ABSTRACT Introduction A tyrosine-kinase inhibitor (TKI) is indicated as first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor – receptor (EGFR) mutation. Chemotherapy (ChT) given in combination with an EGFR-TKI in this setting is of interest. Methods We conducted a meta-analysis of phase III randomized trials comparing EGFR-TKI + ChT vs. EGFR-TKI alone as first-line therapy for advanced NSCLC harboring an activating EGFR mutation. Results Three studies evaluated gefitinib + ChT (NEJ009, GAP-Brain and Noronha et al.) and another evaluated osimertinib + ChT (FLAURA-2). Those four eligible studies included 1413 patients with non-squamous NSCLCs, 826 (58%) with an exon-19 deletion (ex19del) and 541 (38%) with EGFR L858R . The EGFR-TKI + ChT combination was significantly associated with prolonged PFS (hazard ratio [HR]: 0.52 [95% confidence interval (CI): 0.45–0.59]; p < 0.0001) and OS (HR: 0.69 [0.52–0.93]; p = 0.01). PFS was particularly improved for patients with brain metastases (HR: 0.41[0.33–0.51]; p < 0.00001). Conclusions For patients with untreated, advanced, EGFR-mutated NSCLCs, the EGFR-TKI + ChT combination, compared to EGFR-TKI alone, was associated with significantly prolonged PFS and OS. However, further studies are needed to identify which patients will benefit the most from the combination. Registration PROSPERO CRD42024508055

ABSTRACT Introduction Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase over-expressed in various malignancies which is related to various cellular functions such as adhesion, metastasis and proliferation. Areas covered There is growing evidence that FAK is a promising therapeutic target for designing inhibitors by regulating the downstream pathways of FAK. Some potential FAK inhibitors have entered clinical phase research. Expert Opinion FAK could be an effective target in medicinal chemistry research and there were a variety of FAKIs have been patented recently. Here, we updated an overview of design, synthesis and structure–activity relationship of chemotherapeutic FAK inhibitors (FAKIs) from 2017 until now based on our previous work. We hope our efforts can broaden the understanding of FAKIs and provide new ideas and insights for future cancer treatment from medicinal chemistry point of view.

ABSTRACT Introduction Gemini surfactants (GS) are an elite class of amphiphilic molecules that have shown up as a potential candidate in the field of drug delivery because of their exceptional physicochemical properties. They comprise two hydrophilic headgroups connected by an adaptable spacer and hydrophobic tails that has shown promising results in delivering different therapeutic agents to cancer cells at preclinical level. However further studies are in demand to unlock the full potential of GS in this field. Areas covered This review summarizes the new advancements in GS as drug carriers in cancer therapy, their capacity to overcome conventional shortcomings and the demand for innovative approaches in disease treatment. A detailed list of GS-based formulations along with a brief description on oligomeric surfactants have also been provided in this review. This article summarizes data from studies identified through literature database searches including PubMed and Google Scholar (2010-2023). Expert opinion There are major challenges that need to be addressed in this field which restrict their progression toward clinical phase. Further research can focus on developing a theranostic system that can provide simultaneous real-time monitoring along with treatment care. Nevertheless, ensuring the safety parameters of these nanocarriers followed by their regulatory approval is a time-consuming and expensive process. A collaborative approach between regulatory bodies, research institutions and pharmaceutical companies can speed up the process in the upcoming years.

ABSTRACT Introduction Cyclin-dependent kinase-Like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental condition commonly characterized by drug-resistant, refractory epilepsy, and seizures beginning in infancy. Most patients use multiple drugs, yet seizures remain difficult to control. So far, no conventional anti-seizure medications have been proven to be effective in individuals with CDD, in well-conducted studies. Areas covered In this review, the authors assess the pharmacokinetics, early studies and appraise a recent study investigating the efficacy and safety of the oral suspension of ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) as an adjunctive therapy to treat seizures in CDD. The authors also discuss the impact of this drug on non-seizure outcomes. Expert opinion Ganaxolone is a neuroactive 3β-methylated synthetic analogue of the potent agonist of gamma-aminobutyric acid type A receptors, allopregnanolone. Ganaxolone is the only drug that has been studied in a robust randomized controlled trial and been proven to be effective in this population.

