流式细胞仪交叉配型对移植肾1年存活率的影响

目的：探讨流式细胞仪交叉配型（flow cytometry crossmatch, FCXM）对移植肾一年存活率的影响。方法:应用χ2检验比较FCXM阳性与阴性组间1年移植肾死亡有无差异。以“移植后1年肾脏的存活状况(是/否)”为应变量，以移植后早期排斥反应（移植后1月内发生）、血管性排斥反应、移植肾功能延迟（移植后1周内需做血液透析）、FCXM、群体抗原反应抗体(PRA)、 HLA A,B配型、HLA DR配型、供者类型（尸肾/活体供肾）、既往移植次数、免疫抑制药物的使用、血清巨细胞病毒状态、冷缺血时间、供者和受者年龄等可疑影响因素为自变量建立Logistic回归模型，探讨流式细胞仪交叉配型对移植肾1年存活有无影响。结果:258例患者平均随访时间为25个月（12～60个月），期间30例移植肾死亡，其中23例发生在移植后1年内。 χ2检验显示，FCXM阳性与阴性组间1年移植肾死亡无统计学差异（P=0.157?0）。 Logistic 回归显示，对移植肾1年死亡有影响的因素包括移植肾功能延迟（OR=8.00, P=0.001?4），供者类型为尸肾（OR=9.30, P=0.001?7）和血管排斥反应（OR=5.05, P=0.021?9）。FCXM的结果不会影响移植肾一年存活率（OR=1.60, P=0.534?6）。结论: FCXM对移植肾1年后存活尚无肯定的影响。     

Melanoma-Specific Clinical Outcomes of Inpatient Immune Checkpoint Blockade Treatment

BackgroundLittle is known about patient outcomes with advanced melanoma following inpatient initiation or continuation of immune checkpoint blockade (ICB).Methods and ResultsWe conducted a single institution retrospective case series of advanced melanoma patients who initiated ICB as an inpatient (initial inpatient cohort, n = 9), or continued ICB as an inpatient after previously starting as an outpatient (outpatient then inpatient cohort, n = 5). One patient had a partial response to ICB initiated as an inpatient, but ultimately died of melanoma after 13.5 months. Median overall survival for initial inpatient cohort was 1.0 month (95% CI: 0.2-11.2), and 1.4 months (95% CI: 0.4-58.0) for the outpatient then inpatient cohort. Three patients were alive >6 months after inpatient ICB administration.ConclusionDespite overall poor outcomes, some patients may benefit from inpatient ICB. This study provides additional information for clinicians to appropriately counsel patients on expectations following inpatient ICB.     

A Hybrid Markov Chain–von Mises Density Model for the Drug-Dosing Interval and Drug Holiday Distributions

Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9713-5) contains supplementary material, which is available to authorized users.KEY WORDS: adherence, circular distribution, compliance, dosing patterns, runs     

Maternal Consumption of Ultra-Processed Foods-Rich Diet and Perinatal Outcomes: A Systematic Review and Meta-Analysis

The consumption of ultra-processed food (UPF)-rich diets represents a potential threat to human health. Considering maternal diet adequacy during pregnancy is a major determinant for perinatal health outcomes, this study aimed to systematically review and meta-analyze studies investigating the association between maternal consumption of a UPF-rich diet and perinatal outcomes. Conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, five electronic databases and gray literature using Google Scholar and ProQuest Dissertations and Theses Global were searched up to 31 May 2022. No restrictions were applied on language and publication date. Two reviewers independently conducted the study selection and data extraction process. Meta-analysis was conducted according to the random-effects model. In total, 61 studies were included in the systematic review and the overall population comprised 698,803 women from all gestational trimesters. Meta-analysis of cohort studies showed that maternal consumption of UPF-rich diets was associated with an increased risk of gestational diabetes mellitus (odds ratio (OR): 1.48; 95% confidence interval (CI): 1.17, 1.87) and preeclampsia (OR: 1.28; 95% CI: 1.15, 1.42). Neonatal outcomes showed no association. The overall GRADE quality of the evidence for the associations was very low. The findings highlight the need to monitor and reduce UPF consumption, specifically during the gestational period, as a strategy to prevent adverse perinatal outcomes.     

Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma

Bruton’s tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11-knockout cells showed antitumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK/CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K/AKT/mTOR, and integrin signaling. Importantly, cotargeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.     

Promoting Informed Decisions About Colorectal Cancer Screening in Older Adults (PRIMED Study): a Physician Cluster Randomized Trial

BackgroundFor adults aged 76–85, guidelines recommend individualizing decision-making about whether to continue colorectal cancer (CRC) testing. These conversations can be challenging as they need to consider a patient’s CRC risk, life expectancy, and preferences.ObjectiveTo promote shared decision-making (SDM) for CRC testing decisions for older adults.DesignTwo-arm, multi-site cluster randomized trial, assigning physicians to Intervention and Comparator arms. Patients were surveyed shortly after the visit to assess outcomes. Analyses were intention-to-treat.Participants and SettingPrimary care physicians affiliated with 5 academic and community hospital networks and their patients aged 76–85 who were due for CRC testing and had a visit during the study period.InterventionsIntervention arm physicians completed a 2-h online course in SDM communication skills and received an electronic reminder of patients eligible for CRC testing shortly before the visit. Comparator arm received reminders only.Main MeasuresThe primary outcome was patient-reported SDM Process score (range 0–4 with higher scores indicating more SDM); secondary outcomes included patient-reported discussion of CRC screening, knowledge, intention, and satisfaction with the visit.Key ResultsSixty-seven physicians (Intervention n=34 and Comparator n=33) enrolled. Patient participants (n=466) were on average 79 years old, 50% with excellent or very good self-rated overall health, and 66% had one or more prior colonoscopies. Patients in the Intervention arm had higher SDM Process scores (adjusted mean difference 0.36 (95%CI (0.08, 0.64), p=0.01) than in the Comparator arm. More patients in the Intervention arm reported discussing CRC screening during the visit (72% vs. 60%, p=0.03) and had higher intention to follow through with their preferred approach (58.0% vs. 47.1, p=0.03). Knowledge scores and visit satisfaction did not differ significantly between arms.ConclusionPhysician training plus reminders were effective in increasing SDM and frequency of CRC testing discussions in an age group where SDM is essential.Trial RegistrationThe trial is registered on clinicaltrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT03959696","term_id":"NCT03959696"}}NCT03959696).Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-022-07738-4.KEY WORDS: shared decision-making, colorectal cancer screening, patient preferences/patient engagement, online training     

Exploring how pregnant women in a remote northern community select a delivery location

ObjectiveTo explore the perspectives and preferences of pregnant women receiving prenatal care in a rural community regarding delivery location.DesignExploratory qualitative research project.SettingThe La Ronge Medical Clinic in northern Saskatchewan.ParticipantsPregnant women of any parity aged 18 years or older who attended the clinic for prenatal care from March 1, 2018, to March 31, 2019, were invited to participate. The closest obstetric and surgical services are 240 km away.MethodsThis project was undertaken using semistructured interviews. The interviews were audiorecorded, transcribed, and analyzed using an inductive thematic analysis, taking into consideration both saturation and analyst triangulation. The investigators and researchers on this project were family medicine residents and faculty in a remote medical clinic.Main findingsThe factors that played a substantial role in influencing the patients’ decisions regarding delivery location included access to medical services, proximity to home community, perceptions of medical care providers, and some unique features of local hospitals. The participants largely believed they maintained their autonomy in selecting their preferred delivery location while seeking input from their prenatal care providers and families.ConclusionPregnant women in this rural community consider many factors when deciding on their delivery location. These findings can be taken into consideration by physicians when discussing with their rural patients the risks and benefits of delivery in both rural and urban centres. Barriers to local delivery should be addressed, while maintaining a woman’s autonomy to choose where she gives birth.