A document by rawan azzam. Click on the document to view its contents.

The incidence of melanoma among young adults has risen, yet mortality has declined annually since the introduction of immune checkpoint inhibitors (ICI). The utilization of peri-operative ICI has significantly altered the treatment landscape in melanoma, with PD-1 inhibitors showing promising efficacy in improving relapse-free survival rates in high-risk stage II-III disease. With the increasing use of ICI, secondary concerns have emerged regarding the impact of cancer drugs on fertility and reproductive health among child-bearing women, especially in early-stage cancer settings. The exclusion of pregnant women from trials contributes to limited human data and clinical uncertainties, such as maternal and fetal toxicities related to ICI exposure during pregnancy, as well as the value of fertility preservation prior to ICI therapy. Additionally, uncertainty persists regarding pregnancy planning after immunotherapy in an adjuvant setting, given the potential detrimental effects of hormonal and immunological changes during pregnancy on melanoma relapse. These considerations raise questions about whether pregnancy-associated melanoma (PAM) represents a distinct disease entity that warrants tailored management compared to non-pregnant cases.

Abstract

Background: Radiofrequency(RF) ablation of premature ventricular complexes(PVCs) is a well-established treatment for patients high PVCs burden, even when arising from epicardial/intramural localization. Consistent data about safety of using high power RF is lacking in literature in these regions. Aim: The aim of this study is to investigate safety of different RF power settings, efficacy and outcome of non-endocardial PVCs ablation. Methods: Consecutive patients who underwent PVC ablation were included (2017-2023). We defined “Non-Endocardial Radiofrequency Ablation”(NERA) a procedure in which at least one ablation site has been identified into the cardiac venous system, aortic cusps, inter-leaflet region or pulmonary cusps. Results: Total number of NERA sites was 64 in 53 procedures. In 63% of the procedures, high power (≥40W) and in 60% long duration (≥60 seconds) RF was delivered in at least one site (mean power:37±9W(15-50), mean duration of single RF 88±65 seconds (30-304)). In 21% of the procedures, a combination of both high power and long duration RF applications was performed. Procedural success was achieved in 47 procedures(84%). Only one severe complication (pericardial bleeding) was observed. In 22(39%) procedures, multisite ablation was performed which was associated with procedural failure (OR 7,47;p=0,01). During follow-up, mean and median PVC burden reduction were 69±41% and 96% respectively. Multisite ablation and coronary venous system RF were predictors of recurrence (HR 3.6;p=0.026 and HR 3.85;p=0.014). Conclusion: Ablation from non-endocardial sites is a safe and effective procedure, even using high power and/or long duration RF with clear benefit in terms of PVC burden reduction.

