The combination of target and beam motions is a concern in radiotherapy, as it results in the so-called interplay effects. These effects may lead to an inappropriate dose distribution delivered to patients, potentially compromising treatment outcomes, being particularly common in the case of thoracic tumours. An excellent external radiotherapy treatment option - compared to conventional photon modality - is proton beams delivered with pencil beam scanning (PBS), which might offer better sparing of healthy tissues with comparable dose tumour coverage. This study, therefore, aimed to evaluate whether alanine, based on electron spin resonance (ESR), a well-established dosimeter, can be applied in the context of moving targets of clinical photon and proton beams and assessing interplay effects. Alanine/ESR dosimeters (Harwell, UK) inserted in an anthropomorphic moving phantom (CIRS, USA) were irradiated with photon and proton beams, at the San Matteo Hospital and Fondazione CNAO, respectively, both in Pavia (Italy). Different moving conditions, simulating or not abdominal compression (20-mm maximum respiratory excursion), were evaluated. ESR measurements were performed in an ELEXSYS spectrometer (Bruker, Germany), and the peak-to-peak amplitude was used to reconstruct the dose. Good agreement between planned and measured doses was obtained with deviations within 3.3 % and 2.2 % for photons (flattening-filter) and protons, respectively, in all moving conditions. No significant differences were observed as a function of the moving regimen. This study showed that alanine/ESR can be a suitable dosimetric system for use in end-to-end tests for moving targets, including the evaluation of interplay effects.
In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), amyloid can be deposited in the peripheral nerves, causing polyneuropathy (PN). We evaluated the rate of incident PN diagnosis among ATTR-CM patients. This study utilized German claims data from January 2016-December 2023. We included adults newly diagnosed with ATTR-CM without a prior history of PN based upon International Classification of Diseases-Tenth Revision-German Modification (ICD-10-GM) diagnosis codes and coding for diagnostic testing. We identified incident PN using both a narrow (ATTR-PN-related) and broad (also including non-ATTR-specific polyneuropathies) set of ICD-10-GM codes. Incidence rates/100 person-years (PYs) with 95% confidence intervals (CIs) were calculated. We identified 309 newly diagnosed patients with ATTR-CM free of PN. During a median follow-up of 430 days (Q1 = 175, Q3 = 936) the rate of broadly defined incident PN was 10.8 cases/100PYs (7.9-14.3), declining to 2.4 cases/100PYs (1.2-4.1) when the narrow ATTR-related PN definition was used. In German routine care, the incidence of ATTR-related PN in patients with ATTR-CM was 2.4/100PYs, rising to 10.8/100PYs under a broad symptom-based definition. Although ATTR-related PN was infrequently identified in ATTR-CM, PN and ATTR-CM may coincide.
Exposure to space radiation represents a critical issue for astronauts' health, since it can lead to different types of effects including cancer, cataract, skin damage, damage to blood forming organs, cardiovascular diseases, CNS damage etc. Space radiation exposure is characterized by relatively low dose rates over long periods due to Galactic Cosmic Rays, plus short, higher-dose exposures in case of intense Solar Particle Events (SPE). In this framework the BIANCA biophysical model, which until now has been applied to predict cell death and chromosomal aberrations following acute exposure, was extended by integrating the Lea-Catcheside approach, which takes into account the effects of dose fractionation and dose rate; the good agreement between model predictions and proton cell survival data on fractionated irradiation (either obtained in this work, or taken from the literature) allowed validating the model for the considered scenarios. Afterwards, exploiting an interface with the FLUKA radiation transport code, BIANCA was applied to analyze the impact of dose rate for the August 1972 SPE, by calculating RBE-weighted organ doses in a human voxel phantom under different shielding conditions and for different irradiation durations. The results showed differences up to 50 % in the RBE-weighted dose between acute and protracted irradiation; such difference tends to decrease with increasing shielding. Following this work, BIANCA can now predict RBE values for cell survival taking into account not only the RBE dependence on particle type, energy and dose, but also the dependence on dose-rate. This allowed improving the accuracy in the prediction of astronauts' Gy-equivalent doses in case of a SPE exposure.
