A class of Hamilton-Jacobi equations on Banach-Finsler manifolds

The concept of subdifferentiability is studied in the context of $C^1$ Finsler manifolds (modeled on a Banach space with a Lipschitz $C^1$ bump function). A class of Hamilton-Jacobi equations defined on $C^1$ Finsler manifolds is studied and several results related to the existence and uniqueness of viscosity solutions are obtained.Comment: 24 page

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer’s Disease: A Pragmatic Review for Clinicians

\ua9 The Author(s) 2024.This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer’s disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)—parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners

Serum TCA cycle metabolites in Lewy bodies dementia and Alzheimer's disease: Network analysis and cognitive prognosis

Se han documentado anomalías en el ciclo del ácido tricarboxílico (TCA) en la demencia. A través del análisis de redes, los metabolitos del ciclo TCA podrían reflejar indirectamente anomalías conocidas relacionadas con la demencia en las vías bioquímicas, y los metabolitos clave podrían estar asociados con el pronóstico. Este estudio analizó los metabolitos del ciclo de TCA como predictores del deterioro cognitivo en una cohorte de demencia leve y exploró las posibles interacciones con el diagnóstico de demencia con cuerpos de Lewy (LBD) o enfermedad de Alzheimer (EA) y el genotipo APOE-ε4. Se incluyeron 145 pacientes con demencia leve (LBD = 59; AD = 86). Los metabolitos del ciclo de TCA en suero se analizaron al inicio del estudio y se realizaron redes de correlación parcial. El rendimiento cognitivo se midió anualmente durante 5 años con el Mini-examen del estado mental. Los modelos Tobit de efectos mixtos longitudinales evaluaron cada metabolito de referencia como predictor del deterioro cognitivo a los 5 años. Se exploraron las interacciones APOE-ε4 y de diagnóstico. Los resultados mostraron concentraciones de metabolitos comparables en LBD y AD. Las redes corregidas de pruebas múltiples mostraron coeficientes más grandes para una correlación negativa entre piruvato-succinato y correlaciones positivas entre fumarato-malato y citrato-isocitrato tanto en LBD como en AD. En la muestra total, los modelos mixtos ajustados mostraron asociaciones significativas entre la concentración inicial de citrato y las puntuaciones longitudinales del MMSE. En los portadores de APOE-ε4, el isocitrato inicial predijo las puntuaciones del MMSE. Concluimos que, en la demencia leve, las concentraciones de citrato sérico podrían estar asociadas con el deterioro cognitivo posterior, así como las concentraciones de isocitrato en los portadores de APOE-ε4. La regulación a la baja de la actividad enzimática en la primera mitad del ciclo TCA (deshidrogenasas descarboxiladoras), con regulación al alza en la segunda mitad (solo deshidrogenasas), podría reflejarse indirectamente en las redes de metabolitos del ciclo TCA sérico.Q2Abnormalities in the Tri-Carboxylic-Acid (TCA) cycle have been documented in dementia. Through network analysis, TCA cycle metabolites could indirectly reflect known dementia-related abnormalities in biochemical pathways, and key metabolites might be associated with prognosis. This study analyzed TCA cycle metabolites as predictors of cognitive decline in a mild dementia cohort and explored potential interactions with the diagnosis of Lewy Body Dementia (LBD) or Alzheimer's Disease (AD) and APOE-ε4 genotype. We included 145 mild dementia patients (LBD = 59; AD = 86). Serum TCA cycle metabolites were analyzed at baseline, and partial correlation networks were conducted. Cognitive performance was measured annually over 5-years with the Mini-mental State Examination. Longitudinal mixed-effects Tobit models evaluated each baseline metabolite as a predictor of 5-year cognitive decline. APOE-ε4 and diagnostic interactions were explored. Results showed comparable metabolite concentrations in LBD and AD. Multiple testing corrected networks showed larger coefficients for a negative correlation between pyruvate – succinate and positive correlations between fumarate – malate and citrate – Isocitrate in both LBD and AD. In the total sample, adjusted mixed models showed significant associations between baseline citrate concentration and longitudinal MMSE scores. In APOE-ε4 carriers, baseline isocitrate predicted MMSE scores. We conclude that, in mild dementia, serum citrate concentrations could be associated with subsequent cognitive decline, as well as isocitrate concentrations in APOE-ε4 carriers. Downregulation of enzymatic activity in the first half of the TCA cycle (decarboxylating dehydrogenases), with upregulation in the latter half (dehydrogenases only), might be indirectly reflected in serum TCA cycle metabolites' networks.https://orcid.org/0000-0001-5832-0603https://scholar.google.com/citations?user=MrICwaMAAAAJ&hl=enhttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001429659Revista Internacional - IndexadaS

