was conducted as part of the clinical evaluation for each case. The staining procedure was performed using the EnVision two-step technique. Detailed information regarding the antibodies used in this study is provided in Table 1. Two pathologists independently and uniformly evaluated the immunohistochemical expression and intensity. Positive internal control cells (benign epithelial cells or inflammatory cells) were used for SMARCA4, SMARCA2, and INI1 staining to facilitate comparative analysis. The evaluation was performed using a two-tier scoring system based on the absence or retention of nuclear expression. The assessment of the remaining antibody for immunohistochemical staining is interpreted as positive (+) when tumor cells exhibit nuclear, cytoplasmic, and/or membrane expression in no less than 10% of the cell population. For PD-L1 (22C3), the results were interpreted in accordance with established guidelines, and the tumor proportion score (TPS) was defined as the percentage of PD-L1 positive tumor cells among the total number of PD-L1 positive and PD-L1 negative tumor cells.

Table 1 List of Primary Antibodies Used in the Study

Mutations Analyses

Genomic DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) tissue using the DNeasy Tissue Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. All tissue samples underwent pathological assessment to confirm adequacy of the tumor tissues, which required a minimum of 20% tumor content. Sequencing libraries were constructed using a KAPA DNA Library kit (Kapa Biosystems, Wilmington, MA, USA). The libraries were hybridized to a custom-designed panel containing 18 cancer-related genes, including ALK, EGFR, MET, RET, ROS1, KRAS, NRAS, BCL2L11, TP53, NTRK1, NTRK2, NTRK3, ERBB2, BRAF, PIK3CA, AXL, PNET, and RB1. Prepared libraries were sequenced on the Gene+Seq‐2000 apparatus (GenePlus-Suzhou, Suzhou, China) using a paired‐end read protocol. Single nucleotide variants (SNVs) were identified using MuTect (Broad Institute, Cambridge, MA, USA), and small insertions and deletions (indels) were called by GATK (Broad Institute, Cambridge, MA, USA). Copy number variations (CNVs) were detected using Contra (Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia). All final candidate variants were verified using an integrative genomics viewer browser. Germline variants were removed from variants in the tumor samples.

Results

Clinical Findings

The study cohort comprised seven patients, including five males and two females (Table 2). The age range of the patients was between 52 and 79 years, with a mean age of 68.7 years. None of the patients had a history of other malignancies. Smoking history was present in four patients (57.1%), with smoking durations ranging from 20 to 55 years (mean duration: 35 years), three patients were non-smokers. Tumor locations included the left upper lobe in three cases (42.8%) (Figure 1A), the left lower lobe in two cases (28.6%) (Figure 1B), and the right upper lobe in two cases (28.6%). The primary lesions were measured 17 to 59 mm in greatest diameter (mean: 41 mm). Chest computed tomography revealed emphysema and bullae in all four smokers, as well as peripheral pulmonary fibrosis in other three patients. All seven patients exhibited respiratory symptoms, including cough, sputum production, chest tightness, and dyspnea, and pleural effusion was observed in two patients at the time of diagnosis. Tumor marker levels were within normal limits in one patient, while six patients demonstrated elevated levels of one or more tumor markers. Specifically, these included carcinoembryonic antigen (2/7), carbohydrate antigen 15–3 (1/7), non-small cell lung cancer-related antigen 21–1 (4/7), carbohydrate antigen 125 (2/7), serum neuron-specific enolase (2/7), alpha-fetoprotein (1/7), pro-gastrin-releasing peptide (1/7), and carbohydrate antigen 19–9 (1/7). One patient (14.3%) was diagnosed in stage I, two patients (28.6%) at stage II, two patients (28.6%) at stage III, and two patients (28.6%) at stage IV. Among the five patients who underwent lobectomy, two patients received adjuvant chemotherapy (pemetrexed plus carboplatin), two patients received immunotherapy (tislelizumab and sintilimab, respectively), and one patient received chemotherapy and immunotherapy (pemetrexed plus tislelizumab). Additionally, among those who did not undergo surgical resection, one patient received chemotherapy and targeted therapy (cisplatin plus osimertinib), while the other patient received chemotherapy and immunotherapy (pemetrexed plus tislelizumab). The follow-up data for all seven patients ranged from 10 to 33 months, with a mean follow-up duration of 18.3 months. Among the five patients who underwent lobectomy, four patients remained in complete response (CR) with no evidence of disease recurrence or distant metastasis. One patient developed progressive disease (PD), ultimately died of tumor recurrence and hemoptysis. Among the two patients who did not receive surgical intervention, one patient experienced disease progression and died of hemoptysis and pleural effusion, while the other patient remained in CR.

