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High-frequency longitudinal impedances, particularly at wavenumbers k≫1/σ_{z} (where σ_{z} is the bunch length), can drive microwave instability and potentially limit the performance of modern low-emittance electron storage rings. In such rings, the coherent synchrotron radiation (CSR) emerges as a prominent contributor to these high-frequency impedances. This paper undertakes a systematic investigation into the effects of CSR on electron rings, utilizing the fourth-generation storage ring light source Elettra 2.0 and the low-energy ring of the SuperKEKB e^{+}e^{-} circular collider as illustrative examples. Our work revisits theories of microwave instability driven by CSR impedance, extending the analysis to encompass other high-frequency impedances, such as resistive wall and coherent wiggler radiation. Through instability analysis and numerical simulations conducted on the two aforementioned rings, the study explored the impact of high-frequency impedances and their combined effects with broadband impedances caused by discontinuities in vacuum chambers.

Abstract Introduction Generalized myasthenia gravis (gMG) is a rare autoimmune disease. Symptoms of gMG are diverse, and understanding of their impact on patients is limited. This qualitative study aimed to provide an in-depth exploration of patients’ daily experiences of gMG. Methods Published qualitative studies were reviewed to identify the most important signs, symptoms, and functional impacts related to the patient experience in gMG. Semi-structured hybrid concept elicitation interviews (allowing spontaneous generation of disease concepts) and cognitive debriefing interviews (assessing the validity of existing disease assessments) were conducted with clinicians and adult patients with gMG. Signs, symptoms, and impacts were reviewed to understand which were most salient (i.e., reported by at least 50% of patients, with disturbance rating 5 or higher [10-point numeric scale]); concept saturation was also assessed. The disease conceptual model was updated. Existing clinical outcomes assessments (COAs) that capture how patients feel, function, and survive were assessed. Results Interviews with patients (n = 24) identified seven new signs and symptoms and 37 new impacts compared with the literature. Concept saturation was reached. Signs and symptoms identified by patients as most important (salient) were shortness of breath, general fatigue, muscle weakness of arms, legs, and neck, dysphonia, dysarthria, trouble swallowing liquids, choking, and heat sensitivity. Patient-identified salient impacts were work life, depression, difficulty walking, grooming hair, showering, and brushing teeth, eating, personal relationships, family life, and participating in social activities. Clinicians considered ocular, respiratory, swallowing, speech/talking, and extremity function as key clinical manifestations of gMG. Patients and clinicians found clinical outcome assessments (COAs) to be conceptually relevant and comprehensive. Conclusion This research provides a holistic understanding of gMG signs, symptoms, and impacts experienced by patients, as observed by patients and clinicians. The conceptual model of gMG highlights the range of signs, symptoms, and impacts that adult patients with gMG experience in their everyday lives, emphasizing the humanistic impact and unmet needs.

Hyper-/hypoglycemic states are rare but well-established causes of hyperkinetic movements, including chorea and ballismus, usually associated with brain lesions in the basal ganglia. We report a case of hemichorea-hemiballismus (HCHB) syndrome that developed after a severe hypoglycemic episode in a 71-year-old man with poorly controlled type 2 diabetes mellitus. Uncommonly, brain MRI showed contralateral cortical-subcortical T2 and T2-FLAIR-hyperintense frontoparietal lesions, with cingulate gyrus involved, while the basal ganglia were unaffected. In patients with hypoglycemic encephalopathy associated with cortical lesions, the long-term prognosis is usually poor. Nevertheless, in our patient, the dyskinesias and the cerebral lesions progressively regressed by achieving good glycemic control. After four and 12 months, the patient’s neurological examination was normal. To our knowledge, this is the first evidence of hypoglycemic etiology of cortical HCHB syndrome, supporting recent theories that cortical circuitries may independently contribute to the pathogenesis of chorea and ballismus. This is also the first report of cingulate gyrus involvement in hypoglycemic encephalopathy. Finally, this case may indicate that a subset of patients with cortical lesions due to hypoglycemia could present a good clinical outcome, likely depending on the size of the lesions and the duration and severity of the hypoglycemic episode.

