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Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials., Competing Interests: Declaration of competing interest The authors have declared all competing financial interests or personal relationships that could have appeared to influence the work reported in this paper above., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endogenous double-stranded RNA has emerged as a potent stimulator of innate immunity. Under physiological conditions, endogenous dsRNA is maintained in the cell nucleus or the mitochondria; however, if protective mechanisms are breached, it leaches into the cytoplasm and triggers immune signaling pathways. Ectopic activation of innate immune pathways is associated with various diseases and senescence and can trigger apoptosis. Hereby, the level of cytoplasmic dsRNA is crucial. We have enriched dsRNA from two melanoma cell lines and primary dermal fibroblasts, including a competing probe, and analyzed the dsRNA transcriptome using RNA sequencing. There was a striking difference in read counts between the cell lines and the primary cells, and the effect was confirmed by northern blotting and immunocytochemistry. Both mitochondria (10-20%) and nuclear transcription (80-90%) contributed significantly to the dsRNA transcriptome. The mitochondrial contribution was lower in the cancer cells compared to fibroblasts. The expression of different transposable element families was comparable, suggesting a general up-regulation of transposable element expression rather than stimulation of a specific sub-family. Sequencing of the input control revealed minor differences in dsRNA processing pathways with an upregulation of oligoadenylate synthase and RNP125 that negatively regulates the dsRNA sensors RIG1 and MDA5. Moreover, RT-qPCR, Western blotting, and immunocytochemistry confirmed the relatively minor adaptations to the hugely different dsRNA levels. As a consequence, these transformed cell lines are potentially less tolerant to interventions that increase the formation of endogenous dsRNA.

Question: Refugees and asylum seekers are at high risk of mental disorders due to various stressors before, during and after forceful displacement. The WHO Self-Help Plus (SH+) intervention was developed to manage psychological distress and a broad range of mental health symptoms in vulnerable populations. This study aimed to examine the effects and moderators of SH+ compared with Enhanced Care as Usual (ECAU) in reducing depressive symptoms among refugees and asylum seekers., Study Selection and Analysis: Three randomised trials were identified with 1795 individual participant data (IPD). We performed an IPD meta-analysis to estimate the effects of SH+, primarily on depressive symptoms and second on post-traumatic stress, well-being, self-identified problems and functioning. Effects were also estimated at 5-6 months postrandomisation (midterm)., Findings: There was no evidence of a difference between SH+ and ECAU+ in reducing depressive symptoms at postintervention. However, SH+ had significantly larger effects among participants who were not employed (β=1.60, 95% CI 0.20 to 3.00) and had lower mental well-being levels (β=0.02, 95% CI 0.001 to 0.05). At midterm, SH+ was significantly more effective than ECAU in improving depressive symptoms (β=-1.13, 95% CI -1.99 to -0.26), self-identified problems (β=-1.56, 95% CI -2.54 to -0.59) and well-being (β=6.22, 95% CI 1.60 to 10.90)., Conclusions: Although SH+ did not differ significantly from ECAU in reducing symptoms of depression at postintervention, it did present benefits for particularly vulnerable participants (ie, unemployed and with lower mental well-being levels), and benefits were also evident at midterm follow-up. These results are promising for the use of SH+ in the management of depressive symptoms and improvement of well-being and self-identified problems among refugees and asylum seekers., Competing Interests: Competing interests: RGW acted as a consultant reviewer to the WHO in the development of the SH+ intervention, and I am an author on the papers reporting on the RCTs in the EU and Uganda. The rest of the authors have nothing to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background During the coronavirus disease 2019 (COVID-19) pandemic, healthcare workers (HCWs) were required to use personal protective equipment (PPE) for unusually prolonged periods of time in order to protect themselves. This study was conducted to assess the prevalence of adverse skin reactions to PPE among HCWs from occupational and domestic exposure in Oman. Methods This was a cross-sectional study that used a self-administered questionnaire, modified based on the Nordic Occupational Skin Questionnaire, and was conducted in different categories of healthcare facilities in Oman from September to December 2020. This study involved 431 different categories of HCWs. Stata statistical software, version 12 (StataCorp, College Station, TX), was used to analyze the data, with a P value <0.05 indicating statistical significance. Results Findings indicated that 58.24% of HCWs reported new skin symptoms since the pandemic started, compared to 33.41% of HCWs who had skin symptoms before the pandemic (P<0.001). From the multivariate analysis, being female (odds ratio, or OR, 3.512; 95% confidence interval, or CI: 2.193-5.625), allergic rhinitis diagnosis (OR 2.420; 95% CI: 1.097-5.347), history of skin symptoms (OR 3.166; 95% CI: 1.856-5.400), and total glove use time (OR 1.160; 95% CI: 1.078-1.247) were associated with an increased risk of acquiring new skin symptoms. Conclusion This study demonstrates that there is some association between the prolonged use of PPE during an event such as a pandemic and a previous history of allergic rhinitis and skin symptoms. This study also emphasizes the importance of appropriate protective skin care before and after the use of PPE., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Al Badri et al.)