Table 2 Clinical Findings of SMARCA2-Deficient with SMARCA4-Preserved Lung Adenocarcinomas

Figure 1 Computed tomography scan of SMARCA2-deficient lung adenocarcinoma. An irregular nodule exhibiting a lobulated morphology and spiculated margin was identified in the left upper lobe of the lung (A, white arrow). Nodular high-density opacities are observed in the lower lobe of the left lung, exhibiting lobulated features with poorly defined margins (B, white arrow).

Pathologic and IHC Findings

The histological evaluation was conducted on seven cases, comprising five surgically resected specimens, one bronchial biopsy specimen of a primary tumor, and one CT-guided percutaneous lung biopsy specimen of a primary tumor. Seven cases were diagnosed as non-mucinous poorly differentiated adenocarcinomas characterized by typical focal adenoid differentiation, including acinar, cribriform, and papillary structures (Figure 2A). In certain regions, the tumor cells were also observed to exhibit a cable-like distribution pattern (Figure 2B), with their growth predominantly characterized by solid components (Figure 2C). The tumor cells exhibited morphological variability, ranging from oval to rhabdoid morphology (Figure 2D), with neoplastic necrosis observed in five cases, multinucleated giant cells (Figure 2E) in four cases, and hyaline changes (Figure 2F) in three cases. The cytoplasm of the tumor cells was predominantly eosinophilic, with well-defined cell borders. All cases demonstrated marked nuclear atypia, prominent nucleoli, and frequent pathological mitotic figures. Mild interstitial inflammation was noted in two cases, while moderate inflammatory cell infiltration, predominantly lymphocytes, plasma cells, and histiocytes, was observed in five cases. Extracellular mucinous secretion was identified in one case.

Figure 2 The histologic findings of SMARCA2-deficient lung adenocarcinoma. The tumor cells exhibited a cribriform and papillary architecture, with evident necrosis observed within the glandular cavities (A). The tumor cells demonstrated a cable-like structure accompanied by hyalinization of the interstitial tissue (B). Solid components of the tumor were present, characterized by eosinophilic globules and stromal cell infiltration (C). Notable features included the presence of rhabdoid morphology cells (D), giant cells (E), and solid regions with distinct clear cytoplasm (F).

Key immunohistochemical (IHC) findings are summarized in Table 3. SMARCA2 expression was absent in seven tumor samples (Figure 3A), whereas SMARCA4 (Figure 3B) and INI-1 exhibited consistent positivity. TTF-1 (Figure 3C) and Napsin A showed focal expression in three cases that exhibited similar morphological characteristics, while 4 cases demonstrated diffuse positivity. CK7 and E-cadherin were expressed in seven cases, whereas P40, CD34, and ALK were consistently negative. Notably, SALL4 was partially positive in one case, 2 cases showed partial positivity for SOX2 (Figure 3D), and β-catenin exhibited abnormal cytoplasmic and nuclear positivity in three cases (Figure 3E). Immunohistochemical analysis revealed that p53 was diffusely and strongly positive (Figure 3F) in five cases and completely negative in two cases. PD-L1 (22C3) expression was negative in two cases (2/7), low expression in three cases (3/7), and high expression in two cases (2/7) (TPS<1% was defined negative, 1–49% was defined low expression, and >50% was defined high expression). MIB-1 staining indicated a significant increase in proliferative activity, with a nuclear positivity rate ranging from 40% to 80% (mean: 64.3%).

Table 3 Immunohistochemical Results in SMARCA2-Deficient with SMARCA4-Preserved Lung Adenocarcinomas

Figure 3 Immunohistochemical findings in SMARCA2-deficient lung adenocarcinoma. Immunohistochemistry for SMARCA2 is negative (A). SMARCA4 immunohistochemistry exhibits strong diffuse nuclear staining (B). The tumor cells retained expression of TTF-1 (C). The subset of tumor cells expressed SOX2 (D). Aberrant β-catenin expression in tumor cells is observed both in the nucleus and cytoplasm (E). The cells showed strong nuclear positivity of P53 (F).

