Factors influencing presentation delay among cancer patients: a cross-sectional study in Malaysia.

BACKGROUND: Cancer represents a significant global public health challenge, with escalating incidence rates straining healthcare systems. Malaysia, like many nations, has witnessed a rise in cancer cases, particularly among the younger population. This study aligns with Malaysia's National Strategic Plan for Cancer Control Programme 2021-2025, emphasizing primary prevention and early detection to address cancer's impact. Therefore, we aim to describe the timeliness of cancer care for symptom presentation, socio-demographic, patient, as well as organizational-related factors among patients in Malaysia diagnosed with breast, colorectal, nasopharyngeal, and cervical cancer. METHODS: This cross-sectional study enrolled adult cancer patients diagnosed with breast, cervical, colorectal, or nasopharyngeal cancer from 2015 to 2020 in seven public hospitals/oncology centres across Malaysia. Data were collected through patient-administered surveys and medical records. Presentation delay, defined as the duration between symptom onset and the patient's first visit to a healthcare professional exceeding 30 days, was the primary outcome. Statistical analysis included descriptive statistics and chi-square tests. RESULTS: The study included 476 cancer patients, with breast cancer (41.6%), colorectal cancer (26.9%), nasopharyngeal cancer (22.1%), and cervical cancer (9.5%). Over half (54.2%) experienced presentation delays with a median interval of 60 days. Higher proportions of presentation delay were observed among nasopharyngeal cancer patients, employed patients with lower socioeconomic statuses, and those without family history of cancer. Most patients self-discovered their first cancer symptoms (80%), while only one-third took immediate action for medical check-ups. Emotional and organizational factors, such as long waiting times during doctor's visits (47%), were potential barriers to seeking cancer care. CONCLUSION: This study highlights the significant problem of presentation delay among cancer patients in Malaysia. The delay is influenced by various factors encompassing sociodemographic characteristics, health-seeking behaviours, and healthcare system-related issues. A comprehensive approach addressing both individual barriers and institutional obstacles is imperative to mitigate this presentation delay and improve cancer outcomes.

A FRET-based multifunctional fluorescence probe for the simultaneous detection of sulfite and viscosity in living cells.

Viscosity and sulfur dioxide derivatives were significant indicators for the assessment of health threat and even cancers, therefore, on-site and real time detection of viscosity and sulfur dioxide derivatives has obtained considerable attentions. An FRET-based fluorescence probe JZX was designed and synthesized based on a novel energy donor of N,N-diethyl-4-(1H-phenanthro[9,10-d]imidazol-2-yl)benzamide fluorophore. JZX exhibited a large Stokes shift (230 nm), high energy transfer efficiency, wide emission channel gap (135 nm) and excellent stability and biocompatibility. JZX detected sulfur dioxide with low detection limit (55 nM), fast responding (16 min), high selectivity and sensitivity. Additionally, JZX tend to target endoplasmic reticulum of which normal metabolism will be disturbed by the abnormal levels of viscosity and sulfur dioxide derivatives. Prominently, JZX could concurrently detect viscosity and sulfur dioxide derivatives depending on different fluorescence signals in living cells for the screening of cancer cells. Hence, probe JZX will be a promising candidate for the detection of viscosity and sulfur dioxide derivatives, and even for the diagnosis of liver cancers.

The tether function of the anoctamins.

The core functions of the anoctamins are Cl- channel activity and phosphatidylserine (and perhaps other lipids) scrambling. These functions have been extensively studied in various tissues and cells. However, another function of the anoctamins that is less recognized and minimally explored is as tethers at membrane contact sites. This short review aims to examine evidence supporting the localization of the anoctamins at membrane contact sites, their tether properties, and their functions as tethers.

A New Method of Constructing Methyleneindene and Quinoline Frameworks from Methylenecyclopropanes.

In this paper, we have established an operationally convenient protocol for the rapid construction of polysubstituted methyleneindene and quinoline derivatives under mild conditions. This new synthetic method is achieved through the conversion of acetyl-substituted methylenecyclopropanes with TsOH·H2O and ortho-amino-substituted methylenecyclopropanes with aromatic aldehyde and TsOH·H2O, respectively. A variety of transformations of the obtained products was demonstrated. The plausible reaction mechanisms were also proposed.

Palladium catalyzed stereoselective intramolecular [3 + 2] cycloaddition reactions of (E) & (Z)-ene-vinylidenecyclopropanes.

