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Caffeine has significant effects on neurovascular activity and behavior throughout the sleep-wake cycle. We used a minimally invasive microchip/video system to continuously record effects of caffeine in the drinking water of freely behaving mice. Chronic caffeine shifted both rest and active phases by up to 2 h relative to the light-dark cycle in a dose-dependent fashion. There was a particular delay in the onset of rapid eye movement (REM) sleep as compared with non-REM sleep during the rest phase. Chronic caffeine increased wakefulness during the active phase and consolidated sleep during the rest phase; overall, there was no net change in the amount of time spent in the wake, sleep, or REM sleep states during caffeine administration. Despite these effects on wakefulness and sleep, chronic caffeine decreased mean cerebral blood volume (CBV) during the active phase and increased mean CBV during the rest phase. Chronic caffeine also increased heart rate variability in both the sleep and wake states. These results provide new insight into the effects of caffeine on the biology of the sleep-wake cycle. Increased blood flow during sleep caused by chronic caffeine may have implications for its potential neuroprotective effects through vascular mechanisms of brain waste clearance.

BackgroundMaternal migraine has been linked to adverse birth outcomes including low birth weight and preterm birth, as well as congenital anomalies in offspring. It has been speculated that this may be due to the use of medications in pregnancy, but lifestyle, genetic, hormonal, and neurochemical factors could also play a role. There is evidence for varying cancer incidences among adults with migraine. Here, we utilized data from national registries in Denmark to examine associations between maternal diagnoses of migraine and risk for cancer in offspring.MethodsWe linked several national registries in Denmark to identify cases from the Cancer Registry among children less than 20 years (diagnoses 1996–2016) and controls from the Central Population Register, matched to cases by birth year and sex (25:1 matching rate). Migraine diagnoses were identified from the National Patient Register using International Classification of Diseases, versions 8 and 10 codes and migraine-specific acute or prophylactic treatment recorded in the National Pharmaceutical Register. We used logistic regression to estimate the risk of childhood cancers associated with maternal migraine.ResultsMaternal migraine was positively associated with risk for non-Hodgkin lymphoma (odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.01–2.86), central nervous system tumors ([OR = 1.31, 95% CI: 1.02–1.68], particularly glioma [OR = 1.64, 95% CI: 1.12–2.40]), neuroblastoma (OR = 1.75, 95% CI: 1.00–3.08), and osteosarcoma (OR = 2.60, 95% CI: 1.18–5.76).ConclusionsAssociations with maternal migraine were observed for several childhood cancers, including neuronal tumors. Our findings raise questions about the role of lifestyle factors, sex hormones, genetic, and neurochemical factors in the relationship between migraine and childhood cancers.

Oxidative stress (OS) is recognized as a contributing factor in the development and progression of thyroid cancer. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor involved in against OS generated by excessive reactive oxygen species (ROS). It governs the expression of a wide array of genes implicated in detoxification and antioxidant pathways. However, studies have demonstrated that the sustained activation of Nrf2 can contribute to tumor progression and drug resistance in cancers. The expression of Nrf2 was notably elevated in papillary thyroid cancer tissues compared to normal tissues, indicating that Nrf2 may play an oncogenic role in the development of papillary thyroid cancer. Nrf2 and its downstream targets are involved in the progression of thyroid cancer by impacting the prognosis and ferroptosis. Furthermore, the inhibition of Nrf2 can increase the sensitivity of target therapy in thyroid cancer. Therefore, Nrf2 appears to be a potential therapeutic target for the treatment of thyroid cancer. This review summarized current data on Nrf2 expression in thyroid cancer, discussed the function of Nrf2 in thyroid cancer, and analyzed various strategies to inhibit Nrf2.