Mutations

Next-generation sequencing (NGS) analysis revealed that four cases harbored driver gene mutations, specifically two KRAS mutations (c.35G>C p.G12A and c.34G>C p.G12R), one MET mutation (Exon14 c.3054_3082+13del p.V1019_D102 8del), and one EGFR exon 19 in-frame deletion (p.T751_I759d elinsN). Notably, TP53 mutations (c.524G>A p.R175H, c.574C>T p.Q192, c.1010G>T p.R337L, c.808T>G p.F270V, c.785G>T p.G262V, c.1114_1130deli nsG p.K372Afs45, c.469G>T p.V157F) were identified in all seven patients. Additionally, other genetic alterations were observed, including mutations in ERBB2 (c.929C>T p.S310F), PIK3CA (Exon10 c.1624G>A p.E524K), and RB1 (Exon17 c.1510C>p.Q504), as well as amplifications of EGFR and KRAS, and a deletion in CDKN2A.

Discussion

SMARCA2 and SMARCA4 constitute the two core catalytic subunits of the SWI/SNF chromatin remodeling complex and are recognized as tumor suppressors.³ The proteins encoded by these genes, BRM and BRG1, both possess a bromodomain and an ATPase domain with approximately 75% sequence homology.¹ Notably, there are significant differences in expression and function between SMARCA4 and SMARCA2.¹² Mutations in SMARCA4 have been identified in various types of cancer, including rhabdomyosarcoma, small cell ovarian cancer with hypercalcemia, gastric cancer, and lung cancer,¹³ whereas mutations in SMARCA2 are relatively rare in cancer. Multiple studies have demonstrated that the simultaneous or non-simultaneous loss of SMARCA2 and SMARCA4 may accelerate tumor differentiation and epithelial-mesenchymal transition.¹⁴ Additionally, isolated SMARCA2 deletions have been reported in three undifferentiated tumors within the thoracic cavity⁸ and two undifferentiated adenocarcinomas at the gastroesophageal junction.¹⁵ These cancers exhibit morphologic features similar to those observed in SMARCA4-deficient cancers. Agaimy et al have reported a notable increase in undifferentiated morphology and SMARCA2 loss in gastrointestinal cases with metastases of NSCLC.¹⁶ To the best of our knowledge, limited studies have investigated the clinical and histopathological features of lung adenocarcinoma with SMARCA2 deletion but SMARCA4 retention. Therefore, this rare subtype of lung cancer remains inadequately understood by thoracic surgeons. In this study, we present a series of poorly differentiated lung adenocarcinoma cases characterized by SMARCA2 deletion and retained SMARCA4 expression, providing a detailed analysis of morphological features and clinical outcomes.

In this cohort, the majority of cases were male (71.4%), with a significant proportion being smokers (57.1%). The average smoking duration was 35 years, indicating a potential association between SMARCA2 deficiency and smoking. However, it remains undetermined whether smoking is a direct cause of SMARCA2 loss. All cases within this cohort were classified as poorly differentiated adenocarcinomas. Histopathological examination revealed predominantly solid structures with prominent inflammatory infiltrates. Tumor cells exhibited a nested pattern, characterized by abundant eosinophilic cytoplasm. In certain regions, the tumor demonstrated continuity with typical adenocarcinoma features, adenocarcinoma differentiation exhibited acinar, cribriform, and papillary structures. Tumor cells displayed rhabdoid differentiation, granular chromatin, prominent nucleoli, and multinucleated giant cells, often associated with necrosis. Additionally, clear cell-like morphology was observed, characterized by large tumor cells with clear cytoplasm and well-defined cell borders, indicative of intracellular or extracellular mucin production. Notably, 3 cases demonstrated aberrant β-catenin expression in the cytoplasm and nucleus of certain tumor cells, along with diminished TTF-1 expression, providing additional evidence that SMARCA2 deficiency contributes to morphological alterations, changes in cell viability, and dedifferentiation. Literature on isolated cases of SMARCA2 deletion in lung adenocarcinoma remains limited, and in-depth studies investigating the relationship between the Wnt/β-catenin signaling pathway and SMARCA2 loss have been scarce. Therefore, further elucidation of this relationship necessitates larger patient cohort studies. Additionally, in cases of poorly differentiated lung adenocarcinoma exhibiting rhabdoid morphology and tumor giant cells, immunohistochemical testing for SMARCA2 and SMARCA4 can effectively identify such tumors, which is highly significant for clinicians in selecting more precise therapeutic strategies.

