IMPORTANCE: Patients with advanced-stage cancer are receiving increasingly aggressive medical care near death, despite growing concerns that this reflects poor-quality care. OBJECTIVE: To assess the ...association of aggressive end-of-life care with bereaved family members’ perceptions of the quality of end-of-life care and patients’ goal attainment. DESIGN, SETTING, AND PARTICIPANTS: Interviews with 1146 family members of Medicare patients with advanced-stage lung or colorectal cancer in the Cancer Care Outcomes Research and Surveillance study (a multiregional, prospective, observational study) who died by the end of 2011 (median, 144.5 days after death; interquartile range, 85.0-551.0 days). EXPOSURES: Claims-based quality measures of aggressive end-of-life care (ie, intensive care unit ICU admission or repeated hospitalizations or emergency department visits during the last month of life; chemotherapy ≤2 weeks of death; no hospice or ≤3 days of hospice services; and deaths occurring in the hospital). MAIN OUTCOMES AND MEASURES: Family member–reported quality rating of “excellent” for end-of-life care. Secondary outcomes included patients’ goal attainment (ie, end-of-life care congruent with patients’ wishes and location of death occurred in preferred place). RESULTS: Of 1146 patients with cancer (median age, 76.0 years interquartile range, 65.0-87.0 years; 55.8% male), bereaved family members reported excellent end-of-life care for 51.3%. Family members reported excellent end-of-life care more often for patients who received hospice care for longer than 3 days (58.8% 352/599) than those who did not receive hospice care or received 3 or fewer days (43.1% 236/547) (adjusted difference, 16.5 percentage points 95% CI, 10.7 to 22.4 percentage points). In contrast, family members of patients admitted to an ICU within 30 days of death reported excellent end-of-life care less often (45.0% 68/151) than those who were not admitted to an ICU within 30 days of death (52.3% 520/995) (adjusted difference, −9.4 percentage points 95% CI, −18.2 to −0.6 percentage points). Similarly, family members of patients who died in the hospital reported excellent end-of-life care less often (42.2% 194/460) than those who did not die in the hospital (57.4% 394/686) (adjusted difference, −17.0 percentage points 95% CI, −22.9 to −11.1 percentage points). Family members of patients who did not receive hospice care or received 3 or fewer days were less likely to report that patients died in their preferred location (40.0% 152/380) than those who received hospice care for longer than 3 days (72.8% 287/394) (adjusted difference, −34.4 percentage points 95% CI, −41.7 to −27.0 percentage points). CONCLUSIONS AND RELEVANCE: Among family members of older patients with fee-for service Medicare who died of lung or colorectal cancer, earlier hospice enrollment, avoidance of ICU admissions within 30 days of death, and death occurring outside the hospital were associated with perceptions of better end-of-life care. These findings are supportive of advance care planning consistent with the preferences of patients.
During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. ...Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor-ligand interactions occur in the following sequence with the following cellular morphologies; 1) an early heparin-blockable interaction which weakly deforms the erythrocyte, 2) EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite's actin-myosin motor, 3) a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4) an AMA1-RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To develop a magnetic resonance (MR) "fingerprinting" technique for quantitative abdominal imaging.
This HIPAA-compliant study had institutional review board approval, and informed consent was ...obtained from all subjects. To achieve accurate quantification in the presence of marked B0 and B1 field inhomogeneities, the MR fingerprinting framework was extended by using a two-dimensional fast imaging with steady-state free precession, or FISP, acquisition and a Bloch-Siegert B1 mapping method. The accuracy of the proposed technique was validated by using agarose phantoms. Quantitative measurements were performed in eight asymptomatic subjects and in six patients with 20 focal liver lesions. A two-tailed Student t test was used to compare the T1 and T2 results in metastatic adenocarcinoma with those in surrounding liver parenchyma and healthy subjects.