Abstract Quantum batteries are energy storage devices built using quantum mechanical objects, which are developed with the aim of outperforming their classical counterparts. Proposing optimal designs of quantum batteries which are able to exploit quantum advantages requires balancing the competing demands for fast charging, durable storage and effective work extraction. Here we study theoretically a bipartite quantum battery model, composed of a driven charger connected to an energy holder, within two paradigmatic cases of a driven-dissipative open quantum system: linear driving and quadratic driving. The linear battery is governed by a single exceptional point which splits the response of the battery into two regimes, one of which induces a good amount of useful work. Quadratic driving leads to a squeezed quantum battery, which generates plentiful useful work near to critical points associated with dissipative phase transitions. Our theoretical results may be realized with parametric cavities or nonlinear circuits, potentially leading to the manifestation of a quantum battery exhibiting squeezing.

Transcranial ultrasound stimulation (tUS) shows potential as a noninvasive brain stimulation (NIBS) technique, offering increased spatial precision compared to other NIBS techniques. However, its reported effects on primary motor cortex (M1) are limited. We aimed to better understand tUS effects in human M1 by performing tUS of the hand area of M1 (M1hand) during tonic muscle contraction of the index finger. Stimulation during muscle contraction was chosen because of the transcranial magnetic stimulation-induced phenomenon known as cortical silent period (cSP), in which transcranial magnetic stimulation (TMS) of M1hand involuntarily suppresses voluntary motor activity. Since cSP is widely considered an inhibitory phenomenon, it presents an ideal parallel for tUS, which has often been proposed to preferentially influence inhibitory interneurons. Recording electromyography (EMG) of the first dorsal interosseous (FDI) muscle, we investigated effects on muscle activity both during and after tUS. We found no change in FDI EMG activity concurrent with tUS stimulation. Using single-pulse TMS, we found no difference in M1 excitability before versus after sparsely repetitive tUS exposure. Using acoustic simulations in models made from structural MRI of the participants that matched the experimental setups, we estimated in-brain pressures and generated an estimate of cumulative tUS exposure experienced by M1hand for each subject. We were unable to find any correlation between cumulative M1hand exposure and M1 excitability change. We also present data that suggest a TMS-induced MEP always preceded a near-threshold cSP.

BackgroundAlthough observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine, randomized clinical trials have not met their primary efficacy endpoints.ObjectivesThe authors report the results of a pooled analysis of individual participant data from the 2 randomized trials using the Amplatzer PFO Occluder to assess the efficacy and safety of percutaneous device closure as a therapy for episodic migraine with or without aura.MethodsThe authors analyzed individual patient-level data from 2 randomized migraine trials (the PRIMA [Percutaneous Closure of Patent Foramen Ovale in Migraine With Aura] and PREMIUM [Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the Amplatzer PFO Occluder Compared to Medical Management] studies). Efficacy endpoints were mean reduction in monthly migraine days, responder rate (defined as ≥50% reduction in monthly migraine attacks), mean reduction in monthly migraine attacks, and percentage of patients who experienced complete cessation of migraine. The safety endpoint was major procedure- and device-related adverse events.ResultsAmong 337 subjects, 176 were randomized by blocks to device closure and 161 to medical treatment only. At 12-month follow-up, the analysis met 3 of the 4 efficacy endpoints: mean reduction of monthly migraine days (-3.1 days vs. -1.9 days; p = 0.02), mean reduction of monthly migraine attacks (-2.0 vs. -1.4; p = 0.01), and number of subjects who experienced complete cessation of migraine (14 [9%] vs. 1 [0.7%]; p

