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  • Woman’s memoirs give fascinating insight into life in 17th-century northern England | Heritage

    Woman’s memoirs give fascinating insight into life in 17th-century northern England | Heritage

    She was a 17th-century Yorkshirewoman whose memoirs combined commentaries on major political events with local and personal details of her life. Now an academic who has studied the writings of Alice Thornton has said they provide a “northern female perspective” in contrast to the London-based diarist Samuel Pepys.

    Thornton’s memoirs contain accounts of financial catastrophe, rumours of sexual impropriety, childbirth, attempted rapes and repeated interventions by God to deliver her from an early death. Thornton lived to be 80, a remarkable age at the time.

    Two of four autobiographical volumes were discovered by Cordelia Beattie, a history professor at the University of Edinburgh. One was handed by a descendant of Thornton to Beattie’s father in a pub in Ludlow, Shropshire, and the second was unearthed in the library of Durham Cathedral.

    They have been reunited online with two other volumes that were acquired by the British Library from a private collection in 2009. A digital edition was produced earlier this year.

    Dr Alison Cullingford, Prof Suzanne Trill and Prof Cordelia Beattie look at one of Alice Thornton’s manuscripts. Photograph: Durham Cathedral

    Beattie, who has spent the past four years studying the manuscripts, said the volumes were “four versions of Thornton’s life as her circumstances changed and she looked back over the years trying to make sense of what happened”.

    Thornton was “particularly keen to restate her identity as a chaste wife and to lay the blame for the family’s downturn in fortune on various male family members, including her late husband”, she said.

    “Her writings show that, alongside domestic and familial responsibilities, early modern women were fully engaged with the political events of their day.”

    Thornton was born in Yorkshire in 1626. The family moved to Ireland seven years later, where her father became lord deputy shortly before he died. Amid the turmoil of the Irish Rebellion, the family returned to northern England, where they were caught up in the civil war. As royalists, their estates were confiscated, and parliamentarian and Scottish soldiers were billeted on their land.

    Thornton agreed to marry a parliamentarian to secure her family’s financial future. She gave birth to nine babies, later describing both the dangers of childbirth and the deaths of six of her infant children. Her husband, William, died in 1668 without a will and leaving her heavily in debt.

    Pages from Alice Thornton’s Book of Remembrances. Photograph: Durham Cathedral Library

    Her financial woes are detailed in her books, but they show her to be financially shrewd and capable of negotiating complex legal matters. “She was quite switched on and adept at managing finances,” said Beattie.

    In Book One, Thornton defends herself against rumours that she was conducting a clandestine affair with the local curate, Thomas Comber, who was not only nearly 20 years her junior but was also engaged to her 14-year-old daughter.

    “She really struggles with this because she thinks of herself as a godly woman, a chaste wife. I think she does have a good relationship with Comber, but the fact that people think she might be cheating on her husband really worried her,” said Beattie.

    Comber is later appointed dean of Durham Cathedral. “He does well for himself. But people wonder why she married off her daughter at the age of 14, and the rumour is that it’s about Alice trying to get Comber for herself.”

    Thornton also writes about two attempted rapes. One of her attackers was a captain in the Scottish army “who did swear to ravish me … but I was saved”. The second was a man whose overtures she rejected. He “laid wait to have catched me … to have forced me to marry or destroy me”.

    A one-woman play, The Remarkable Deliverances of Alice Thornton, based on her writings, prompted one audience member to describe her life as a “17th-century EastEnders”. Beattie said: “This shows that the themes explored in these manuscripts are still relevant, important and engrossing.”

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  • Intel XeSS 2 Super Resolution and Frame Generation now works on NVIDIA and AMD GPUs – TweakTown

    1. Intel XeSS 2 Super Resolution and Frame Generation now works on NVIDIA and AMD GPUs  TweakTown
    2. The latest version of Intel’s XeSS 2 now lets other GPUs run its AI-based frame generation system, throwing RTX 30-series owners a Team Blue-shaped bone  PC Gamer
    3. Intel XeSS 2.1 SDK Brings XeSS 2 Upscaling, Frame-Generation & Low-Latency Support To NVIDIA & AMD GPUs  Wccftech
    4. Intel XeSS2 now supported by AMD and NVIDIA GPUs  VideoCardz.com
    5. Intel XeSS 2.1 now supports NVIDIA and AMD GPUs  DSOGaming

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  • ‘No nosebleed, no comment from Andrew’: Prince Harry rejects explosive new Royal biography claims; sends legal notice to Daily Mail

    ‘No nosebleed, no comment from Andrew’: Prince Harry rejects explosive new Royal biography claims; sends legal notice to Daily Mail

    Prince Harry has refuted claims of a physical fight with Prince Andrew during a 2013 family gathering, where he allegedly caused his uncle’s nose to bleed.The Daily Mail published excerpts on Saturday from Andrew Lownie’s new biography, suggesting a heated argument turned physical after “Punches were thrown over something Andrew said behind Harry’s back”. The alleged fight began when “Harry told [his uncle] he was a coward not to say it to his face. Harry got the better of Andrew by all accounts, leaving him with a bloody nose before the fight was broken up.”Lownie’s book, Entitled: The Rise and Fall of the House of York, alleges Andrew made disparaging remarks about Meghan Markle, suggesting their marriage would be brief and calling her an opportunist who was too old for Harry. Andrew allegedly “accused Meghan of being an opportunist and thought she was too old for Harry, adding that his nephew was making the biggest mistake ever,” and told his nephew he had gone “bonkers”, accusing him of not doing “any due diligence into her past” before they got engaged in 2017.A spokesperson for Harry and Meghan issued a statement late Saturday categorically denying both the physical confrontation and Andrew’s alleged comments about the Duchess of Sussex. “I can confirm Prince Harry and Prince Andrew have never had a physical fight, nor did Prince Andrew ever make the comments he is alleged to have made about the Duchess of Sussex to Prince Harry.” The couple has sent legal correspondence to the Daily Mail regarding these claims, The Guardian reported.The biography suggests both Harry and William had difficult relationships with Andrew, who lost his royal and military titles in 2021 following controversy over his association with Jeffrey Epstein. The book claims Andrew also made unfavourable comments about Catherine, the Princess of Wales.King Charles continues to allow Andrew residence at the Royal Lodge, despite ending his annual £1m allowance. The biography suggests Prince William desires to remove both Andrew and Sarah Ferguson, who share the residence despite their 1996 divorce.Harry distanced himself from royal duties, citing institutional problems and alleged racism, relocating to North America in 2020. Following his 2022 memoir Spare, he expressed openness to family reconciliation in a BBC interview.


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  • Relative Importance of Disease-Modifying Antirheumatic Drug Attributes

    Relative Importance of Disease-Modifying Antirheumatic Drug Attributes

    Nabin Poudel,1,2 Jingjing Qian,2 Kimberly B Garza,2 Peng Zeng,3 Jeffrey R Curtis,4 Surachat Ngorsuraches2

    1Department of Practice, Sciences, and Health Outcomes Research (P-SHOR), University of Maryland Baltimore, Baltimore, Maryland, USA; 2Department of Health Outcomes Research and Policy, Auburn University, Harrison College of Pharmacy, Auburn, Alabama, USA; 3Department of Mathematics and Statistics, Auburn University, Mathematics and Statistics, Auburn, Alabama, USA; 4Department of Medicine – Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Correspondence: Surachat Ngorsuraches, Health Outcomes Research and Policy, Auburn University, Harrison College of Pharmacy, 4306a Walker Building, Auburn, AL, 36849, USA, Tel +1 334-844-8357, Email [email protected]

    Purpose: The significance of fatigue reduction in rheumatoid arthritis (RA) is well recognized. However, prior patient preference studies on disease-modifying antirheumatic drugs (DMARDs) have not adequately explored the relative importance of fatigue reduction compared to other DMARD attributes or accounted for preference heterogeneity. The objective of this study is to determine the relative importance of DMARD attributes, including fatigue reduction, from the patient perspective.
    Patients and Methods: We conducted a web-based discrete choice experiment (DCE) survey among RA patients in the US. Six DMARD attributes were included: chance of pain reduced by 50% or more, chance of physical function improved by 50% or more, chance of fatigue reduced by 10 points or more, chance of serious side effects, the route and frequency of administration, and out-of-pocket cost per month. Choice sets were constructed using a Bayesian efficient design. Mixed logit (ML) and latent class (LC) models were developed to determine preference weights and to calculate the conditional relative importance of each attribute.
    Results: Of 228 patients, the ML model showed that the chance of pain reduction had the highest conditional relative importance (2.4), followed by out-of-pocket cost (2.1), the chance of physical function improvement (1.6), the chance of fatigue reduction (1.5), the chance of experiencing serious adverse events (0.6), and the route and frequency of administration (0.09). Preference heterogeneity was observed. The LC model identified two patient classes. The chance of fatigue reduction and the out-of-pocket cost were the most important attributes for class 1 and class 2, respectively.
    Conclusion: Pain reduction, physical function improvement, fatigue reduction, and out-of-pocket cost were relatively important DMARD attributes for RA patients. However, the presence of preference heterogeneity underscores the need for individualized treatment. Future studies should explore fatigue preferences and generalizability in the broader RA population.

