Abstract Previous research has noted that many persons are referred to hospice in the last days of life. The National Hospice and Palliative Care Organization collaborated with Brown Medical School ...to create the Family Evaluation of Hospice Care (FEHC) data repository. In 2005, 106,514 surveys from 631 hospices were submitted with complete data on the hospice length of stay and bereaved family member perceptions of the timing of hospice care. Of these surveys, 11.4% of family members believed that they were referred “too late” to hospice. This varied from 0 to 28.1% among the participating hospice programs with 30 or more surveys. Among those with hospice lengths of stay of less than a month, only 16.2% reported they were referred “too late.” Although the bereaved family member perceptions of the quality of end-of-life care did not vary by length of stay for each of the FEHC domains, the perception of being referred “too late” was associated with more unmet needs, higher reported concerns, and lower satisfaction. Our results suggest that family members' perception of the timing of hospice referral—not the length of stay—is associated with the quality of hospice care. This perception varies substantially among the participating hospice programs. Future research is needed to understand this variation and how hospice programs are delivering high quality of care despite short length of stay.
Abstract Context Nursing homes (NHs) are increasingly the site of hospice care. High quality of care is dependent on successful NH-hospice collaboration. Objectives To examine bereaved family ...members' perceptions of NH-hospice collaborations in terms of what they believe went well or could have been improved. Methods Focus groups were conducted with bereaved family members from five diverse geographic regions, and included participants from inner city and rural settings, with oversampling of African Americans. Results A total of 28 participants (14.8% African American, mean age 61.4 years) identified three major aspects of collaboration as important to care delivery. First, most (67.9%) voiced concerns with knowing who (NH or hospice) is responsible for which aspects of patient care. Second, nearly half (42.9%) stated concern about information coordination between the NH and hospice. Finally, 67.9% of the participants mentioned the need for hospice to advocate for high-quality care rather than their having to directly do so on behalf of their family members. Conclusion The important concerns raised by bereaved family members about NH-hospice collaboration have been incorporated into the revised Family Evaluation of Hospice Care, a post-death survey used to evaluate quality of hospice care.
Abstract Context Many family members of patients enrolled in hospice for less than seven days state that the hospice referral was made “at the right time.” Objectives To examine bereaved family ...members’ perceptions of the timing of hospice referral to identify aspects of the referral process that can be improved. Methods Open-ended interviews were conducted in seven hospice programs, interviewing bereaved family members of hospice patients who died within the first week of hospice enrollment. Results Of the 100 narrative interviews, 99 respondents stated that their family member was either referred “too late” ( n = 41) or “at the right time” ( n = 58) to hospice services. When families stated that referral was “at the right time,” their perceptions were based on the patient having refused earlier referral ( n = 8), a rapid decline in the patient’s condition resulting in the late referral ( n = 20), or a belief in all things coming together as they were meant to ( n = 11). In contrast, when families stated that referral was “too late,” their reasons were centered on concerns with the health care providers’ role in decision making ( n = 24), with the leading concerns being inadequate physician communication ( n = 7), not recognizing the patient as dying ( n = 11), or problematic hospice delays in referral from the nursing home or home health agency ( n = 4). Despite the patient refusing an earlier hospice referral, five family members believed the referral was “too late.” Conclusion Whereas family members identified expected concerns with communication, more than one in three stated an earlier hospice referral was not possible.
Melanoma is a heterogeneous tumour, but the impact of this heterogeneity upon therapeutic response is not well understood.
Single cell mRNA analysis was used to define the transcriptional ...heterogeneity of melanoma and its dynamic response to BRAF inhibitor therapy and treatment holidays. Discrete transcriptional states were defined in cell lines and melanoma patient specimens that predicted initial sensitivity to BRAF inhibition and the potential for effective re-challenge following resistance. A mathematical model was developed to maintain competition between the drug-sensitive and resistant states, which was validated in vivo.
