Search Results (60)

Dementia is a neurodegenerative disorder characterized by progressive cognitive impairment that significantly affects daily living. Early detection of Alzheimer’s disease—the most common form of dementia—remains essential for prompt intervention and treatment, yet clinical diagnosis often requires extensive and resource-intensive procedures. This article explores the effectiveness of automated Natural Language Processing (NLP) methods for identifying Alzheimer’s indicators from audio transcriptions of the Cookie Theft picture description task in the PittCorpus dementia database. Five NLP approaches were compared: a classical Tf–Idf statistical representation and embeddings derived from large language models (GloVe, BERT, Gemma-2B, and Linq-Embed-Mistral), each integrated with a logistic regression classifier. Transcriptions were carefully preprocessed to preserve linguistically relevant features such as repetitions, self-corrections, and pauses. To compare the performance of the five approaches, a stratified 5-fold cross-validation was conducted; the best results were obtained with BERT embeddings (84.73% accuracy) closely followed by the simpler Tf–Idf approach (83.73% accuracy) and the state-of-the-art model Linq-Embed-Mistral (83.54% accuracy), while Gemma-2B and GloVe embeddings yielded slightly lower performances (80.91% and 78.11% accuracy, respectively). Contrary to initial expectations—that richer semantic and contextual embeddings would substantially outperform simpler frequency-based methods—the competitive accuracy of Tf–Idf suggests that the choice and frequency of the words used might be more important than semantic or contextual information in Alzheimer’s detection. This work represents an effort toward implementing user-friendly software capable of offering an initial indicator of Alzheimer’s risk, potentially reducing the need for an in-person clinical visit. Full article

Background: The efficacy of EA575 in the treatment of respiratory diseases is described in various clinical studies, improving patients’ disease-related symptoms. However, mechanistic in vivo data proving its beneficial effects are limited. Methods: Focusing on the treatment of acute airway inflammation and accompanying cough, this study aimed to elucidate antitussive and mucoactive properties of EA575, applying two animal models. Animals were treated orally twice daily for 7 days, resulting in 43, 215.2, or 430.5 mg/kg bw/d of EA575. Antitussive effects were investigated within an acute lung inflammation model of bleomycin-treated guinea pigs after citric acid exposure. Hereby, the number of coughs, enhanced pause (penH), and bronchoalveolar lavage fluid (BALF) were investigated. Mucoactivity of EA575 was assessed within a murine model, determining phenol red concentration in BALF. Results: EA575 treatment within the acute lung inflammation model reduced cough events up to 56% while reducing inflammatory cell influx in BALF dose-dependently, e.g., reducing neutrophils in BALF up to 70.9%. This suggests a strong connection between anti-inflammatory and antitussive properties of EA575. Furthermore, penH decreased in a dose-dependent manner, suggesting an ease in respiration. Mucoactivity was shown by a dose-dependent increase in phenol red concentration in BALF up to 38.9%. Notably, EA575/salbutamol co-administration resulted in enhanced phenol red secretion compared to respective single administrations. Conclusions: These data highlight the benefits of EA575 in treating cough-related respiratory diseases, particularly when accompanied by sputum, as EA575 has been shown to obtain mucoactivity. Furthermore, the combinatory effect of EA575/salbutamol treatment provides a foundation for future research in the treatment of chronic respiratory diseases. Full article