    Keywords: discrete choice experiment, fatigue, patient preference, preference heterogeneity

    Introduction

    Rheumatoid arthritis (RA) management involves disease-modifying antirheumatic drugs (DMARDs).1–3 Methotrexate, a conventional synthetic DMARDs (cDMARDs), is often used as the first-line treatment and can lead to low disease activity or remission in 25–50% of patients.3,4 However, given the progressive nature of RA, biological DMARDs (bDMARDs), and targeted synthetic DMARDs (tDMARDs) may be required as monotherapy or combination therapy for patients with RA.1

    American College of Rheumatology (ACR) recommends shared treatment decisions between clinicians and patients, considering patient preferences.5–7 A systematic review summarized the findings from eight studies on patients’ preferences for DMARDs in the US.8–15 Overall results showed that patients with RA valued treatment benefits (eg, functional improvement) over other treatment attributes (eg, side effects). African American patients placed more emphasis on the risk of toxicity and less on the potential benefits, indicating preference heterogeneity for DMARDs.8,16 However, five of these studies relied on conjoint analysis (CA), potentially lacking the ability to capture human preference.8–11,13,15 Additionally, two studies used a discrete choice experiment (DCE) to examine patient preferences but did not account for preference heterogeneity.12,14 Another study, using a DCE to evaluate the preference-based value of DMARDs and preference heterogeneity, was conducted in 2009 prior to the introduction of various DMARDs, such as subcutaneous and intravenous tocilizumab, intravenous golimumab, and oral upadacitinib.15

    Recent studies indicated that fatigue was a crucial outcome for patients with RA in the US.16–18 Specifically, the Innovation and Value Initiative (IVI) and Arthritis Foundation-led studies qualitatively interviewed patients with RA and reported that the patients factored fatigue into their choices of DMARDs. The introduction of fatigue as one of the patient-valued domains has been a landmark in RA in multiple European countries.19 However, to the best of our knowledge, previous patient preference studies never examined the relative importance of fatigue reduction as compared to other attributes from the perspective of patients with RA in the US.16 Thus, the objective of this study was to determine the relative importance of DMARD attributes, including fatigue reduction, based on the patient perspective.

    Materials and Methods

    A cross-sectional, web-based, DCE questionnaire survey was used in this study.20 The design of this study followed the User’s DCE guide and the Good Research Practices Task Force report from The Professional Society for Health Economics and Outcomes Research (ISPOR).21–23 The study protocol was approved by the Auburn University Institutional Review Board (IRB). Before commencing the survey, all participants granted their consent online and complied with the Declaration of Helsinki.

    Study Samples

    A purposive sample of RA patients were recruited through a national online QualtricsXM research panel, a market research company, between January 29 and February 10, 2023. The Qualtrics research panel consists of survey respondents who have been pre-recruited and have agreed to participate in surveys on an ongoing basis. We defined our target respondents as RA patients in the US who were 18 years and older, proficient in English and used DMARDs. Additionally, to further ensure the accuracy of the RA diagnosis, we included only patients who met our screening criteria, those who reported a physician diagnosed RA and had taken DMARDs at any point prior to the survey. QualtricsXM distributed the survey hosted on the Qualtrics platform, exclusively to panelists whose self-reported profile information matched the study’s inclusion criteria, until we met our target sample size. This targeted recruitment approach helped ensure relevance while introducing some selection limitations due to reliance on a pre-existing panel. Based on the best research practices, at least 200 patients were deemed appropriate for the study sample size.21,24,25 The final dataset, including responses from over 200 participants, was delivered in an anonymized format for analysis. Participants were compensated for their time by QualtricsXM.

    Study Attributes and Levels

    Supplemental materials Appendix I (Table S1–Table S5) lists important DMARD-related attributes generated from the systematic literature search process. Prior DCE/conjoint analysis studies (Supplemental materials Appendix II Table S1) also informed our attribute selection. Based on the literature review and one-on-one interview with five purposely sampled RA patients (no new information was generated from the fifth patient) and a rheumatologist, six important attributes were selected. Essentially, these attributes included the benefits, risks, route and frequency of administration, and the cost of DMARDs. Clinical knowledge, literature, and qualitative interviews (ie, one-on-one interviews) were used to ensure independence of attribute. The levels of all attributes, except cost, were obtained from the clinical trials of DMARDs gathered from the Drugs@FDA.26 The levels of the cost attribute were based on the willingness-to-pay estimates obtained from our pilot study. Table 1 lists the attributes and levels included.

    Table 1 Attributes and Levels for the Discrete Choice Experiments (DCE) Survey Instrument

    Survey Development

    The survey was built on a QualtricsXM web-based platform. A Bayesian efficient design was used to draw 36 choice tasks from all possible combinations of the selected attributes and levels.22,27 Prior parameters were obtained from a pilot study with 30 patients with RA. These 36 choice tasks were divided into four blocks. Each choice task consisted of two unlabeled alternatives describing hypothetical DMARDs: Medication A or Medication B. Patients with RA were asked to choose one of these hypothetical medications and then were allowed to choose neither medication A nor medication B to resemble real-world choices. An example of the DCE choice set is presented in Figure 1. The survey incorporated two validity check choice tasks: a within-task dominant alternative (a medication with the highest benefits, lowest risks, and lowest cost) and a repeated choice task to assess the stability of patient responses. Questions on patient characteristics and RA experiences were also added to the survey instrument.

    Figure 1 An example DCE choice set.

    Abbreviations: IV, Intravenous Infusion; SC, Subcutaneous Injection.

    Notes: Preference weights on the y-axis represent the relative utility or importance of each attribute level shown on the x-axis. Higher weights indicate greater preference. Preference weights were derived from β estimates of the mixed logit model. A Wald test assessed statistical differences between attribute levels; *Denotes statistical significance at the 5% level. For example, preferences for $75 per month were significantly lower than $25 per month, while there was no difference in preferences for $0 and $25 per month. The strongest drivers of patient choice were treatment benefits, particularly pain reduction followed by cost and physical function improvement, indicating a strong desire for improved quality of life. While serious side effects were a concern, patients were willing to accept higher risks for more effective or affordable treatments. Fatigue reduction also emerged as a meaningful driver, underscoring the need to consider broader impacts of RA on daily functioning. Preference heterogeneity (not displayed in the figure) was assessed by evaluating the significance of the random parameter (see Supplemental Material, Appendix III, Table S1). Model fit statistics: Akaike Information Criterion (AIC) = 3190.2, McFadden Pseudo R- squared = 0.31.

    To ensure the patient understood the study attributes, lay language was used, and a tutorial with clear explanations and practice questions was provided. The effectiveness of the lay language and tutorial was assessed using follow-up questions administered after the explanation of each attribute level. If a respondent answered incorrectly, the correct response was displayed along with a brief explanation to reinforce comprehension. A “cheap talk” script (non-binding communication between the researcher and respondents to encourage greater effort and attention to the preference-elicitation task) was incorporated to enhance survey response validity.15 The survey was reviewed by a clinical expert and two social scientists and then validated with five RA patients using the think-aloud method until no new insights emerged. Finally, the survey was piloted-tested with 30 patients recruited through the QualtricsXM panel. Based on pilot study feedback, adjustments were made, such as setting the maximum cost attribute to $150 per month and reducing the number of practice questions for each attribute from three to two to reduce cognitive burden.

    Data Analysis

    The demographic characteristics of the patients were descriptively analyzed. Mixed logit (ML) and latent class (LC) models were developed to examine preference weights and preference heterogeneity. Effect coding was applied, and participants who chose neither Medication A nor Medication B were treated as selecting a third, opt-out alternative. The general form of the utility function (Unsj) of the ML model was: and for the LC model was . For ML model, Unsj is a utility function relating to individual n and alternative j on the choice set s. Xnsjk is a full vector of observed attributes relating to individual n and alternative j on the choice set s, and βk is a vector of individual-specific coefficients of attribute k. ήnk is a random error term whose distribution depends on alternative j and individual n. τnj is an error distribution that did not depend on underlying parameters or data. The variation in the estimated mean of the coefficients across individuals reflected preference heterogeneity.28 Each individual was assumed to have their own set of preferences, which were modeled as random coefficients. Similarly, for the LC model, in addition to the previously defined notations, c represents the number of classes (unknown to the researchers) defined by using various model fit parameters, eg, Akaike Information Criteria (AIC). ԑnsj|c is a class-specific error term whose distribution depended on alternative j and individual n. The LC model assumed that individual behavior depended on observable attributes and latent heterogeneity that differed from factors unobserved by researchers.29 As the focus of this study was to identify distinct preference pattern across subgroup without underlying decision variability, scale adjustment was not performed for the LC analysis for simplicity. The conditional relative importance for each attribute was determined by comparing the change in preference weights between its most and least favorable levels.

    Results

    The responses from 228 patients were included in the analysis. These patients correctly responded to the validity choice tasks. Table 2 shows their demographic characteristics. The average age of these patients was 50.3 (SD 13.7) years, and the average disease duration was 33.2 (SD 9.2) years. Most patients were female (82.5%) and white (87.7%). Most had less than a 4-year college degree (81.4%). All participants used at least one DMARD. Most patients correctly answered the practice questions assessing their understanding of the attributes and levels, including attributes and levels of pain (85.1%), physical function (74.6%), fatigue (93.4%), serious side effects (87.3%), and the method of DMARD administration (95.2%), indicating that respondents comprehended the survey content.