Past experiences stored in long-term memory (LTM) provide a valuable resource for making predictions that shape perception and guide goal-directed behavior. Contents from the high-capacity LTM system guide contextual selective attention to enhance sensory and higher-order processing of memory-predicted targets, in a process known as LTM-guided attention. While this essential cognitive function is believed to depend on the hippocampus, evidence is still scarce. In this study, we used a neuropsychological approach to test LTM-guided attention in the context of isolated hippocampal pathology and to explore structure-behavior covariance patterns. We tested healthy individuals (n = 20) and individuals suffering from focal epilepsy, with isolated, unilateral left (n = 20) or right (n = 17) hippocampal sclerosis (HS), in a task probing LTM-guided attention. Behavioral data indicated that individuals with left or right HS retained LTM-guided attention. We also assessed structure-behavior covariance using a multivariate structural neuroimaging approach. Hierarchical clustering analysis revealed that, in healthy individuals, LTM-guided attention performance covaried with atlas-derived subfield measures of the left hippocampal body. The volume of the left hippocampal body also covaried with attentional benefit in individuals with right HS. Interestingly, for individuals with left HS, LTM-guided attention covaried with the volume of the left hippocampus and with part of the right hippocampal volume. Together, these findings suggest that LTM-guided attention can be preserved in unilateral HS, with differences in hippocampal volume-behavior covariance depending on the side of hippocampal pathology.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).
Pediatric immunological and allergic conditions represent a broad spectrum, ranging from highly prevalent polygenic disorders (e.g., food allergy, atopic dermatitis, asthma, and allergic rhinitis) to rarer monogenic primary atopic disorders. The management of these conditions has undergone a paradigm shift in recent years. Moving away from a "one-size-fits-all" approach, precision medicine aims to deliver the right treatment to the right patient at the right time. By integrating clinical phenotypes with molecular endotypes and using specific biomarkers and "Omics" techniques, scientists and clinicians can now employ targeted biological therapies that significantly improve patient outcomes. By identifying early therapeutic windows and specific biomarkers, pediatric specialists can implement personalized interventions that halt the atopic march and mitigate the global burden of chronic allergic diseases. By shifting the focus from symptom management to the neutralization of specific molecular pathways, it is now possible to achieve better disease control, reduce side effects associated with broad-spectrum treatments such as systemic corticosteroids, and improve the quality of life for patients with refractory allergic diseases. This review, generated during a seminar funded by the Clemens von Pirquet Foundation, aims to delineate the "rare to common" pipeline, illustrating how precision medicine tools, including multi-omics, biomarkers, and artificial intelligence methods, can connect mechanistic pathways across the immunological spectrum.
Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive. Here Aβ/tau biomarkers were used to distinguish positive (MCI+- prodromal Alzheimer's disease) and negative (MCI-) subjects in a cohort of 30 MCI patients (18 MCI+ and 12 MCI-). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance. While virtual brain simulations did not reveal E/I differences between MCI+ and MCI-, a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI+ largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert. This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.
This work presents a numerical investigation of interacting chiral oscillators (COs), characterized by an intrinsic rotational handedness. The coupling of positional and orientational degrees of freedom drives a mutual influence between synchronization and spatial dynamics. The control parameter, Δ (anisotropy or detuning), represents the frequency difference between two COs (for the two-body case) or between two families of COs (for the many-body case) with opposite handedness. For two COs with opposite handedness, interaction forces generate a helical excitable dipole (HED), where excitability is a spatiotemporal act characterized by a helical trajectory. For many COs moving in two dimensions, the model displays a locking-to-unlocking transition of the Kuramoto kind driven by Δ, leading the system from ordered states to irregular spatiotemporal dynamics. Within the locking region, many "superexcitable" states emerge, sustained by a global saddle-node bifurcation, detected by the collective period behavior versus Δ. These coherent, topological states are characterized by dissipationless phase-momentum locking, which I quantified using appropriate global metrics, including the Kuramoto order parameter and parameter S, capable of detecting the phase-momentum locking. These states exhibit a wide variety of topologically protected vortex complexes, whose complexity increases with system size. The model provides a unified framework for diverse biophysical applications-from molecular ratchets to cardiac looping-identifying the symmetry breaking of motile excitable units as a fundamental process for large-scale, robust collective transport.
