Changes in the Care Setting of First Consults to Palliative and Supportive Care Over a Seven-Year Period.

CONTEXT: Optimal benefits from palliative care (PC) are achieved when first consults (PC1) occur early, in the outpatient setting. Late PC1, like those in the intensive care unit (ICU), limit these benefits. OBJECTIVES: The objective of this study was to determine the proportion of PC1 over time in the outpatient, ICU, and inpatient non-ICU settings. We also examined patients' baseline characteristics and the timing of PC access (from PC1 to death) by the setting of PC1. METHODS: We retrospectively evaluated consecutive cancer patients' records at our cancer center to ascertain the annual number of PC1 and its distribution across settings (2011-2017). ICU PC1 (n = 309) and a random sample of an equal number of outpatient and inpatient non-ICU PC1 were reviewed to retrieve patients' characteristics and death date. RESULTS: PC1 total annual number increased by 58% from 2011 (n = 2286) to 2017 (n = 3615). We found a significant decrease in the proportion of ICU PC1 (from 2.3% in 2011 to 1% in 2017, P < 0.001). There were no significant changes in the proportion of PC1 at outpatient versus inpatient settings (P = 0.2). Hematologic cancer patients were more likely to have an ICU PC1 (P < 0.001). Median survival (months) was 7.7 (6.3-9.7), 3.4 (2.4-4.5), and 0.1 (0.1-0.1) for outpatient, inpatient, and ICU, respectively (P < 0.01). CONCLUSION: PC1 total annual number has increased, and the proportion of PC1 at ICU, a very late clinical setting, is decreasing. Further efforts are needed to integrate PC in hematologic cancer care.

Patterns of Care for Locally Advanced Pancreatic Adenocarcinoma Using the National Cancer Database.

OBJECTIVES: The role of radiotherapy (RT) in locally advanced pancreatic cancer (LAPC) is uncertain. This study examines patterns of care and survival outcomes of LAPC undergoing chemotherapy alone versus chemotherapy plus RT (C + RT). METHODS: The National Cancer Database was queried for nonmetastatic LAPC patients who received chemotherapy alone or C + RT. RESULTS: Of the 13,695 patients included, 5306 underwent chemotherapy alone and 4971, C + RT. Use of C + RT declined from 2003 to 2011 (73%-53%), whereas chemotherapy alone increased. Of those receiving RT, rates of intensity-modulated radiotherapy (IMRT) increased (27%-72%), whereas 3-dimensional (3D) RT decreased (73%-28%). Unadjusted 1-year overall survival (OS) was longer for versus chemotherapy (45.6% vs 38.7%), as was 2-year OS (12.9% vs 11.9%) (hazard ratio, 0.88; 0.85-0.91; P < 0.001). Under multivariate analysis, C + RT was associated with improved OS (hazard ratio, 0.84; 0.81-0.87; P < 0.001). On subgroup analysis comparing C + IMRT, C + 3D RT, and chemotherapy alone, 1-year OS was 49.1%, 45.1%, and 38.7%, and 2-year OS was 13.1%, 11.6%, and 11.9% accordingly. CONCLUSIONS: Utilization of RT in LAPC is decreasing, whereas chemotherapy alone is increasing. Of patients undergoing RT, rates of IMRT are increasing. Whereas C + IMRT appeared to be associated with improved OS compared with chemotherapy alone, 3D RT was not.

Prostate brachytherapy, either alone or in combination with external beam radiation, is associated with longer overall survival in men with favorable pathologic Group 4 (Gleason score 8) prostate cancer.