    Table 2 Demographic characteristics of the RA patients

    Preference Weights of the DMARD Attributes from the ML Model

    Figure 2 illustrates the preference weights for the study attributes from the ML model. The preference weights of all attributes and their levels, except the chance of fatigue reduced by 10 points or more, were in the expected directions. Higher chances of pain reduced, and physical function improved by 50% or more, along with the lower chance of serious side effects and lower out-of-pocket cost, had higher preference weights. The adjacent levels of the chances of pain reduced and physical function improved by 50% or more were significantly different. The differences in the preference weights for the chances of serious side effects at 0% and 3%, as well as for the out-of-pocket cost at $0 (no cost) and $25 per month, were not significant. No adjacent level of the route and frequency of administration attribute was significantly different. A kink (unexpected sharp change) in preferences for increasing the chance of fatigue reduction was observed. Patients showed a significant preference for a 30% chance of fatigue reduction over a 10% chance. However, the preference weight for a 70% chance of fatigue reduction was lower than a 30% chance.

    Figure 2 Preference weights of attributes of DMARDs from the mixed logit model.

    Abbreviations: IV, Intravenous Infusion, SC, Subcutaneous Injection.

    Note: Latent class analysis identified two distinct patient classes based on model fit statistics (Akaike Information Criterion (AIC)) and interpretability. Preference weights on the y-axis represent the relative utility or importance of each attribute level shown on the x-axis. Higher weights indicate greater preference. Preference weights were derived from β estimates of a latent class model. A Wald test assessed statistical differences between attribute levels; * denotes statistical significance at the 5% level. For example, for class 1 (A), preferences for $75 per month were significantly lower than $25 per month, while there was no difference in preferences for $0 and $25 per month. Both Class 1 (A) and Class 2 (B) prioritized pain reduction and lower out-of-pocket costs. However, Class 1 patients emphasized the importance of a lower risk of serious side effects and favored IV infusion, while Class 2 (B) patients preferred lower risk of serious side effects and preferred oral versus injectable DMARDs. These differences in preferences across class highlight preference heterogeneity and the need for shared decision-making regarding the efficacy, affordability and administration of DMARDs. Model fit statistics: Akaike Information Criterion (AIC) = 2960, McFadden Pseudo R- squared = 0.36.

    The highest conditional relative importance estimate was attributed to the chance of pain reduced by 50% or more (2.4), followed by the out-of-pocket cost (2.1), the chance of physical function improved by 50% or more (1.6), the chance fatigue reduced by 10 points or more (1.5), the chance of experiencing severe adverse events (0.6), and the administration of the medication (0.09). The standard deviations of the preference weights of all attributes were statistically significant, indicating the presence of preference heterogeneity for these study attributes. For details, see supplemental material Appendix III (Table S1).

    Preference Weights of the DMARDs Attributes from the LC Model

    Based on the AIC values, the best LC model suggested two distinct classes. Figure 3 displays the preference weights of DMARD attributes for RA patients in both classes. Similar to the results of the ML model, the preference weights for all attributes, except the chance of fatigue reduced by 10 points or more, in both classes tended to have expected directions. In class 1, all adjacent levels of the chance of pain reduction differed significantly. Only the difference between the preference weights of medications offering a 10% chance and a 30% chance of physical function improved by 50% or more was significant. All adjacent levels of the out-of-pocket cost, except the difference between the preference weights of $0 and $25 per month, were significantly different. Adjacent level of 3% and 10% chance of serious side effects was significantly different. IV infusion every six- or 12-month or every four- or eight week had significantly higher preference weights than subcutaneous injection every 1 or two weeks. In class 2, all adjacent levels of the chance of pain reduction, physical function improvement, and serious side effects differed significantly. All adjacent levels of the out-of-pocket cost, except the difference between the preference weights of $0 and $25 per month, were significantly different. Oral, daily medications had a significantly higher preference weight than the subcutaneous injection of every one- or two-week. A kink in preferences for increasing the chance of fatigue reduction for this class mirrored the ML results. Compared with a 10% chance of fatigue reduction, patients significantly preferred a 30% chance. There was a significant reduction in the preference weight between medications, offering a 70% chance of fatigue reduction compared to a 30% chance.

    Figure 3 Continued.

    Figure 3 Preference weights of attributes of DMARDs from the latent class model.

    In class 1, the conditional relative importance estimate of the chance of fatigue reduced by 10 points or more was the highest (2.5), followed by the chance of pain reduced by 50% or more (1.8), the out-of-pocket cost (1.6), the chance of physical function improved by 50% or more (1.3), the administration of medication (0.5), and the chance of serious side effects (0.5). In class 2, the highest conditional relative importance estimate was the out-of-pocket cost attribute (2.3), the chance of pain reduced by 50% or more (1.4), the chance of fatigue reduced by 10 points or more (1.3), the chance of physical function improved by 50% or more (1.3), the administration of medication (1.1), and the chance of serious side effects (0.8). For details, see supplemental material Appendix III (Table S2).

    Discussions

    RA patients preferred DMARDs that provided greater chances of pain reduction and physical function improvement (treatment benefits), a lower chance of severe side effects, and a lower out-of-pocket cost. These findings were consistent with the findings of previous studies.30–32 Interestingly, although patients with RA assigned a greater preference weight to a 30% chance of fatigue reduction compared to a 10% chance, their lower preference weight for a 70% chance of fatigue reduction compared to a 30% chance was counterintuitive. This pattern may reflect a diminishing marginal value of fatigue reduction with additional units of fatigue reduction.33 Given the long disease duration among our study participants (mean duration of RA = 33 years), it is possible that many had adapted to living with chronic fatigue. As a result, once fatigue levels are perceived as manageable, additional reductions may not significantly enhance quality of life. Additional analyses, exploring the interaction between the chance of physical function improvement and the chance of reduction in fatigue (see supplemental material Appendix IV: Figures S1 and S2), revealed that, for each of the three levels of chance of physical function improvement, a 30% chance of reduction in fatigue had a higher preference weight than a 10% chance. Only for a 30% chance of physical function improvement, the preference weight was marginally significant for a 70% chance of reduction in fatigue compared to a 30% chance of reduction. These results suggested that patients with RA exhibited similar preferences for a 30% chance and a 70% chance of reduction in fatigue when DMARDs provided either a low or high chance of physical function improvement. It was plausible that when DMARDs performed well and improved physical function, patients might view the reduction in fatigue as just only an additional benefit, and this benefit might no longer be a priority. Conversely, a high chance of fatigue reduction might not be important for RA patients if DMARDs performed poorly in improving physical function since the patients might focus more on the effects of DMARDs on physical activity. This could likely explain the counterintuitive shift in the preference weight from a 30% to a 70% chance of a reduction in fatigue in the main ML model.

    The ML results revealed a statistically significant and positive alternative-specific constant, suggesting that, on average, respondents exhibited a preference for taking medication over choosing neither option. There was no variation in preference weights across different levels of the route and frequency of administration. Previous studies, despite heterogeneity, suggested that patients with RA in the US generally favored oral treatments over SC injections or IV infusions and preferred less frequent administration over more frequent administration.9,12–14 Although our findings could not be directly compared to the findings of these previous US-based DCE studies—since the levels of the route and frequency of administration differed across these studies—one possible reason might be that RA patients might trade between convenience resulting from a lower frequency of administration and inconvenience from the injection for this study attribute.

    Several choice-based studies investigated the conditional relative importance of DMARD attributes in the US.8–15 The conditional relative importance of the chance of pain reduction, followed by out-of-pocket cost, physical function improvement, and serious side effects, in this study was in line with the previous study findings. A strong preference for treatment benefits might stem from a patient’s desire to attain a normal life by experiencing symptom relief and enhanced capacity to engage in daily activities.34 This sentiment was also captured in the current treatment guidelines with a strong recommendation for a treat-to-target to achieve low disease activity or remission.35 Although patients favored a lower chance of a serious side effect, this attribute was relatively less important to treatment benefits or cost, implying patients’ willingness to accept a treatment with a higher risk for greater treatment for higher benefits or lower cost of treatment. Notably, we used a generic term for the serious side effects (chance of serious side effects). However, previous studies suggested that the level of details of risk descriptions (eg, chance of cancer) did not affect the hierarchical order of the attribute importance.12,30 Additionally, we observed a heterogeneity of preference, which indicated the presence of RA patients with varying degrees of risk tolerance. This heterogeneity underscored that RA treatments should be customized to meet individuals’ risk-taking levels and align with their preferences.