Multiple routes of allergen immunotherapy (AIT) are approved for several IgE-mediated allergic diseases; however, the use of AIT in eosinophilic esophagitis (EoE) remains controversial and is supported by limited evidence. This review, conducted within the frame of an EAACI Task Force, aims to systematically evaluate the use of AIT as a potential treatment for EoE. The protocol was registered and prepared in accordance with PRISMA guidelines. The literature search was conducted across three online databases (PubMed, Embase, and Scopus) and included studies published through January 31st, 2025. Risk of Bias was assessed for each eligible study. Four articles met the inclusion criteria. Three articles evaluated EPIT for milk-induced EoE in pediatric patients, all from the SMILEE (Study of Efficacy and Safety of Viaskin Milk for milk-induced EoE) trial and its extensions. These included a randomized, placebo-controlled trial, its open-label extension, and a pilot immunological study. The SMILEE trial found no statistically significant difference in tissue eosinophilia between the active (EPIT) and control (placebo) arms in the intention-to-treat population, while 47% of treated EoE patients tolerated milk without recurrence of esophageal eosinophilia. This finding was further supported by a subsequent open-label study with a 2-year follow-up. In the third publication, the researchers found that EPIT was associated with decreased Th2-related transcripts and increased regulatory T-cell-associated transcripts. Only one eligible study evaluated the use of SCIT for treating EoE. It was a retrospective case-control study reporting that SCIT had a neutral effect and yielded inconclusive findings regarding the course of EoE. There is insufficient high-quality evidence to support the effectiveness of alternative routes of AIT for the treatment of EoE, either as an add-on or a standalone treatment.
Fluoropyrimidines are among the most common chemotherapeutic agents associated with cardiotoxicity, typically presenting as angina due to coronary vasospasm. Severe manifestations such as myocarditis and cardiogenic shock are rare, and rechallenge after cardiotoxicity is generally discouraged. We report a case of acute 5-fluorouracil-induced myocarditis with successful rechallenge after multidisciplinary evaluation. A 30-year-old man with unresectable rectal adenocarcinoma developed acute cardiotoxicity during the first FOLFOX-6 cycle, presenting with abdominal pain and palpitations. ECG showed atrial fibrillation and ST-segment elevation. Echocardiography revealed severe biventricular dysfunction with elevated cardiac biomarkers. Coronary angiography excluded obstructive disease, and cardiac magnetic resonance confirmed acute myocarditis with diffuse oedema and non-ischaemic late gadolinium enhancement. Guideline-directed heart failure therapy led to rapid functional recovery within days. Following multidisciplinary cardio-oncology assessment, chemotherapy rechallenge under continuous monitoring was performed without recurrence of major adverse events. Subsequent cycles were well tolerated, and follow-up CMR showed preserved ventricular function with residual non-ischaemic LGE. This case highlights the importance of early recognition of fluoropyrimidine cardiotoxicity, the role of multidisciplinary cardio-oncology management, and the potential feasibility of rechallenge in carefully selected patients.
