Evaluation of a Digital Amsler Grid (PocDoc) for Macular Disease Screening: A Comparative Analysis with the Conventional Method.

INTRODUCTION: Macular diseases are major contributors to visual impairment and blindness worldwide. This study introduces PocDoc, a digital version of the conventional Amsler grid, aimed at enhancing the screening and monitoring of macular diseases. We conducted a comprehensive evaluation to compare the effectiveness of PocDoc against the conventional method. METHODS: Our comparative analysis involved two distinct phases. Initially, we assessed the capability of both PocDoc and the conventional method in detecting central visual field abnormalities. This phase included a cohort of 72 healthy and 155 eyes affected by various conditions such as age-related macular degeneration (AMD), uveitis, polypoidal choroidal vasculopathy (PCV), and macular telangiectasia. We primarily focused on the area of compromise and observed the correlation between the results obtained from both methods, measuring their concordance using a correlation coefficient. In the second phase, we evaluated the accuracy of both methods in diagnosing AMD. This involved a group of 127 eyes, including 70 healthy and 57 AMD-affected eyes. We determined the sensitivity, specificity, and overall accuracy of each method in diagnosing AMD. RESULTS: In the initial phase, both PocDoc and the conventional Amsler grid demonstrated a high correlation in detecting central visual field defects across various macular diseases (correlation coefficient > 0.9). In the second phase, focused on AMD diagnosis, PocDoc showed a sensitivity of 50%, specificity of 100%, and an overall accuracy of 78%. Comparatively, the conventional method exhibited a sensitivity of 49%, specificity of 100%, and accuracy of 77%. CONCLUSION: PocDoc's digital Amsler grid exhibits comparable effectiveness to the conventional method in both detecting visual field abnormalities across a range of macular diseases and specifically in the diagnosis of AMD. The high correlation in results, combined with the digital advantages of PocDoc, such as ease of use and potential for telemedicine applications, suggests its viability as a valuable tool in the screening and monitoring of macular diseases.

Ibrutinib-associated cutaneous mucormycosis due to an Apophysomyces species: report of a case and review of the literature.

The use of ibrutinib, a Bruton tyrosine kinase inhibitor, has been associated with invasive fungal infections (IFIs). We describe a case of Apophysomyces infection associated with long-term use of ibrutinib for the treatment of chronic lymphocytic leukemia as well as perform a literature review of Mucormycosis infections in patients on ibrutinib. Our review found that the onset of IFI can occur within months to years of starting tyrosine kinase inhibitors. These reports provide a more complete picture of the risk of IFI while patients are on ibrutinib. Our case also demonstrates the utility of molecular techniques in the diagnosis of IFI, as the diagnosis was made using 28S rDNA/internal transcribed spacer PCR.

Diverse axonal morphologies of individual callosal projection neurons reveal new insights into brain connectivity.

In the mature brain, functionally distinct areas connect to specific targets, mediating network activity required for function. New insights are still occurring regarding how specific connectivity occurs in the developing brain. Decades of work have revealed important insights into the molecular and genetic mechanisms regulating cell type specification in the brain. This work classified long-range projection neurons of the cerebral cortex into three major classes based on their primary target (e.g. subcortical, intracortical, and interhemispheric projections). However, painstaking single-cell mapping reveals that long-range projection neurons of the corpus callosum connect to multiple and overlapping ipsilateral and contralateral targets with often highly branched axons. In addition, their scRNA transcriptomes are highly variable, making it difficult to identify meaningful subclasses. This work has prompted us to reexamine how cortical projection neurons that comprise the corpus callosum are currently classified and how this stunning array of variability might be achieved during development.

Arsenic-induced neurotoxicity in patients with acute promyelocytic leukaemia.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

Corneal Confocal Microscopy Predicts Cardiovascular and Cerebrovascular Events and Demonstrates Greater Peripheral Neuropathy in Patients with Type 1 Diabetes and Foot Ulcers.