    The chance of fatigue reduction significantly impacted the patients’ choices of DMARDs. These findings were consistent with the findings of various studies indicating that fatigue could affect as many as 80%–98% of patients with RA, causing significant disruption and distress that had a detrimental effect on their quality of life.16,36–39 Previous qualitative studies suggested that fatigue could be as important as improving pain and physical function.32,34,40–42 Its importance was slightly lower than physical function improvement, aligning with a UK study where pain and mobility were prioritized over fatigue.43

    For LC analysis, two distinct patient classes were identified based on model fit statistics (Akaike Information Criterion (AIC)) and interpretability. Patients in class 1 demonstrated a general preference for initiating treatment, favoring taking medication over opting out of treatment altogether. In contrast, individuals in class 2 showed a tendency to avoid treatment, preferring neither of the available medication options. Both classes considered pain reduction and out-of-pocket costs among the most important attributes. According to previous studies, greater importance was expected for the treatment benefits, such as the chance of pain reduction.32,44 Despite having insurance, a larger number of older age people (average age 50 years) who were not employed (58%) and had less than $50,000 in annual income (58%) in this study might be the reasons for the greater importance given by the patients to the cost attribute. These results suggested the need for shared decision-making among the patients and providers regarding the affordability of DMARDs.45

    Interestingly, the relative importance of fatigue reduction was highest for class 1. It was possible that persistent fatigue might limit their ability to work, engage in social activities, or maintain independence. Additionally, statistically non-significant, consistent with prior studies, patients in this class preferred lower levels of serious side effects.13 They might be aware of side effect of medication given higher education level among these group (Supplemental materials Appendix III Table S3). They also favored IV infusion over SC injection or oral, daily medication. The greater preference weight given to IV therapy might be attributed to a reluctance to self-inject and less frequent dosing requirements.46 For patients in class 2, the preference weights significantly decreased with the increased chance of serious side effects. These findings suggested that patients in class 2 were more sensitive to the serious side effects. Similar to some previous studies, they were reluctant to use injectable DMARDs.8,11,47 It was possible that these patients might have different levels of awareness and experience with DMARDs, and therefore, they were concerned about the side effects and the treatment injection. Additionally, it is important to note that variation across classes may be influenced not only by true differences in preferences but also by differences in response consistency among two subgroups. Therefore, observed heterogeneity in this study should be interpreted in light of potential differences in how consistently individuals engage with the choice tasks.

    This study had several implications for making treatment decisions. First, even though most RA patients had health insurance coverage, the out-of-pocket cost remained one of the most important factors influencing treatment preferences. Thus, clinicians should provide patients with comparative out-of-pocket cost information while making a treatment decision.11 Second, this study confirmed that the RA patients weighed the importance of the chance of fatigue improvement, so clinicians should assess the impact of DMARDs on the fatigue of their patients to improve their quality of life.48 Third, risk-benefit trade-offs may be more acceptable to patients who are educated and informed in their treatment choices, highlighting the importance of patient education. Furthermore, the existence of diverse preferences among patients reinforced that treatment decisions should be tailored to individual patients, considering their preferences through a shared decision-making process.

    Our study had limitations. First, the patients were recruited from QualtricsXM panel, primarily white, female, highly educated, and had RA for approximately 32 years potentially limiting the generalizability to the broader RA population in the US. The dynamic effects of disease duration, racial differences, prior DMARD exposure, and disease activity on patient preferences for RA treatments should be considered while interpreting our results.8 Second, patient preferences were derived from hypothetical treatment options, which might not fully reflect real-world behavior. Third, the use of a self-administered, web-based questionnaire to identify RA patients might also introduce the possibility of response bias due to misdiagnosis and misinterpreting attribute levels. However, various measures, such as an expert review and the inclusion of validity check choice sets, were implemented to minimize this bias. Fourth, only six treatment attributes were included, although other treatment attributes could influence patient preferences. Finally, although it is the best practice to also include RA patients who did not correctly respond to the validity choice questions and perform analysis using statistical control,49 given the lack of availability of data on these patients from QualtricsXM, only those RA patients who provided a valid response were included in the analyses.

    Conclusions

    This study provided a deeper understanding of the DMARD attributes that were important to patients with RA. Patients with RA tended to weigh the importance of the benefits, including fatigue reduction, and out-of-pocket cost higher than the serious side effects and the route and frequency of administration of DMARDs. However, preference heterogeneity was present, implying each patient’s need for individualized treatments. Future studies should further investigate the counterintuitive preferences for improvements in fatigue, as well as examine preference and scale heterogeneity across diverse groups of RA patients to enhance generalizability.

    Data Sharing Statement

    All data are available upon reasonable request.

    Ethics

    This study was approved by the Auburn University Institutional Review Board (IRB). Protocol number 22-372 EX 2210.

    Acknowledgments

    This paper is based on the dissertation of [Poudel N]. It has been published on the institutional website: https://auetd.auburn.edu/handle/10415/8889

    Author Contributions

    All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

    Funding

    No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

    Disclosure

    JRC declare to receive grants/contracts from AbbVie, Amgen, BMS, Janssen, Lilly, Novartis, Pfizer, Sanofi, Setpoint, and UCB. JRC declare to receive consulting fees from AbbVie, Amgen, AQTUAL, Janssen, Lilly, Novartis, Moderna, Pfizer, Sanofi, Setpoint, and UCB. KBG and JRC receive support from NIH P30AR072583. All other authors declare no conflict of interest.

    References

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    31. Zartab S, Nikfar S, Karimpour-Fard N, et al. A systematic review of discrete choice experiment studies in rheumatoid arthritis biological medicines. Mediterr J Rheumatol. 2021;32(2):104–111. doi:10.31138/mjr.32.2.104

    32. Durand C, Eldoma M, Marshall DA, Bansback N, Hazlewood GS. Patient preferences for disease-modifying antirheumatic drug treatment in rheumatoid arthritis: a systematic review. J Rheumatol. 2020;47(2):176–187. doi:10.3899/jrheum.181165

    33. Rachlin H. Diminishing marginal value as delay discounting. J Exp Analysis Behav. 1992;57(3):407–415. doi:10.1901/jeab.1992.57-407

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    36. Chauffier K, Salliot C, Berenbaum F, Sellam J. Effect of biotherapies on fatigue in rheumatoid arthritis: a systematic review of the literature and meta-analysis. Rheumatology. 2012;51(1):60–68. doi:10.1093/rheumatology/ker162

    37. Hewlett S, Cockshott Z, Byron M, et al. Patients’ perceptions of fatigue in rheumatoid arthritis: overwhelming, uncontrollable, ignored. Arthritis Care & Res. 2005;53(5):697–702. doi:10.1002/art.21450

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    41. Sanderson T, Hewlett S, Richards P, Morris M, Calnan M. Utilizing qualitative data from nominal groups: exploring the influences on treatment outcome prioritization with rheumatoid arthritis patients. J Health Psychol. 2012;17(1):132–142. doi:10.1177/1359105311410758

    42. van TuylLH, Sadlonova M, Hewlett S, et al. The patient perspective on absence of disease activity in rheumatoid arthritis: a survey to identify key domains of patient-perceived remission. Ann Rheum Dis. 2017;76(5):855–861. doi:10.1136/annrheumdis-2016-209835

    43. Stamuli E, Torgerson D, Northgraves M, Ronaldson S, Cherry L. Identifying the primary outcome for a randomised controlled trial in rheumatoid arthritis: the role of a discrete choice experiment. J Foot Ankle Res. 2017;10(1):57. doi:10.1186/s13047-017-0240-3

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  • Glymphatic system dysfunction in elderly patients with comorbid late-o

    Glymphatic system dysfunction in elderly patients with comorbid late-o

    Introduction

    Epilepsy incidence rises significantly during late adulthood, peaking among individuals over 50 years of age at nearly double that of young adults.1 The majority of elderly individuals diagnosed with late-onset epilepsy (LOE) exhibit risk factors for seizures such as neurovascular trauma, tumor, encephalitis, or other brain injuries,2 but over one quarter of LOE cases remain without an identifiable etiology despite extensive diagnostic evaluations, termed late-onset epilepsy of unknown etiology (LOEU).3 Recent studies have demonstrated that LOE is independently associated with cognitive decline and increased risk of dementia, particularly Alzheimer’s disease (AD).4 According to epidemiological data, roughly 30% of LOEU patients with active seizures exhibit deposition of amyloid-β (Aβ) and hyperphosphorylated Tau protein, the core neuropathological signs of AD.5 Consequently, it is now acknowledged that LOEU may be a prodromal phase of AD. These findings suggest a potential chain effect wherein amyloidosis acts as a critical intermediary in the bidirectional exacerbation of LOE and AD.

    Chronic insomnia is defined as difficulty falling asleep, maintaining sleep, and (or) awakening early in the morning, and often leads to fatigue, attention deficits, and emotional instability during the daytime.6 Sleep disturbances, including chronic insomnia, are highly prevalent among patients with LOE.7 Seizures alone can reduce sleep efficiency and total sleep duration while exacerbating sleep fragmentation,8 and this chronic insomnia or sleep deprivation may in turn worsen seizure control.9 Moreover, both epileptic activity and chronic insomnia accelerate brain Aβ plaque deposition,10 suggesting that LOEU and chronic insomnia can act synergistically to accelerate age-related neurodegeneration and cognitive decline.

    The glymphatic system (GS) is the primary clearance pathway for metabolic waste products in the central nervous system (CNS) and so is implicated in numerous disorders associated with the accumulation of neurotoxic byproducts such as AD and epilepsy.11,12 The clearance of waste products by the GS is mediated by glial cells expressing aquaporin-4 (AQP-4) water channels that direct the flow of cerebrospinal fluid (CSF) from the arterial perivascular space to the interstitial compartment and subsequently into surrounding veins, deep cervical lymphatic vessels, and meningeal lymphatic vessels, providing a bulk-flow pathway for movement of metabolic waste from the interstitium to the systemic circulation.13 Animal experiments have demonstrated that impaired GS function results in the accumulation of Aβ and tau proteins within the CNS parenchyma,14 suggesting that GS dysfunction may link LOE, chronic insomnia, and cognitive impairment. Notably, preclinical intervention studies have demonstrated that accelerating GS clearance can reduce epileptic discharge frequency and improve cognitive performance.15

    Extending these findings to humans requires a non-invasive and safe method for the assessment of GS function. Taoka et al16 introduced diffusion tensor image analysis along the perivascular space (DTI-ALPS) as a novel method to assess the efficiency of GS function in clinical studies.17,18 The DTI-ALPS index measures water molecule movement within the perivascular space (PVS) by quantifying diffusivity19 and is based on the premise that the PVS is predominantly oriented orthogonally to white matter association and projection tracts located near the body of the lateral ventricle.19 The DTI-ALPS index is then calculated based on the diffusion coefficients of projection fibers along the x-axis (Dxxproj) plus association fibers along the x-axis (Dxxassoc), and is further refined by incorporating the diffusion coefficients of association fibers along the z-axis and well as projection fibers along the y-axis.19 Consequently, a lower DTI-ALPS index value signifies reduced PVS diffusivity, which may in turn indicate GS dysfunction. This method eliminates the need for tracer injection while still demonstrating strong intergroup consistency.