BackgroundDesigning clinical trials with the emphasis on the patient-centered approach and focusing on clinical outcomes that are meaningful to patients is viewed as a priority by drug developers, regulatory agencies, payers, clinicians, and patients. This study aimed to capture information on clinical trial endpoints that would be most important and relevant for patients with advanced breast cancer, based on patient-reported outcomes.MethodsPatients with either advanced triple-negative breast cancer [TNBC] and a maximum of two lines of systemic therapy or hormone receptor-positive/human epidermal growth factor receptor 2-negative [HR+/HER2-] breast cancer and a maximum of three lines of systemic therapy, participated in semi-structured concept elicitation interviews. Concept saturation was assessed. A sign, symptom, or impact was defined as "salient" if mentioned by ≥ 60% of participants, with an average bother rating of ≥ 5 (0-10 Scale). Participants were also asked about treatment priorities and to evaluate hypothetical scenarios showing different health-related functioning and quality-of-life treatment outcomes, using graphical representations.ResultsThirty-two participants (97% women; aged 29+ years) with TNBC (n = 17) or HR+/HER2- breast cancer (n = 15) provided generally similar reports on symptom experience, with fatigue and pain being most salient, though importance of certain treatment-related symptoms varied between the two groups. Patients reported consistent perspectives on the importance of treatment outcomes: when considering a new treatment, they prioritized efficacy of the therapy, acceptable tolerability, stability, predictability of symptoms over time, and the duration of preserved health-related quality of life and physical functioning. The meaningful difference in preserved physical functioning was 2-3 months for 46% of participants with TNBC, whereas for most participants with HR+/HER2- breast cancer it started from 6-7 months. Both groups of participants found it easier to accept some toxicity at the beginning of therapy if it was followed by improvement, as opposed to improvement followed by deterioration.ConclusionThe results may help to inform the design of patient-centered clinical trials, to interpret health-related quality of life and/or patient-reported outcomes, and to optimize care for patients with advanced breast cancer.

Abstract Background Wilson disease (WD) is a rare disease wherein copper accumulates in tissues, leading to hepatic degeneration, neurological impairments, and psychiatric symptoms. This study aimed to characterize the patient experience of WD and develop a conceptual model containing key symptoms and impacts of the disease. Results A targeted literature review was conducted to develop a preliminary conceptual model of WD that was subsequently refined through one-on-one interviews with 3 WD clinicians and finalized following concept elicitation interviews with 11 patients and 1 caregiver. The literature review returned 30 articles, from which 45 concepts (35 signs/symptoms and 10 impacts) were selected for inclusion in the preliminary conceptual model. After interviews with clinicians, the model was expanded to include 45 signs/symptoms and 14 impacts. The final comprehensive conceptual model developed after interviews with patients included 54 symptoms in total (n = 22 hepatic, n = 19 neurological, n = 13 psychiatric), and 21 impacts. Across symptoms, patients reported a high level of bother, with approximately 49% of symptoms reported by patients having an average peak bother rating of ≥ 7 out of 10 (10 = most bothersome). Patient interviews identified 2 subgroups of patients: those who experience neurological, psychiatric, and hepatic symptoms and those who experience mostly hepatic and some psychiatric symptoms, but no neurological symptoms. Conclusions This research underscores the substantial multisystemic symptoms and impacts that patients with WD describe as highly bothersome in their lives. Hepatic symptoms emerged as especially common and important to patients with WD, possibly beyond what is commonly understood in research and clinical practice. Further, the description of 2 distinct patient groups may help to inform patient management and support more targeted drug development processes.

Primary progressive apraxia of speech (PPAOS) is a progressive disorder impairing the motor speech act leaving linguistic function unattained. Although apraxia of speech frequently co-occurs with other neurodegenerative conditions, PPAOS defines a clinical syndrome where apraxia of speech is the sole or prominent symptom for much of the disease’s natural history. Mounting evidence is beginning to fully define this disease as the epiphenomenon of 4-repeat (4R) tau pathology although other pathologic signatures have been reported. Indeed, PPAOS patients generally present a parkinsonian syndrome late into their natural history mostly qualifying for either corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP). This is starting to be reflected in diagnostic criteria for PSP, namely, in the PSP speech and language (SL) subcategory; however, this inclusion is not reflected for CBS. Here, we present a single case of a patient with PPAOS and her clinical follow-up lasting 6 years, from the time she sought our attention to her death which occurred 8 years into the disease. PPAOS was the only and prominent symptom for most of the illness with extrapyramidal signs overtly presenting in the last months of its course. Clinical evaluation, imaging, genetic, and cerebrospinal fluid biomarkers all pointed toward an underlying CBD pathology, albeit the eventual anatomopathological confirmation was not performed. Had her clinical course been more suggestive of PSP, she would have qualified for criteria as PSP-SL. Our case therefore suggests the hypothetic need to discuss the broadening of the existing CBS criteria to encompass isolated PPAOS.