Efficacy and safety profile of animal dander immunotherapy: a multicentre UK studyTo the Editor,The prevalence of animal dander sensitisation has increased worldwide, with sensitisation rates in Europe as high as 26.3% to cat dander and 27.2% to dog dander.1 These aeroallergens can be found in environments such as schools, public transport or places of work, where the animals do not live and sensitisation may occur by direct or indirect contact.2 The recommended treatment for most patients in the UK is avoidance, which is not always practical or possible, particularly in public areas or places of work.Evidence for animal dander allergen specific immunotherapy (AIT) is limited, with cat dander AIT demonstrating the most consistent improvement after 12 months in a small study.3 Studies of dog dander AIT over the past 40 years have not confirmed statistically significant clinical efficacy.3,4 Other therapies described include horse dander and rat epithelium AIT.5,6In view of the limited data on animal AIT, we conducted a multi-centre review. Data on 35 patients aged 17 to 62 years (demographics in Table s1) treated with cat, dog and horse dander subcutaneous (SCIT) or sublingual (SLIT) AIT within five allergy services was analysed. All patients had confirmation of sensitisation by specific IgE or skin-prick testing. The commonest reason for AIT was workplace exposure, almost a third of which were veterinary workers (Supplementary Table s2). Efficacy was measured with different methods across different patients (Table 1). Side effects are reported in Table 2.Our data shows a higher compliance rate for SCIT patients, with 3-year completion rates at 60% compared with SLIT at 43%, accounting for 4 patients currently on treatment, which aligns with published data (Table 1). The most common reason for incomplete therapy was loss to follow-up and there were varied reasons for this (Supplementary table S3).For those who completed the full 3-year therapy, there were excellent efficacy rates for both SCIT and SLIT with 100% of patients achieving either complete or partial response (Table 2). Patient reported symptoms was the most used indicator of efficacy. A negative in-hospital cat challenge was performed in one patient and a negative home dog provocation in one patient. Efficacy was better in SCIT, with 100% complete response compared with 67% complete response in SLIT. All products established a complete response, except Oralvac cat and horse.The side effect profiles were acceptable with only one patient receiving cat dander SCIT reporting systemic side effects of rhinitis and wheeze during updosing. This patient completed updosing but did not complete maintenance therapy due to side effects. The majority of reported side effects were limited to localised reactions (Table 2). 3 SLIT patients withdrew from treatment due to undocumented side effects. Overall, 23/35 (66%) patients reported no side effects.Although numbers are small, our data demonstrates significant benefits from animal dander AIT with high efficacy rates, and side effects mainly limited to mild, localised reactions. The therapy may be most beneficial in those who are unable to avoid exposure, most commonly from workplace, or those suffering from systemic symptoms, such as asthma exacerbations when exposed to dander without the presence of the animal itself, making avoidance near impossible. Despite the benefits, animal dander AIT is used less than other inhalant allergens.One limitation of the study is that we do not have long-term follow-up data, so the durability of the response is uncertain. Adherence is also a significant issue and means to improve this should be considered.There is limited research on animal dander AIT compared with other aeroallergens, and our data has shown positive findings, although mostly with cat and dog dander. Larger cohorts are required to understand the full benefits of animal dander AIT.Table 1. Documented efficacy and compliance rates for those who completed 3 years AIT therapy.

Unmasking tuberculous lymphadenitis in a middle-aged male with Hashimoto’s Thyroiditis: navigating diagnostic challenges in Primary carePratik Ramkumar1, Yousuf Yaqub1, Waseem Jerjes1,2,31. Imperial College School of Medicine, London SW7 2DD, UK.2. Research and Development Unit, Hammersmith and Fulham Primary Care Network, UK3. North End Medical Centre, Hammersmith and Fulham Partnership, London, UK

Pinus brutia (pine) and Cupressus sempervirens (cypress) are two important forestry species in the Mediterranean region, with different strategies to cope with water stress. The overall goal of this study is to investigate ecohydrological processes of these two species. Specific objectives are: (i) to quantify their transpiration; (ii) to analyze relations between meteorological variables, soil moisture, sap flow, leaf conductance and twig water potential; and (iii) to assess differences in soil water balances and dynamics between three canopy cover conditions (under canopy, edge of canopy, open area). The study site is a plantation forest in Athalassa Forest Park, in Cyprus with a long-term average annual rainfall of 315 mm. The site was converted from rainfed agriculture in 2011. Observations of sap flow (12 trees for 20 months, 4 trees for 24 months) and soil moisture (66 sensors, 24 months) were made hourly. Soil moisture sensors were installed under the tree canopy, at the edge of the canopy and in the open area at 10-, 30- and 50-cm soil depths. Mid-day twig water potential ( Ψ) and leaf conductance ( gs) were measured monthly. The sap flow of cypress trees was double that of pine. Pine seems to regulate its stomata and shows less response to rainfall compared to cypress. Soil water balance computations showed that evapotranspiration from the 60-cm soil depth of the areas without tree canopy cover was higher than that of areas with canopy cover, likely due to preferential flows caused by the tree canopy and roots.

Process heat electrification offers the prospect of deep decarbonization of the process industries. Replacing fossil fuel-fired boilers with electric ones can reduce carbon emissions if power is supplied from a grid with a high proportion of renewables. For multinational firms with plants in multiple locations, the electrification decisions should be scheduled based on grid carbon intensity projections and coordinated among these subsidiaries; in addition, carbon credits can be traded among the multiple sites to allow lagging plants to reduce their carbon footprints. Here we develop a novel mathematical model to optimize process heat electrification policies in multinational corporations. The model determines the optimal timing of electrification at each location, and also the necessary level of carbon trading within the multinational firm. An illustrative case study demonstrates how the proposed model can be used to generate electrification plans that are superior to those based on simple heuristics.

