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Timothy Yap, MBBS, PhD, vice president and head of clinical development in the Therapeutics Discovery Division and professor in the Department of Investigational Cancer Therapeutics (Phase I Program) at The University of Texas MD Anderson Cancer Center in Houston, spoke with Cancer Discovery's Suzanne Rose about how clinical trials have evolved, the role of AI, and the challenges facing today's drug developers. His research focuses on the first-in-human and combinatorial development of molecularly targeted agents, immunotherapies, antibody drug conjugates, and radioconjugates.
As parts of the UK experience one summer heatwave after another, Suzanne Jarvis discusses a recent episode of The Vet Record Podcast focusing on heatstroke in dogs and how vets can help clients reduce the risk to their pets.
Li-Fraumeni syndrome, caused by germline TP53 pathogenic sequence variants (PSVs), is among the most penetrant hereditary cancer syndromes. With broader genetic testing and improved survivorship, more women with TP53 PSVs now seek reproductive and hormonal guidance throughout their lifespan. Yet, no evidence-based framework currently exists to support women's health care in this population. In this review, we searched the available literature and found an absence of data regarding contraception, fertility preservation, pregnancy, and menopause, resulting in inconsistent counseling and both under- and overtreatment. Drawing on analogies from other high-risk cancer syndromes and our multidisciplinary clinical experience, we present interim suggestions centered on shared decision-making, individualized hormonal management, and avoiding unnecessary interventions. These findings underscore the need for prospective studies and international registries to establish evidence-based and equitable women's health care for women with TP53 PSVs.
Immunocompromised patients, including transplant recipients, individuals receiving chemotherapy or chronic immunosuppression, and those with primary or acquired immunodeficiency, are at increased risk for severe viral infections and treatment failure due to antiviral drug resistance (ADR). In these populations, prolonged viral replication under antiviral pressure promotes the emergence of resistance-associated mutations (RAMs). ADR testing using phenotypic and genotypic approaches can support effective clinical management, particularly for clinically actionable double-stranded DNA viruses such as cytomegalovirus and herpes simplex virus. Genotypic testing offers faster turnaround time (TAT) and improved scalability but is limited to known resistance mutations. Phenotypic testing enables functional assessment of antiviral susceptibility but is labor-intensive and less widely available. This review summarizes available evidence on antiviral resistance mechanisms and testing for double-stranded DNA viruses, emphasizing both their clinical utility and current limitations.
Urinary incontinence (UI) is a prevalent health issue among older adults. Depressive symptoms often accompany UI; however, the pathways linking these conditions remain understudied. In this study, we conceptualized sleep quality as a potential mediator in the association between UI and depressive symptoms. The mental health burden of UI is anticipated to be indirectly associated with impaired sleep quality. The mediating role of sleep quality was tested in a sample of 306 older Korean Americans living in low-income senior housing (mean age = 79.4 years, range = 65-102). Regression analyses showed a significant association between UI and depressive symptoms. Mediation analysis using the Hayes PROCESS macro showed that the indirect effect of UI on depressive symptoms through sleep quality was significant (B [SE] = 0.59 [0.21], bias-corrected 95% CI = [0.20, 1.02]), accounting for approximately 24% of the total effect. The findings suggest that compromised sleep quality may serve as a potential pathway linking UI and depressive symptoms. Sleep quality should be addressed in efforts to promote the mental health of older adults experiencing UI.
Dextroamphetamine transdermal system (d-ATS) is the first and only amphetamine-based transdermal system FDA-approved for attention-deficit/hyperactivity disorder (ADHD) in adults and children aged ≥ 6 years, providing an alternative to oral stimulants. Although transdermal systems can cause local skin reactions, in the d-ATS pivotal study, no discontinuations due to patch application site reactions occurred, and discomfort/pain typically resolved within 2-4 h post-application. d-ATS is approved for five bilateral application sites (10 unique locations). This paper evaluates the pharmacokinetic (PK) bioequivalence between different application sites and summarizes dermal safety and irritation findings from four d-ATS clinical studies (studies 1-4). The application site PK bioequivalence study was a single-dose, open-label, 5-way crossover study assessing amphetamine bioavailability, discomfort, and irritation in healthy adults after a 9 h application of 20 mg/19.05 cm2 d-ATS to five distinct sites. Other studies, studies 1-4, conducted in healthy adults or patients with ADHD, evaluated dermal irritation from d-ATS alone or vs placebo under intended-use or exaggerated-use conditions. The application site PK study population included 50 patients. All 90% CIs for key exposure parameters fell within the FDA-specified bioequivalence limit of 80-125%, demonstrating bioequivalence across five application sites, with no discontinuations related to irritation or discomfort. Under intended-use conditions (site rotation consistent with approved d-ATS use; studies 1 and 2), instances of skin irritation were not clinically meaningful (≥ 3 point Bowman and Berger scale combination score). Under exaggerated-use conditions consistent with FDA guidance (studies 3 and 4), clinically meaningful irritation occurred in 55-61% of patients; 3/249 discontinued because of d-ATS-associated skin irritation, which generally resolved within 15-27 h after patch removal. d-ATS's benefits as an additional treatment option for ADHD in children, adolescents, and adults likely outweigh any minor irritation concerns. Transdermal delivery confers practical advantages, and the range of bioequivalent application sites can help minimize dermal irritation. d-ATS's efficacy has been established in prior clinical studies and published elsewhere. Overall, d-ATS represents a valuable, flexible treatment option for children and adolescents with ADHD.