    However, despite numerous studies on the contributions of the GS to diverse age-related neurodegenerative diseases,20,21 there is limited research on the associations of GS function with LOE and comorbidities. Furthermore, the plasma Aβ42: Aβ40 concentration ratio (Aβ42/40), a biomarker of brain amyloid plaque load and AD risk, may also indicate elevated LOE risk.22 Therefore, the current retrospective study investigated the potential contributions of GS dysfunction to LOE with comorbid chronic insomnia by evaluating associations of the DTI-ALPS index with various clinical markers and age-associated cognitive decline.

    Methods

    Participants

    Associations among epilepsy, the DTI-ALPS index, sleep quality, plasma Aβ42/40, and cognitive deficits were assessed by retrospectively reviewing the clinical findings of LOE patients (n = 42) enrolled from our hospital’s epilepsy center from January 2022 to October 2024. Selection criteria for newly diagnosed LOE with or without chronic insomnia were as follows: (1) age 50 years old and older; (2) meeting 2017 ILAE diagnostic criteria for LOE;23 (3) chronic insomnia compliant according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5);24 (4) no evident responsible lesions for epilepsy (eg, tumors, cortical or lobar injuries) identified upon visual evaluation of routine 3.0-T brain magnetic resonance imaging (MRI) scans; (5) DTI data of sufficient quality for quantitative analysis; (6) no systemic or mental illnesses; (7) clinical data including cognitive, sleep, and neuropsychological assessments. In addition, healthy controls (HCs, n = 22) matched for sex ratio and age distribution and demonstrating no evidence of severe structural lesions on brain 3.0-T MRI scans were enrolled from the hospitalization database. All participants were right-handed.

    Clinical Evaluations

    General cognitive function was assessed using the Chinese version of the Mini-Mental State Examination (MMSE),25 while anxiety was assessed using the Hamilton Anxiety Scale (HAMA), insomnia by the Pittsburgh Sleep Quality Index (PSQI), and depression using the Hamilton Depression Scale (HAMD).

    It is worth noting that the MMSE scales have been authorized from PAR Inc. Reproduced with explicit permission from the Publisher, Psychological Assessment Resources, Inc. (PAR), located at 16204 North Florida Avenue, Lutz, Florida 33549. This material is excerpted from the MMSE developed by Marshal Folstein and Susan Folstein. Copyright 1975, 1998, 2001 by Mini Mental LLC, Inc. First published in 2001 by PAR. Unauthorized reproduction or distribution without the prior written consent of PAR is strictly prohibited. For copyright inquiries, please contact [[email protected]].

    Quantification of Plasma Aβ42/Aβ40 Concentrations

    Peripheral blood samples were collected from all participants in anticoagulant tubes the morning after an overnight fast and centrifuged for 10 min at 4000 g to isolate plasma. Plasma samples was stored at −80°C until analysis. Concentrations of Aβ42 and Aβ40 were measured using digital immunoassay technology (Simoa) on an HD-X analyzer (Quanterix Corp., Billerica, MA, USA). Plasma samples were diluted fourfold as per the manufacturer’s protocol for the Human Neuro 3-Plex A kit (Quanterix, #101995).

    MRI Acquisition and Processing

    Diffusion tensor images were acquired from all participants using a 3.0-T MRI scanner (GE Healthcare) equipped with a 32-channel head coil. Images were obtained by a single echo planar imaging (EPI) sequence of the following parameters: 32 diffusion-weighted directions; b-values of 0 and 1000 s/mm2; flip angle of 90°; repetition time (TR) = 8620 ms; matrix size, 120 × 120; echo time (TE) = 85 ms; slice thickness of 2.25 mm; field of view (FOV) of 240×240 mm2; interslice gap of 1 mm.

    Images data were processed using the 2021 version of DSI Studio Software (available at http://dsi-studio.labsolver.org). The DTI-ALPS index was calculated using established protocols (Figure 1). Briefly, the processing pipeline encompassed opening source images, correcting for vortex and phase distortion artifacts, determining processing parameters (smoothing, thresholds, defragmentation, etc.), recreating the DTI data, and fiber tracking. The left hemisphere projection fibers (Dxxproj) and association fibers (Dxxassoc) at the lateral ventricle body level were selected to define 5-mm diameter regions of interest (ROIs). Subsequently, fiber orientations and diffusivities were extracted from the ROIs along the x-, y-, and z-axes at the voxel level. The ROIs with the highest directional coherence were selected for each fiber type (projection, subcortical fibers, association, etc.) based on the same diffusivity along the x-axis. The DTI-ALPS index was then computed according to the formula,


    Figure 1 The process for obtaining DTI analysis along the perivascular space index. (A) Place the region of interests in the areas with projection and association fibers. (B) The direction of the paravascular space (gray columns) and the orientation of the three neural fiber tracts. (C) The directions of the projection fiber tracts (blue; z-axis), association fibers tracts (green, Y-axis), and subcortical fibers tracts (red, X-axis). (D) Flowchart illustrating the process of calculating DTI-ALPS index.

    where the numerators Dxxproj and Dxxassoci are the diffusivities of the projection and association fibers along the x-axis, and the denominators Dyyproj and Dzzassoc are the diffusivities of the projection fibers along the y-axis and association fibers along the z-axis, respectively.

    Statistical Analysis

    Group differences in categorical variables were evaluated by chi-squared tests, while group differences in continuous variables were evaluated by analysis of variance (ANOVA). Associations between the DTI-ALPS index and clinical parameters (age, PSQI, scores of MMSE, HAMA and HAMD, Aβ42/40, and frequency and duration of seizures) were evaluated by calculating Spearman correlation coefficients. Diffusivities along fiber axes were corrected for multiple comparisons using the Bonferroni method (P =0.05/9 =0.0055). Independent risk factors associated with the DTI-ALPS index were identified by linear regression models. MedCalc® Statistical Software (version 20) and GraphPad Prism (version 7) were employed for statistical analyses and mapping, respectively. A P < 0.05 (two-tailed) was considered statistically significant for all tests.

    Results

    Clinical Characteristics of Participants

    The LOE group (n = 42) included 25 patients without chronic insomnia and 17 patients with chronic insomnia. Average age, sex ratio, mean years of education, and cerebrovascular risk factors did not differ significantly among LOE patient subgroups and HCs (Table 1). As expected, PSQI scores were significantly higher among LOE patients with chronic insomnia than patients without chronic insomnia and HCs (P < 0.05). In addition, both HAMD and HAMA scores were higher, while MMSE scores were lower in the comorbid LOE subgroup (P < 0.05). Thus, the comorbid subgroup exhibited more severe symptoms of depression, anxiety, and cognitive decline. Moreover, both the frequency and duration of seizures were higher in the chronic insomnia subgroup (P < 0.05). However, antiseizure medication load did not differ between LOE subgroups (P > 0.05). The Aβ42/40 was lower in the chronic insomnia subgroup compared to LOE patients with normal sleep, suggest that comorbid patients were at higher risk of AD.

    Table 1 Demographic and Clinical Characteristics of LOE Patients and Healthy Controls

    Comparative Analysis of Diffusivities and the DTI-ALPS Index

    Table 2 summarizes the fiber diffusion coefficients along the x-, y-, and z-axes as well as the DTI-ALPS indices for all groups. Dxxproj was significantly lower in LOE patients than HCs while Dxxassoc, Dyyassoc, and Dzzproj did not differ among groups. The DTI-ALPS index was significantly lower in LOE patients than HCs. Additionally, the DTI-ALPS index was lower among comorbid LOE patients than LOE patients without comorbid chronic insomnia.

    Table 2 Comparison of the Diffusivities Among LOE Patients and HCs

    Correlation Analysis

    There was a significant negative correlation between the DTI-ALPS index and age for the entire participant cohort (r = −0.700, P < 0.001, Figure 2A). In the total LOE patient group, there were significant positive correlations between DTI-ALPS index and both Aβ42/40 (r=0.752, P < 0.001, Figure 2B) and MMSE score (r = 0.803, P < 0.001, Figure 2C). There were also significant negative correlations between DTI-ALPS index and disease duration (r = −0.026, P < 0.001, Figure 2D), HAMA score (r = −0.725, P < 0.001, Figure 2E), and PSQI score (r = −0.786, P <0.001, Figure 2F).

    Figure 2 Linear correlation between DTI-Alps index and clinical indicators. (A) Negative correlation between the DTI-ALPS index and ages in all participants. (B) Positive correlation between the DTI-ALPS index and Aβ42/40 in LOE patients. (C) Positive correlation between DTI-ALPS index and MMSE scores in LOE patients. (D) Negative correlation between DTI-ALPS index and seizure duration in LOE patients. (E) Negative correlation between the DTI-ALPS index and HAMA scores. (F) Negative correlation between the DTI-ALPS index and PSQI scores.