OBJECTIVE: In this study, we evaluate small and large nerve fibre pathology in relation to diabetic foot ulceration (DFU) and incident cardiovascular and cerebrovascular events in type 1 diabetes (T1D). METHODS: A prospective observational study was conducted on people with T1D without diabetic peripheral neuropathy (DPN) (n = 25), T1D with DPN (n = 28), T1D with DFU (n = 25) and 32 healthy volunteers. ROC analysis of parameters was conducted to diagnose DPN and DFU, and multivariate Cox regression analysis was performed to evaluate the predictive ability of corneal nerves for cardiac and cerebrovascular events over 3 years. RESULTS: Corneal nerve fibre length (CNFL), fibre density (CNFD) and branch density (CNBD) were lower in T1D-DPN and T1D-DFU vs. T1D (all p < 0.001). In ROC analysis, CNFD (sensitivity 88%, specificity 87%; AUC 0.93; p < 0.001; optimal cut-off 7.35 no/mm2) and CNFL (sensitivity 76%, specificity 77%; AUC 0.90; p < 0.001; optimal cut-off 7.01 mm/mm2) had good ability to differentiate T1D with and without DFU. Incident cardiovascular events (p < 0.001) and cerebrovascular events (p < 0.001) were significantly higher in T1D-DPN and T1D-DFU. Corneal nerve loss, specifically CNFD predicted incident cardiovascular (HR 1.67, 95% CI 1.12 to 2.50, p = 0.01) and cerebrovascular (HR 1.55, 95% CI 1.06 to 2.26, p = 0.02) events. CONCLUSIONS: Our study provides threshold values for corneal nerve fibre metrics for neuropathic foot at risk of DFU and further demonstrates that lower CNFD predicts incident cardiovascular and cerebrovascular events in T1D.

Clinical Course, Immunogenicity, and Efficacy of BNT162b2 mRNA Vaccination Against SARS-CoV-2 Infection in Liver Transplant Recipients.

Background: Immunocompromised individuals have been excluded from landmark studies of messenger RNA vaccinations for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In such patients, the response to vaccination may be blunted and may wane more quickly compared with immunocompetent patients. We studied the factors associated with decreased antibody response to SARS-CoV-2 vaccination and risk factors for subsequent breakthrough infections in liver transplant (LT) patients undergoing coronavirus disease 2019 vaccination with at least 2 doses of messenger RNA vaccine from April 28, 2021, to April 28, 2022. Methods: All LT recipients received at least 2 doses of the BNT162b2 (Pfizer BioNTech) vaccine 21 d apart. We measured the antibody response against the SARS-CoV-2 spike protein using the Roche Elecsys immunoassay to the receptor-binding domain of the SARS-CoV-2 spike protein, and the presence of neutralizing antibodies was measured by the surrogate virus neutralization test (cPass) before first and second doses of vaccination and also between 2 and 3 mo after the second dose of vaccination. Results: Ninety-three LT recipients who received 2 doses of BNT162b2 were included in the analysis. The mean time from LT was 110 ± 154 mo. After 2-dose vaccination, 38.7% of LT recipients (36/93) were vaccine nonresponders on the cPass assay compared with 20.4% (19/93) on the Roche S assay. On multivariable analysis, increased age and increased tacrolimus trough were found to be associated with poor neutralizing antibody response (P = 0.038 and 0.022, respectively). The use of antimetabolite therapy in conjunction with tacrolimus approached statistical significance (odds ratio 0.21; 95% confidence interval, 0.180-3.72; P = 0.062). Breakthrough infection occurred in 18 of 88 LT recipients (20.4%). Female gender was independently associated with breakthrough infections (P < 0.001). Conclusions: Among LT recipients, older age and higher tacrolimus trough levels were associated with poorer immune response to 2-dose SARS-CoV-2 vaccination. Further studies are needed to assess variables associated with breakthrough infections and, hence, who should be prioritized for booster vaccination.

Targeting Inflammation in Non-Small Cell Lung Cancer through Drug Repurposing.