In the United States, the suicide death rate for military veterans is higher than the rate for the general population. Several risk factors of suicide (e.g., housing instability) occur at elevated prevalence among veterans, and gender is a well-documented moderator of suicide. The objective of the present study was to parse factors risk for suicide attempts at the intersection of gender and housing instability among veterans. Data were from Veterans Health Administration electronic health records (EHR) from 2013 to 2017 for veterans with indicators of housing instability (n = 659,987). Because EHR did not include gender identity data, gender was defined by sex recorded in the EHR (male or female) and transgender and gender diverse (TGD) status using ICD-10 diagnosis codes related to gender dysphoria. A discrete-time survival analysis was used, with person-month as the unit of analysis, to examine correlates of suicide attempt over time within each gender group (i.e., cisgender men, cisgender women, or TGD). TGD veterans had 2 × to 3 × greater prevalence of suicide attempt than cisgender men and women veterans. Suicide attempt during follow-up was lower than suicide attempt at baseline for both cisgender men veterans and TGD veterans, however, for cisgender women veterans, suicide attempt during follow-up was greater than at baseline. Both baseline and recent suicidal ideation were strong predictors of suicide attempt during follow-up across all 3 gender groups. Utilization of social services was positively related to suicide attempt for cisgender males. Among a population of veterans with high risk for suicide (i.e., experienced housing instability), TGD veterans had the greatest prevalence of suicide attempt. Future studies are needed to determine how VA suicide prevention efforts reach TGD veterans. Social service programs may indicate acute risk, particularly cisgender men, and may benefit from greater synergy with suicide prevention efforts.
Intravascular imaging (IVI), including intravascular ultrasound and optical coherence tomography, has been associated with improved outcomes when used with angiography-guided percutaneous coronary intervention (PCI). Adoption in the United States and Europe has been limited by factors such as operator familiarity with the technology, device cost, and additional procedure time, although use is increasing. In the context of value-based care and constrained health care budgets, understanding whether the long-term clinical benefits of IVI justify its higher upfront procedural costs is essential. To evaluate the economic implications of IVI, a scoping review was performed to synthesize literature on the upfront costs and longer-term cost-effectiveness, with the aim of identifying drivers of cost-effectiveness and highlighting patient populations for whom IVI may yield greater economic benefit. Twenty-five studies published between January 2006 and October 2024 were included, with costs converted to 2023 US dollars. Across studies assessing costs alone, IVI-guided PCI was consistently associated with increased provider costs, typically 10% to 30% higher than angiography-guided PCI. However, among studies evaluating both costs and clinical outcomes, IVI was most often found to be cost effective or economically dominant over longer time horizons. Subgroup analyses suggested IVI is particularly cost effective in patients at a higher risk of adverse events, including those with complex lesions, ST-elevation myocardial infarction, diabetes, reduced ejection fraction, or chronic kidney disease. Time horizon and the assumed duration of IVI benefit were key drivers of cost-effectiveness. Overall, these findings suggest IVI may deliver long-term economic value despite higher initial procedural costs.