The top differential diagnosis is thoracic SMARCA4-deficient undifferentiated tumor primarily involves tumor cells characterized by rhabdoid morphology, poor cellular cohesion, and a lack of epithelial differentiation. These tumors typically exhibit focal positivity or complete negativity for epithelial markers and lack immunohistochemical expression of BRG1 and Claudin-4.¹⁷ Other differential diagnosis should be discussed with primary tumors, including poorly differentiated squamous cell carcinoma, large cell carcinoma, and sarcomatoid carcinoma. Poorly differentiated squamous cell carcinomas usually express squamous markers such as CK5/6, p40, and p63. Morphological evidence of adenocarcinoma, including intracellular mucin and glandular differentiation, can be identified using immunohistochemical markers like TTF-1 and Napsin A, as well as special stains for mucin. Large cell carcinomas may display striated muscle-like cytological features, necessitating adequate surgical specimens for definitive diagnosis. In these cases, there is no evidence of adenocarcinoma differentiation, and TTF-1 and Napsin A are negative. SWI/SNF complex-deficient cancers have been reported in various systems,² with the lung being a common site of metastasis for many malignancies. For SMARCA2-deficient lung adenocarcinomas, comprehensive immunohistochemical labeling combined with imaging studies is essential to rule out metastatic disease. Non-small cell carcinomas with clear characteristics of lung adenocarcinoma and positive expression of TTF-1 and Napsin A can be diagnosed as SMARCA2-deficient lung adenocarcinoma.

In all seven patients, next-generation sequencing (NGS) was conducted to identify mutations in 18 genes associated with lung cancer development. These mutations encompassed point mutations, small fragment insertions and deletions, copy number variations, and known fusion genes. Driver gene mutations were identified in four patients: two harbored KRAS mutations, one had a MET mutation, and another exhibited an EGFR exon 19 non-frameshift deletion. Notably, TP53 mutations were present in all seven cases. Additional genetic alterations detected included ERBB2, PIK3CA, and RB1 mutations, as well as EGFR and KRAS amplifications, and CDKN2A deletions. SMARCA2 may represent an additional genetic event independent of EGFR and ALK mutations.¹⁸ Further investigation is required to determine whether SMARCA2 functions as a direct driver gene, a passenger gene, or if its role is influenced by epigenetic regulatory factors.¹⁹ Previous studies utilizing mouse models have demonstrated that the preservation of SMARCA2 deficiencies in the context of SMARCA4 mutations promotes the onset and/or progression of lung cancer.^1,20 Research has confirmed that promoter methylation results in the inactivation of SMARCA2, thereby facilitating lung cancer development. The silencing of SMARCA2 is driven by promoter polymorphisms and is associated with histone deacetylase (HDAC) activity.²¹ Recent studies have demonstrated that hypermethylation of the ABCG1 gene results in reduced ABCG1 gene expression and decreased protein levels in non-small cell lung cancer (NSCLC), which is significantly correlated with overall survival in lung adenocarcinoma (LUAD) patients.²² These findings indicate that the alterations in SMARCA2 resulting from promoter methylation may serve as a promising epigenetic biomarker for predicting the clinical prognosis of non-small cell lung cancer.

The significant heterogeneity observed among lung cancer tumors has prompted increased research efforts directed toward the identification of cell type-specific genes. This approach holds promise for improving the classification of tumor subtypes and predicting responses to therapeutic interventions.²³ Previous studies have indicated that SMARCA2-deficient lung adenocarcinoma exhibits a poor prognosis and a significantly lower 5-year survival rate, serving as an independent prognostic factor for lung adenocarcinoma.¹⁸ Currently, there is no specific treatment regimen established for SMARCA2-deficient lung adenocarcinoma. Protein acetyltransferase inhibitors have been shown to restore the expression levels of various mRNAs and proteins, which can be further modulated by HDAC inhibitor therapy.¹ If SMARCA2 loss co-occurs with other driver gene mutations, a combination of targeted therapies may be considered to enhance clinical outcomes. Studies have indicated that this subtype of lung adenocarcinoma demonstrates sensitivity to platinum-based chemotherapy, CDK4/6 inhibitors, and PD-1 inhibitors, all of which exhibit significant therapeutic efficacy.¹⁰ Notably, four patients who received immunotherapy achieved complete remission during the follow-up period (12 to 33 months), suggesting a potentially favorable response to immunotherapy in this patient cohort.

One limitation of our study is the relatively small number of cases included in the retrospective analysis, which makes it difficult to conduct effective statistical analysis to establish a clear association between this rare tumor subtype and clinical treatment or patient prognosis. Importantly, this study represents the first report of abnormal β-catenin expression in SWI/SNF-deficient lung cancer, despite the absence of functional validation. Further investigation into the role of SMARCA2 in tumor dedifferentiation may yield valuable insights into the molecular heterogeneity of lung cancer. Expanding the sample size to further characterize the clinicopathological features and underlying molecular mechanisms of this subgroup of lung adenocarcinoma is crucial for advancing precision medicine in the treatment of lung cancer.