A palladium-catalyzed ring-opening cyclization of (E) & (Z)-ene-vinylidenecyclopropanes has been developed via an intramolecular [3 + 2] cycloaddition process in the presence of a sterically bulky biaryl phosphine ligand, stereoselectively affording fused cis- & trans-bicyclo[4.3.0] skeletal products in good yields with a broad substrate scope and good functional tolerance. A plausible reaction mechanism was proposed on the basis of previous work and the DFT calculations.

GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14.

Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1ß expression levels and interleukin-1ß (IL-1ß) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor-/- mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor-/- Nlrp3-/- double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1ß transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.

The Causal Relationship between Angina Pectoris and Gout Based on Two Sample Mendelian Randomization.

Purpose: Two-sample Mendelian randomization (MR) was conducted to assess the causal relationship between angina pectoris and gout. Material and Methods. Based on genome-wide association studies, single nucleotide polymorphisms (SNPs) that were closely associated with gout were selected from the UK Biobank-Neale Lab (ukb-a-107) as genetic instrumental variables. Considering that gout is characterized by elevated blood uric acid levels, SNPs related to blood uric acid levels were screened from BioBank Japan (bbj-a-57) as auxiliary gene instrumental variables. SNPs closely associated with angina pectoris onset were screened from the FINN dataset (finn-b-I9_ANGINA) as outcome variables. Two-sample MR was conducted, with inverse variance weighting (IVW) of the random effects model as the primary result, along with the weighted median method (WME) and the MR-Egger regression method. To further confirm the causal relationship between angina and gout incidence, a meta-analysis was conducted on the IVW results of the ukb-a-107 and bbj-a-57. Results: The odds ratios and 95% confidence intervals of the IVW, WME, and MR-Egger results of ukb-a-107 were (OR = 33.72; 95% CI: 2.07∼550.38), (OR = 57.94; 95% CI: 2.75∼1219.82), and (OR = 96.38; 95% CI: 0.6∼15556.93), respectively. The P values of IVW and WME were 0.014 and 0.014 (both <0.05), respectively, indicating that the development of angina pectoris was significantly associated with the incidence of gout. The odds ratios and 95% confidence intervals of the IVW, WME, and MR-Egger about bbj-a-57 were (OR = 1.20; 95% CI: 1.07∼1.34), (OR = 1.19; 95% CI: 1.02∼1.38), and (OR = 1.30; 95% CI; 1.06∼1.60), respectively. The P values of IVW, WME and MR-Egger were 0.001, 0.027 and 0.017 (all <0.05), respectively, indicating a significant correlation between angina and blood uric acid levels. Scatter plots of ukb-a-107 and bbj-a-57 showed that the causal association estimates of the IVW, MR-Egger, and weighted median methods were similar and that the MR results were accurate. Funnel plots and the MR-Egger intercept of ukb-a-107 and bbj-a-57 showed the absence of horizontal pleiotropy. The leave-out sensitivity analysis results of ukb-a-107 and bbj-a-57 are stable. The meta-analysis of IVW results for ukb-a-107 and bbj-a-57 showed (OR = 1.20; 95% CI: 1.07-1.34, P=0.02), confirming that gout characterized by high blood uric acid levels significantly increases the risk of angina attacks. Conclusions: This MR study found a clear causal relationship between angina pectoris and gout, which increases the risk of angina pectoris.

Elucidation of antioxidant activities of intracellular and extracellular polysaccharides from Cordyceps militaris in vitro and their protective effects on ulcerative colitis in vivo.

In this study, we extracted the polysaccharides from C. militaris fruiting bodies (CFIPs), mycelial intracellular polysaccharides (CMIPs), and fermentation broth extracellular polysaccharides (CFEPs) to investigate their physicochemical properties, antioxidant capacities, and effects on oxazolone-induced zebrafish ulcerative colitis (UC). Our results revealed differences in monosaccharide composition and surface structure among CFIPs, CMIPs, and CFEPs. The molar ratios of glucose to mannose in CFIPs, glucose to xylose in CMIPs, and xylose to glucose in CFEPs were 7.57: 1.6, 7.26: 1.81, and 5.44: 2.98 respectively. Moreover, CFEPs exhibited significantly (p < 0.05) higher chemical antioxidant capacity compared to CMIPs and CFIPs. Surprisingly, CFEP treatment didn't show a significant effect in protecting against H2O2-induced oxidative damage in RAW 264.7 cells. After 3 d of treatment, the levels of ROS, MDA, and MPO in the CFIPs group exhibited a significant (p < 0.05) reduction by 37.82 %, 68.15 %, and 22.77 % respectively. Additionally, the ACP and AKP increased by 60.33 % and 96.99 %. Additionally, C. militaris polysaccharides (CMPs) were found to effectively improve UC by activating the MyD88/NF-κB signaling pathway in vivo. These findings confirm the distinct physicochemical properties of these three types of CMP and their potential for development into antioxidant-rich anti-inflammatory health foods.