    Linear regression model 1 controlling for education level and sex identified a significant independent association between DTI-ALPS and age (β = −0.751, P < 0.001) (Table 3). Model 2 controlling for neuropsychological scores and both frequency and duration of seizures revealed significant independent associations between DTI-ALPS index and age (β = −0.139, P = 0.015), Aβ42/40 (β = 0.238, P = 0.014), MMSE (β = 0.222, P = 0.010), and PSQI score (β = −0.192, P = 0.020), and these associations remained significant in linear regression model 3 adjusted for cerebrovascular risk factors (age, β = −0.109 and P = 0.039; Aβ42/40, β = 0.294 and P = 0.035; MMSE, β = 0.273 and P = 0.025; PSQI, β = −0.338 and P = 0.043).

    Table 3 The Multivariable Linear Regression for the DTI-ALPS Index in LOE Patients

    Discussion

    This study is the first to explore potential GS dysfunction in LOE complicated by chronic insomnia using the DTI-ALPS index. The DTI-ALPS index was significantly lower in LOE patients than HCs and even lower among patients with comorbid chronic insomnia, suggesting that sleep disruption among LOE patients may be associated with GS dysfunction. Additionally, a negative correlation was observed between the DTI-ALPS index and epilepsy duration, indicating a gradual deterioration in GS function during disease progression. Moreover, the DTI-ALPS index was negatively associated with age across all participants, implying that GS function diminishes with age even in the absence of overt pathology. While the DTI-ALPS index was not associated with depression or anxiety among LOE patients, a lower index was associated with greater plaque load as evidenced by the plasma Aβ42/40 ratio. Collectively, these findings suggest that GS dysfunction may ultimately enhance AD risk in LOE patients. Causal associations among DTI-ALPS index, epilepsy severity, insomnia, and AD risk warrant future study.

    An age-related decline in GS activity is implicated in several neurodegenerative conditions, including AD.26 Further, LOE patients are more susceptible to cognitive impairments than age-matched controls, suggesting that LOE may exacerbate the underlying neuropathology.5,27 Increases in tau phosphorylation and Aβ deposition have been detected in LOE patients28 and further implicated in epileptogenicity. Effective nighttime sleep enhances glymphatic clearance, thereby reducing pathological burden.29 However, in LOE with comorbid chronic insomnia, the decline in sleep efficiency may reduce glymphatic clearance of metabolic waste products,30 potentially worsening the neuropathologies underlying epileptogenesis and cognitive decline. Notably, pathogenic Aβ deposition may also disrupt the sleep–wake cycle,31 thereby triggering a mutually reinforcing cycle of progressively worsening sleep disruption and Aβ deposition. Glymphatic system insufficiency may also contribute to epileptogenesis long before the deposition of insoluble Aβ.32 Sleep disorders and abnormal electroencephalogram (EEG) activity are often among the earliest signs of dementia.33 Additionally, recurrent epileptic seizures compromise the integrity of the blood-brain barrier (BBB), resulting in the accumulation of peripheral proinflammatory cytokines in the CNS and triggering potentially neurodegenerative inflammation. Loss of BBB integrity also shifts the intracellular and extracellular ion concentrations in the CSF, contributing to cerebral edema.34 Aquaporin-4 helps mitigate brain edema by facilitating CSF-interstitial fluid (ISF) exchange via GS flow, restoring ionic balance.34,35 Downregulation of AQP-4 expression and ensuing disruption of ionic homeostasis following seizure activity may further compound GS dysfunction and increase AD risk. For instance, administration of the AQO-4 inhibitor TGN-20 to mice markedly diminished lymphatic CSF-ISF exchange and enhanced amyloid deposition,36 suggesting that the AQP-4 protein as a promising therapeutic target for neurodegenerative conditions like LOE and AD.37 In summary, age-associated reductions in CSF production, proinflammatory/anti-inflammatory imbalances, epileptiform seizure-induced brain edema, and diminished expression or localization of astrocytic AQP-4 may collectively disrupt CSF-ISF flow and reduce the efficiency of metabolic waste removal from the brain.

    Extensive studies have corroborated DTI-ALPS detection technology as an effective tool for evaluating GS function. Among its advantages are high sensitivity to molecular micro-motion, non-invasive detection capabilities, and a relatively brief scanning time, making it particularly suitable for clinical application. Clinical investigations of epilepsy in particular, including focal epilepsy, refractory epilepsy, as well as status epilepticus (SE),12,38 have revealed a strong association between a reduced DTI-ALPS index and impaired GS function. Notably, the DTI-ALPS index was reported to rise significantly in both ASM responders and postoperative patients receiving epilepsy surgery compared to pretreatment baseline.39 Furthermore, Yu et al recently reported lower DTI-ALPS indices among elderly chronic insomnia patients, and even greater reductions among those exhibiting cognitive decline.40 In fact, others have reported that shorter N2 sleep duration is both predictive of increased epileptic activity and an independent factor influencing DTI-ALPS decline.41 However, no previous study had evaluated alterations in GS function among LOE patients with comorbid chronic insomnia. In the current study, the DTI-ALPS index was positively associated MMSE score (implying that lower DTI-ALPS predicts poorer cognition) and negatively associated with Aβ42/40 and PSQI scores (implying that lower DTI-ALPS predicts greater pathological load and poorer sleep). This study thus highlights the importance of cognitive assessment in studies of epilepsy. Moreover, the DTI-ALPS index was negatively correlated with epilepsy duration, implying that a longer disease course and more numerous epileptic seizures may progressively exacerbate GS impairment, that GS dysfunction results in epilepsy progression, or that both processes are mutually reinforcing. Based on these findings, we hypothesize that GS function acts as a crucial mechanism for mitigating cognitive decline and reducing the risk of AD in LOE patients. These findings strongly suggest that enhancing GS function may serve as a promising therapeutic approach for managing epilepsy and associated comorbidities.42 In support of this notion, knockout of the Trpm4 gene and treatment with glibenclamide both promoted earlier recovery of GS function and brain edema following SE in mice, and these effects were accompanied by reduced phosphorylated tau protein accumulation and improved cognitive outcomes.42

    This study has several limitations. First, the limited sample size and single-center retrospective design limit applicability to other clinical populations and preclude the investigation of other potentially significant associations. However, the same MRI scanner was utilized to maintain inter-data comparability. Second, some LOE patients may exhibit mild white matter lesions or brain atrophy undetectable by DTI that could nonetheless affect the DTI-ALPS index calculation. Third, it is possible that ASM may activate the GS, consequently influencing the DTI-ALPS index. Also, some ASMs can indirectly improve sleep, thereby reducing comorbid psychiatric disorders43 as well as seizures. Therefore, the clinical value of ASMs for improving sleep in LOE patients requires further investigation. Fourth, the retrospective design and lack of follow-up preclude drawing definitive causal associations between GS dysfunction and cognitive decline in LOE patients. Last, other sleep disorder types such as obstructive sleep apnea (OSA), REM sleep behavior disorder, and parasomnia may be associated with GS dysfunction.44 Given that our study only evaluated LOE comorbid with chronic insomnia, we cannot not rule out the potential confounding effects of these other sleep disorders.

    Conclusions

    Measurements of DTI-ALPS revealed weaker GS activity in LOE patients with chronic insomnia. Further, GS insufficiency was associated with more severe disease phenotype, greater AD risk, and cognitive decline, suggesting that the GS is a promising therapeutic target for age-related diseases.

    Data Sharing Statement

    The data generated and analyzed during the current study are not publicly accessible owing to patient privacy considerations but can be obtained from the corresponding author upon reasonable request.

    Ethics Statement and Consent to Participate

    The principles outlined in the 2013 revision of the Helsinki Declaration were strictly complied with in this study. The Ethics Committee of the Second People’s Hospital of Hefei issued an approval for the research protocol. As the present study was retrospective, our Institutional Review Board waived the written informed consent. The data of the participants would be anonymized or kept confidential, without infringing upon any of their rights and interests.

    Acknowledgments

    Natural Science Foundation project of Bengbu Medical University (No. 2025byzd0373) offered support to this study together with the Hefei Second People’s Hospital Doctoral Special Research Fund (Grant No. 2025bszx11).

    Disclosure

    The authors report no conflicts of interest in this work.