Actionable quality gaps persist in low-density lipoprotein cholesterol (LDL-C) management after acute myocardial infarction (AMI). We aimed to quantify diagnostic and therapeutic inertia in LDL-C management after discharge in a real-world AMI population with verified and quantified consecutive inclusion. We conducted a quality improvement audit of patients discharged alive with a primary diagnosis of AMI. Consecutiveness was quantified using the consecutive index (e.g., the ratio of included patients with available 6-month follow-up information to the total AMI discharges). Diagnostic inertia was defined as no evidence of LDL-C measurement post-discharge. Therapeutic inertia was defined as LDL-C ≥ 55 mg/dL in the absence of optimal lipid-lowering therapy among patients with at least one post-discharge LDL-C measurement. A multivariable model was developed to identify risk-adjusted probability of LDL-C target achievement at follow-up. Among 3490 AMI patients, 3130 had at least a follow-up assessment after discharge. At six months, 2603 patients had available information on vital status, follow-up assessment, and post-discharge LDL-C assessment status (consecutive index: 74.6% [95% CI: 73.1-76.0%]). Diagnostic inertia occurred in 19.3% (95% CI: 17.8-20.9%) and therapeutic inertia in 38.1% (95% CI: 35.7-40.6%). In a multivariable model, the explained variance was modest (R2=14.4%; 95% CI: 12.0-18.2%). In a contemporary cohort including approximately 75% of patients surviving hospitalization for AMI, one in five patients did not undergo LDL-C testing during follow-up and two in five did not receive adequate lipid-lowering therapy despite failing to reach guideline-recommended targets. These findings highlight a substantial opportunity for structured quality improvement initiatives targeting LDL-C management after AMI.
Borderline personality disorder (BPD) often occurs alongside treatment-resistant depression (TRD), but the impact of BPD on real-world outcomes with intranasal esketamine is unclear. Consecutive TRD outpatients initiating intranasal esketamine treatment at four Italian centres between 1 September 2024 and 30 September 2025 were enrolled in the study (n = 90): 45 with comorbid BPD and 45 without any personality disorder. The primary outcome was the trajectory of depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline (T0) to 2 weeks (T1), 1 month (T2), 3 months (T3) and 6 months (T4). A response was defined as a ≥ 50% reduction in MADRS score, and remission as a MADRS score of ≤10 at T4. Secondary outcomes (exploratory) included anxiety (HAM-A), impulsivity (BIS-11) and cognitive function (MoCA). MADRS scores decreased over time (F(2.45, 215.50)=365.10, p < 0.001, ηp²=0.81), with a significant time × BPD interaction (F(2.45, 215.50)=17.31, p < 0.001), indicating faster early improvement in the BPD group. Remission at six months was 53.3%, with no difference by BPD status (48.9%vs. 57.8%, p = 0.398). However, response rates were higher in the BPD group from month one onwards (T4 OR=12.57, p = 0.004). Sensitivity analyses adjusting for baseline psychotherapy/medications and excluding patients with a history of hypomanic episodes yielded consistent results. Across the whole sample, anxiety and impulsivity decreased, and there was no evidence of worsening of the MoCA score over six months, supporting cognitive safety. No serious adverse events occurred and no patients dropped out. In routine care, intranasal esketamine was associated with sustained improvement in TRD over six months, and comorbid BPD did not affect remission outcomes.