Numerous remediation strategies exist for cyanobacterial harmful algal blooms (cyanoHABs); however, most are limited by challenges of scalability and adverse off-target effects on the surrounding ecosystem. Germicidal ultraviolet light (UV-C) has emerged as a promising method for suppressing cyanoHABs in a sustainable, chemical-free manner that is both scalable and results in limited off-target ecological effects in the surrounding area. In this study, the US Army Engineer Research and Development Center’s (ERDC)’s CyanoSTUN^TM (Cyanobacterial Suppression Through Ultraviolet-Light-C Neutralization) vessel was deployed to a cyanoHAB as part of a field trial to determine whether UV-C could effectively suppress cellular growth, degrade associated cyanotoxins, and inhibit harmful phytoplankton species more readily than beneficial species without the addition of chemicals. The cyanoHAB exhibited an average cyanobacteria abundance of 3.75 × 10⁵ cells/mL (n = 5, SD = 6.76 × 10⁴ cells/mL) and average total microcystin concentration of 3.5 µg/L (n = 5; SD = 0.24 µg/L). Pre- and post-treatment samples were collected and re-grown for 9 days in the laboratory to observe differences in microcystin, chlorophyll a, and phycocyanin concentrations, optical density, cell density, and community composition. The results of the field trial showed that the CyanoSTUN UV-C treatment effectively suppressed the growth of the cyanobacteria community for approximately two days at the three tested UV-C doses. The CyanoSTUN UV-C treatment also demonstrated a sustained, dose-dependent effect on microcystin concentration; the average reduction in microcystin concentration for 15, 30, and 45 mJ/cm² treatment doses was 31.6% (n = 10, SD = 20.1%; 1.3 µg/L reduced), 45.7% (n = 10, SD = 10.8%; 1.9 µg/L reduced), and 49.9% (n = 10, SD = 8.2%; 1.7 µg/L reduced), respectively, over the 9-day regrowth period. Non-cyanobacteria were too scarce in this CyanoHAB to conclude whether the CyanoSTUN UV-C inhibits harmful phytoplankton species more readily than beneficial species. Further field studies with the CyanoSTUN^TM are required to validate performance under more severe cyanoHAB conditions, however the results reported herein from the first field trial with the CyanoSTUN^TM suggest that this treatment method may offer water managers confronted with a CyanoHAB the ability to rapidly and safely pause a bloom for multiple days and reduce the risks posed by its associated cyanotoxins without adding chemicals. Full article

Purpose: Assess mental health professionals’ attitudes regarding the timing and characteristics of therapeutic interventions for children whose parents have incurable cancer, and whether professionals would use artificial intelligence (AI) in these interventions. Methods: Professionals were surveyed about their therapeutic approaches to caring for children when parents have incurable cancer under different scenarios. Data from N = 294 (69% male, 72% white, 26% Latine, 56% rural or underserved communities) physicians, psychologists, social workers, hospital chaplains, community health workers, and others were analyzed. Attitudes surrounding the timing and characteristics of interventions across the parent’s cancer journey were compared, including how professionals believed interventions should attend to dimensions of the child or family, and if, how, and when AI technology could be introduced. Results: Across 10 dimensions of childhood, (1) the child’s premorbid exposure to traumatic events, (2) a surviving parent’s presence, and (3) the child’s age were important factors to consider when making mental health care decisions in this context. The professionals reported being more likely to introduce therapeutic resources as early as possible in the parent’s illness (i.e., upon diagnosis). Regarding the use of AI, 87% foresaw its role in supporting children’s mental health. While 93.2% agreed that a grieving child could be helped by interacting with an AI-generated likeness of the deceased parent, when AI’s use was contextualized in providing support for a child who lost a parent to cancer, only 49% believed AI was appropriate. The participants were conflicted over when AI could be first introduced, either upon a parent’s illness diagnosis (19.4%), during a parent’s treatment (19.0%), or as part of a parent’s hospice care (12.6%). None believed it to be appropriate following the loss of the parent to cancer. Conclusions: AI is increasingly present in children’s daily lives and quickly infiltrating health care with widely accessible mental health chatbots. Concerns about privacy, the accuracy of information, and the anthropomorphism of AI tools by children give professionals pause before introducing such technology. Proceeding with great caution is urged until more is known about the impact of AI on children’s mental health, grief, and psychological well-being in the context of parental cancer. Full article