Phantom experiments showed good agreement with standard methods in T1 and T2 after B1 correction. In vivo studies demonstrated that quantitative T1, T2, and B1 maps can be acquired within a breath hold of approximately 19 seconds. T1 and T2 measurements were compatible with those in the literature. Representative values included the following: liver, 745 msec ± 65 (standard deviation) and 31 msec ± 6; renal medulla, 1702 msec ± 205 and 60 msec ± 21; renal cortex, 1314 msec ± 77 and 47 msec ± 10; spleen, 1232 msec ± 92 and 60 msec ± 19; skeletal muscle, 1100 msec ± 59 and 44 msec ± 9; and fat, 253 msec ± 42 and 77 msec ± 16, respectively. T1 and T2 in metastatic adenocarcinoma were 1673 msec ± 331 and 43 msec ± 13, respectively, significantly different from surrounding liver parenchyma relaxation times of 840 msec ± 113 and 28 msec ± 3 (P < .0001 and P < .01) and those in hepatic parenchyma in healthy volunteers (745 msec ± 65 and 31 msec ± 6, P < .0001 and P = .021, respectively).
A rapid technique for quantitative abdominal imaging was developed that allows simultaneous quantification of multiple tissue properties within one 19-second breath hold, with measurements comparable to those in published literature.
Summary Background The global burden of disease attributable to respiratory syncytial virus (RSV) remains unknown. We aimed to estimate the global incidence of and mortality from episodes of acute ...lower respiratory infection (ALRI) due to RSV in children younger than 5 years in 2005. Methods We estimated the incidence of RSV-associated ALRI in children younger than 5 years, stratified by age, using data from a systematic review of studies published between January, 1995, and June, 2009, and ten unpublished population-based studies. We estimated possible boundaries for RSV-associated ALRI mortality by combining case fatality ratios with incidence estimates from hospital-based reports from published and unpublished studies and identifying studies with population-based data for RSV seasonality and monthly ALRI mortality. Findings In 2005, an estimated 33·8 (95% CI 19·3–46·2) million new episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years (22% of ALRI episodes), with at least 3·4 (2·8–4·3) million episodes representing severe RSV-associated ALRI necessitating hospital admission. We estimated that 66 000–199 000 children younger than 5 years died from RSV-associated ALRI in 2005, with 99% of these deaths occurring in developing countries. Incidence and mortality can vary substantially from year to year in any one setting. Interpretation Globally, RSV is the most common cause of childhood ALRI and a major cause of admission to hospital as a result of severe ALRI. Mortality data suggest that RSV is an important cause of death in childhood from ALRI, after pneumococcal pneumonia and Haemophilus influenzae type b. The development of novel prevention and treatment strategies should be accelerated as a priority. Funding WHO; Bill & Melinda Gates Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This study aimed to characterize the perceived priorities of state and county policy makers for youth mental health services and the factors that influence those priorities.OBJECTIVEThis study aimed ...to characterize the perceived priorities of state and county policy makers for youth mental health services and the factors that influence those priorities.Mental health agency officials (N=338; N=221 state officials, N=117 county officials) representing 49 states completed a Web-based survey in 2019-2020. On 5-point scales, respondents rated the extent to which 15 issues were priorities for their agency in providing youth mental health services and the extent to which nine factors influenced those priorities.METHODSMental health agency officials (N=338; N=221 state officials, N=117 county officials) representing 49 states completed a Web-based survey in 2019-2020. On 5-point scales, respondents rated the extent to which 15 issues were priorities for their agency in providing youth mental health services and the extent to which nine factors influenced those priorities.Suicide was identified as the highest priority (mean±SD rating=4.38±0.94), followed by adverse childhood experiences and childhood trauma and then increasing access to evidence-based treatments. Budget issues (mean=4.27±0.92) and state legislative priorities (mean=4.01±0.99) were perceived as having the greatest influence on setting priorities.RESULTSSuicide was identified as the highest priority (mean±SD rating=4.38±0.94), followed by adverse childhood experiences and childhood trauma and then increasing access to evidence-based treatments. Budget issues (mean=4.27±0.92) and state legislative priorities (mean=4.01±0.99) were perceived as having the greatest influence on setting priorities.These findings provide insights into youth mental health policy priorities and can be used to guide implementation and dissemination strategies for research and program development within state and county systems.CONCLUSIONSThese findings provide insights into youth mental health policy priorities and can be used to guide implementation and dissemination strategies for research and program development within state and county systems.