Our analyses showed melanoma cell lines and patient specimens to be composed of >3 transcriptionally distinct states. The cell state composition was dynamically regulated in response to BRAF inhibitor therapy and drug holidays. Transcriptional state composition predicted for therapy response. The differences in fitness between the different transcriptional states were leveraged to develop a mathematical model that optimized therapy schedules to retain the drug sensitive population. In vivo validation demonstrated that the personalized adaptive dosing schedules outperformed continuous or fixed intermittent BRAF inhibitor schedules.
Our study provides the first evidence that transcriptional heterogeneity at the single cell level predicts for initial BRAF inhibitor sensitivity. We further demonstrate that manipulating transcriptional heterogeneity through personalized adaptive therapy schedules can delay the time to resistance.
This work was funded by the National Institutes of Health. The funder played no role in assembly of the manuscript.
Abstract Introduction Laser Doppler imaging (LDI) has been investigated and used since 1993 for the assessment of burn wounds. Here we describe tests that validate use of the dedicated colour ...palette, derived in Part 1, for a standardised interpretation of LDI images for prediction of healing time (<14 days, 14–21 days or >21 days). We also describe clinical and technical factors to be taken into account during LDI imaging and during image interpretation. Methods (1) A cohort of images, selected at random, were assessed, according to strict rules of interpretation, by 6 clinicians against photographs of healing, for accuracy of healing time prediction and clinical usefulness using five-point scales. (2) All images were assessed technically in a similar way for accuracy and the accuracy was further studied by analysing the data by ordinal logistic regression to predict the dependence of burn injury healing time on demographic variables (age, sex, race, %TBSA, burn injury cause and site). (3) Where average LDI blood flow could be determined, regression analysis was used to assess the potential accuracy of the technique. Results (1) Clinical accuracy was found to be 93% and usefulness was 89%; (2) technical accuracy was found to be 96%; (3) regression analysis found that a potential accuracy of 90.9% could be achieved using LDI results alone, increasing to 92% if gender was also considered; no other parameters had an influence on healing time prediction. Conclusion LDI can be used in a standardised way as a valid tool for improving on clinical assessment of burn wounds. This can enable earlier appropriate management.
The aphorism, ‘All models are wrong, but some models are useful’, originally referred to statistical models, but is now used for scientific models in general. When presenting results from a marine ...simulation model, this statement effectively stops discussions about the quality of the model, as there is always another observation to mismatch, and thereby another confirmation why the model cannot be trusted. It is common that observations are less challenged and are often viewed as a ‘gold standard’ for judging models, whereas proper interpretations and the true value of models are often overlooked. Models are not perfect, and there are many examples where models are used improperly to provide misleading answers with great confidence, but to what extent does an observation represent the truth? The precision of the observational gear may be high, but what about representativeness? The interpretation of observations is simply another model, but this time not coded in a computer language but rather formed by the individual observer. We submit that it would be more productive to initiate a process where the norm is that models and observations are joined to strengthen both. In the end, neither method is the goal, but both are useful tools for disclosing the truth. Biased views on either observational or modeling approaches would limit us from achieving this goal.
Mild traumatic brain injuries (mTBIs) are one of the most prevalent neurological disorders, and humans are severely limited in their ability to repair and regenerate central nervous system (CNS) ...tissue postinjury. However, zebrafish (
) maintain the remarkable ability to undergo complete and functional neuroregeneration as an adult. We wish to extend knowledge of the known mechanisms of neuroregeneration by analyzing the differentially expressed genes (DEGs) in a novel adult zebrafish model of mTBI. In this study, a rodent weight drop model of mTBI was adapted to the adult zebrafish. A memory test showed significant deficits in spatial memory in the mTBI group. We identified DEGs at 3 and 21 days postinjury (dpi) through RNA-sequencing analysis. The resulting DEGs were categorized according to gene ontology (GO) categories. At 3 dpi, GO categories consisted of peak injury response pathways. Significantly, at 21 dpi, GO categories consisted of neuroregeneration pathways. Ultimately, these results validate a novel zebrafish model of mTBI and elucidate significant DEGs of interest in CNS injury and neuroregeneration.