Previous observational studies found associations between Helicobacter pylori infection and autoimmune thyroid diseases (AITDs), but the causal nature of this association is still uncertain. We investigated the causal effect of six crucial antibodies against H. pylori on AITDs using a bidirectional Mendelian randomization (MR). We found that anti-H. pylori outer membrane protein (OMP) significantly increased the risk of hyperthyroidism and Graves' disease (GD). In addition, our reverse MR analysis indicated that hyperthyroidism could increase the levels of cytotoxin-associated gene A and OMP antibodies. We also observed causal roles of GD on anti-H. pylori OMP. Our analyses indicate the mutual effects of H. pylori infection and AITDs, suggesting the existence of a gut-thyroid axis. These results also provide evidence of the bidirectional causal association between anti-H. pylori OMP with hyperthyroidism and GD, resulting in a vicious circle.

ABSTRACT Scholars have recognised the significance of museums for establishing and maintaining national legitimacy and shaping identity. Following the transfer of sovereignty over Hong Kong from the United Kingdom to the People’s Republic of China in 1997, tensions emerged between Chinese national identity and local Hong Kong identity. Drawing inspiration from studies of the role of museums in nation-building, research on Hong Kong museums, and Ackbar Abbas’ notion of cultures of disappearance, we conducted a comparative analysis of two Bruce Lee exhibitions at the Hong Kong Heritage Museum, the first of which was held between 2013 and 2020 and the second of which opened in November 2021. A comparison of these exhibitions demonstrates their distinct approaches to appropriating Lee’s legacy by drawing attention to changes in the associated narratives that reflect changes in the cultural and political climate. While both exhibitions engaged with the concept of disappearance, the earlier one did so by adhering to the conventional ‘East-meets-West’ framework, resulting in the effacement of Hong Kong culture. In contrast, the deployment of techniques of disappearance in the later exhibition challenged viewers’ perception of reality, prompting contemplation of the self and identity by embracing strategies of disappearance while resisting a culture of disappearance. However, this came at the cost of downplaying Lee’s significance as a symbol of resistance.

High perceived stress from academic pressure is associated with intraocular pressure elevation and reduced fluctuation in juvenile-onset open-angle glaucoma patients. Personalized stress assessment and relief strategies may serve as an adjunct therapy in glaucoma. To evaluate the effect of higher perceived stress, resulting from academic pressure, on intraocular pressure (IOP) in juvenile-onset open-angle glaucoma (JOAG) patients compared to healthy individuals. The study included 48 university students aged 18 to 27, comprising 24 JOAG patients on antiglaucoma eyedrops and 24 healthy controls. In an examiner-blind pretest-posttest design, participants' IOP was measured weekly using Goldmann tonometry during three follow-up visits at the beginning and end of the academic semester. Perceived Stress Scale (PSS) scores were also evaluated at these two time points to capture the contrast in perceived stress between periods of low and high academic pressure. Baseline PSS score at the semester's start was lower in both groups (14.1±1.9 in glaucoma vs. 13.5±2.4 in control) and significantly increased by the end of the semester (29.2±2.1 vs. 28.5±1.3; P<0.001), indicating increased perceived stress. Concurrently, IOP rose from 22.01±5.87mmHg to 25.08±5.84mmHg in the glaucoma group and from 11.36±2.03mmHg to 13.65±2.11mmHg in the control group. Factorial analysis revealed a significant interaction between stress and JOAG [F(1,94)=15.94, P=0.001], partial η2=0.08, with stress having a greater increase on IOP in the glaucoma group (+3.10mmHg) compared to the control group (+2.23mmHg) [t(94)=4.457, P<0.001]. Higher perceived stress significantly increases IOP, especially in JOAG patients, suggesting personalised stress management as a potential adjunct therapy for patients.