Social Worker’s undertake psycho-social assessments and facilitate access to evidence-informed psychological and practical supports to optimize the physical, psychological, and social wellbeing of the community members in their care. Social workers employed at an aged and community care organization undertook a review of the gray and peer reviewed literature and did not identify any existing evidence-based tools. However, 10 key domains were identified from the search. Gaps in the domains were discovered, together with the need for guidance and prompts for less experienced staff and students. Five Social Workers, using co-design principles, reviewed the domains, and added further domains from their social work practice. An evidence-based assessment tool was developed which incorporated 11 domains. The tool can be used to assess the needs of people living in the community who are older and/or have compromised health and wellbeing. Further work is required to pilot test the tool.

The Elettra synchrotron radiation facility in Trieste, Italy has been operating since 1994 and is currently the only facility operating at 2.0 or 2.4 GeV. Plans are underway to construct a new facility, Elettra 2.0, which will have improved capabilities and a wider range of experiments. The project was approved in 2017 and is expected to be operational in 2027, offering diverse beamlines for various energy ranges and advanced imaging and spectroscopy techniques. The construction will include 12 new beamlines and upgrades to existing ones. [Extracted from the article]

We describe the machine layout and major performance parameters for the FERMI FEL project funded for construction at Sincrotrone Trieste, Italy, within the next five years. The project will be the first user facility based on seeded harmonic cascade FELs, providing controlled, high peak-power pulses. With a high-brightness rf photocathode gun, and using the existing 1.2 GeV S-band linac, the facility will provide tunable output over a range from ~;100 nm to ~;10 nm, with pulse duration from 40 fs to ~; 1 ps, peak power ~;GW, and with fully variable output polarization. Initially, two FEL cascades are planned; a single-stage harmonic generation to operate > 40 nm, and a two stage cascade operating from ~;40 nm to ~;10 nm or shorter wavelength. The output is spatially and temporally coherent, with peak power in the GW range. Lasers provide modulation to the electron beam, as well as driving the photocathode and other systems, and the facility will integrate laser systems with the accelerator infrastructure, including a state-of-the-art optical timing system providing synchronization of rf signals, lasers, and x-ray pulses. Major systems and overall facility layout are described, and key performance parameters summarized.

Background: Neuroinflammation is one of the cardinal mechanisms of Alzheimer's disease (AD). with amyloid-β (Aβ) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aβ species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. Objective: We aimed to evaluate the role of the oligomeric Aβ1-42 isoform at inducing peripheral monocyte chemotaxis, and the possible involvement of TSPO in this process. Methods: In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n = 60), and comparable cognitively intact controls (n = 30) were used. Chemotaxis analyses were carried out through both μ-slide chambers and Boyden assays, using 125 pM oligomeric Aβ1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). Results: Oligomeric Aβ directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aβ-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. Conclusion: Oligomeric Aβ1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS. [ABSTRACT FROM AUTHOR]

Objective: Recruitment of a sufficiently large and representative patient sample and its retention during central nervous system (CNS) trials presents major challenges for study sponsors. Technological advances are reshaping clinical trial operations to meet these challenges, and the COVID-19 pandemic further accelerated this development. Method of Research: The International Society for CNS Clinical Trials and Methodology (ISCTM; www.isctm.org) Innovative Technologies for CNS Trials Working Group surveyed the state of technological innovations for improved recruitment and retention and assessed their promises and pitfalls. Results: Online advertisement and electronic patient registries can enhance recruitment, but challenges with sample representativeness, conversion rates from eligible prescreening to enrolled patients, data privacy and security, and patient identification remain hurdles for optimal use of these technologies. Electronic medical records (EMR) mining with artificial intelligence (AI)/machine learning (ML) methods is promising but awaits translation into trials. During the study treatment phase, technological innovations increasingly support participant retention, including adherence with the investigational treatment. Digital tools for adherence and retention support take many forms, including patient-centric communication channels between researchers and participants, real-time study reminders, and digital behavioral interventions to increase study compliance. However, such tools add technical complexities to trials, and their impact on the generalizability of results are largely unknown. Conclusion: Overall, the group found a scarcity of systematic data directly assessing the impact of technological innovations on study recruitment and retention in CNS trials, even for strategies with already high adoption, such as online recruitment. Given the added complexity and costs associated with most technological innovations, such data is needed to fully harness technologies for CNS trials and drive further adoption. [ABSTRACT FROM AUTHOR]