Lung cancer is the most common cause of cancer-related deaths. Lung cancers can be classified as small-cell (SCLC) or non-small cell (NSCLC). About 84% of all lung cancers are NSCLC and about 16% are SCLC. For the past few years, there have been a lot of new advances in the management of NSCLC in terms of screening, diagnosis and treatment. Unfortunately, most of the NSCLCs are resistant to current treatments and eventually progress to advanced stages. In this perspective, we discuss some of the drugs that can be repurposed to specifically target the inflammatory pathway of NSCLC utilizing its well-defined inflammatory tumor microenvironment. Continuous inflammatory conditions are responsible to induce DNA damage and enhance cell division rate in lung tissues. There are existing anti-inflammatory drugs which were found suitable for repurposing in non-small cell lung carcinoma (NSCLC) treatment and drug modification for delivery via inhalation. Repurposing anti-inflammatory drugs and their delivery through the airway is a promising strategy to treat NSCLC. In this review, suitable drug candidates that can be repurposed to treat inflammation-mediated NSCLC will be comprehensively discussed together with their administration via inhalation from physico-chemical and nanocarrier perspectives.

Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation.

Oncogenic KRAS is the key driver oncogene for several of the most aggressive human cancers. One key feature of oncogenic KRAS expression is an early increase in cellular reactive oxygen species (ROS) which promotes cellular transformation if cells manage to escape cell death, mechanisms of which remain incompletely understood. Here, we identify that expression of oncogenic as compared to WT KRAS in isogenic cellular systems renders cells more resistant to ferroptosis, a recently described type of regulated necrosis. Mechanistically, we find that cells with mutant KRAS show a specific lack of ferroptosis-induced lipid peroxidation. Interestingly, KRAS-mutant cells upregulate expression of ferroptosis suppressor protein 1 (FSP1). Indeed, elevated levels of FSP1 in KRAS-mutant cells are responsible for mediating ferroptosis resistance and FSP1 is upregulated as a consequence of MAPK and NRF2 pathway activation downstream of KRAS. Strikingly, FSP1 activity promotes cellular transformation in soft agar and its overexpression is sufficient to promote spheroid growth in 3D in KRAS WT cells. Moreover, FSP1 expression and its activity in ferroptosis inhibition accelerates tumor onset of KRAS WT cells in the absence of oncogenic KRAS in vivo. Consequently, we find that pharmacological induction of ferroptosis in pancreatic organoids derived from the LsL-KRASG12D expressing mouse model is only effective in combination with FSP1 inhibition. Lastly, FSP1 is upregulated in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) as compared to the respective normal tissue of origin and correlates with NRF2 expression in PDAC patient datasets. Based on these data, we propose that KRAS-mutant cells must navigate a ferroptosis checkpoint by upregulating FSP1 during tumor establishment. Consequently, ferroptosis-inducing therapy should be combined with FSP1 inhibitors for efficient therapy of KRAS-mutant cancers.

Career and Professional Development for Young Oncologists.

Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have contributed to more accessible access to information and opportunities that some young oncologists could not profit from due to their traveling constraints. On the other hand, this virtual setting has shown us the asymmetries in opportunities for these professionals. Knowledgeable of all this, we summarize in this article some of the career and professional development offers available to all young oncologists, which we consider could help them deal with current and future challenges.

FEZ1 participates in human embryonic brain development by modulating neuronal progenitor subpopulation specification and migrations.

Mutations in the human fasciculation and elongation protein zeta 1 (FEZ1) gene are found in schizophrenia and Jacobsen syndrome patients. Here, using human cerebral organoids (hCOs), we show that FEZ1 expression is turned on early during brain development and is detectable in both neuroprogenitor subtypes and immature neurons. FEZ1 deletion disrupts expression of neuronal and synaptic development genes. Using single-cell RNA sequencing, we detected abnormal expansion of homeodomain-only protein homeobox (HOPX)- outer radial glia (oRG), concurrent with a reduction of HOPX+ oRG, in FEZ1-null hCOs. HOPX- oRGs show higher cell mobility as compared to HOPX+ oRGs. Ectopic localization of neuroprogenitors to the outer layer is seen in FEZ1-null hCOs. Anomalous encroachment of TBR2+ intermediate progenitors into CTIP2+ deep layer neurons further indicated abnormalities in cortical layer formation these hCOs. Collectively, our findings highlight the involvement of FEZ1 in early cortical brain development and how it contributes to neurodevelopmental disorders.

Complications Associated with Continuous RRT.