Experimental study of different silicon sensor options for the upgrade of the CMS Outer Tracker

CMS Collaboration: et al.During the high-luminosity phase of the LHC (HL-LHC), planned to start in 2027, the accelerator is expected to deliver an instantaneous peak luminosity of up to 7.5×1034 cm−2 s−1. A total integrated luminosity of 0300 or even 0400 fb−1 is foreseen to be delivered to the general purpose detectors ATLAS and CMS over a decade, thereby increasing the discovery potential of the LHC experiments significantly. The CMS detector will undergo a major upgrade for the HL-LHC, with entirely new tracking detectors consisting of an Outer Tracker and Inner Tracker. However, the new tracking system will be exposed to a significantly higher radiation than the current tracker, requiring new radiation-hard sensors. CMS initiated an extensive irradiation and measurement campaign starting in 2009 to systematically compare the properties of different silicon materials and design choices for the Outer Tracker sensors. Several test structures and sensors were designed and implemented on 18 different combinations of wafer materials, thicknesses, and production technologies. The devices were electrically characterized before and after irradiation with neutrons, and with protons of different energies, with fluences corresponding to those expected at different radii of the CMS Outer Tracker after 0300 fb−1. The tests performed include studies with β sources, lasers, and beam scans. This paper compares the performance of different options for the HL-LHC silicon sensors with a focus on silicon bulk material and thickness.The research leading to these results has received funding from the European Commission under the FP7 Research Infrastructures project AIDA, grant agreement no. 262025.Peer reviewe

Family Firms and Firm Performance: Evidence from Japan

Corrigendum: Nature Structural and Molecular Biology 16 (12), 1331 (2009) doi:10.1038/nsmb1209-1331bInternational audienceThioredoxins (Trxs) are oxidoreductase enzymes, present in all organisms, that catalyze the reduction of disulfide bonds in proteins. By applying a calibrated force to a substrate disulfide, the chemical mechanisms of Trx catalysis can be examined in detail at the single-molecule level. Here we use single-molecule force-clamp spectroscopy to explore the chemical evolution of Trx catalysis by probing the chemistry of eight different Trx enzymes. All Trxs show a characteristic Michaelis-Menten mechanism that is detected when the disulfide bond is stretched at low forces, but at high forces, two different chemical behaviors distinguish bacterial-origin from eukaryotic-origin Trxs. Eukaryotic-origin Trxs reduce disulfide bonds through a single-electron transfer reaction (SET), whereas bacterial-origin Trxs show both nucleophilic substitution (SN2) and SET reactions. A computational analysis of Trx structures identifies the evolution of the binding groove as an important factor controlling the chemistry of Trx catalysis

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

The CMS Phase-1 pixel detector upgrade

The CMS detector at the CERN LHC features a silicon pixel detector as its innermost subdetector. The original CMS pixel detector has been replaced with an upgraded pixel system (CMS Phase-1 pixel detector) in the extended year-end technical stop of the LHC in 2016/2017. The upgraded CMS pixel detector is designed to cope with the higher instantaneous luminosities that have been achieved by the LHC after the upgrades to the accelerator during the first long shutdown in 2013–2014. Compared to the original pixel detector, the upgraded detector has a better tracking performance and lower mass with four barrel layers and three endcap disks on each side to provide hit coverage up to an absolute value of pseudorapidity of 2.5. This paper describes the design and construction of the CMS Phase-1 pixel detector as well as its performance from commissioning to early operation in collision data-taking.Peer reviewe