Abstract Snowfall forecasting has historically been an area of difficulty for operational meteorologists, particularly in regions of complex terrain, such as the western United States. Attempts at improving forecasts have been made, but skill is still poor, with snowfall routinely overpredicted. A major reason for this overprediction has been the failure to accurately predict snow–liquid ratios (SLR) ahead of major events. This research proposes, develops, and tests multiple machine learning methods for dynamic SLR prediction for the Sky Islands of southeast Arizona by objectively comparing a multiple linear regression (MLR) against several more complex and flexible machine learning methods. Input parameters for each method were chosen based on variables found by previous studies to have a regression‐based relationship with SLR, with a focus on the lower mid‐levels of the troposphere. These parameters were also used to construct the MLR model, and its performance was compared objectively with the machine learning methods. When tested on historical events, a very high percentage of the network‐predicted SLR values fall within the margin of error of observed SLRs, which were calculated using gridded snow depth and snow water equivalent (SWE) data from the University of Arizona daily 4‐km SWE, SD, and SCE dataset (UASnow). A support vector machine (SVM), a k‐nearest neighbor (KNN) algorithm, and a random forest also showed high accuracies when tested on the dataset, and each showed a significant gain in skill compared with the MLR model, with skill being evaluated by multiple metrics.

Introdução: Pseudomonas aeruginosa com resistência a carbapenêmicos é um patógeno considerado prioritário (nível crítico) pela Organização Mundial da Saúde para o desenvolvimento de novos antimicrobianos. A resistência a antimicrobianos é um problema de saúde pública crescente no Brasil, principalmente entre pacientes de unidades de terapia intensiva (UTI), se correlacionando a maior risco de mortalidade. Objetivos: Comparar a atividade de ceftolozana/tazobactam (C/T), ceftazidima/avibactam (CAZ/AVI), piperacilina/tazobactam (P/T) e meropeném (MEM) entre isolados de P. aeruginosa coletados no Brasil entre 2018 a 2021, como parte do programa de vigilância global SMART (Study for Monitoring Antimicrobial Resistance Trends). Métodos: Isolados clínicos de P. aeruginosa coletados em 9 centros do Brasil entre 2018 a 2021 foram analisados quanto à suscetibilidade para C/T, CAZ/AVI, P/T e MEM. Foram incluídos apenas isolados de amostras do trato respiratório inferior e provenientes de pacientes em UTI. A suscetibilidade antimicrobiana foi definada através do EUCAST (European Committee on Antimicrobial Susceptibility Testing) 2023. Foram considerados sensíveis os isolados com sensibilidade e sensibilidade com aumento de exposição (S + SIE), conforme padronizado pelo EUCAST. Resultados: O tamanho total da amostra foi de 268 isolados. Destes, oito isolados (3%) apresentavam produção de carbapenemases. C/T e CAZ-AVI mantiveram sensibilidade acima de 90% entre os isolados (92,9% e 91,4%, respectivamente). MEM e P/T apresentaram suscetibilidade menores que 80%: sendo 77,6% e 69%, respectivamente. Quando analisamos as cepas resistentes a P/T (n = 83), C/T foi o antibiótico com maior suscetibilidade, com 78,3% de sensibilidade; CAZ-AVI e MEM apresentaram suscetibilidade de 72,2% e 50,6%, respectivamente. Ao analisar cepas resistentes a MEM (n = 60), C/T, CAZ/AVI e P/T mantiveram suscetibilidade de 75%, 66,6% e 31,6%, respectivamente. Nas amostras resistentes a P/T e MEM concomitantemente (n = 41), C/T manteve suscetibilidade em 63,4% dos isolados, enquanto CAZ/AVI manteve 51% de sensibilidade. Em isolados resistentes a CAZ/AVI (n = 23), C/T manteve-se ativo em 30,4% das amostras. Conclusão: Dentre os antimicrobianos testados, C/T manteve a maior taxa de suscetibilidade em todos os cenários de cross-resistência testados, posicionando-se como um agente relevante entre as opções para o tratamento de pneumonias, especialmente em UTIs.