Background: Cabozantinib is a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor (VEGFR-TKI). These drugs are employed as therapy for several malignancies. In detail, Cabozantinib has demonstrated its efficacy against several malignancies. On the other hand, Cabozantinib and other VEGFR-TKIs can be responsible for various adverse events (AEs), in particular hepatic and dermatological AEs. Methods: To date, limited data are available in the literature regarding ocular AEs due to therapy with these drugs. In this regard, one case of corneal perforation during treatment with a VEGFR-TKI, Regorafenib, has been reported, while there are no data about Cabozantinib. In this paper, we present another clinical case of corneal perforation in a patient affected by advanced RCC and treated with Cabozantinib as a second-line therapy. The patient started Cabozantinib at the dosage of 60 mg/die although it was necessary to apply some dose reductions because of grade 2 AEs (according to CTCAE v6.0), such as asthenia, diarrhea, dysgeusia, and loss of appetite. Results: After approximately 15 months of treatment, the patient began to experience pain and vision loss in the right eye. A diagnosis of corneal perforation was made, followed by medical and surgical treatment. As regards the etiology of this pathology, all other possible causes were excluded, including a history of ocular disease, contact trauma, exposure to damaging agents (e.g., chemical agents and prolonged use of drugs such as topical NSAIDs), infections, or dry eye. Therefore, we hypothesized a correlation with Cabozantinib’s mechanisms of action and paused its administration. Conclusions: Cabozantinib may alter the ocular environment due to a lack of or imbalance in growth factors in the tear film, with a reduction in corneal epithelium proliferation. This condition might cause dry eye and a delay in corneal healing. Therefore, particular importance should be placed on ophthalmologic surveillance during treatment with these drugs in patients who develop ocular symptoms. Further in vitro and in vivo studies are necessary to deepen the knowledge about VEGFR-TKI-mediated ocular AEs. Full article

Background/Objectives: Cerebral folate transporter deficiency is characterized by pauses and regression in general development stages, with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment. The aim of this study was to comprehensively evaluate cases followed up in two centres in Türkiye for a diagnosis of folate receptor-α deficiency. Methods: The study included nine cases from six different families. Results: The patients comprised 22.2% males and there was parental consanguinity in 88.9% of cases. The mean age at which complaints were first noticed was 3.7 years, and the age of definitive diagnosis was 10.4 years. The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties. The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years. On cranial imaging, white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often. Definitive diagnosis was established solely through clinical findings and genetic analysis. Three different variants in the FOLR1 gene were determined. Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at the age of 9.8 years on average, and intravenous folinate was started at different doses. Conclusions: This study stands out as one of the largest case series in the literature and identifies a previously unreported novel variant. Our study suggests that FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy. Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective. Incorporating FOLR1 gene analysis into newborn screening programmes could facilitate early diagnosis and treatment. It is thought that the application of vagus nerve stimulation, in addition to folinic acid and anticonvulsant drug treatment, could be effective in seizure control. Full article

Hypopituitarism is a condition characterized by the deficiency of several hormones produced by the pituitary gland. Genetic factors play an important role. Variants in the POU1F1 gene are associated with combined pituitary hormone deficiency 1 (CPHD1), which manifests as deficiencies in growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL). This study aimed to analyze the phenotype, genotype, treatment, and outcomes of Vietnamese patients with deficiency. Six patients from five unrelated families, initially diagnosed with hypopituitarism, were enrolled in this study. Data on physical characteristics, biochemical tests, treatment, outcomes, and follow-up were collected. Exome sequencing and Sanger sequencing were conducted to identify disease-causing variants in five probands and their families. All six patients exhibited anterior pituitary hypoplasia on brain magnetic resonance imaging and presented with TSH, GH, and PRL deficiencies. Exome sequencing identified three variants in the POU1F1 gene: c.428G>A p.(Arg143Gln), c.557T>G p.(Leu186Arg), and c.811C>T p.(Arg271Trp). The c.811C>T p.(Arg271Trp) variant was found in three patients, while c.557T>G p.(Leu186Arg) is a novel variant. Based on the ACMG classification, these variants were categorized as likely pathogenic or pathogenic variants. All patients were definitively diagnosed with CPHD1 caused by POU1F1 variants. All patients received levothyroxine and recombinant human growth hormone (rhGH) replacement therapy, leading to considerable growth. During the first year of treatment, all patients showed excellent growth response, with height increases ranging from 11 to 24 cm. After three years of treatment, two patients achieved normal height. One of the six patients developed scoliosis during treatment, which resolved after a one-year pause in rhGH therapy. Upon resuming treatment, no recurrence of scoliosis was observed. Our findings reveal the importance of early hormone testing and genetic analysis in improving the care and outcomes for patients with combined pituitary hormone deficiency. Full article