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    26. Cullell N, Caruana G, Elias-Mas A, et al. Glymphatic system clearance and Alzheimer’s disease risk: a CSF proteome-wide study. Alzheimers Res Ther. 2025;17(1):31. doi:10.1186/s13195-024-01612-7

    27. Kamondi A, Grigg-Damberger M, Loscher W, et al. Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums. Nat Rev Neurol. 2024;20(3):162–182. doi:10.1038/s41582-024-00932-4

    28. Sen A, Jette N, Husain M, et al. Epilepsy in older people. Lancet. 2020;395(10225):735–748. doi:10.1016/S0140-6736(19)33064-8

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    30. Xiong R, Feng J, Zhu H, et al. Quantitative evaluation of dynamic glymphatic activity in insomnia: a contrast-enhanced synthetic MRI study. Sleep Med. 2025;127:16–23. doi:10.1016/j.sleep.2024.12.038

    31. Lucey BP, Mawuenyega KG, Patterson BW, et al. Associations between beta-amyloid kinetics and the beta-amyloid diurnal pattern in the central nervous system. JAMA Neurol. 2017;74(2):207–215. doi:10.1001/jamaneurol.2016.4202

    32. Mao R, Hu M, Liu X, et al. Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer’s disease. Cell Commun Signal. 2024;22(1):147. doi:10.1186/s12964-024-01528-7

    33. Devulder A, Vanderlinden G, Van Langenhoven L, et al. Epileptic activity on foramen ovale electrodes is associated with sleep and tau pathology in Alzheimer’s disease. Brain. 2025;148(2):506–520. doi:10.1093/brain/awae231

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    38. Lee DA, Lee J, Park KM. Glymphatic system impairment in patients with status epilepticus. Neuroradiology. 2022;64(12):2335–2342. doi:10.1007/s00234-022-03018-4

    39. Lee DA, Ko J, Kim ST, et al. The association between structural connectivity and anti-seizure medication response in patients with temporal lobe epilepsy. Epilepsia Open. 2024;9(6):2408–2418. doi:10.1002/epi4.13076

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    41. Loddo G, Baldassarri L, Zenesini C, et al. Seizures with paroxysmal arousals in sleep-related hypermotor epilepsy (SHE): dissecting epilepsy from NREM parasomnias. Epilepsia. 2020;61(10):2194–2202. doi:10.1111/epi.16659

    42. Liu K, Zhu J, Chang Y, et al. Attenuation of cerebral edema facilitates recovery of glymphatic system function after status epilepticus. JCI Insight. 2021;6(17):e151835. doi:10.1172/jci.insight.151835

    43. Liguori C, Toledo M, Kothare S, et al. Effects of anti-seizure medications on sleep architecture and daytime sleepiness in patients with epilepsy: a literature review. Sleep Med Rev. 2021;60:101559. doi:10.1016/j.smrv.2021.101559

    44. Yang Z, Gong S, Zhang J, et al. Sleep disturbances are related to glymphatic dysfunction in blepharospasm. Neuroscience. 2025;573:S0306–4522(25)00246–5.

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  • Far-right Israeli minister Ben-Gvir’s al-Aqsa visit triggers backlash – Euronews.com

    1. Far-right Israeli minister Ben-Gvir’s al-Aqsa visit triggers backlash  Euronews.com
    2. Israeli minister sparks anger by praying at sensitive Jerusalem holy site  BBC
    3. ‘Shameless actions’: Pakistan condemns Israeli ministers storming Al-Aqsa mosque  Dawn
    4. Israel-Gaza war: anger grows over Israeli far-right minister praying at al-Aqsa mosque – as it happened  The Guardian
    5. Far-right Israeli minister prays at Jerusalem’s most sensitive holy site, breaching decades-old agreement  CNN

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  • Victoria police criticised for Gaza protest tactics while thousands marched ‘freely’ in Sydney | Victorian politics

    Victoria police criticised for Gaza protest tactics while thousands marched ‘freely’ in Sydney | Victorian politics

    An organiser of a pro-Palestine protest in Melbourne’s CBD says demonstrators were left “traumatised and confused” after police blocked their path at King Street Bridge – while thousands in New South Wales were able to march across the Sydney Harbour Bridge.

    Tasnim Sammak from Free Palestine Coalition Naarm told Guardian Australia police did not inform protest organisers they were going to block the bridge before they arrived on Sunday afternoon.

    Police had previously urged protesters to change their plans, claiming that blocking King Street Bridge – a major thoroughfare into Melbourne’s CBD – could delay emergency services and put lives at risk.

    Sammak estimated about 25,000 people protesting against the ongoing starvation in Gaza and demanding a ceasefire marched from the State Library of Victoria through the city to the bridge and were “shocked” to be met by a “heavy police presence”.

    “It was a huge display of force by Victoria police against civilians and against members of the public who have been protesting for over 90 weeks in Melbourne,” Sammak said.

    Images showed police in riot gear behind barricades on King Street Bridge, backed by a row of mounted officers and riot squad vans.

    Sammak said protesters initially sat down at the bridge crossing, with footage showing fellow organiser Mohammad Sharab urging the crowd to remain calm.

    “We are sitting here for Palestine … peacefully,” Sharab said.

    Police mostly stood behind their shields, says Jordan van den Lamb, who attended the rally. Photograph: Con Chronis/EPA

    “We have women, children, vulnerable people.”

    Jordan van den Lamb, a Victorian Socialists candidate known online as PurplePingers, attended the protest. He said he was “shocked” to turn on to King Street and see the bridge closed and police “kitted out in riot gear, shields, horses, armoured vehicles, the lot”.

    “I think they assumed that if they shut down the bridge, the protest would be less visible but really it’s drawn more attention to the protest,” van den Lamb said.

    “It would have just been done in half an hour if they hadn’t closed the bridge. It’s a bit stupid of them, really.”

    Sign up: AU Breaking News email

    He said police mostly stood silently behind their shields, with the main protest dispersing around 3pm as most attenders turned back towards the State Library.

    A “small group” wearing masks and goggles stayed, van den Lamb said. Footage shows the group stopped traffic, burnt an Australian flag and spray-painted “Abolish Australia” on to Spencer Street.

    In a statement, police said about 3,000 protesters gathered at the State Library on Sunday and “despite repeated requests from police, they marched to King Street”.

    “As a result of this, Victoria police closed the King Street Bridge and diversions were put in place,” the statement said.

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    They confirmed there were no arrests but they were following up a report that an egg was thrown at a person during the protest.

    Police did not answer specific questions about how many officers were deployed or the decision-making behind blocking the bridge, citing operational reasons. They said there had been no reports made to them of disruption to emergency services.

    Sammak said protesters were left “feeling very traumatised and confused” by the police response, suggesting it was made at the “the encouragement” of the premier, Jacinta Allan.

    “The Sydney Harbour Bridge was facilitated quite freely and easily, and there was a positive atmosphere. So why in Melbourne did we have to face riot cops?” Sammak said.

    On Saturday, Allan had warned any protesters disrupting emergency services “will be dealt with swiftly”. She defended her comments on Monday, telling ABC Radio Melbourne she had been focused on “ensuring that safety wasn’t compromised”.

    Thousands of protesters marching across the Sydney Harbour Bridge during a pro-Palestinian rally on the same day. Photograph: David Gray/AFP/Getty Images

    Allan said the protest was peaceful and backed the police response. She also said there was “a small group of extremists behaving in an extreme way”.

    David Mejia-Canales, senior lawyer at the Human Rights Law Centre, said there had also been a heavy-handed response to Sydney’s protest. On Saturday, NSW police had sought an order to prohibit the protest going ahead but it was rejected by the supreme court.

    “In NSW and Victoria we are seeing how anti-protest laws from the Minns and Allan governments are emboldening heavy handed policing and the repressive treatment of protesters and attempts to shut down protests,” Mejia-Canales said.

    “Governments and police have a legal obligation to protect protesters, not punish or hinder people who are peacefully demonstrating and exercising their human right to demand justice.”

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  • EMEA Morning Briefing: Stock Futures Start Week on a Positive Note

    EMEA Morning Briefing: Stock Futures Start Week on a Positive Note

    MARKET WRAPS

    Watch For:

    No major economic events or corporate trading updates expected

    Opening Call:

    European stock futures traded higher early Monday. Asian stock benchmarks were mixed; the dollar weakened; Treasury yields were up; while oil futures and gold fell.

    Equities:

    Stock futures were up at the start of the week. The gains took hold after President Trump told reporters that he plans to name a new Federal Reserve governor this week, after Adriana Kugler stepped down Friday, as well as a new leader of the Bureau of Labor Statistics, after he fired Commissioner Erika McEntarfer on Friday following worse-than-expected jobs data. The moves could help Trump solidify his economic agenda.

    Forex:

    Trump’s firing of McEntarfer after the agency published new data showing that U.S. hiring slowed sharply this summer has deeply troubled some in the money markets.

    Trump said the data was “rigged.” The risk of actual or perceived manipulation of U.S. labor data-which could be as simple as stopping publishing some data based on the experience with environmental and health statistics-would add to volatility in financial markets, said Kieran Davies, chief macro strategist at Coolabah Capital.

    The unease also comes amid attacks on the independence of the Federal Reserve. ANZ said financial market participants highly value independence of data reporting and the move to fire McEntarfer “could justifiably be seen as another dent in the U.S. standing as the world’s economic safe haven.”

    Bonds:

    The U.S. 10-year Treasury yield’s downward momentum seems to be building, though this momentum isn’t strong for now, said UOB. On Friday, the 10-year yield fell sharply and tested the base of the weekly Ichimoku cloud, the bank added.

    For a continued decline, the 10-year yield must close below this cloud’s base, which is currently at 4.204%. If the 10-year yield breaks clearly below this key support, the focus will shift to the weekly rising trendline at 4.025%, UOB said.

    Energy:

    Oil fell amid a darkening U.S. economic outlook spurred by a wave of weak data, analysts said. “A sharply cooling U.S. jobs market and the fastest contraction in factory activity in nine months raised concerns of weaker demand” for crude oil, ANZ Research analysts said.

    Media reports that OPEC+ agreed over the weekend that the group will increase oil production by 547,000 barrels a day in September could also be weighing on oil prices.

    Metals:

    Gold edged lower in Asian trading on a likely technical correction. However, gold’s decline may be limited by rising expectations for Fed rate cuts that bolster the appeal of the nonyielding precious metal. The jobs data was “in no uncertain terms, a wake-up call,” said Fawad Razaqzada, market analyst at City Index and FOREX.com.

