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"Nelson, Maria"
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Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation
Background
Pharmacogenetic (PGx) testing for germline variants in the
DPYD
and
UGT1A1
genes can be used to guide fluoropyrimidine and irinotecan dosing, respectively. Despite the known association between PGx variants and chemotherapy toxicity, preemptive testing prior to chemotherapy initiation is rarely performed in routine practice.
Methods
We conducted a qualitative study of oncology clinicians to identify barriers to using preemptive PGx testing to guide chemotherapy dosing in patients with gastrointestinal malignancies. Each participant completed a semi-structured interview informed by the Consolidated Framework for Implementation Research (CFIR). Interviews were analyzed using an inductive content analysis approach.
Results
Participants included sixteen medical oncologists and nine oncology pharmacists from one academic medical center and two community hospitals in Pennsylvania. Barriers to the use of preemptive PGx testing to guide chemotherapy dosing mapped to four CFIR domains: intervention characteristics, outer setting, inner setting, and characteristics of individuals. The most prominent themes included 1) a limited evidence base, 2) a cumbersome and lengthy testing process, and 3) a lack of insurance coverage for preemptive PGx testing. Additional barriers included clinician lack of knowledge, difficulty remembering to order PGx testing for eligible patients, challenges with PGx test interpretation, a questionable impact of preemptive PGx testing on clinical care, and a lack of alternative therapeutic options for some patients found to have actionable PGx variants.
Conclusions
Successful adoption of preemptive PGx-guided chemotherapy dosing in patients with gastrointestinal malignancies will require a multifaceted effort to demonstrate clinical effectiveness while addressing the contextual factors identified in this study.
Journal Article
Maintenance tobramycin primarily affects untargeted bacteria in the CF sputum microbiome
RationaleThe most common antibiotic used to treat people with cystic fibrosis (PWCF) is inhaled tobramycin, administered as maintenance therapy for chronic Pseudomonas aeruginosa lung infections. While the effects of inhaled tobramycin on P. aeruginosa abundance and lung function diminish with continued therapy, this maintenance treatment is known to improve long-term outcomes, underscoring how little is known about why antibiotics work in CF infections, what their effects are on complex CF sputum microbiomes and how to improve these treatments.ObjectivesTo rigorously define the effect of maintenance tobramycin on CF sputum microbiome characteristics.Methods and measurementsWe collected sputum from 30 PWCF at standardised times before, during and after a single month-long course of maintenance inhaled tobramycin. We used traditional culture, quantitative PCR and metagenomic sequencing to define the dynamic effects of this treatment on sputum microbiomes, including abundance changes in both clinically targeted and untargeted bacteria, as well as functional gene categories.Main resultsCF sputum microbiota changed most markedly by 1 week of antibiotic therapy and plateaued thereafter, and this shift was largely driven by changes in non-dominant taxa. The genetically conferred functional capacities (ie, metagenomes) of subjects’ sputum communities changed little with antibiotic perturbation, despite taxonomic shifts, suggesting functional redundancy within the CF sputum microbiome.ConclusionsMaintenance treatment with inhaled tobramycin, an antibiotic with demonstrated long-term mortality benefit, primarily impacted clinically untargeted bacteria in CF sputum, highlighting the importance of monitoring the non-canonical effects of antibiotics and other treatments to accurately define and improve their clinical impact.