Background. Cervical spondylitis is accompanied by segmental instability and sagittal imbalance. The purpose of this work is to conduct a search of correlation between sagittal parameters and clinical outcomes in cervical spondylitis. Materials and Methods. The monocentric cohort study encompassed the clinical and radiological data of 59 patients who underwent reconstructive surgeries on the suboccipital, subaxial, and cervicothoracic spine. We evaluated local cervical sagittal parameters: cervical sagittal vertical axis (CSVA), T1 slope (T1S), Health-Related Quality of Life—HRQOL (Oswestry Disability Index—ODI)—and others pre- and postoperatively. Results. The duration of the therapeutic pause and T1S correlated with HRQOL. It revealed the direct relationship between the age of the patient and the value of CSVA. A significant predictor of postoperative complications is the level of comorbidity with an index of 7 or more on the Charlson scale. Conclusions. The factors influencing HRQOL in this pathology are the duration of the therapeutic pause and the magnitude of T1S compensation. Anterior reconstruction of the cervical spine in the presence of spondylitis yields a correction of the sagittal balance parameters. The leading predictors of complications from the surgical treatment of cervical spondylitis are the Charlson comorbidity index and the variant of anterior reconstruction. Full article

Objectives: Cyclosporine A promotes gingival fibrosis by enhancing the proliferation of gingival fibroblasts, leading to gingival overgrowth. The population of gingival fibroblasts is regulated by cell cycle machinery, which balances cell growth and inhibition. Cells that detect DNA damage pause at the G1/S checkpoint to repair the damage instead of progressing to the S phase. Previous studies have linked drug-induced gingival overgrowth to the response of fibroblasts to lipopolysaccharide (LPS) and cyclosporine A. This research investigates the effects of cyclosporine A on the G1/S checkpoint and its mediators in LPS-treated gingival fibroblasts to clarify the mechanisms behind cyclosporine-A-induced gingival overgrowth. Methods: Semi-confluent human gingival fibroblasts were treated with LPS or cyclosporine A in DMEM. Cell proliferation was evaluated by counting the total number of cells. The distribution of the cell cycle phases was analyzed using flow cytometry. Additionally, the expression levels of mRNAs and proteins related to cell cycle regulators were quantified by reverse-transcription quantitative PCR and Western blotting, respectively. Results: Cyclosporine A treatment significantly enhanced cell proliferation and the G1-S cell cycle transition. It increased the mRNA levels of CDC25A and CYCLIN D while decreasing those of RB1, SMAD3, and SMAD4. Additionally, it upregulated the protein levels of CDC25A, CYCLIN D, CDK4, CDK6, and pRB and downregulated the protein levels of SMAD3 and SMAD4. Conclusions: Gingival overgrowth induced by cyclosporine A could be attributed to these alterations. Full article

We present a patient treated with personalized ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) for non-small cell lung cancer (NSCLC) using the adaptive Varian Ethos™ system equipped with the novel HyperSight imaging platform. Three pulses of 12 Gy were separated by a pause of four weeks during which the tumor was given enough time to respond to treatment. Only initial planning computed tomography (CT) was acquired on a CT simulator (Siemens Somatom Definition Edge), whereas other pulses were adapted using online cone beam computed tomography (CBCT) images (iCBCT Acuros reconstruction) acquired while the patient was lying on the treatment couch and delivered immediately. Significant tumor reduction was achieved between pulses, resulting in improved organs-at-risk sparing. In addition, the on-couch plan optimization based on CBCT greatly reduced the patient’s stay at the clinic and the duration of treatment preparation. Full article