Addressing contemporary environmental and social crises requires solutions-based, systems-level changes. To achieve these changes, transdisciplinary research approaches are needed to align problem framing with solution deployment at landscape scales. However, practical frameworks to guide this work are lacking. Here we propose a new framework to help bridge this gap: regenerative landscape design (RLD). We define RLD as a process for finding pattern-based solutions, emphasizing cooperative, iterative, and facilitated engagement for the co-production of locally relevant knowledge for desirable landscape stewardship. To do so, we review how key components of RLD (e.g., landscapes, design thinking, and regenerative processes) have been differentially and unevenly applied in disciplines ranging from resilience, landscape ecology, geography, architecture, agriculture, sociology, tourism, and more. We then put forward research considerations of a RLD approach to enhance social and environmental well-being. We use two emerging case studies (i.e., Chesapeake Bay Watershed, Pennsylvania, USA and Narok County, Kenya) to put forward pathways for implementation of the RLD strategy.

The use of advanced imaging in routine diagnostic practice appears to provide only limited value in patients with migraine who have not experienced recent changes in headache characteristics or symptoms. However, advanced imaging may have potential for studying the biological manifestations and pathophysiology of migraine headaches. Migraine with aura appears to have characteristic spatiotemporal changes in structural anatomy, function, hemodynamics, metabolism, and biochemistry, whereas migraine without aura produces more subtle and complex changes. Large, controlled, multicenter imaging-based observational trials are needed to confirm the anecdotal evidence in the literature and test the scientific hypotheses thought to underscore migraine pathophysiology.

PREMISE:Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. PROBLEM:One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. CONCLUSION:This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.

Objective: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. Background: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. Methods: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health‐care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. Results: Twenty‐five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non‐pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. Conclusions: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise. Plain Language Summary: The American Headache Society led a large, international, multistakeholder process to identify headache research topics that should be prioritized during the next 10 years. With input from headache clinicians, scientists, people with headache, representatives from headache organizations, health‐care industry representatives, and the public, 25 research priorities within 8 categories were identified. These research priorities can help guide headache researchers when planning their studies and as benchmarks by which the headache field can measure its progress over time. [ABSTRACT FROM AUTHOR]

Cellular stress responses often require transcription-based activation of gene expression to promote cellular adaptation. Whether general mechanisms exist for stress-responsive gene downregulation is less clear. A recently defined mechanism enables both up- and downregulation of protein levels for distinct gene sets by the same transcription factor via coordinated induction of canonical mRNAs and long undecoded transcript isoforms (LUTIs). We analyzed parallel gene expression datasets to determine whether this mechanism contributes to the conserved Hac1-driven branch of the unfolded protein response (UPRER), indeed observing Hac1-dependent protein downregulation accompanying the upregulation of ER-related proteins that typifies UPRER activation. Proteins downregulated by Hac1-driven LUTIs include those with electron transport chain (ETC) function. Abrogated ETC function improves the fitness of UPRER-activated cells, suggesting functional importance to this regulation. We conclude that the UPRER drives large-scale proteome remodeling, including coordinated up- and downregulation of distinct protein classes, which is partly mediated by Hac1-induced LUTIs.

BACKGROUND AND PURPOSE:Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. METHODS:Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. RESULTS:Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. CONCLUSIONS:In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs is most likely because of a paradoxical embolus. Future cryptogenic stroke classification schemes should consider including PFO as a separate etiologic category.

Open quantum systems governed by non-Hermitian dynamics provide a platform to explore PT symmetric phases. Here, a general theory is derived to describe the location of exceptional points in a 1D oligomer chain of arbitrary length.

The Asia-Pacific region is extremely vulnerable to climate variability and change. This reflects high exposure to hydroclimatic hazards such as tropical cyclones, floods, droughts, and heatwaves. Rapidly growing cities and low-lying coastal zones/estuaries also face threats from sea level rise and storm surges. However, climate model projections remain very uncertain about most of these risks, so water infrastructure and operations need to consider a range of plausible futures. Against this background, the Asian Development Bank (ADB) has been developing frameworks, tools, and capacities in climate risk and adaptation assessment and management. Project teams are often operating in data-scarce situations and under significant time constraints, so the emphasis has been on creating pragmatic guidance and training resources. This paper charts the transition of climate risk management (CRM) within the ADB from a predominantly scenario-led to decision-led approach to adaptation. Examples are given of light-touch procedures for screening climate risks, strengthening the transparency and rigour of scenario analysis, raising awareness of a broad range of adaptation options, streamlining identification of CRM options, and embedding allowances for climate change in detailed engineering designs. Such practical innovations would benefit communities of practice beyond the Asia-Pacific region. HIGHLIGHTS Water infrastructure and operating rules must be adapted such that they continue to deliver intended benefits despite climate change.; The Asian Development Bank has been developing frameworks, tools, and capacity for climate risk assessment and adaptation investments.; Pragmatic procedures for screening climate risk are particularly helpful in information- and resource-constrained situations.;