Patients with obstructive hypertrophic cardiomyopathy (oHCM) endure life-altering exercise limitations. Current treatment guidelines recommend β-blockers as first-line therapy primarily based on expert opinion. The Metoprolol vs Aficamten in Patients with Left Ventricular Outflow Tract Obstruction on Exercise Capacity in HCM (MAPLE-HCM) trial characterizes comprehensive exercise response to aficamten monotherapy vs β-blockade (metoprolol). To determine the effect of aficamten compared with metoprolol across all stages of exercise using 16 quantitative measures in individuals with oHCM. This was a prespecified secondary analysis of the MAPLE-HCM study, a phase 3, randomized, active-control trial conducted from June 2023 to March 2025 with data analyzed between May and July 2025 at 71 sites in North America, South America, Europe, Israel, and China. Patients with symptomatic oHCM with objective evidence of exercise intolerance (peak oxygen uptake [pVO2] <100% of predicted) were included. Those with a history of atrial fibrillation (paroxysmal or persistent), medical indication for β-blockers or calcium channel blockers prohibiting drug discontinuation, or intolerance or medical contraindication to β-blockers were excluded. Randomized 1:1 to titrated aficamten (5-20 mg daily) or matching titrated metoprolol (50-200 mg daily) for 24 weeks. The main outcomes were submaximal exercise minute ventilation (VE)/carbon dioxide output (VCO2) slope and anaerobic threshold; peak exercise duration, workload, heart rate and heart rate reserve; and postexercise oxygen recovery rates; and composite variables, such as circulatory power. Of 175 randomized participants (mean [SD] age, 57.7 [13.2] years; 102 [58.3%] male), 165 (94%) had core laboratory-validated exercise tests at baseline and week 24. Compared with metoprolol, aficamten treatment improved multiple stages of exercise; including submaximal exercise VE/VCO2 slope (-2.8; 95% CI, -4.0 to -1.5; P < .001) and anaerobic threshold (76 mL/min; 95% CI, 41 to 111; P < .001); peak workload (8 watts; 95% CI, 3 to 13; P = .003); the time required for VO2 to recover by 12.5% postexercise (-11 seconds; 95% CI, -16 to -5; P < .001); and circulatory power (819 mm Hg × mL/min per kg; 95% CI, 569 to 1070; P < .001). Large improvements (≥3.0 mL/kg/min) in peak VO2 were more common with aficamten compared with metoprolol (17 [20.5%] vs 3 [3.7%], respectively; odds ratio, 6.8; 95% CI, 2.0 to 22.5; P < .001). In contrast, large reductions in peak VO2 (≥3.0 mL/kg/min) were significantly more common with metoprolol than aficamten (17 [20.7%] vs 2 [2.4%], respectively; odds ratio, 10.6; 95% CI, 2.6 to ∞; P < .001). This prespecified analysis of MAPLE-HCM demonstrated monotherapy with aficamten was superior to metoprolol in promoting adaptation to multiple phases of exercise in patients with symptomatic oHCM and supports aficamten as first-line therapy for oHCM. ClinicalTrials.gov Identifier: NCT05767346.
β-Blockers have been traditionally prescribed after acute myocardial infarction (MI), but contemporary evidence in patients with preserved or mildly reduced left ventricular ejection fraction (LVEF ≥40%) have not provided consistent results. We assessed the robustness of the evidence for the efficacy of β-blocker therapy in this population using contemporary randomized controlled trials (RCTs) and pooled analyses. We systematically searched PubMed, Scopus, and Embase through August 1, 2025, for phase 3-4 RCTs evaluating β-blockers in patients with LVEF ≥40% during index MI hospitalization. Primary outcomes included robustness of each trial's primary endpoint; secondary outcomes included all-cause and cardiovascular mortality, recurrent MI, heart failure hospitalization, and unplanned revascularization. Fragility index (FI) and fragility quotient (FQ) were calculated. Data were pooled using random-effects meta-analysis. Four trials (REDUCE-AMI, CAPITAL-RCT, BETAMI-DANBLOCK, REBOOT) with 19,245 patients were included. Event rates were low across the various outcomes with limited robustness: FI and FQ values indicated high sensitivity to small changes in events. BETAMI-DANBLOCK suggested modest benefit for recurrent MI, while REDUCE-AMI and REBOOT showed no significant effect. Pooled analysis revealed a 9% relative risk reduction and 0.9% absolute risk reduction for the composite of death, recurrent MI, or heart failure hospitalization (number needed to treat = 111; FI = 5). In patients with MI and LVEF ≥40%, β-blocker therapy confers only modest absolute benefits, with trial results that are fragile. Routine use in this population may not provide consistent or clinically meaningful benefit, underscoring the need for individualized therapy.