Drug abuse continues to pose a significant challenge in HIV control efforts. In our investigation, we discovered that cocaine not only upregulates the expression of the DNA-dependent protein kinase (DNA-PK) but also augments DNA-PK activation by enhancing its phosphorylation at S2056. Moreover, DNA-PK phosphorylation triggers the higher localization of the DNA-PK into the nucleus. The finding that cocaine increases the nuclear localization of the DNA-PK provides further support to our observation of enhanced DNA-PK recruitment at the HIV long terminal repeat (LTR) following cocaine exposure. By activating and facilitating the nuclear localization of the DNA-PK, cocaine effectively orchestrates multiple stages of HIV transcription, thereby promoting HIV replication. Additionally, our study demonstrates that the cocaine-induced DNA-PK promotes the hyper-phosphorylation of the RNA polymerase II (RNAP II) carboxyl-terminal domain (CTD) at Ser5 and Ser2 sites, enhancing both the initiation and elongation phases, respectively, of HIV transcription. The cocaine-mediated enhancement of transcriptional initiation is supported by its activation of cyclin-dependent kinase 7 (CDK7). Additionally, the induction of transcriptional elongation is marked by higher LTR recruitment and the increased phosphorylation of CDK9, which indicates the stimulation of positive transcriptional elongation factor b (P-TEFb). We demonstrate for the first time that cocaine, through DNA-PK activation, promotes the specific phosphorylation of TRIM28 at serine 824 (p-TRIM28, S824). This modification converts TRIM28 from a transcriptional inhibitor to a transactivator for HIV transcription. Additionally, we observed that the phosphorylation of TRIM28 (p-TRIM28, S824) promotes the transition from the pausing phase to the elongation phase of HIV transcription, thereby facilitating the production of full-length HIV genomic transcripts. This finding corroborates the previously observed enhanced RNAP II CTD phosphorylation at Ser2, a marker of transcriptional elongation, following cocaine exposure. Accordingly, upon cocaine treatment, we observed the elevated recruitment of p-TRIM28-(S824) at the HIV LTR. Overall, our results unravel the intricate molecular mechanisms underlying cocaine-induced HIV transcription and gene expression. These findings hold promise for the development of highly targeted therapeutics aimed at mitigating the detrimental effects of cocaine in individuals living with HIV. Full article

Background: Hyperbaric oxygen therapy (HBOT) involves inhaling nearly 100% oxygen in a pressurized environment and is commonly used to treat various diseases and injuries. Despite its well-known safety, HBOT is associated with side effects, with frequent middle ear barotrauma (MEB) and oxygen toxicity. Understanding the characteristics and risk factors associated with these side effects is critical for improving patient compliance and treatment outcomes. Methods: This retrospective multicenter study aimed to analyze the characteristics and factors associated with side effects during HBOT using a computer-controlled pressurized monoplace hyperbaric chamber. We conducted a retrospective observational study across the two tertiary hospitals in Korea, involving patients who received HBOT from October 2016 for one hospital and October 2017 for another hospital to June 2020. Data were extracted from electronic medical records and hyperbaric chamber logs, including patient demographics, medical history, HBOT indications, and details of side effects. Statistical analyses, including chi-square and t-tests, were used to compare variables. Results: A total of 247 patients (mean age: 59.35 ± 15.05 years, 63.56% male) were included. The most common indications for HBOT were sudden sensorineural hearing loss (27.94%) and post-graft/flap (24.29%). Hypertension (46.15%) and diabetes mellitus (39.27%) were the most frequent comorbidities. Otalgia was the most prevalent side effect (33.20%), followed by chest discomfort (2.02%) and headache (1.62%). A significant proportion of patients (11.74%) terminated HBOT due to side effects, with most pauses occurring at pressures between 1.2 and 1.4 ATA (26.67%). Side effects, particularly otalgia, significantly impact patient compliance with HBOT. Conclusions: The incidence of side effects varies by pressure level during treatment, suggesting the need for tailored strategies to minimize side effects. This study highlights the importance of patient monitoring and education to improve the safety and efficacy of HBOT in monoplace chambers. Full article