Objective: To compare results of simulator-based vs traditional training of medical students in direct ophthalmoscopy., Design: Randomized controlled trial., Methods: First-year medical student volunteers completed 1 hour of didactic instruction regarding direct ophthalmoscopes, fundus anatomy, and signs of disease. Students were randomized to an additional hour of training on a direct ophthalmoscope simulator (n = 17) or supervised practice examining classmates (traditional method, n = 16). After 1 week of independent student practice using assigned training methods, masked ophthalmologist observers assessed student ophthalmoscopy skills (technique, efficiency, and global performance) during examination of 5 patient volunteers, using 5-point Likert scales. Students recorded findings and lesion location for each patient. Two masked ophthalmologists graded answer sheets independently using 3-point scales. Students completed surveys before randomization and after assessments. Training groups were compared for grades, observer- and patient-assigned scores, and survey responses., Results: The simulator group reported longer practice times than the traditional group (P = .002). Observers assigned higher technique scores to the simulator group after adjustment for practice time (P = .034). Combined grades (maximum points = 20) were higher for the simulator group (median: 5.0, range: 0.0-11.0) than for the traditional group (median: 4.0, range: 0.0-9.0), although the difference was not significant. The simulator group was less likely to mistake the location of a macular scar in 1 patient (odds ratio: 0.28, 95% confidence interval: 0.056-1.35, P = .013)., Conclusions: Direct ophthalmoscopy is difficult, regardless of training technique, but simulator-based training has apparent advantages, including improved technique, the ability to localize fundus lesions, and a fostering of interest in learning ophthalmoscopy, reflected by increased practice time., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The devastation of the Syrian war can lead to a drastic re-evaluation of oneself and alteration in self-capacities. Yet, little is known regarding its impact on these domains among Syrian refugees., Aims: To investigate the inter-relationship between trauma characteristics, trauma centrality, self-efficacy, emotional suppression, PTSD and psychiatric co-morbidity among Syrian refugees., Methods: 1197 refugees from Turkey and Sweden completed the Harvard Trauma Questionnaire, General Health Questionnaire-28, Centrality of Event Scale, Generalized Self-Efficacy Scale and Courtauld Emotional Control Scale., Results: Using the DSM-IV criteria for PTSD from the Harvard Trauma Questionnaire, 43% met the criteria. The PTSD group reported significantly higher levels of trauma characteristics, trauma centrality and psychiatric co-morbidity but a lower level of self-efficacy than the non-PTSD group. Trauma characteristics were positively associated with trauma centrality; trauma centrality was negatively correlated with self-efficacy. Contrary to hypothesis, self-efficacy was positively correlated with emotional suppression which was positively correlated with psychiatric co-morbidity but not PTSD., Conclusions: The experience of war can lead to the emergence of PTSD among Syrian refugees. Exposure to war can alter self-perception, belief of personal mastery over one's future and the way emotion is expressed, all of which can have specific effects on general psychological symptoms.

Purpose: To evaluate the effect of brimonidine tartrate 0.025% ophthalmic solution on pupil size under scotopic conditions in healthy adults METHODS: Pupil size was measured in 56 eyes of 28 volunteer participants using a pupillometer under scotopic conditions. Age, gender, and iris color were recorded. Subjects using any ophthalmic medications other than artificial tears were excluded. The pupil size was subsequently measured again under scotopic conditions 60 min after instillation of brimonidine tartrate 0.025% ophthalmic solution., Results: Statistically significant miosis was seen after instillation of brimonidine tartrate 0.025% (p = 0.04). Average pupil size prior to brimonidine 0.025% instillation was 7.28 ± 1.05 mm, and average pupil size after instillation of brimonidine 0.025% was 6.36 ± 1.68 mm, a reduction of - 23.7% in pupil area. Subjects with light irides demonstrated a greater miotic effect than subjects with dark irides (1.55 mm vs. 0.67 mm, p < 0.0001), with a pupil area reduction of - 37.6% and - 17.4%, respectively. The amount of miosis was independent of initial pupil size., Conclusions: Brimonidine tartrate 0.025% causes significant miosis in scotopic settings, although the effect is not as great in darker colored eyes. Further studies are needed to determine the latency and duration of the effect and whether the amount of miosis is clinically significant., (© 2021. The Author(s).)