Continuous renal replacement therapy (CRRT) is a form of renal replacement therapy that is used in modern intensive care units (ICUs) to help manage acute kidney injury (AKI), end stage kidney disease (ESKD), poisonings, and some electrolyte disorders. CRRT has transformed the care of patients in the ICU over the past several decades. In this setting, it is important to recognize CRRT-associated complications but also up-to-date management of these complications. Some of these complications are minor, but others may be more significant and even life-threatening. Some CRRT complications may be related to dialysis factors and others to specific patient factors. Our overarching goal in this article is to review and discuss the most significant CRRT-related complications at the different stage of management of CRRT. With the advent of newer solutions, there have been newer complications as well.

Adaptive therapy to circumvent drug resistance to tyrosine kinase inhibitors in cancer: is it clinically relevant?

INTRODUCTION: Cancer is highly adaptable and is constantly evolving against current targeted therapies such as tyrosine kinase inhibitors. Despite advances in recent decades, the emergence of drug resistance to tyrosine kinase inhibitors constantly hampers therapeutic efficacy of cancer treatment. Continuous therapy versus intermittent clinical regimen has been a debate in drug administration of cancer patients. An ecologically-inspired shift in cancer treatment known as 'adaptive therapy' intends to improve the drug administration of drugs to cancer patients that can delay emergence of drug resistance. AREAS COVERED: We discuss improved understanding of the concept of drug resistance, the basis of continuous therapy, intermittent clinical regimens, and adaptive therapy will be reviewed. In addition, we discuss how adaptive therapy provides guidance for future cancer treatment. EXPERT OPINION: The current understanding of drug resistance in cancer leads to poor prognosis and limited treatment options in patients. Fighting drug resistance mutants is constantly followed by new forms of resistance. In most reported cases, continuous therapy leads to drug resistance and an intermittent clinical regimen vaguely delays it. However, adaptive therapy, conceptually, exploits multiple parameters that can suppress the growth of drug resistance and provides safe treatment for cancer patients in the future.

Melanoma metastasis: What role does melanin play? (Review).

Melanoma is an extremely aggressive form of skin cancer that can spread to the lungs, brain, and liver, among other vital organs. Melanoma cells, unlike any other cancer cells, can produce significant amounts of melanin by a process known as melanogenesis, causing them to become heavily pigmented. Melanogenesis, specifically the melanin pigment, is well known for its ability to protect the skin from the harmful effects of UV light, which can lead to the development of skin cancer. Nevertheless, uncontrolled melanogenesis plays a role in the advancement of melanotic melanoma, and melanin pigments can reduce the effectiveness of radiotherapy and immunotherapy. Therefore, studies are being performed that focus on inhibiting melanogenesis to prevent melanoma metastasis. However, it is worth noting that, in addition to its UV­protective function, melanin also plays a role in preventing melanoma metastasis. Microphthalmia­associated transcription factor (MITF) and melanin have been demonstrated to attenuate the aggressiveness of melanoma by suppressing numerous essential metastatic processes. Eumelanin and pheomelanin (two types of melanin), which cause oxidative stress, can also prevent melanoma progression in the early stages. Hence, it is vital to explore the role of inducing melanogenesis rather than inhibiting melanogenesis in preventing melanoma metastasis.

One-week intramuscular or intradermal pre-exposure prophylaxis with human diploid cell vaccine or Vero cell rabies vaccine, followed by simulated post-exposure prophylaxis at one year: A phase III, open-label, randomized, controlled trial to assess immunogenicity and safety.