Licensed, ready-to-administer injectable medicines can reduce medication errors, minimise waste, and streamline perioperative workflows, but higher acquisition costs have limited uptake in England. This study evaluated the economic impact of switching selected anaesthetic and critical care medicines from conventional ampoules and vials to licensed prefilled syringes within NHS practice. An economic model compared current mixed-use practice with a hypothetical switch to 100% licensed ready-to-administer products for eight medicines: epinephrine 1 mg in 10 ml, ephedrine 30 mg, atropine 3 mg, rocuronium 100 mg in 10 ml, lidocaine (1% and 2%), and midazolam (5 mg in 5 ml and 50 mg in 50 ml). Modelled cost components included medicine acquisition, wastage, nursing preparation time, consumables and preventable adverse drug events. Preparation time reductions were interpreted as capacity release rather than workflow substitution. Deterministic sensitivity analyses explored variation in key assumptions and procurement thresholds. Under the modelling assumptions, epinephrine, ephedrine, atropine and lidocaine 2% were associated with reduced overall system costs of more than £5.3 million annually, largely driven by reduced wastage, preparation workload and modelled adverse drug events. Rocuronium and midazolam were associated with increased costs because of higher acquisition prices despite operational advantages. Sensitivity analyses did not alter the direction of findings. Substantial price reductions would be required for certain medicines to achieve cost neutrality. Licensed ready-to-administer injectable medicines can provide safety and workflow advantages and be associated with economic benefit. Acquisition cost remains a barrier, but broader adoption and market development could improve affordability.
For many people entering custody, abrupt changes in alcohol or other drug use is associated with the risk of experiencing a withdrawal syndrome. Management of withdrawal from alcohol and other drugs in a custodial setting is complicated by both a limited evidence base and structural barriers to the delivery of best practice healthcare interventions to people in custody. A multidisciplinary expert panel representing all Australian states and territories participated in a modified Delphi process. The process generated 22 recommendations to custodial services, health services and government for the management of withdrawal from alcohol and other drugs in custodial settings across five domains: screening for withdrawal risk; assessment of withdrawal; management of withdrawal; specific considerations for the care of First Nations people; and organisational support. Notable recommendations include using universal and timely assessment for withdrawal at reception to custody; using validated clinical tools and evidence-based interventions to assess and manage withdrawal syndromes; and ensuring that the safest location for withdrawal from alcohol or other drugs is provided. This statement presents best practice standards for the management of withdrawal from alcohol and other drugs in Australian custodial settings, as informed by evidence and expert consensus. Implementing the recommendations set out in this statement will improve the quality and consistency of withdrawal care provided to people entering Australian custodial settings and reduce harms associated with incarceration for people who use alcohol and other drugs. This statement has been endorsed by the Royal Australasian College of Physicians, the Australasian Professional Society on Alcohol and Other Drugs, the National Prisons Hepatitis Network, the Pharmaceutical Society of Australia and the Australian Injecting and Illicit Drug Users League. The statement is also approved as an Accepted Clinical Resource by the Royal Australian College of General Practitioners.
Colonoscopy is a diagnostic technique used for gastrointestinal tract pathologies that presents additional challenges when used in individuals with phenylketonuria (PKU). The dietary requirements for colonoscopy preparation conflict with a phenylalanine (Phe) restricted diet essential in classical PKU, and aspartame containing laxatives must also be avoided. This case study highlights the complexities of applying conventional colonoscopy protocols to patients with PKU and emphasis the importance of personalized preparation strategies that consider strict dietary requirements. A 24-year-old White British woman with classical PKU, with a Phe tolerance of 250 mg/day (5 g/day natural protein) and a consistent maintenance of blood Phe < 360 µmol/L, required an urgent colonoscopy/gastroscopy for investigation of bowel cancer. In the 3 days preceding the procedure, for the first 48 h she followed a low fibre/residue diet (avoiding fruit/vegetables), followed by 24 h of clear fluids only, omitting the Phe-free amino acid supplements. On the evening before the procedure, the first dose of a bowel preparation solution (Plenvu®, containing Macrogol 3350 but aspartame-free) was taken. Immediately, she was lightheaded, had a headache with extreme fatigue. Three hours later, she took the second dose of Plenvu®, containing aspartame (0.88 g/493 mg Phe). Her headache became intense, she felt exhausted and was unaware of her surroundings. It was unclear if the symptoms were caused by side effects associated with the bowel preparation solution or probable high Phe levels following 3 days of a very low energy diet with cessation of protein substitute, together with a high Phe intake associated with the aspartame load. Awareness of potential dietary conflicts with standard procedures, together with effective communication within and between healthcare teams, is essential to ensure patient-centered care. Developing practical guidelines and specific warnings could significantly support both patients and healthcare providers.