Conclusions

We present a series of seven cases of lung adenocarcinoma characterized by the absence of SMARCA2 expression while maintaining intact SMARCA4 expression. The tumors demonstrate diverse histological features, including rhabdoid morphology and the presence of tumor giant cells, with some cases exhibiting aberrant β-catenin expression. Genetically, all cases harbor TP53 mutations, and certain cases present concomitant alterations in known lung cancer driver genes. This distinct subtype of lung adenocarcinoma is predominantly observed in advanced stages, and 5 patients demonstrates favorable responses to platinum-based chemotherapy and immune checkpoint inhibitor therapy. However, two patients experienced disease progression that ultimately resulted in death, long-term monitoring remains necessary. Future studies involving larger, multi-institutional cohorts are expected to make meaningful contributions to the more comprehensive understanding of SWI/SNF complex involvement in lung cancer pathogenesis, prognosis, and potential therapeutic strategies.

Ethical Approval

This study conformed to the Declaration of Helsinki on Human Research Ethics standards and was approved by the Medical Ethics Committee of the Zhejiang Hospital, Zhejiang Province, People’s Republic of China (approval ZJHIRB-014K). The requirement of patients’ informed consent was waived owing to the retrospective nature of the study. And we confirmed that the data was anonymized or maintained with confidentiality.

Acknowledgments

We greatly appreciate the assistance of the staff of the Department of Pathology, Zhejiang Hospital, and thank them for their efforts.

Author Contributions

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

Funding

This research received no funding.

Disclosure

The authors report no conflicts of interest in this work.

This paper has been uploaded to SSRN as a preprint: https://papers.ssrn.com/sol3/papers.cfm/abstract_id=5185537

References

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2. Biegel JA, Busse TM, Weissman BE. SWI/SNF chromatin remodeling complexes and cancer. Am J Med Genetics Part C. 2015;166(3):350–366. doi:10.1002/ajmg.c.31410

3. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J. Crabtree GRJNG: proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nature Genet. 2013;45(6):592–601. doi:10.1038/ng.2628

4. Chung SY, Kenee P, Mitton T, et al. SMARCB1(INI-1)-deficient sinonasal carcinoma: an evolving entity. J Neurol Surg Rep. 2023;84(1):e1–e5. doi:10.1055/a-1996-1283

5. Schaefer IM, Hornick JL. SWI/SNF complex-deficient soft tissue neoplasms: an update. Seminars Diagn Pathol. 2021;38(3):222–231. doi:10.1053/j.semdp.2020.05.005

6. Daisuke M, Yuka K, Shumpei I, et al. Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. Cancer Sci. 2012;104(2).

7. Nicholson A, Tsao M, Beasley M, et al. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Thorac Oncol. 2021.

8. Akari I, Eiichi S, Mariko S, et al. Thoracic SMARCA2-deficient but SMARCA4-preserved tumors with undifferentiated morphology combined with Claudin-4 negativity. Am J Surg Pathol. 2022;46(7).

9. Herpel E, Rieker RJ, Dienemann H, et al. SMARCA4 and SMARCA2 deficiency in non–small cell lung cancer: immunohistochemical survey of 316 consecutive specimens. Ann Diagn Pathol. 2017;26:47. doi:10.1016/j.anndiagpath.2016.10.006

10. Naito T, Udagawa H, Umemura S, et al. Non-small cell lung cancer with loss of expression of the SWI/SNF complex is associated with aggressive clinicopathological features, PD-L1-positive status, and high tumor mutation burden. Lung Cancer. 2019;138:35–42. doi:10.1016/j.lungcan.2019.10.009

11. Han W, Jiening G, Yong W, Yao Z, Li J, Weijing L. Ciprofol suppresses glycolysis and EMT in colorectal cancer cells by activating APC to modulate the Wnt/β -catenin signaling pathway. Sci Rep. 2025;15(1).

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14. Panozzi M, Alí G, Proietti A, et al. SMARCA4 as a support for the differential diagnosis of poorly differentiated lung carcinomas. Pathologica. 2023;115(3):164–171. doi:10.32074/1591-951X-847

15. Rachel KH, Mahsa A, Anthony JG, et al. SMARCA4/SMARCA2-deficient carcinoma of the esophagus and gastroesophageal junction. Am J Surg Pathol. 2020;45(3).

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ALSO READ: Fitness trainer reveals 5 things that made her weight loss journey easier: Walk a lot, fix sleep and more

Other than going up a clothing size, the exercises he suggested also focus on areas where losing weight may be a bit challenging.