Journal Article
Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection
Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated in the context of its interaction with the extracellular protozoan Trypanosoma brucei brucei , to which it confers sterile immunity. We previously showed that TLF could act against an intracellular pathogen Leishmania , and here we dissected the role of TLF and its synergy with host-immune cells. Leishmania major is transmitted by Phlebotomine sand flies, which deposit the parasite intradermally into mammalian hosts, where neutrophils are the predominant phagocytes recruited to the site of infection. Once in the host, the parasites are phagocytosed and shed their surface glycoconjugates during differentiation to the mammalian-resident amastigote stage. Our data show that mice producing TLF have reduced parasite burdens when infected intradermally with metacyclic promastigotes of L . major , the infective, fly-transmitted stage. This TLF-mediated reduction in parasite burden was lost in neutrophil-depleted mice, suggesting that early recruitment of neutrophils is required for TLF-mediated killing of L . major . In vitro we find that only metacyclic promastigotes co-incubated with TLF in an acidic milieu were lysed. However, amastigotes were not killed by TLF at any pH. These findings correlated with binding experiments, revealing that labeled TLF binds specifically to the surface of metacyclic promastigotes, but not to amastigotes. Metacyclic promastigotes of L . major deficient in the synthesis of surface glycoconjugates LPG and/or PPG ( lpg1 - and lpg5A - /lpg5B - respectively) whose absence mimics the amastigote surface, were resistant to TLF-mediated lysis. We propose that TLF binds to the outer surface glycoconjugates of metacyclic promastigotes, whereupon it kills the parasite in the acidic phagosome of phagocytes. We hypothesize that resistance to TLF requires shedding of the surface glycoconjugates, which occurs several hours after phagocytosis by immune cells, creating a relatively short-lived but effective window for TLF to act against Leishmania .
Journal Article
I can listen
Good listening skills help make communicating with others a better experience. Being quiet when another person is talking allows them to pass on information more easily. It implies that the listener respects the speaker. Nodding and smiling when someone speaks can help them know they are being listened to, as well.
Book
Clinician perspectives on machine learning prognostic algorithms in the routine care of patients with cancer: a qualitative study
Purpose
Oncologists may overestimate prognosis for patients with cancer, leading to delayed or missed conversations about patients’ goals and subsequent low-quality end-of-life care. Machine learning algorithms may accurately predict mortality risk in cancer, but it is unclear how oncology clinicians would use such algorithms in practice.
Methods
The purpose of this qualitative study was to assess oncology clinicians’ perceptions on the utility and barriers of machine learning prognostic algorithms to prompt advance care planning. Participants included medical oncology physicians and advanced practice providers (APPs) practicing in tertiary and community practices within a large academic healthcare system. Transcripts were coded and analyzed inductively using NVivo software.
Results
The study included 29 oncology clinicians (19 physicians, 10 APPs) across 6 practice sites (1 tertiary, 5 community) in the USA. Fourteen participants had previously had exposure to an automated machine learning-based prognostic algorithm as part of a pragmatic randomized trial. Clinicians believed that there was utility for algorithms in validating their own intuition about prognosis and prompting conversations about patient goals and preferences. However, this enthusiasm was tempered by concerns about algorithm accuracy, over-reliance on algorithm predictions, and the ethical implications around disclosure of an algorithm prediction. There was significant variation in tolerance for false positive vs. false negative predictions.
Conclusion
While oncologists believe there are applications for advanced prognostic algorithms in routine care of patients with cancer, they are concerned about algorithm accuracy, confirmation and automation biases, and ethical issues of prognostic disclosure.
Journal Article
Heroes of the US Marines
Discusse the history of the United States Marine Corps and various heroes who have fought in different wars.
Book
A mixed methods study on factors that promote and ameliorate burnout in academic dermatologists
The burnout literature is replete with burnout score results from quantitative surveys. There is a paucity of qualitative research that seeks to understand the impact of physician stressors on work–life balance and burnout. This study aimed to identify factors that support and disrupt work–life balance, drivers of burnout, and potential solutions among academic dermatologists. The objective was to better understand factors that promote wellness and ameliorate burnout. Concurrent explanatory mixed methods consisted of scores on the Abbreviated Maslach Burnout Inventory and open-ended semi-structured telephone interviews. The results were that positive factors, such as supportive home life and satisfaction derived from academic endeavors, compete with ongoing feelings of exhaustion, frustration, and apathy. Negative stressors include the electronic medical record, insufficient staffing, administrative and clinical task burden, and perceived lack of interest from mid-level and senior health system leadership in addressing clinicians’ needs. This was a single-center academic study. As with all qualitative studies, these results may not be generalizable to all dermatologists. In addition, some participants were concerned about their anonymity. Modifiable root causes of burnout require institutional commitment to sustain the pace required by academic dermatologists.
Journal Article