Seizure diaries are unreliable for tracking absence seizures, given their brief duration and subtle presentation. Ultra-long-term EEG monitoring provides a more objective alternative by capturing their characteristic spike-wave discharges. Here, we present a CNN-based approach for detecting spike-wave discharges in ultra-long-term EEG. We obtained ultra-long-term two-channel EEG recordings from patients with pharmacoresistant epilepsy participating in our ongoing PREDYct study using a subcutaneous electrode. For each patient with absence seizures, approximately 96 h of continuous EEG data was annotated. We trained and evaluated patient-specific and cross-patient CNN-based spike-wave detectors using five-fold cross-validation within the study cohort. Patient-specific detectors were applied to the full dataset to estimate probability density functions of discharge durations. We applied the UNEEG EpiSight Analyzer to the annotated data and calculated its sensitivity and false positive rate. We included five patients with a median of 2,175 h of EEG data per patient (range: 279-4,827). We annotated a median of 1,050 (695-3,332) spike-wave discharges per patient. Patient-specific detectors achieved a median AUC-ROC of 0.99 (0.98-1.00) and AUC-PR of 0.93 (0.81-0.95). Cross-patient models showed comparable performance. We detected a median of 19,249 spike-wave discharges per patient (2,763-45,442), with more short- than long-duration discharges. The UNEEG EpiSight Analyzer demonstrated high sensitivity for long discharges (>10 s), but sensitivity declined for shorter events. Patient-specific CNN-based detectors demonstrated excellent performance, and cross-patient detectors performed comparably. This pilot study supports the integration of automated spike-wave detection into long-term EEG monitoring to improve objective assessment of absence seizures.
Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), remains undiagnosed in > 90% of individuals, delaying access to timely evaluation and interventions. Self-administered digital cognitive assessments (SA-DCAs) offer scalable approaches for early detection, yet their real-world validation and clinical readiness remain uncertain. We developed a use-case-specific framework to evaluate SA-DCAs intended for community and primary-care MCI screening and applied it to a comprehensive scoping review of published evidence (2012-2025). Among 79 identified SA-DCAs, only four tools met predefined framework criteria across nine eligible studies. Common limitations included restricted population representativeness, inconsistent diagnostic performance reporting, limited biomarker anchoring, and reliance on prefiltered cohorts. Overall, the current evidence base is methodologically heterogeneous and incomplete for clinical deployment. The proposed framework characterizes requirements including anchoring strength, prevalence-adjusted performance reporting, and representative sampling establishing a foundation for advancing robust real-world evidence needed to translate SA-DCAs from research to clinical practice.
Data regarding mitral valve (MV) abscess, a severe complication of infective endocarditis, are limited. This study aimed to describe the clinical, microbiological, echocardiographic, and surgical characteristics of MV abscess. We conducted a retrospective study of adults (≥18 years) with MV abscess identified from the echocardiographic (October 2010-August 2020) and cardiothoracic surgical databases (April 2002-January 2020) at our centre. Data were obtained from electronic medical records. The primary endpoint was all-cause mortality. A total of 154 patients were included [median age 59 years, interquartile range (IQR): 47-68 years; 45% female], with a follow-up of 296 days (IQR: 6-1825 days). Native valves were affected in 69% of cases. Coagulase-negative Staphylococci (22%) were the most common pathogens, followed by Streptococci (20%), methicillin-resistant staphylococcus (16%), and methicillin-sensitive staphylococcus (14%). Surgery was performed in 146 patients, while 8 were managed conservatively. Bioprosthetic MV replacement was the common surgery (77%), and 27% required a Commando procedure. At surgery, MV abscess (64%) and abscess cavity (32%) were the predominant findings. Surgical classification specified the location and extension of the abscess, with posteromedial annulus being most commonly involved (64%). Mortality was 10% at 30 days, 33% at 1 year, and 71% during the entire follow-up period, without significant differences between native and prosthetic valve groups (P = 0.116). MV abscess is a highly morbid condition. Detailed surgical classification supports operative planning and assessment of disease extent. Despite high rates of complex surgery, mortality remains substantial, underscoring the aggressive nature of this condition.
This study aimed to examine whether employment transitions are associated with within-person variation in binge drinking and whether unemployment insurance may buffer this risk. Using 19 waves of data from the Understanding America Study (May 2020-March 2021; N = 1710) in the United States, mixed-effects models examined within-person associations between employment transitions and binge drinking days. Postestimation contrasts evaluated restorative changes associated with upward employment transitions. Shifts from secure employment to underemployment (β = 0.033, p < .10) or unemployment without benefits (β = 0.055, p < .10) were associated with more binge drinking. Loss of benefits while unemployed (β = 0.130, p < .05) and remaining unemployed without benefits (β = 0.083, p < .01) were also associated with more binge drinking. Patterns consistent with restorative changes were observed only for shifts to secure employment and not for those involving underemployment. Gaining unemployment benefits while unemployed was also associated with less binge drinking, compared to remaining unemployed without benefits (β = -0.116, p < .05). Employment transitions are differentially associated with binge drinking. Underemployment may represent a distinct state for alcohol-related risk, and unemployment insurance may mitigate binge drinking during employment insecurity.