Background: Refugees and asylum seekers face various stressors due to displacement and are especially vulnerable to common mental disorders. To effectively manage psychological distress in this population, innovative interventions are required. The World Health Organization (WHO) Self-Help Plus (SH+) intervention has shown promising outcomes in reducing symptoms of common mental disorders among refugees and asylum seekers. However, individual participant differences in response to SH+ remain largely unknown. The Individual Participant Data (IPD) meta-analysis synthesizes raw datasets of trials to provide cutting-edge evidence of outcomes that cannot be examined by conventional meta-analytic approaches., Objectives: This protocol outlines the methods of a series of IPD meta-analyses aimed at examining the effects and potential moderators of SH+ in (a) reducing depressive symptoms at post-intervention and (b) preventing the six-month cumulative incidence of mental disorders in refugees and asylum seekers., Method: RCTs on SH+ have been identified through WHO and all authors have agreed to share the datasets of the trials. The primary outcomes of the IPD meta-analyses are (a) reduction in depressive symptoms at post-intervention, and (b) prevention of six-month cumulative incidence of mental disorders. Secondary outcomes include post-traumatic stress disorder symptoms, well-being, functioning, quality of life, and twelve-month cumulative incidence of mental disorders. One-stage IPD meta-analyses will be performed using mixed-effects linear/logistic regression. Missing data will be handled by multiple imputation., Conclusions: These results will enrich current knowledge about the response to SH+ and will facilitate its targeted dissemination. The results of these IPD meta-analyses will be published in peer-reviewed journals., Competing Interests: Dr. Ross White acted as a consultant reviewer to the WHO in the development of the SH+ intervention, and I am an author on the papers reporting on the RCTs in the EU and Uganda., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The testis transcriptome is highly complex and includes RNAs that potentially hybridize to form double-stranded RNA (dsRNA). We isolated dsRNA using the monoclonal J2 antibody and deep-sequenced the enriched samples from testes of juvenile Dicer1 knockout mice, age-matched controls, and adult animals. Comparison of our data set with recently published data from mouse liver revealed that the dsRNA transcriptome in testis is markedly different from liver: In testis, dsRNA-forming transcripts derive from mRNAs including promoters and immediate downstream regions, whereas in somatic cells they originate more often from introns and intergenic transcription. The genes that generate dsRNA are significantly expressed in isolated male germ cells with particular enrichment in pachytene spermatocytes. dsRNA formation is lower on the sex (X and Y) chromosomes. The dsRNA transcriptome is significantly less complex in juvenile mice as compared to adult controls and, possibly as a consequence, the knockout of Dicer1 has only a minor effect on the total number of transcript peaks associated with dsRNA. The comparison between dsRNA-associated genes in testis and liver with a reported set of genes that produce endogenous siRNAs reveals a significant overlap in testis but not in liver. Testis dsRNAs also significantly associate with natural antisense genes-again, this feature is not observed in liver. These findings point to a testis-specific mechanism involving natural antisense transcripts and the formation of dsRNAs that feed into the RNA interference pathway, possibly to mitigate the mutagenic impacts of recombination and transposon mobilization., (© 2021 Werner et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: To report complications of cosmetic artificial iris implantation and explantation outcomes., Design: Retrospective case series., Methods: Medical records of 12 patients (24 eyes) who presented to us after being implanted with cosmetic artificial irises elsewhere were reviewed. Data collected included baseline demographics, presenting symptoms, examination findings, and management outcomes., Results: Eight eyes had NewColorIris implants and 16 had BrightOcular implants. The mean interval from cosmetic iris implantation to presentation was 61.7 ± 60.0 months. The mean follow-up after explantation was 35.5 ± 38.1 months. Complications at presentation included iris abnormalities (11 eyes, 45.8%), elevated intraocular pressure (8 eyes, 33.3%), corneal edema (6 eyes, 25%), intraocular inflammation (5 eyes, 20.8%), and cataract (4 eyes, 16.7%). Surgical interventions included cosmetic iris removal (19 eyes, 79.2%), cataract extraction (7 eyes, 29.2%), corneal transplantation (7 eyes, 29.2%), and glaucoma surgery (4 eyes, 16.7%). Complications at the last follow-up examination included native iris defects (11 eyes, 45.8%), persistent glaucoma (7 eyes, 29.2%), cataract (5 eyes, 20.8%), corneal edema (4 eyes, 16.7%), and intraocular inflammation (2 eyes, 8.3%). The mean logarithm of the minimum angle of resolution was 0.56 ± 0.47 at presentation and 0.78 ± 0.88 at the last examination (P = .30). The mean intraocular pressure was 22.7 ± 15.8 mm Hg at presentation and 13.4 ± 6.99 mm Hg at the last examination (P = .02)., Conclusion: Cosmetic iris implantation was associated with serious complications at the time of presentation, and adverse sequelae persisted for years after explantation., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The birth of long non-coding RNAs (lncRNAs) is closely associated with the presence and activation of repetitive elements in the genome. The transcription of endogenous retroviruses as well as long and short interspersed elements is not only essential for evolving lncRNAs but is also a significant source of double-stranded RNA (dsRNA). From an lncRNA-centric point of view, the latter is a minor source of bother in the context of the entire cell; however, dsRNA is an essential threat. A viral infection is associated with cytoplasmic dsRNA, and endogenous RNA hybrids only differ from viral dsRNA by the 5' cap structure. Hence, a multi-layered defense network is in place to protect cells from viral infections but tolerates endogenous dsRNA structures. A first line of defense is established with compartmentalization; whereas endogenous dsRNA is found predominantly confined to the nucleus and the mitochondria, exogenous dsRNA reaches the cytoplasm. Here, various sensor proteins recognize features of dsRNA including the 5' phosphate group of viral RNAs or hybrids with a particular length but not specific nucleotide sequences. The sensors trigger cellular stress pathways and innate immunity via interferon signaling but also induce apoptosis via caspase activation. Because of its central role in viral recognition and immune activation, dsRNA sensing is implicated in autoimmune diseases and used to treat cancer.