Weight loss exercises target problem areas. Overweight or obese women often have challenging areas like thicker thighs, belly fat, and flabby arms. Hence, the exercises added to a workout regimen need to effectively address these focus areas.

The fitness coach listed these exercises:

1. Squat

For overweight women, the problem area is often the lower body. Squat targets and tones the lower body. Akkani explained, “This tones your legs and lifts your butts so that your jeans and dresses fit smoother and your thighs don’t rub together.”

2. Back rows

Back rolls and flabby arm fat are usually some of the common insecurities. According to the fitness coach, back row exercises help target the upper back and arms.

3. RDLS

RDLs, or Romanian Deadlifts, target specific muscle groups in the legs, like the hamstrings and glutes, and further assist in reducing lower-body fat. Akkani said, “This firms the back of your legs and glutes, which smoothes out trouble spots and helps tighten your lower body so that your clothes fit more flattering.”

4. Planks

Belly fat is one of the most difficult areas to lose weight. This is where planks come in, strengthening the core and helping to target stubborn belly fat.

He added, “This tightens your midsection so you have a flatter stomach and a better posture.”

All in all, these four exercises fall under strength training. This indicates that women looking to lose weight should definitely include strength training in their routine to target common problem areas like belly fat, flabby arms, and back rolls, which cardio alone may not effectively address.

Note to readers: This report is based on user-generated content from social media. HT.com has not independently verified the claims and does not endorse them.

This article is for informational purposes only and not a substitute for professional medical advice.

Similar to back pain, there are a few other symptoms of kidney diseases in the early stages that often go unnoticed. Dr Kshitij Raghuvanshi listed them:

1. Persistent fatigue

When kidney function declines, toxins and impurities accumulate in the blood. This can cause constant tiredness, weakness, and difficulty concentrating. In addition, reduced production of a hormone that supports red blood cell formation may lead to anemia, further contributing to fatigue.

2. Dry, itchy skin

Healthy kidneys maintain the balance of minerals and nutrients in the blood while removing waste products. Impaired function disrupts this balance, often resulting in dry, persistently itchy skin that does not respond well to topical remedies. Also read | Doctor says these 8 symptoms could mean your kidneys are failing: Are you at risk of kidney disease?

3. Changes in urination

Kidney problems often manifest through noticeable changes in urination patterns. These include:

• Increased or decreased frequency, particularly at night
• Foamy or bubbly urine, which may indicate excess protein
• Blood in the urine
• Difficulty or discomfort while urinating

4. Swelling (edema)

When the kidneys cannot efficiently eliminate excess fluid and sodium, fluid retention occurs. This commonly causes swelling in the legs, ankles, feet, hands, or even the face.

5. Loss of appetite and nausea

The buildup of waste products in the bloodstream can reduce appetite, trigger nausea, and even cause a metallic taste in the mouth. Over time, this can lead to poor nutrition and unintended weight loss.

“Kidney disease rarely presents with dramatic early warning signs. Instead, it progresses quietly. If you experience unusual back pain alongside any of these symptoms, it is important to seek medical advice promptly. Early detection through regular health check-ups can significantly improve outcomes,” the urologist highlighted. Also read | Urologist shares why young Indians are getting kidney diseases without realising it

Note to readers: This article is for informational purposes only and not a substitute for professional medical advice. Always seek the advice of your doctor with any questions about a medical condition.

Introduction

Helicobacter pylori (H. pylori)¹ is a bacterium known for colonizing the stomach lining and causing gastrointestinal conditions such as chronic gastritis, peptic ulcers, and gastric cancer, has also been investigated for its potential role in extra-gastric diseases,² including rosacea.³ While the exact relationship between H. pylori and rosacea remains under investigation, the evidence suggests that H. pylori may play a role in the pathogenesis or exacerbation of rosacea in certain individuals.⁴ Further research is needed to clarify the mechanisms and establish whether H. pylori eradication should be considered as part of the treatment strategy for rosacea patients with concurrent H. pylori infection.

Previous studies have shown that patients with H. pylori infection may have an increased risk of rosacea,⁵ and the cure of H. pylori led to partial regression of the skin symptoms in rosacea patients.^3,6 However, whether there is a potential link between rosacea and H. pylori infection remains uncertain, and no genetic association studies between the two have been conducted up to now.