Mechanistic Studies on Rhodium-Catalyzed Chemoselective Cycloaddition of Ene-Vinylidenecyclopropanes: Water-Assisted Proton Transfer.

Rhodium-catalyzed cycloaddition reactions are a powerful tool for the construction of polycyclic compounds. Combined experimental and DFT studies were used to investigate the temperature-controlled chemoselectivity of cationic rhodium-catalyzed intramolecular cycloaddition reactions of ene-vinylidenecyclopropanes. After a series of mechanistic studies, it was found that trace amounts of water in the reaction system play an important role in generating the product with endo double bond located on a five-membered ring and revealed that trace amounts of water in the reaction system, including the rhodium catalyst, substrate and solvent, were sufficient to promote the formation of the product with endo double bond located on a five-membered ring, and additional water could not further accelerate the reaction. DFT calculation results show that the addition of water indeed significantly lowers the energy barrier of the proton transfer step, making the formation of the product with endo double bond located on a five-membered ring more likely to occur and confirming the rationality of water-assisted proton transfer occurring in the selective access to the product with endo double bond located on a five-membered ring.

A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility.

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population.

Corydecusines A-H, new phthalideisoquinoline hemicetal alkaloids from the bulbs of Corydalis decumbens inhibit Tau pathology by activating autophagy mediated by AMPK-ULK1 pathway.

Twelve phthalideisoquinoline hemiacetal alkaloids including eight new ones (1-8) and one natural alkaloid characterized by an aziridine moiety with unassigned NMR data (9), were isolated and identified from the bulbs of Corydalis decumbens. Their structures were established by comprehensive analyses of HRESIMS, NMR, X-ray crystallography, and ECD analyses. The unambiguously established structures of the phthalideisoquinoline hemiacetal alkaloids indicated that the absolute configurations of C-1, C-9, and C-7' were confusable only relied on coupling constants. A summary of their ECD spectra was concluded and provided an insight for C-1, C-9, and C-7' absolute configuration assignment. These new compounds were evaluated to induce autophagy flux through flow cytometry analysis. Moreover, compounds 2 and 6 could significantly induce autophagy and inhibit Tau pathology by AMPK-ULK1 pathway activation, which provided an avenue for anti-AD lead compounds discovery.

Trends in cataract surgery and healthcare system response during the COVID-19 lockdown in Malaysia: Lessons to be learned.

Background: Elective surgeries were suspended during the national lockdown in March 2020 to curb the spread of the COVID-19 pandemic in Malaysia. We sought to evaluate the impact of the lockdown on cataract surgeries and suggest lessons for future outbreaks. Study design: We conducted an interrupted time series analysis to examine rates of cataract surgery before and during the lockdown. Methods: We used national cataract surgical data between 2015 and 2021 from the Malaysian Cataract Surgery Registry. Segmented regression with a seasonally adjusted Poisson model was used for the analysis. Stratified analyses were performed to establish whether the effect of the lockdown on cataract surgeries varied by hospital designation, type of cataract service, sex, and age groups. Results: Cataract surgeries began falling in March 2020 at the onset of the lockdown, reached a trough in April 2020, and subsequently increased but never recovered to pre-lockdown levels. Cataract surgical rates in December 2021 were still 43 % below the expected surgical volume, equivalent to 2513 lost cataract surgeries. There was no evidence of a differential effect of the lockdown between COVID-19 designated and non-COVID-19 designated hospitals. The relative decrease in cataract surgical rates appears to have been greatest in outreach services and in people 40 years and older. Conclusions: The lockdown caused an immediate reduction in cataract surgical rates to nearly half of its baseline rate. Despite its gradual recovery, further delays remain to be expected should there be no redistribution or increase in resources to support backlogs and incoming new cases.

A Novel Respiratory Rate Estimation Algorithm from Photoplethysmogram Using Deep Learning Model.