A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo ...pre‐clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain‐dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.
The authors report the development of an in vivo, pre‐clinical, human model to test safety and feasibility tenets and show that major barriers to human xenotransplantation have been surmounted. Kirk comments on page 1007.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this study, the acquisition of ASL data and quantification of multiple hemodynamic parameters was explored using a Magnetic Resonance Fingerprinting (MRF) approach. A pseudo-continuous ASL ...labeling scheme was used with pseudo-randomized timings to acquire the MRF ASL data in a 2.5 min acquisition. A large dictionary of MRF ASL signals was generated by combining a wide range of physical and hemodynamic properties with the pseudo-random MRF ASL sequence and a two-compartment model. The acquired signals were matched to the dictionary to provide simultaneous quantification of cerebral blood flow, tissue time-to-peak, cerebral blood volume, arterial time-to-peak, B1, and T1. A study in seven healthy volunteers resulted in the following values across the population in grey matter (mean ± standard deviation): cerebral blood flow of 69.1 ± 6.1 ml/min/100 g, arterial time-to-peak of 1.5 ± 0.1 s, tissue time-to-peak of 1.5 ± 0.1 s, T1 of 1634 ms, cerebral blood volume of 0.0048 ± 0.0005. The CBF measurements were compared to standard pCASL CBF estimates using a one-compartment model, and a Bland-Altman analysis showed good agreement with a minor bias. Repeatability was tested in five volunteers in the same exam session, and no statistical difference was seen. In addition to this validation, the MRF ASL acquisition's sensitivity to the physical and physiological parameters of interest was studied numerically.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
PIK3CA, which codes for the p110α catalytic subunit of phosphatidylinositol 3-kinase, is one of the most frequently mutated genes in human breast cancer. Here, we describe a mouse model for ...PIK3CA-induced breast cancer by using the ROSA26 (R26) knock-in system, in which targeted Pik3ca alleles can be activated through transgenic expression of Cre recombinase. We mated Pik3ca(H1047R) and Pik3ca(wt) knock-in lines with MMTV-Cre transgenics, which express Cre in mammary epithelium. Starting at approximately 5 months of age, female R26-Pik3ca(H1047R);MMTV-Cre mice, but not control R26-Pik3ca(wt);MMTV-Cre mice, developed mammary tumors, as well as lymphoid and skin malignancies. R26-Pik3ca(H1047R);MMTV-Cre mammary tumors were typically either adenosquamous carcinoma or adenomyoepithelioma. As p53 is the most commonly mutated gene in breast cancer, we tested for genetic interaction between Pik3ca(H1047R) and p53 loss-of-function mutations in R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mice. This led to decreased survival of double-mutant animals, which developed lymphoma and mammary tumors with rapid kinetics. Mammary tumors that formed in p53(loxP/+);MMTV-Cre conditional mutants were either poorly differentiated adenocarcinoma or spindle cell/EMT, whereas R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mammary tumors were mostly adenosquamous carcinoma or spindle cell/EMT indicating that double-mutant mice develop a distinct spectrum of mammary tumors. Thus, an oncogenic variant of PIK3CA implicated in multiple human breast cancer subtypes can induce a very diverse spectrum of mammary tumors in mice. Furthermore, Pik3ca(H1047R) shows cooperation with p53, which altered the specific tumors that formed. Thus, the two most frequently mutated genes in human breast cancer show cooperation in mammary tumor formation.
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