GWAS database is a public resource that stores and shares data. By analyzing associations between genomic variants and specific traits or diseases across large populations, GWAS aims to identify genetic links to complex diseases, physiological traits, or drug responses. Mendelian randomization (MR) is an epidemiological approach that employs genetic variants as instrumental variables to proxy for the exposure of interest, thereby investigating the effect of the exposure on a specific outcome.^7,8 Due to the random assortment of single nucleotide polymorphisms (SNPs), they are less likely to be influenced by confounding factors. The MR design can mitigate residual confounding and reverse causation, strengthening the causal inference of the exposure’s association with the outcome. In this study, we conducted a two-sample MR analysis to assess the causal relationship between H. pylori infection and rosacea.

Materials and Methods

Data Sources

We retrieved GWAS data for H. pylori infection from MRC-IEU Open GWAS (https://gwas.mrcieu.ac.uk) and GWAS catalog (https://www.ebi.ac.uk/gwas/), and the GWASID were “ieu-b-4905” and “ebi-a-GCST90006910”, and we call them H. pylori infection (ieu) and H. pylori infection (ebi) separately in this study. Data for rosacea were retrieved from FinnGen database (https://r12.finngen.fi/), and the GWASID were “finngen_R12_L12_ROSACEANAS”. The study population consisted exclusively of individuals with European ancestry, potentially limiting the generalizability of our findings.

Instrumental Variants (IVs) Selection

We use Linkage-disequilibrium pruning to remove the influence of highly correlated single nucleotide polymorphisms (SNPs). These SNPs were clumped based on the linkage disequilibrium (LD) structure of European ancestry (r2 < 0.001, 10000 kb). We selected SNPs with P < 5×10⁻⁸ and found that the H. pylori dataset contained fewer than 3 SNPs in the MR analysis. Therefore, we adjusted the SNPs screening threshold to P < 5×10⁻⁶. Additionally, the F-statistics was calculated using the formula F = [(n-k-1)/k] × [R²/(1-R²)], where an F-value > 10 indicated sufficient strength of the instrumental variables. For datasets missing the effect allele frequency (eaf), the formula F = β²/SE² was applied for calculation. Conceptual framework diagram was shown in Figure 1.

Figure 1 The frame chart of the MR analysis.

Finally, 12 SNPs associated with “H. pylori infection (ieu)” and 11 SNPs related to “H. pylori infection (ebi)” were retrieved from GWAS. After removing SNPs for being unavailable or being palindromic with intermediate allele frequencies (rs7281117), there were 12 SNPs left as IVs for “H. pylori infection (ieu)” and 10 for “H. pylori infection (ebi)”.

Statistical Analysis

Inverse-variance weighted (IVW) method was the main method we used in this study. To make the results more accurate, MR Egger, simple mode, weighted median, and weighted mode were also performed by using the “TwoSampleMR” package in R (version 4.2.3). We used MR-PRESSO test to eliminate outliers and the heterogeneity was also carried out by Cochran’s Q test. And the reliability of the results is also proved by the method of leave-one-out.

Results

We conducted an MR analysis between H. pylori infection and rosacea. In the H. pylori infection (ieu) group, we identified 12 SNPs. All instrumental variables showed sufficient strength (F > 10), comfortably exceeding the weak instrument threshold. The IVW results indicated no genetic association between H. pylori infection and rosacea (OR = 0.894, 95% CI 0.70–1.013, P = 0.078). In the H. pylori infection (ebi) group, we obtained 10 SNPs. Similarly, the IVW analysis showed no significant genetic association (OR = 1.021, 95% CI 0.932–1.119, P = 0.655). Results were similar in the analysis based on the weighted median method: H. pylori infection (ieu) (OR = 0.98, 95% CI 0.83–1.17, P = 0.849), H. pylori infection (ebi) (OR = 1.0, 95% CI 0.88–1.13, P = 0.965). Meanwhile, results based on the simple mode: H. pylori infection (ieu) (OR = 1.04, 95% CI 0.78–1.38, P = 0.802), H. pylori infection (ebi) (OR = 0.95, 95% CI 0.79–1.15, P = 0.600), and results based on the weighted mode: H. pylori infection (ieu) (OR = 1.03, 95% CI 0.82–1.29, P = 0.817), and H. pylori infection (ebi) (OR = 0.97, 95% CI 0.83–1.15, P = 0.772). They all contribute to enhancing the credibility of this causal inference. The main results of this study are shown in Figure 2. And two scatters are shown in Figures 3 and 4.

Figure 2 Forest plot of MR results.

Figure 3 Scatterplot of SNP potential effects of H. pylori infection ebi-a-GCST90006910 to rosacea.

Figure 4 Scatterplot of SNP potential effects of H. pylori infection ieu-b-4905 to rosacea.