Shorter rabies pre-exposure prophylaxis (PrEP) regimens may offer improved convenience and feasibility over classic 3-week regimens, for example in regions with poor access to vaccines or for travelers to rabies-endemic regions. In this multicenter, open-label, controlled trial, 570 healthy participants aged 2-64 years were randomized to receive: 1-week PrEP (vaccination days [D]0 and 7; Group 1) or classic 3-week PrEP regimen (D0, D7, and D21; Group 2) with one 1.0 mL intramuscular [IM] dose of human diploid cell culture rabies vaccine (HDCV) at each visit; 1-week PrEP with two 0.1 mL intradermal (ID) HDCV doses at each visit (Group 3); or 1-week PrEP with one 0.5 mL IM dose (Group 4) or two 0.1 mL ID doses (Group 5) of Vero cell rabies vaccine (PVRV) at each visit. Participants received simulated post-exposure prophylactic (PEP) vaccination (two IM or ID doses of HDCV or PVRV three days apart) one year later. Rabies virus neutralizing antibody titers and seroconversion (titers ≥ 0.5 IU/mL) rates were assessed 14 days and up to 1 year post-PrEP, and pre- and post-PEP. Safety was assessed throughout the study. Seroconversion rates were high 14 days post-last PrEP injection (ranging from 96.7 % to 97.2 % across groups 1, 3-5; 1-week PrEP) and reached 100 % in Group 2 (3-week PrEP). Non-inferiority of Group 1 versus Group 2 in terms of seroconversion rates 14 days post-last PrEP injection (primary objective) was not demonstrated. After simulated PEP, all groups showed rapid and robust immune responses, with all but one participant achieving seroconversion (titers ≥ 0.5 IU/mL). There were no safety concerns, and the tolerability profiles of the vaccines were similar across the groups. A 1-week, IM or ID PrEP regimen with HDCV or PVRV provided efficacious priming, enabling rapid robust anamnestic responses to simulated PEP 1 year later across age groups. ClinicalTrials.gov number: NCT03700242. WHO Universal Trial Number (UTN): U1111-1183-5743.

Molecular and immunomodulatory actions of new antiasthmatic agents: Exploring the diversity of biologics in Th2 endotype asthma.

Asthma is a major respiratory disorder characterised by chronic inflammation and airway remodelling. It affects about 1-8% of the global population and is responsible for over 461,000 deaths annually. Until recently, the pharmacotherapy of severe asthma involved high doses of inhaled corticosteroids in combination with ß-agonist for prolonged action, including theophylline, leukotriene antagonist or anticholinergic yielding limited benefit. Although the use of newer agents to target Th2 asthma endotypes has improved therapeutic outcomes in severe asthmatic conditions, there seems to be a paucity of understanding the diverse mechanisms through which these classes of drugs act. This article delineates the molecular and immunomodulatory mechanisms of action of new antiasthmatic agents currently being trialled in preclinical and clinical studies to remit asthmatic conditions. The ultimate goal in developing antiasthmatic agents is based on two types of approaches: either anti-inflammatory or bronchodilators. Biologic and most small molecules have been shown to modulate specific asthma endotypes, targeting thymic stromal lymphopoietin, tryptase, spleen tyrosine kinase (Syk), Janus kinase, PD-L1/PD-L2, GATA-3, and CD38 for the treatment and management of Th2 endotype asthma.

Pharmacological Modulation of Apoptosis and Autophagy in Pancreatic Cancer Treatment.

BACKGROUND: Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles. OBJECTIVE: This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC. METHOD: Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords. DISCUSSION/CONCLUSION: Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.

A general architecture for modeling the dynamics of goal-directed motivation and decision-making.

We present a unified model of the dynamics of goal-directed motivation and decision-making. The model-referred to as the GOAL architecture-provides a quantitative framework for integrating theories of goal pursuit and for relating their predictions to different types of data. The GOAL architecture proposes that motivation changes over time according to three gradients that capture the effects of the distance to the goal (i.e., the progress remaining), the time to the deadline, and the rate of progress required to achieve the goal. This enables the integration and comparison of six theoretical perspectives that make different predictions about how these dynamics unfold when pursuing approach and avoidance goals. Hierarchical Bayesian modeling was used to analyze data from three experiments which manipulate distance to goal, time to deadline, and goal type (approach vs. avoidance), and data from the naturalistic context of professional basketball. The results show that people rely on the distance and rate gradients, and to a lesser degree the time gradient, when making resource allocation decisions during goal pursuit, although the relative influence of the gradients depends on the goal type. We also demonstrate how the GOAL architecture can be used to answer questions about the influence of goal importance. Our findings suggest that goal pursuit unfolds in a complex manner that cannot be accounted for by any one previous theoretical perspective, but that is well-characterized by our unified framework. This research highlights the importance of theoretical integration for understanding motivation and decision-making during goal pursuit. (PsycInfo Database Record (c) 2022 APA, all rights reserved).