Since 2017, Puerto Rico has faced environmental, economic, and political crises, leading to the emigration of healthcare workers and weakening the healthcare system. These challenges have affected cancer treatment continuity, exacerbating healthcare access challenges island-wide. In this study, we estimate the effect of the residence region on cancer treatment disruption following Hurricanes Irma and María (2017). Telephone surveys were conducted with 241 breast and colorectal cancer patients aged 40 and older who were diagnosed within six months before the hurricanes and were receiving treatment at the time of the hurricanes. Treatment disruption was defined as any pause in surgery, chemotherapy, radiotherapy, or oral treatment due to the hurricanes. Prevalence ratios (PRs) of treatment disruption by residence region were estimated using the San Juan Metropolitan Area (SJMA) as the reference. Fifty-nine percent of respondents reported treatment disruption; among them, half experienced disruptions lasting more than 30 days, with 14% of these enduring disruptions longer than 90 days. Adjusted models showed a 48% higher prevalence of disruption outside the SJMA (PR = 1.48, 95% CI: 1.06–2.07). Specific geographic regions (Arecibo, Bayamón, Caguas, and Mayagüez) exhibited higher disruption prevalence. These findings emphasize the need for disaster preparedness strategies that ensure equitable healthcare access for all cancer patients following environmental calamities. Full article

Background/Objectives: Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series: Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions: Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities. Full article

Disturbance or insufficiency of the tear film challenges the regulatory systems of the ocular surfaces. The reaction of the surfaces includes temporary mechanisms engaged in the preservation of homeostasis. However, strong or persisting challenges can lead to the potential exhaustion of the coping capacity. This again activates the vicious circle with chronic inflammation and autocatalytic deterioration. Hence, the factors challenging the homeostasis should be addressed in time. Amongst them are a varying osmolarity, constant presence of small lesions at the epithelium, acidification, attrition with mechanical irritation, and onset of pain and discomfort. Each of them and, especially when occurring simultaneously, impose stress on the coping mechanisms and lead to a stress response. Many stressors can culminate, leading to an exhaustion of the coping capacity, outrunning normal resilience. Reaching the limits of stress tolerance leads to the manifestation of a lubrication deficiency as the disease we refer to as dry eye disease (DED). To postpone its manifestation, the avoidance or amelioration of stress factors is one key option. In DED, this is the target of lubrication therapy, substituting the missing tear film or its components. The latter options include the management of secondary sequelae such as the inflammation and activation of reparative cascades. Preventive measures include the enhancement in resilience, recovery velocity, and recovery potential. The capacity to handle the external load factors is the key issue. The aim is to guard homeostasis and to prevent intercellular stress responses from being launched, triggering and invigorating the vicious circle. Considering the dilemma of the surface to have to cope with increased time of exposure to stress, with simultaneously decreasing time for cellular recovery, it illustrates the importance of the vicious circle as a hub for ocular surface stress. The resulting imbalance triggers a continuous deterioration of the ocular surface condition. After an initial phase of the reaction and adaption of the ocular surface to the surrounding challenges, the normal coping capacity will be exhausted. This is the time when the integrated stress response (ISR), a protector for cellular survival, will inevitably be activated, and cellular changes such as altered translation and ribosome pausing are initiated. Once activated, this will slow down any recovery, in a phase where apoptosis is imminent. Premature senescence of cells may also occur. The process of prematurization due to permanent stress exposures contributes to the risk for constant deterioration. The illustrated flow of events in the development of DED outlines that the ability to cope, and to recover, has limited resources in the cells at the ocular surface. The reduction in and amelioration of stress hence should be one of the key targets of therapy and begin early. Here, lubrication optimization as well as causal treatment such as the correction of anatomical anomalies (leading to anatomical dry eye) should be a prime intent of any therapy. The features of cellular stress as a key hub for the vicious circle will be outlined and discussed. Full article