aim: This audit describes variation in the time from referral to starting disease modifying drug (DMARD) for people with newly diagnosed seropositive rheumatoid arthritis (RA), how frequently this was within the recommended 6 weeks and whether regional, service-level or patient-level factors were associated with this variation. method: Rheumatologists submitted data on new patients with a new diagnosis of rheumatoid factor and/or cyclic-citrullinated peptide antibody positive RA. The association between visit funding, ethnicity, socio-economic deprivation, rurality, local specialist staffing levels and the time to DMARD treatment was assessed using Cox proportional-hazard models. results: Data were collected on 355 patients over 12 months. Overall, 64.8% of patients commenced DMARD treatment within 6 weeks of referral and this was associated with rheumatologist FTE per 100,000 population (adjusted HR 2.47, 95%CI 1.27–4.81; p=0.008) and the rurality (Geographic Classification of Health [GCH]) of the patient (for R2 compared to U1 adjusted HR 0.20, 95%CI 0.09–0.43; p&lt;0.001). There was no association between time to DMARD and ethnicity or socio-economic deprivation. conclusion: There was significant variation in time to DMARD treatment, mainly related to variation in rheumatologist staffing levels and patient rurality. Rheumatologist staffing levels of 1.0 FTE/100,000 population was associated with 80% of patients meeting the recommended 6-week time to DMARD treatment.

Unprecedented precipitation deficits in the 2022-2023 growing season across the primary wheat-producing region in the United States caused delays in winter wheat emergence and poor crop growth. Using an integrated approach, we quantitatively unraveled a 37% reduction in wheat production as being attributable to both per-harvested acre yield loss and severe crop abandonment, reminiscent of the Dust Bowl years in the 1930s. We used random forest machine learning and game theory analytics to show that the main driver of yield loss was spring drought, whereas fall drought dominated abandonment rates. Furthermore, results revealed, across the US winter wheat belt, the La Niña phase of the El Niño Southern Oscillation (ENSO), increased abandonment rates compared to the El Niño phase. These findings underscore the necessity of simultaneously addressing crop abandonment and yield decline to stabilize wheat production amid extreme climatic conditions and provide a holistic understanding of global-scale ENSO dynamics on wheat production.

Amid the coronavirus disease 2019 (COVID-19) pandemic, the pervasive threat of infection has heightened public and individual health concerns. In the context of instability, although the dysfunctional aspect of self-focus was prominent, preoccupation with viral infection was greater. This study explored the applicability of a cognitive-behavioral model of hypochondriasis to individuals infected with COVID-19 and assessed whether dysfunctional self-focus were associated with the development of preoccupation. An anonymous online survey was conducted via a professional survey platform in December 2022. Participants' clinical characteristics and responses to rating scales were collected, including Obsession with COVID-19 Scale (OCS), Coronavirus Reassurance-Seeking Behaviors Scale (CRBS), Stress and Anxiety to Viral Epidemic-6 items (SAVE-6), Patient Health Questionnaire-2 items (PHQ-2), and Dysfunctional Self-focus Attributes Scale (DSAS). Among the 265 participants, preoccupation with COVID-19 was predicted using CRBS (β=0.60, p<0.001), SAVE-6 (β=0.20, p=0.007), and PHQ-2 (β=0.13, p<0.001) scores. Mediation analysis revealed that viral anxiety influenced this COVID-19 preoccupation, with the relationship mediated by coronavirus reassurance-seeking behavior. Another analysis indicated that dysfunctional self-focus had a significant total effect on preoccupation with COVID-19. However, its direct impact was statistically insignificant, with the association primarily influenced by three mediating factors: viral anxiety, depression, and reassurance-seeking behavior. Preoccupation with coronavirus is influenced by viral anxiety, depression, and reassurance-seeking behavior. Two mediation analyses showed that the application of the cognitive-behavioral model of hypochondriasis is feasible among COVID-19-infected cases and the association of dysfunctional self-focus with mediating factors. This finding highlights the need for personalized psychological support in managing COVID-19 cases.