BackgroundMigraine is a prevalent and disabling disorder. Patent foramen ovale (PFO) has been associated with migraine, but its role in the disorder remains poorly understood.ObjectivesThis study examined the efficacy of percutaneous PFO closure as a therapy for migraine with or without aura.MethodsThe PREMIUM (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management) was a double-blind study investigating migraine characteristics over 1 year in subjects randomized to medical therapy with a sham procedure (right heart catheterization) versus medical therapy and PFO closure with the Amplatzer PFO Occluder device (St. Jude Medical, St. Paul, Minnesota). Subjects had 6 to 14 days of migraine per month, had failed at least 3 migraine preventive medications, and had significant right-to-left shunt defined by transcranial Doppler. Primary endpoints were responder rate defined as 50% reduction in migraine attacks and adverse events. Secondary endpoints included reduction in migraine days and efficacy in patients with versus without aura.ResultsOf 1,653 subjects consented, 230 were enrolled. There was no difference in responder rate in the PFO closure (45 of 117) versus control (33 of 103) groups. One serious adverse event (transient atrial fibrillation) occurred in 205 subjects who underwent PFO closure. Subjects in the PFO closure group had a significantly greater reduction in headache days (-3.4 vs. -2.0 days/month, p = 0.025). Complete migraine remission for 1 year occurred in 10 patients (8.5%) in the treatment group versus 1 (1%) in the control group (p = 0.01).ConclusionsPFO closure did not meet the primary endpoint of reduction in responder rate in patients with frequent migraine. (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management [PREMIUM]; NCT00355056).

PurposeMigraine, particularly with aura, has been associated with ocular and systemic ischemic complications, but there are limited data on the ocular vasculature in migraine. We used optical coherence tomography angiography (OCTA) to assess perfusion of the macula and optic nerve in migraine patients, with (MA) and without (MO) aura, compared to healthy controls (HC).MethodsWe recruited 15 MA (mean age 42 years), 12 MO (mean age 46 years), and 22 HC (mean age 39 years) participants from neurology and neuro-ophthalmology clinics. Participants underwent optical coherence tomography and 3 × 3 mm OCTA of the macula and optic nerve. Foveal avascular zone area was automatically measured using AngioVue software, and vessel density was calculated as blood vessel length divided by scan area (mm-1) after skeletonization of OCTA images.ResultsOn macular OCTA, MA participants had an enlarged foveal avascular zone area when compared with HC (0.300 ± 0.019 vs. 0.220 ± 0.066 mm2, P = 0.006). In addition, superficial foveal vessel density was decreased in MA participants when compared with MO participants (7.8 ± 0.31 vs. 9.3 ± 0.44, P = 0.04) and HC (7.8 ± 0.31 vs. 9.4 ± 0.21 mm-1, P = 0.002). On optic nerve OCTA, the MA participants had reduced superior peripapillary vessel density when compared with the MO participants (12.0 ± 0.45 vs. 14.0 ± 0.38 mm-1, P = 0.031) and HC (12.0 ± 0.45 vs. 14.1 ± 0.53 mm-1, P = 0.035). There were no significant differences between the MO and HC groups.ConclusionsMigraine with, but not without, aura was associated with foveal and peripapillary vascular decrements, which may possibly mediate increased risk of ocular and systemic vascular complications in these patients. OCTA could potentially be useful as a biomarker for migraine with aura.