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Adolescents and young adults with chronic health conditions often struggle to adhere to their daily oral medications. Transdiagnostic mobile health (mHealth) interventions have the potential to promote medication adherence by reaching youth at a large scale. This study aimed at designing an adaptive medication adherence mHealth intervention (Adaptive Cell Phone Support), guided by iterative feasibility, usability, and acceptability feedback. A secondary objective was to explore changes in self-reported medication adherence during a field trial. Using human-centered design methods, researchers collaborated with a community advisory board of young adult patients to conduct 3 cycles of iterative design and usability testing. Adolescents and young adults aged 15-20 years (N=22) were recruited from a large pediatric hospital to user-test the intervention. Data collection included self-report questionnaires, think-aloud usability testing, semistructured interviews, and a 3-week field trial. Quantitative measures included the mHealth App Usability Questionnaire Ease of Use and Usefulness subscales, the Theoretical Framework of Acceptability Questionnaire, and visual analogue scales assessing medication adherence, as well as enrollment and engagement metrics. Qualitative data were analyzed using rapid assessment methods to identify actionable design insights, while quantitative data were analyzed using descriptive statistics and paired-samples t tests with a Holm-Bonferroni correction. Enrollment was 63% and participants completed a mean of 67.2% (SD 23.5) of automated check-ins. Usability and acceptability ratings were relatively high across prototypes (eg, mHealth App Usability Questionnaire Ease of Use was mean 6.40, SD 0.64 for the initial prototype and mean 6.31, SD 0.61 for the third prototype, on a 7-point scale; Theoretical Framework of Acceptability was mean 4.33, SD 0.52 for the initial prototype and mean 4.50, SD 0.53 for the third prototype, on a 5-point scale). Qualitative data emphasized that the intervention was simple, easy to use, convenient, appropriate, and helpful for staying accountable for medication adherence, while also highlighting areas for improvement. Uncontrolled, 2-tailed, pre-post t tests estimated medium-sized improvements in self-reported medication adherence. However, only the percentage of time taking medications over the past month significantly increased (t21=3.26, d=0.70, 95% CI 0.22-1.16; P=.004). Integrated qualitative and quantitative results still suggest that more refinement is needed to optimize the intervention. Partnering with community members early in the development of an intervention may improve the ultimate feasibility, usability, and acceptability of digital health tools. Human-centered design offers a rapid, practical, and creative framework for identifying what works and what needs to be improved early in the lifecycle of a new intervention.
Leaflet modification is a necessary element in the armamentarium of the structural interventionalist and will remain an area of active investment in the future. Although leaflet splitting is proven, there are limitations in certain extreme cases. Although intraleaflet techniques are emerging and potentially have more broad applicability, there remain safety concerns with these techniques. The proposed systematic algorithms on aortic and mitral leaflet modification procedures can serve as a guide to structural operators when selecting the appropriate approach on the basis of anatomy, pathology, and procedural goals.
Suicide prevention is a top clinical priority in the United States, and healthcare systems are increasingly addressing adverse life circumstances and social drivers that heighten suicide risk. Within the Veterans Health Administration (VHA), Suicide Prevention Coordinators (SPCs) play a central role in identifying and supporting Veterans at risk of suicide, including efforts to address adverse social determinants of health (SDH). This study explores (1) barriers SPCs face when addressing Veterans' adverse SDH within the context of suicide prevention care and (2) strategies SPCs employ to address these barriers. We analyzed transcripts from semi-structured telephone interviews conducted with SPCs between February and May 2022 using a rapid turn-around qualitative approach informed by the Consolidated Framework for Implementation Research (CFIR). We recruited 15 SPCs using purposive sampling to ensure maximum variation by facility complexity, as defined by VHA. The CFIR-informed interview guide elicited SPCs' perspectives across multiple topics, including how SPCs connect Veterans with services to address adverse SDH within and outside of VHA, perceived challenges to these processes, and strategies used to address identified barriers. Barriers and strategies were identified across three CFIR domains. Outer setting barriers included eligibility policies and resource constraints; strategies focused on leveraging specialized VHA staff to connect Veterans with available services. Inner setting barriers included limited staff capacity and communication challenges between programs; SPCs responded by initiating improvements to referral tracking and follow-up. Barriers in the individuals (Veteran) domain included limited awareness of available services; strategies included engaging Veterans' families when feasible. These findings inform ongoing suicide prevention efforts with VHA and other healthcare systems by highlighting the importance of leveraging community resources, expanding and supporting specialized roles, engaging Veterans' families and other supports, and formalizing collaboration and communication across programs.