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not-yet-known not-yet-known not-yet-known unknown Case Report

Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of dysfunctional B cells, resulting in significant immune dysregulation. Patients with CLL exhibit varied responses to B-cell receptor (BCR) targeted therapies, emphasizing the need for tailored immunotherapy approaches. This study investigated B cell function in untreated patients with CLL, and we further explored the effects of ex vivo protein kinase C activation on immune checkpoint expression and B cell profiles. Peripheral blood samples were collected from 21 untreated patients with CLL at King Edward Hospital in South Africa, between 2019 and 2022. B cells were stimulated with phorbol myristate acetate (PMA) and ionomycin. Using flow cytometry, the study explored the levels of B cell subsets and immune checkpoint proteins programmed cell death-ligand 2 (PD-L2) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) expression on various B cell subsets. PMA and ionomycin B cell stimulation upregulated CTLA-4 and PD-L2 expression on B cell subsets (p<0.0001). As expected, monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 significantly downregulated the CTLA-4 expression of B cell subsets (p<0.05), while PD-L2 exhibited varied responses in different B cell subsets. In addition, these monoclonal antibodies increased the levels of memory B cells (p<0.0128) and activated memory B cells (p<0.01). Protein kinase C activation on B cells stimulates immune checkpoint expression. The use of monoclonal antibodies on B cells play a critical role in the B cell function through the reduction of CD38 expressing activated B cells and upregulation of memory B cells. Moreover, the monoclonal antibody targeting PD-1, PD-L1 and CTLA-4 are effective in reducing the expression of CTLA-4 on B cell subsets.

not-yet-known not-yet-known not-yet-known unknown Objective: To investigate use of asthma controller medications and their effect on lung function in pediatric patients with SCD. Methods: Retrospective study in pediatric patients of African American ethnicity with SCD treated at PCH between 2014-2021. Associations of asthma controller medications with changes in lung symptoms (cough, wheeze, chest pain, shortness of breath with exercise, sleep disturbance), Acute Chest Syndrome (ACS), and percent predicted spirometry (FEV 1, FVC, FEV 1/FVC, FEF 25%-75%)) were examined (Fisher exact, Wilcoxon rank sum) separately in SCD patients with and without asthma. Results: Of the total 98 SCD patients, 28 (29%) had an asthma diagnosis. Asthma controller medications were prescribed to 20 (71% of 28) with asthma and 37 (53% of 70) without asthma. Patients with vs without asthma were more likely to receive combined medications (55% vs 8.1%), but less ICS alone (35% vs 48 %) or LTRA alone (10% vs 43%) (p<0.0003). Medication use vs non-use improved cough (38% vs 9%, P=0.006) and shortness of breath with exercise (32% vs 12%, P=0.03) in SCD patients without asthma, but these were non-significant in asthmatics. Medications also improved the mean percent change in both non-asthmatics FEV 1 (10.2 vs -3.2; P<0.0001), FVC (8.8 vs -0.7; P=0.002), and FEF 25%-75%, (17.6 vs -9.7; P=0.0005), and asthmatics FEV 1 (16.4 vs -5.2; P=0.001), FVC (13.7 vs -3.8; P=0.0009), and FEF 25%-75%, (26.1 vs -5.0; P=0.02). Conclusion: These findings, demonstrating improved lung function with asthma controller medications in pediatric patients with SCD, irrespective of an asthma diagnosis, holds great promise for this undertreated population.

Background and Purpose Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. Development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R-selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A1R and/or through a disease specific mechanism, we assessed the effect of MRS5474 on the hippocampus. Experimental Approach Excitatory synaptic currents, field potentials, spontaneous activity, [3H]GABA uptake and GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in adenosine A3 receptor (A3R) density in human tissue were assessed by Western Blot. Key Results MRS5474 (50-500nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. This contrasted with the effect of other A1R agonists. MRS5474 inhibited GAT-1 mediated GABA uptake, an action not blocked by an A1R antagonist but blocked by an A3R antagonist and mimicked by an A3R agonist. A3R was overexpressed in human hippocampal tissue samples from patients with epilepsy that had focal resection from surgery. MRS5474 induced a concentration-dependent potentiation of GABA-evoked currents in oocytes micro-transplanted with human hippocampal membranes prepared from epileptic hippocampal tissue but not from non-epileptic tissue, an action blocked by an A3R antagonist. Conclusion and Implications We identified a drug that activates A3R and has selective actions on epileptic hippocampal tissue. This underscores A3R as a promising target for the development of antiseizure medications.