Background: Coronavirus disease 2019 (COVID-19) had a significant impact on the National Health Service in the United Kingdom (UK), with over 35 000 cases reported in London by July 30, 2020. Detailed hospital-level information on patient characteristics, outcomes, and capacity strain is currently scarce but would guide clinical decision-making and inform prioritisation and planning., Methods: We aimed to determine factors associated with hospital mortality and describe hospital and ICU strain by conducting a prospective cohort study at a tertiary academic centre in London, UK. We included adult patients admitted to the hospital with laboratory-confirmed COVID-19 and followed them up until hospital discharge or 30 days. Baseline factors that are associated with hospital mortality were identified via semiparametric and parametric survival analyses., Results: Our study included 429 patients: 18% of them were admitted to the ICU, 52% met criteria for ICU outreach team activation, and 61% had treatment limitations placed during their admission. Hospital mortality was 26% and ICU mortality was 34%. Hospital mortality was independently associated with increasing age, male sex, history of chronic kidney disease, increasing baseline C-reactive protein level, and dyspnoea at presentation. COVID-19 resulted in substantial ICU and hospital strain, with up to 9 daily ICU admissions and 41 daily hospital admissions, to a peak census of 80 infected patients admitted in the ICU and 250 in the hospital. Management of such a surge required extensive reorganisation of critical care services with expansion of ICU capacity from 69 to 129 beds, redeployment of staff from other hospital areas, and coordinated hospital-level effort., Conclusions: COVID-19 is associated with a high burden of mortality for patients treated on the ward and the ICU and required substantial reconfiguration of critical care services. This has significant implications for planning and resource utilisation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Savvas Vlachos et al.)

Background: Keratitis-ichthyosis-deafness (KID) syndrome is characterized by a congenital triad of keratitis, ichthyosis, and deafness, and is most commonly associated with mutations in the gap junction protein beta 2 gene (GJB2) on chromosome 13q11-q12., Methods: Multimodal anterior segment imaging and genetic testing were used to supplement clinical examination findings in the diagnosis and management of a 12-year-old boy with suspected KID syndrome., Results: The patient presented with hearing loss, ichthyosis of the face and extremities, and corneal scarring and keratinization. The corneal limbal stem cell population was found to be normal on in vivo confocal microscopy, whereas the basal epithelium of the cornea demonstrated scarring and areas of cellular loss. Screening of GJB2 revealed a presumed pathogenic heterozygous missense mutation, c.148G>A, confirming the diagnosis of KID syndrome., Conclusions: Multimodal imaging including in vivo confocal microscopy suggests that dysfunctional corneal basal epithelium maturation might contribute to the pathophysiology of keratopathy in KID syndrome.