Respiratory rate (RR) is a critical vital sign that can provide valuable insights into various medical conditions, including pneumonia. Unfortunately, manual RR counting is often unreliable and discontinuous. Current RR estimation algorithms either lack the necessary accuracy or demand extensive window sizes. In response to these challenges, this study introduces a novel method for continuously estimating RR from photoplethysmogram (PPG) with a reduced window size and lower processing requirements. To evaluate and compare classical and deep learning algorithms, this study leverages the BIDMC and CapnoBase datasets, employing the Respiratory Rate Estimation (RRest) toolbox. The optimal classical techniques combination on the BIDMC datasets achieves a mean absolute error (MAE) of 1.9 breaths/min. Additionally, the developed neural network model utilises convolutional and long short-term memory layers to estimate RR effectively. The best-performing model, with a 50% train-test split and a window size of 7 s, achieves an MAE of 2 breaths/min. Furthermore, compared to other deep learning algorithms with window sizes of 16, 32, and 64 s, this study's model demonstrates superior performance with a smaller window size. The study suggests that further research into more precise signal processing techniques may enhance RR estimation from PPG signals.

Supramolecular assemblies of Cu(II) with a tetraphenylethene-imidazole ligand for tuning photocatalytic CO2 reduction.

Cu(II) supramolecular assemblies [Cu2(tipe)2(H2O)2](NO3)4·2.5H2O (CuN4) and [Cu2Cl4(tipe)(CH3CN)]·H2O (CuN2Cl2) (tipe = 1,1,2,2-tetrakis(4-(imidazole-1-yl)phenyl)ethene) were synthesized and utilized for photocatalytic CO2 reduction. CuN4 exhibits CO production of up to 891 µmol gcat-1 with a selectivity of 79.9%, while CuN2Cl2 gives low CO production of 206 µmol gcat-1 but with a high selectivity of >99.9% in 5 h. The experimental and DFT calculation results indicate that the coordination environment and non-covalent interactions within the assemblies have a great impact on the photocatalytic CO2 reduction behavior. This work provides useful insights on Cu(II) assembly catalyzed CO2 photoreduction.

Pickering stabilization mechanism revealed through direct imaging of particles with tuneable contact angle in a phase-separated binary solvent.

Pickering emulsions have attracted increasing attention from multiple fields, including food, cosmetics, healthcare, pharmaceutical, and agriculture. Their stability relies on the presence of colloidal particles instead of surfactant at the droplet interface, providing steric stabilization. Here, we demonstrate the microscopic attachment and detachment of particles with tunable contact angle at the interface underlying the Pickering emulsion stability. We vary the interfacial tension continuously by varying the temperature offset of a phase-separated binary liquid from its critical point, and employ confocal microscopy to directly observe the particles at the interface to determine their coverage and contact angle as a function of the varying interfacial tension. When the interfacial tension decreases upon approaching the binary liquid's critical point, the contact angle and detachment energy (ΔE) drop, and the particles move out of the interface. Microscopic imaging suggests necking and capillary interactions lead to clustering of the particles, before they eventually desorb from the interface. Macroscopic measurements show that concomitantly, coalescence takes place, and the emulsion loses its stability. These results reveal the interplay of interfacial energies, contact angle and surface coverage that underlies the Pickering emulsion stability, opening up ways to manipulate and design the stability through the microscopic behavior of the adsorbed particles.

Recent updates on central nervous system prophylaxis in patients with high-risk diffuse large B-cell lymphoma.

The use of central nervous system (CNS) prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) remains controversial. Although uncommon, CNS relapses are invariably fatal in this otherwise curable disease. Accurate identification of patients at risk and the optimal approach to CNS prophylaxis therefore remains an area of unmet need. The existing literature, largely retrospective in nature, provides mixed conclusions regarding the efficacy of CNS prophylaxis. The utility of CNS prophylaxis has itself been challenged. In this review, we dissect the issues which render the value of CNS prophylaxis uncertain. We first compare international clinical guidelines for CNS prophylaxis. We then interrogate the factors that should be used to identify high-risk patients accurately. We also explore how clinical patterns of CNS relapse have changed in the pre-rituximab and rituximab era. We then discuss the efficacy of CNS-directed approaches, intensification of systemic treatment and other novel approaches in CNS prophylaxis. Improved diagnostics for early detection of CNS relapses and newer therapeutics for CNS prophylaxis are areas of active investigation. In an area where prospective, randomized studies are impracticable and lacking, guidance for the use of CNS prophylaxis will depend on rigorous statistical review of retrospective data.

Enhanced EPR effects by tumour stromal cell mimicking nanoplatform on invasive pituitary adenoma.