Structure determination of proteins and other macromolecules has historically required the growth of high-quality crystals sufficiently large to diffract x-rays efficiently while withstanding ...radiation damage. We applied serial femtosecond crystallography (SFX) using an x-ray free-electron laser (XFEL) to obtain high-resolution structural information from microcrystals (less than 1 micrometer by 1 micrometer by 3 micrometers) of the well-characterized model protein lysozyme. The agreement with synchrotron data demonstrates the immediate relevance of SFX for analyzing the structure of the large group of difficult-to-crystallize molecules.
To determine the maximum-tolerated dose (MTD) of paclitaxel administered as a 3-hour infusion in patients with recurrent malignant glioma.
Patients were stratified by starting dose of paclitaxel and ...concurrent anticonvulsant (AC) use and were treated in cohorts of three patients. The starting dose was 240 mg/m2 administered intravenously with escalations of 30 mg/m2 until the MTD was established. Pharmacokinetic data were obtained for each patient for the first infusion. Tumor response was assessed at 6-week intervals and treatment was continued until documented tumor progression, unacceptable toxicity, or a total of 12 paclitaxel infusions.
From April 1995 to December 1996, 34 patients were treated; 27 patients in the AC group and seven patients in the non-AC group. The MTD for patients who received ACs was established at 360 mg/m2 and the dose-limiting toxicity (DLT) was central neurotoxicity, characterized as transient encephalopathy and seizures. In contrast, the MTD for patients who did not receive ACs was 240 mg/m2, and myelosuppression, gastrointestinal toxicity, and fatigue were the DLTs. Pharmacokinetic data confirmed that the plasma drug levels and clearance rates were similar for patients in both groups at the respective dose levels that produced DLTs.
The pharmacokinetics of paclitaxel are altered by ACs, and significantly larger doses of the drug can be administered to patients with brain tumors on AC therapy. The toxicity profile is different for patients on AC therapy treated at these higher doses. A phase II study has been initiated that uses a dose of 330 mg/m2 for patients on AC therapy and 210 mg/m2 for patients not on AC therapy.
OBJECTIVE: This study examined whether there were differences in the rate of depressive and anxiety disorders between HIV-infected women (N=93) and a comparison group of uninfected women (N=62). ...Secondary objectives were to examine correlates of depression in HIV-infected women-including HIV disease stage and protease inhibitor use-and the associations between symptoms of depression or anxiety and other potential predictor variables. METHOD: Subjects underwent extensive semiannual clinical, psychiatric, neuropsychological, and immunological evaluations. Depressive and anxiety disorder diagnoses were assessed by using the Structured Clinical Interview for DSM-IV. Symptoms of depression and anxiety were evaluated with the Hamilton Depression Rating Scale (the 17-item version and a modified 11-item version) and the Hamilton Anxiety Rating Scale, respectively. RESULTS: The rate of current major depressive disorder was four times higher in HIV-seropositive women (19.4%) than in HIV-seronegative women (4.8%). Mean depressive symptom scores on the 17-item Hamilton depression scale also were significantly higher, overall, in the HIV-infected women (mean=8.7, SD=8.0) relative to comparison subjects (mean=3.3, SD=5.8). There was no significant between-group difference in the rate of anxiety disorders. However, HIV-seropositive women had significantly higher anxiety symptom scores (mean=8.8, SD=8.9) than did HIV-seronegative women (mean=3.6, SD=5.5). Both groups had similar substance abuse dependence histories, but adjusting for this factor had little impact on the relationship of HIV status to current major depressive disorder. CONCLUSIONS: HIV-seropositive women without current substance abuse exhibited a significantly higher rate of major depressive disorder and more symptoms of depression and anxiety than did a group of HIV-seronegative women with similar demographic characteristics. These controlled, clinical findings extend recent epidemiologic findings and underscore the importance of adequate assessment and treatment of depression and anxiety in HIV-infected women.
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