Additionally, the results of heterogeneity and pleiotropy are presented in Table 1. As for heterogeneity, no statistically significant findings were observed in either the H. pylori infection (ieu) group (p = 0.4840) or the H. pylori infection (ebi) group (p = 0.5188). As for the MR-Egger pleiotropy test, no statistically significant results were detected in either the H. pylori infection (ieu) group (p = 0.3908) or the H. pylori infection (ebi) group (p = 0.4308), indicating the reliability of the findings. Furthermore, MR-PRESSO did not identify any outliers, confirming the stability and robustness of the results.

Table 1 Sensitivity Analyses of MR

Discussion

Rosacea is a common, sometimes hereditary, chronic inflammatory facial skin condition that primarily affects adults, mostly in women.^9,10 Although the underlying causes of rosacea are not fully understood, several studies have suggested there is an association with H. pylori infection.^11,12 Some studies have also observed that symptoms in rosacea patients can improve following the eradication of H. pylori.^3,6,13 It has been reported that H. pylori can stimulate the immune system to produce a large number of inflammatory mediators, resulting in the occurrence and aggravation of rosacea inflammation.^14,15 H. pylori increases the synthesis of oxygen metabolites,^15,16 such as superoxide and pro-inflammatory cytokines, which can affect skin physiology, including vasodilation, inflammation and immune regulation.^14,17 And TLR2 and TLR4 can activate Toll-like receptors, leading to NF-κB pathway activation, along with nonspecific release of chemokines such as IL-8. Additionally, H. pylori infection may alter neuropeptide levels, impairing the Nrf2 antioxidant pathway and amplifying local inflammatory responses.^18,19 These mechanisms could potentially exacerbate rosacea. However, these shared pathways only indicate correlation and cannot establish a causal relationship.

In our study, we found that all methods used in this study suggested no association between H. pylori infection and rosacea, align with a previously published meta-analysis²⁰ concluded that there was weak correlation association between rosacea and H. pylori infection and that no significant improvement in rosacea skin symptoms was observed after H. pylori treatment. It seems like H. pylori is an aggravating factor rather than a cause. Moreover, we postulated that the lifestyle of H. pylori-infected individuals might potentially exert an influence on the outcomes of previous studies. We employed MR methodology, which effectively mitigated the influence of confounding factors through the utilization of genetic variants as instrumental variables.

We identified multiple H. pylori-related datasets in the GWAS database, among which only the Anti-H. pylori IgG dataset contained a sufficient number of SNPs, thus justifying our selection of these two specific datasets for this study. Additionally, our analysis was confined to northern European populations to ensure genetic homogeneity, as genetic variations across different ethnic groups could potentially confound the results. While this approach enhances the reliability of our findings within this specific population, it may introduce a degree of bias, limiting the generalizability of our conclusions. Future research should aim to include diverse racial and ethnic groups to explore the association between rosacea and H. pylori infection. Rosacea comprises multiple clinical subtypes.²¹ However, since current rosacea GWAS databases lack subtype classification and do not provide specific case numbers or proportions for each subtype, we were unable to conduct MR analyses between H. pylori infection and distinct rosacea subtypes—a significant limitation of this study. Nevertheless, our null findings do not preclude potential associations in specific subtypes, as substantial literature reports elevated H. pylori infection rates in papulopustular rosacea patients. Current studies on the association between H. pylori infection and rosacea have covered a wide range of regions, including Egyptian, Chinese, Russian, and German patients. Studies suggesting no significant association between H. pylori and rosacea^5,22 may also be influenced by factors such as: sample size limitations, heterogeneous composition of rosacea subtypes, geographical variations and sensitivity of detection methods. Future research should prioritize the following directions to address current limitations: 1. Precision subtype stratification of rosacea; 2. broader geographical representation; 3. standardized high-sensitivity detection protocols; 4. expand the sample size.

Conclusion

Our MR analysis provides no evidence of a causal relationship between H. pylori infection and rosacea. This indicates that patients with rosacea may not need routine testing for H. pylori infection and routine eradication of H. pylori may not benefit rosacea patients.

Ethics Approval and Consent to Participate

According to item 1 and 2 of Article 32 of the Measures for Ethical Review of Life Science and Medical Research Involving Human Subjects adopted by the National Science and Technology Ethics Committee of the People’s Republic of China dated February 18, 2023, since the data used in this study will not cause any harm to humans, does not involve any sensitive personal information or commercial interests, and the selected database is open and legal, approval from the ethics review committee is not required.

Funding

There is no funding for this study.

Disclosure

The authors declare that there is no conflict of interest.

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