Rapid advances in nanomedicine have enabled potential applications in cancer therapy. The enhanced permeability and retention (EPR) effect is the primary rationale for the passive targeting of nanoparticles in oncology. However, growing evidence indicates that the accumulation of nanomaterials via the EPR effect could be more efficient. Inspired by our clinical observation of the Gap Junction connecpion between folliculostellate cells and pituitary adenoma cells, we designed a novel drug delivery system that targets tumours by coating folliculostellate cell (FS) membranes onto PLGA nanoparticles (NPs). The resulting FSNPs, inheriting membrane proteins from the folliculostellate cell membrane, significantly enhanced the EPR effect compared to nanoparticles without cancer cell membranes. We further demonstrated that mitotane encapsulation improved the therapeutic efficacy of mitotane in both heterotopic and orthotopic pituitary adenoma models. Owing to its significant efficacy, our FS cell membrane-coated nanoplatforms has the potential to be translated into clinical applications for the treatment of invasive pituitary adenoma.

Assessing the efficacy of machine learning algorithms for syncope classification: A systematic review.

Syncope is a transient loss of consciousness with rapid onset. The aims of the study were to systematically evaluate available machine learning (ML) algorithm for supporting syncope diagnosis to determine their performance compared to existing point scoring protocols. We systematically searched IEEE Xplore, Web of Science, and Elsevier for English articles (Jan 2011 - Sep 2021) on individuals aged five and above, employing ML algorithms in syncope detection with Head-up titl table test (HUTT)-monitored hemodynamic parameters and reported metrics. Extracted data encompassed subject count, age range, syncope protocols, ML type, hemodynamic parameters, and performance metrics. Of the 6301 studies initially identified, 10 studies, involving 1205 participants aged 5 to 82 years, met the inclusion criteria, and formed the basis for it. Selected studies must use ML algorithms in syncope detection with hemodynamic parameters recorded throughout HUTT. The overall ML algorithm performance achieved a sensitivity of 88.8% (95% CI: 79.4-96.1%), specificity of 81.5% (95% CI: 69.8-92.8%) and accuracy of 85.8% (95% CI: 78.6-92.8%). Machine learning improves syncope diagnosis compared to traditional scoring, requiring fewer parameters. Future enhancements with larger databases are anticipated. Integrating ML can curb needless admissions, refine diagnostics, and enhance the quality of life for syncope patients.

Piggybacking functionalized DNA nanostructures into live cell nuclei.

DNA origami (DO) are promising tools for in vitro or in vivo applications including drug delivery; biosensing, detecting biomolecules; and probing chromatin sub-structures. Targeting these nanodevices to mammalian cell nuclei could provide impactful approaches for probing visualizing and controlling important biological processes in live cells. Here we present an approach to deliver DO strucures into live cell nuclei. We show that labelled DOs do not undergo detectable structural degradation in cell culture media or human cell extracts for 24 hr. To deliver DO platforms into the nuclei of human U2OS cells, we conjugated 30 nm long DO nanorods with an antibody raised against the largest subunit of RNA Polymerase II (Pol II), a key enzyme involved in gene transcription. We find that DOs remain structurally intact in cells for 24hr, including within the nucleus. Using fluorescence microscopy we demonstrate that the electroporated anti-Pol II antibody conjugated DOs are efficiently piggybacked into nuclei and exihibit sub-diffusive motion inside the nucleus. Our results reveal that functionalizing DOs with an antibody raised against a nuclear factor is a highly effective method for the delivery of nanodevices into live cell nuclei.

Silver frameworks based on a tetraphenylethylene-imidazole ligand for electrocatalytic reduction of CO2 to CO.

Metal-organic frameworks (MOFs) can be used as electrocatalysts for the CO2 reduction reaction (CO2RR) because of their well-dispersed metal centers. Silver is a common electrocatalyst for reduction of CO2 to CO. In this study, two Ag-MOFs with different structures of [Ag8O2(TIPE)6](NO3)4 (Ag-MOF1) and [Ag(TIPE)0.5CF3SO3] (Ag-MOF2) [TIPE = 1,1,2,2-tetrakis(4-(imidazol-1-yl)phenyl)ethene] were synthesized and used for CO2 electroreduction. The results show that Ag-MOF2 is superior to Ag-MOF1 and exhibits high CO faradaic efficiency (FE) of 92.21% with partial current density of 29.51 mA cm-2 at -0.98 V versus reversible hydrogen electrode (RHE). The FECO is higher than 80% in the potential range of -0.78 to -1.18 V. The difference may be caused by different framework structures leading to different electrochemical active surface areas and charge transfer kinetics. This study provides a new strategy for designing and constructing CO2 electroreduction catalysts and provides potential ways for solving environmental and energy problems caused by excessive CO2 emission.