    “The Fed’s dual mandate includes employment, and this data screams weakness. The [Fed] doves are circling.”

    –

    Copper was slightly higher. Trade developments, including front-loading and a shift in global trade flows, continue to support industrial metal prices, ANZ Research said.

    However, copper is showing emerging signs of demand weakness amid dwindling London Metal Exchange stockpiles, the commodity strategists said.

    –

    Iron ore edged higher amid solid demand. The ferrous metal’s prices remain resilient even as markets have digested Beijing’s new focus on reducing overcapacity, Nanhua Futures said. Also, rising profit margins for steel mills will likely support sustainable production, it added.

    TODAY’S TOP HEADLINES

    It’s a Scorching Hot Summer for Deals on Wall Street. Vacation Can Wait.

    Late summer is typically one of the slowest times for dealmakers. Not this one.

    A sudden rebound in corporate tie-ups has bankers and lawyers scrambling. Vacation homes are sitting empty, families are being left in the lurch-and dealmakers are more energized than they have been in years.

    China Is Choking Supply of Critical Minerals to Western Defense Companies

    China is limiting the flow of critical minerals to Western defense manufacturers, delaying production and forcing companies to scour the world for stockpiles of the minerals needed to make everything from bullets to jet fighters.

    Earlier this year, as U.S.-China trade tensions soared, Beijing tightened the controls it places on the export of rare earths. While Beijing allowed them to start flowing after the Trump administration agreed in June to a series of trade concessions, China has maintained a lock on critical minerals for defense purposes. China supplies around 90% of the world’s rare earths and dominates the production of many other critical minerals.

    It’s a pivotal week for earnings – and a reality check for consumers battling tariffs and high prices

    Wall Street’s optimism has proven surprisingly durable – even with tariffs back in the headlines. In fact, analysts nudged third-quarter profit estimates higher in recent weeks, according to FactSet. It marked a rare uptick of 0.1% in earnings-per-share estimates for the S&P 500 companies through July – a small move, but notable given that estimates are typically reduced over time.

    Second-quarter earnings are already in for about two out of every three S&P 500 companies, and so far, 82% have topped profit expectations, FactSet said.

    Trump’s ‘Slap in the Face’ Puts Neutral Switzerland in Trade-War Crossfire

    MEZZOVICO-VIRA, Switzerland-When Nicola Tettamanti looked at his phone Friday morning, his first reaction was disbelief: Overnight, President Trump had slapped Switzerland with close to the highest tariffs of any country in the world.

    Tettamanti is the chief executive of a 55-year-old precision toolmaking business nestled in this mountain-hugged town. He had planned in the near future to expand further into the U.S. by opening an office in Indiana.

    Ukraine’s Supporters Plan New NATO Fund to Buy U.S. Weapons

    Ukraine’s supporters will set up a new NATO holding account to allow allies to buy billions of dollars of U.S. weapons for Ukraine, part of President Trump’s latest scheme to arm Kyiv, according to three Western officials.

    The creation of the new account marks the first tangible step in making Trump’s vow to have North Atlantic Treaty Organization allies pay for U.S. weapons for Ukraine a reality. Trump and NATO Secretary-General Mark Rutte announced the deal last month but didn’t provide details.

    Microsoft Is an AI Darling, but Its Core Businesses Are Booming Too

    Microsoft’s blockbuster earnings last week cemented its status as one of the biggest winners of the artificial-intelligence boom. Investors should draw additional comfort from what is happening with less fanfare elsewhere in its business.

    Outside the AI race, Microsoft is minting money from corporate customers spending on regular technology-long a sweet spot for the company.

    Write to singaporeeditors@dowjones.com

    Expected Major Events for Monday

    06:00/ROM: Jun PPI

    06:00/DEN: Jun Industrial production & new orders

    06:30/SWI: Jul CPI

    07:00/SPN: Jul Unemployment

    07:00/TUR: Jul PPI

    07:00/TUR: Jul CPI

    07:30/SWI: Jul procure.ch Purchasing Managers’ Index

    15:00/DEN: Jul Foreign Exchange & Liquidity

    All times in GMT. Powered by Onclusive and Dow Jones.

    Write to us at newsletters@dowjones.com

    We offer an enhanced version of this briefing that is optimized for viewing on mobile devices and sent directly to your email inbox. If you would like to sign up, please go to https://newsplus.wsj.com/subscriptions.

    This article is a text version of a Wall Street Journal newsletter published earlier today. 

    
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  August 04, 2025 00:25 ET (04:25 GMT)
    

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  • Perfectly timed cancer combo wipes out tumors by supercharging the immune system

    Perfectly timed cancer combo wipes out tumors by supercharging the immune system

    Head and neck squamous cell carcinomas (HNSCC) are a group of cancers that affect cells in and around our mouth and nose. With 890,000 new cases and 450,000 deaths annually, HNSCC accounts for roughly 4.5% of cancer diagnoses and deaths worldwide. Treatment options for HNSCC are very limited, so nearly half of affected patients with HNSCC die from the disease. Current therapies consist of surgery, radiotherapy and chemotherapy, which can be effective but often have limited success and significant side effects.

    To meet this unmet medical need, researchers at the University of California San Diego School of Medicine are exploring new approaches to improve the effectiveness of treatments for HNSCC. In a new study of oral cancer, a type of HNSCC, they demonstrate how precisely timing two different treatments can potentially improve treatment outcomes by protecting tumor-draining lymph nodes, which are located close to tumors and have an important role in mediating the immune system’s response to the tumor.

    The researchers found:

    • In mice with oral cancer, delivering radiation therapy that preserves tumor-draining lymph nodes then later delivering immunotherapy resulted in a complete and durable tumor response, meaning the tumors became undetectable. This happened in 15/20 mice treated with this approach.
    • The two treatments synergized to enhance migration of a specific type of immune cell, called activated CCR7+ dendritic cells, from tumors into lymph nodes. These cells helped trigger a stronger immune response to the tumor. This occurred in all treated mice.

    The study’s results could have significant implications for the treatment of HNSCC, as well as other cancers that are resistant or unresponsive to current standard treatment approaches. The research also provides valuable biological insight into the role of tumor-draining lymph nodes in cancer biology, which could have further implications for developing new therapies. While it will take further research to fully explore the potential of this timed treatment approach, the findings demonstrate the importance of optimizing the sequence and timing of therapies to maximize their benefit to the patient. The researchers are now conducting clinical trials in collaboration with investigators at Providence Earl Chiles Cancer Center to leverage these strategies to improve outcomes in head and neck cancer patients.

    The study, published in Nature Communications, was led by Robert Saddawi-Konefka, M.D., Ph.D.,PGY-8, resident physician and Joseph Califano, M.D., professor and interim chair in the Department of Otolaryngology and Iris and Matthew Strauss Chancellor’s Endowed Chair in Head and Neck Surgery at UC San Diego School of Medicine. Califano is also director of the Hanna and Mark Gleiberman Head and Neck Cancer Center at Moore’s Cancer Center. The study was supported, in part by a National Cancer Institute funded R01 grant led by. Califano and Andrew Sharabi, M.D., Ph.D., associate professor and Jacobs Chancellor’s Endowed Chair in the Department of Radiation Medicine and Applied Sciences at UC San Diego School of Medicine, as well as a member of the Head and Neck Cancer Center at Moores Cancer Center. The authors declare no competing interests.

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  • Lionel Messi injury update — When will the Argentina captain return for Inter Miami?

    Lionel Messi injury update — When will the Argentina captain return for Inter Miami?

    Inter Miami captain Lionel Messi will be sidelined indefinitely with what the Major League Soccer (MLS) team described as a ‘minor muscle injury in his right leg’ in a statement on Sunday.

    The 38-year-old Argentine legend suffered an upper right leg injury early in Miami’s penalty-kicks home win over Mexico’s Necaxa on Saturday in a Leagues Cup match.

    Messi went out in the 11th minute but walked off the field and into the locker room.

    Messi ‘underwent medical tests to evaluate the extent of the muscle discomfort’, which forced him out of the match, Inter Miami said in its statement.

    Messi leaves the pitch with a injury during the Leagues Cup Phase One match between Inter Miami CF and Club Necaxa at Chase Stadium.
    | Photo Credit:
    Getty Images via AFP

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    Messi leaves the pitch with a injury during the Leagues Cup Phase One match between Inter Miami CF and Club Necaxa at Chase Stadium.
    | Photo Credit:
    Getty Images via AFP

    ‘The results confirmed a minor muscle injury in his right leg. His medical clearance will depend on his clinical progress and response to treatment.’

    That means there is no timetable for a return by the Miami talisman, who shares the MLS season lead with 18 goals and also has nine assists in 18 matches.

    Jordi Alba, who netted an equaliser for Miami in second-half stoppage time to set up the penalty shootout the hosts won 5-4, said Messi’s early exit was “a huge sadness for the whole team.”

    Inter Miami has won 12 of 22 matches this season and — with 42 points — is fifth in the Eastern Conference, eight points adrift of leader Philadelphia but with three matches in hand.

    Any extended absence also would be a major blow for Miami in the Leagues Cup, which Inter won in 2023 just after Messi arrived in South Florida.

    Miami, which will host UNAM Pumas on Wednesday, ranks second on the MLS table to qualify for the Leagues Cup knockout stage with five points and would clinch a quarterfinal berth with a victory.

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