not-yet-known not-yet-known not-yet-known unknown Synchronous retrograde replantation method for repairing complete severed of five toes: a 4-year follow-up

While body experience is a key focus of treatment in psychomotor therapy (PMT), research has largely overlooked this important topic. In this study we explored three domains of body experience – body satisfaction, body attitude, and interoceptive awareness – in individuals with mental disorders in a clinical sample receiving PMT. We expected these patients to have a more negative body experience than non-clinical controls, with PTSD, mood disorders, personality disorders and sex negatively affecting all three domains of body experience. The study involved 235 participants aged 18-59 with various mental disorders that were referred to PMT between 2008 and 2017 at a mental health center in the Netherlands. They completed questionnaires on all three of the aforementioned body experience domains. One sample t-tests revealed that patients had significantly more negative body satisfaction and body attitude than non-clinical control samples obtained from the literature, with no significant difference in interoceptive awareness. Regression analyses within the patient sample revealed that female patients and patients with mood disorders or PTSD, displayed more negative body satisfaction than patients with other mental disorders. Additionally, female patients and patients with mood disorders displayed more negative body attitude. Although the total patient group and controls had comparable interoceptive awareness, only PTSD significantly predicted lower interoceptive awareness. Age and personality disorders did not predict differences on any domain of body experience. This research demonstrates that body experience is disturbed in patients with mental disorders who received PMT, and that there are disorder-specific patterns in disturbances on domains of body experience.

not-yet-known not-yet-known not-yet-known unknown The regularized ψ-Hilfer derivative within the sense of Caputo is an improved version of the ψ-Hilfer fractional derivative, primarily because it addresses the issue where the initial conditions of problems involving the ψ-Hilfer fractional derivative lack clear physical significance unless p=1. This article’s main contribution is the use of the ψ-Laplace transform, which is the first provide an explicit expression for mild solutions to the fractional diffusion equations with the regularized ψ-Hilfer derivative. Additionally, we investigate the existence and attractivity of mild solutions for fractional diffusion equations involving the regularized ψ-Hilfer fractional derivatives. Finally, we provide two examples to illustrate our main resuits.

As human-modified landscape and climate changes proliferate, maintaining biodiversity and understanding the function and quality of available habitat is imperative. As Anurans (frogs/toads) can be indicator species of habitat quality and ecosystem productivity, studying the Anuran community in a mixed-land use region provides an opportunity to better understand the relationship between species and landscape modification. Certain species, such as Pseudacris crucifer, can also be utilized as indicator species. We explored this relationship by assessing the effects of spatial and temporal heterogeneity on the presence of Anurans across an urbanization gradient. Within the Toledo Metropolitan Area, including the biodiversity hotspot Oak Openings Region, we surveyed 67 different wetlands (N=1800) over three years. There was a difference in community assemblage between rural and suburban/urban habitats driven by human-modification (impervious surface), composition (landcover type) and productivity (e.g., NDVI). The differences in spatial structure but lack of differences in temporal variables among sites suggest spatial factors explain these discrepancies. Areas with more impervious surface, lower amounts of swamp forest, and lower NDVI had fewer species, lower average species per survey, and lower relative abundance of Anuran species. Utilizing Generalized Linear Mixed Modeling, we found that P. crucifer relative abundance and greater richness were the best predictors of ecosystem productivity. Our research demonstrates the value of non-invasive Anuran call surveys to assess ecosystem productivity and species richness on a large scale, while also offering a method to evaluate conservation efforts internationally. This scalable approach can be applied anywhere with sufficient environmental data, and we recommend utilizing Anurans as indicator taxa for understanding ecosystem function, especially in human-modified landscapes.

A document by prudhvi Narayana Bandaru. Click on the document to view its contents.