Patient satisfaction after modern day cataract surgery requires excellent surgical technique but increasingly demands superior refractive outcomes as well. In many cases, there exists an expectation from patients, as well as surgeons, to achieve emmetropia after cataract surgery. This is particularly true in patients electing premium intraocular lens technology to correct astigmatism and presbyopia to minimize spectacle dependence. Despite continued advances in preoperative and intraoperative diagnostics, refractive planning, and surgical technology, residual refractive error remains a primary source of dissatisfaction after cataract surgery. The need to enhance refractive outcomes and treat residual astigmatic or spherical refractive errors postoperatively becomes paramount to meeting the expectations of patients in their surgical outcome. This article reviews the potential preoperative and intraoperative pitfalls that can be the source of refractive error, the various options to enhance refractive outcomes, and potential future technologies to limit residual refractive error after cataract surgery.

Background: Anterior segment optical coherence tomography (AS OCT) is a helpful tool used to diagnose and manage many corneal conditions, but its use has not been reported in case of peripheral ulcerative keratitis (PUK). The aim of this study is to describe AS OCT findings in cases of PUK., Methods: Retrospective observational case series of six eyes presenting with a PUK and proven systemic vasculitis. Clinical course, slit lamp photographs, and AS OCT findings were the main outcomes., Results: The AS OCT findings were found to correlate with the ocular disease's level of activity. In the acute stage, an absence of corneal epithelium, a scrambled appearance of the anterior stroma and a heterogeneous stromal reflectivity were observed. During the reduction of disease level activity, an irregular hyporeflective epithelium, a smoother anterior stroma, and a homogenous hyperreflective stroma were seen. At the healed stage, a filling of the corneal defect by a hyporeflective thick epithelium, the persistence of the hyperreflective underlying stroma, and a demarcation line were observed. The mean total corneal thickness at last follow-up was significantly thicker (509 ± 147 μm) compared with the mean corneal thickness at onset (408 ± 131 μm; P = 0.03)., Conclusions: AS OCT provides an assessment of structural changes occurring in PUK, useful for its diagnosis and monitoring.

We report a method for sensing analytes in tear-fluid using commercial contact lenses (CLs) as sample collectors for subsequent analysis with a cost-effective and field-portable reader. In this study we quantify lysozyme, the most prevalent protein in tear fluid, non-specifically bound to CLs worn by human participants. Our mobile reader uses time-lapse imaging to capture an increasing fluorescent signal in a standard well-plate, the rate-of-change of which is used to indirectly infer lysozyme concentration through the use of a standard curve. We empirically determined the best-suited CL material for our sampling procedure and assay, and subsequently monitored the lysozyme levels of nine healthy human participants over a two-week period. Of these participants who were regular CL wearers (6 out of 9), we observed an increase in lysozyme levels from 6.89 ± 2.02 μg mL -1 to 10.72 ± 3.22 μg mL -1 (mean ± SD) when inducing an instance of digital eye-strain by asking them to play a game on their mobile-phones during the CL wear-duration. We also observed a lower mean lysozyme concentration (2.43 ± 1.66 μg mL -1 ) in a patient cohort with dry eye disease (DED) as compared to the average monitoring level of healthy (no DED) human participants (6.89 ± 2.02 μg mL -1 ). Taken together, this study demonstrates tear-fluid analysis with simple and non-invasive sampling steps along with a rapid, easy-to-use, and cost-effective measurement system, ultimately indicating physiological differences in human participants. We believe this method could be used in future tear-fluid studies, even supporting multiplexed detection of a panel of tear biomarkers toward improved diagnostics and prognostics as well as personalized mobile-health applications.

Salzmann's nodular degeneration (SND) typically occurs in patients who are female, 50-60 years old, and have a history of corneal inflammation and irritation. Multiple case reports have documented associations between SND and trachoma, viral infections, trauma, contact lens wear, corneal surgeries and corneal exposure. The authors describe a patient with bilateral SND confirmed by anterior segment optical coherence tomography (OCT) imaging in the context of thyroid eye disease (TED) and history of LASIK. Treatment involved propylthiouracil (PTU), artificial tear use, loteprednol etabonate ophthalmic gel, eyelid taping and selenium supplementation and prospective superficial keratectomy with diamond burr polish.

Various machine learning techniques have been developed for keratoconus detection and refractive surgery screening. These techniques utilize inputs from a range of corneal imaging devices and are built with automated decision trees, support vector machines, and various types of neural networks. In general, these techniques demonstrate very good differentiation of normal and keratoconic eyes, as well as good differentiation of normal and form fruste keratoconus. However, it is difficult to directly compare these studies, as keratoconus represents a wide spectrum of disease. More importantly, no public dataset exists for research purposes. Despite these challenges, machine learning in keratoconus detection and refractive surgery screening is a burgeoning field of study, with significant potential for continued advancement as imaging devices and techniques become more sophisticated.