Self-disorders, or anomalous disturbances in the basic sense of self, have been described in psychosis-risk states and may contribute to social cognitive impairment and functioning. This study examined self-disorder severity and associations with social cognition and functioning across individuals at clinical high risk for psychosis (CHR-P), autism spectrum disorder (ASD), and controls. ASD was included due to overlapping difficulties in social cognition/functioning with CHR-P. We hypothesized a graded pattern of self-disorders (CHR-P > ASD > controls) and stronger associations between self-disorders and social cognition in CHR-P. We included 39 CHR-P, 39 ASD, and 30 controls (mean age ≈24 years; 51% female). Self-disorders were assessed with the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE). Social cognitive domains included social cognitive bias and theory of mind alongside measures of social functioning. Analyses of covariance and bootstrapped regression models with IPASE as predictor were used, adjusting for age, sex, and IQ. Multiple comparisons were Benjamini-Hochberg corrected. Self-disorders followed a graded distribution (CHR-P > ASD > controls) across all IPASE subscores. Both clinical groups showed elevated social cognitive bias and reduced social functioning compared to controls. Self-disorders were associated with social cognitive bias in ASD (B = 0.392, 95%CI 0.236-0.544, p < 0.001), but not in CHR P. Group differences in associations between self-disorders and social cognition/functioning did not survive correction for multiple comparisons. Self-disorders showed a graded distribution across groups but was only associated with social cognitive deficits in ASD. Findings suggest that shared symptom profiles may reflect divergent experiential processes across groups. Further research is needed to clarify clinical implications and generalizability.
The excited-state dynamics and photochemical behavior of mono-, di-, and trisubstituted triphenylamines were investigated in different media by nanosecond laser flash photolysis. Photoexcitation produces the triplet excited state of the triarylamines, which undergoes competitive radiationless decay and intramolecular [6π]-electrocyclization to form the corresponding triplet N-aryl-4a,4b-dihydrocarbazoles. These intermediates subsequently yield singlet dihydrocarbazoles that undergo back-electrocyclization, disproportionation, or oxygen trapping. The transient species were characterized by their absorption spectra, lifetimes, quantum yields, and kinetic parameters. Both the efficiency of electrocyclization and the rate of radiationless deactivation depend strongly on solvent polarity and substituent electronic effects. Linear correlations between rate constants and Reichardt's solvent polarity parameter point out that cyclization is favored in polar solvents, whereas radiationless decay predominates in nonpolar media. Hammett analyses further demonstrate systematic substituent effects on the competing excited-state pathways, including triarylamines bearing perfluoroalkyl substituents. These results provide a comprehensive kinetic and mechanistic description of the photoinduced electrocyclization of substituted triphenylamines and establish quantitative relationships between molecular structure, solvent environment, and excited-state reactivity.
Chronic Kidney Disease (CKD) affects over 674 million people globally and can lead to kidney failure, which significantly impairs quality and duration of life. While various oral pharmacological treatment options are available, limited research exists on how patients and carers prioritise treatment attributes. This study explored preferences for oral CKD medication across eight countries, involving 2,324 participants (1,511 patients and 813 carers). A Discrete Choice Experiment (DCE) was conducted in which participants completed seven hypothetical scenarios, each with two unlabelled treatment options and a "neither" (or "stay on current treatment") option. Five attributes were assessed: delay in dialysis or transplant, life extension, reduced risk of heart failure hospitalisation, risk of side effects, and out-of-pocket costs. Data were analysed using Mixed Multinomial Logit models, generating separate patient and carer models for each country (16 models), enabling cross-country comparisons. Participants across countries placed the highest importance on delaying dialysis or transplant, followed by life extension, with minimising treatment side effects ranked next. They preferred longer delays for dialysis or transplant, with the seven-year delay being most preferred. Regional and patient-carer variations were observed in attribute importance. Model parameters were used to calculate utility for treatment profiles and simulate preference shares, enabling country-level comparisons. Patients and carers consistently prioritised oral medications that delay the need for dialysis or transplant and extend life, although the relative importance of these attributes differed by country and respondent group. The choice of oral medication in CKD is preference-sensitive, and these results have direct implications for shared decision-making in clinical practice. To support application of these findings, we have developed an interactive dashboard that simulates the impact of medication attributes on predicted uptake across all eight countries: https://cappre.shinyapps.io/CKD_Dapa_DCE/.
Amyloidosis refers to a heterogenous group of systemic diseases characterized by the presence of a misfolded protein that deposits as amyloid fibrils in the interstitium of organs and tissues. The vast majority of cases of cardiac involvement (cardiac amyloidosis-CA) are due to immunoglobulin light chain (AL) amyloidosis, or transthyretin (ATTR) amyloidosis (either in its wild-type form-ATTRwt, or variant-ATTRv). The diagnostic workup of these diseases reflects the differences in terms of aetiology. Although imaging techniques represent fundamental tools in the diagnosis and follow-up of patients CA, they present several limitations. Cardiac biomarkers, particularly natriuretic peptides and troponins, overcome most of these limitations. They can be more sensitive in the detection of early phases of the disease but, overall, they currently represent the most powerful tool to define disease stage, organ response and disease progression. There is mounting evidence regarding the use of specific laboratory biomarkers to monitor treatment response. The information provided by advanced imaging techniques should be regarded as complementary and not as substitute for that provided by laboratory biomarkers, as only these can often be able to unveil the unseen.
Chronic pain is increasingly recognized as a multidimensional condition in which neuroimmune interactions shape disease vulnerability and persistence. Among the emerging pain phenotypes, nociplastic pain (defined as an alteration of nociceptive processing in the absence of clear tissue damage or somatosensory lesion) remains mechanistically elusive and therapeutically challenging. Emerging evidence suggests that early life stress, particularly social isolation, may be a potent psychosocial stressor associated with an increased risk of nociplastic pain. However, this relationship remains incompletely understood and is largely inferred from indirect, model-dependent, or related lines of research. Preclinical and clinical studies indicate that prolonged social isolation can induce sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis, systemic low-grade inflammation, and immune changes. These changes have been shown to promote persistent microglial activation, astrocytic reactivity, and dysregulated neuron-glia communication within pain-processing regions, including the spinal dorsal horn and supraspinal affective circuits. In parallel, peripheral neuroimmune alterations, particularly involving satellite glial cells and Schwann cells may contribute to increased sensory neuron excitability and processes consistent with central sensitization. Notably, much of this evidence derives from studies on stress-related conditions, neuroinflammation, and disorders such as fibromyalgia, rather than being specific to nociplastic pain per se. Early life social isolation stress has also been associated with changes in limbic and prefrontal networks implicated in the affective components of pain, suggesting a potential interaction between emotional dysregulation and pain amplification, although causal pathways remain to be clarified. Sex-dependent differences in neuroimmune signalling further add complexity to this framework, suggesting that biological sex may influence vulnerability to isolation-induced pain states and response to glial-targeted interventions. This narrative review proposes a putative neuroimmune model linking early life social isolation stress to nociplastic pain vulnerability and persistence. By integrating evidence from stress biology, glial dysfunction, and central sensitization, we aim to outline a conceptual model that may help guide future research and inform therapeutic strategies targeting central and peripheral neuroinflammatory processes.
Healing success for fifth metatarsal fracture nonunions is challenging and hindered by risk factors for nonunion. Pulsed electromagnetic field stimulation (PEMF) promotes bone healing and can help overcome biological deficiencies in patients at risk. The current study assessed the impact of PEMF treatment to promote successful bone healing in metatarsal nonunion. A multi-center, retrospective study was conducted to evaluate PEMF treatment for fifth metatarsal fracture nonunion. Subjects undergoing treatment and eligible for treatment with PEMF (PhysioStim™ device) were enrolled. Subjects were followed for up to 12 months to determine bone healing status determined by radiographic assessment. Subjects were assessed for healing status and impact of risk factors for nonunion. Fifty-six (n=56) subjects were included in the analysis. Subjects were 89.3% female with a mean age of 59.7 years. Of the risk factors studied, 75.0% of subjects had at least 1 risk factor associated with compromised bone healing. PEMF treatment started shortly after the nonunion diagnosis, and the average time from nonunion diagnosis until successful healing was 154.7 days. Approximately 62.5% of subjects showed successful healing of their 5th metatarsal fracture by 4 months; 75.0% of subjects healed by 6 months; 91.1% of subjects healed by 12-months. The number of risk factors (up to 5 total per subject) was associated with longer heal times (p<0.02). Of the risk factors studied, only nicotine use was associated with longer healing times (p<0.03). Metatarsal nonunion subjects treated with PEMF achieved favorable time to healing despite having risk factors for compromised healing.