PURPOSE: Conventional prostate cancer risk stratification results in considerable heterogeneity within each prognostic group. Men with pathologic grade Group 4 (Gleason score 8) but otherwise low-risk features have been identified as a favorable subset of high-risk prostate cancer. Given recent randomized data supporting improved cancer outcome with brachytherapy in intermediate- and high-risk prostate cancer, we sought to evaluate brachytherapy utilization and overall survival (OS) for these patients. METHODS AND MATERIALS: We queried the National Cancer Database for clinical T1c-T2a N0 M0 prostate cancer with prostate-specific antigen <10 ng/mL and Gleason score 8 adenocarcinoma on biopsy. All patients received androgen deprivation therapy and either external beam radiation therapy (EBRT) alone, brachytherapy alone, or a combination of EBRT with brachytherapy boost (brachytherapy + EBRT). Kaplan-Meier OS estimates as well as univariate and multivariate Cox proportional hazards regression analyses were performed. Propensity score-matched analyses were performed to further control for baseline confounders. RESULTS: Four thousand four hundred ninety-six patients were identified with a median followup of 62.5 months (range, 2.3-119.8). Median age was 72 years (range, 41-90+). Utilization of brachytherapy decreased from 2004 to 2009. The odds ratio for brachytherapy by year (continuous variable) was 0.86 (p < 0.001). Five-year OS was 84%, 88%, and 89% for the EBRT alone, brachytherapy alone, and brachytherapy + EBRT groups, respectively. On multivariate analysis, higher median income, low comorbidity score, and treatment with brachytherapy alone (hazard ratio, 0.66; p = 0.005) or brachytherapy + EBRT (hazard ratio, 0.70; p = 0.001) remained associated with longer OS. Propensity score matching confirmed longer OS associated with either brachytherapy regimen. CONCLUSIONS: Of those men with World Health Organization pathologic grade Group 4 (Gleason score 8) prostate cancer and otherwise favorable prognostic features treated with androgen deprivation therapy and radiation therapy, longer OS was achieved when prostate brachytherapy was included, whether used alone or in combination with supplemental EBRT. In spite of these excellent outcomes, prostate brachytherapy utilization is declining in the United States.

Spinal cord stimulation improves forelimb use in an alpha-synuclein animal model of Parkinson's disease.

Neuromodulation by spinal cord stimulation has been proposed as a symptomatic treatment for Parkinson's disease. We tested the chronic effects of spinal cord stimulation in a progressive model of Parkinson's based on overexpression of alpha-synuclein in the substantia nigra. Adult Sprague Dawley rats received unilateral injections of adeno-associated virus serotype 6 (AAV6) in the substantia nigra to express alpha-synuclein. Locomotion and forepaw use of the rats were evaluated during the next 10 weeks. Starting on week 6, a group of AAV6-injected rats received spinal cord stimulation once a week. At the end of the experiment, tyrosine hydroxylase and alpha-synuclein immunostaining were performed. Rats with unilateral alpha-synuclein expression showed a significant decrease in the use of the contralateral forepaw, which was mildly but significantly reverted by spinal cord stimulation applied once a week from the 6th to the 10th week after the AAV6 injection. Long-term spinal cord stimulation proved to be effective to suppress or delay motor symptoms in a sustained and progressive model of Parkinson's and might become an alternative, less invasive neuromodulation option to treat this disease.

Treatment Selection and Survival Outcomes With and Without Radiation for Unresectable, Localized Intrahepatic Cholangiocarcinoma.

PURPOSE: Most patients with intrahepatic cholangiocarcinoma present with locally advanced disease not amenable to surgical resection. For these inoperable patients, chemotherapy alone is generally considered the standard of care, with limited data regarding the role of radiotherapy. We used the National Cancer Database to investigate care patterns and the impact of radiation as a component of combined modality therapy on overall survival. METHODS: We queried the National Cancer Database for patients with nonmetastatic intrahepatic cholangiocarcinoma diagnosed from 2001 to 2011. Those undergoing surgery were excluded. All included patients were coded as having received chemotherapy. Kaplan-Meier overall survival estimates and univariate and multivariate Cox proportional hazards regression analyses were performed. Propensity score-matched analysis was performed to account for indication bias and mitigate heterogeneity between treatment groups. RESULTS: One thousand six hundred thirty-six patients were identified with a median follow-up of 11.3 months. Median age was 63 years; 23% received combined modality therapy with radiation. Two-year overall survival for the entire cohort was 21%, and for the chemotherapy-alone and combined modality therapy groups, it was 20% versus 26%, respectively. On univariate analysis, overall survival was improved with combined modality therapy. On multivariate analysis, combined modality therapy remained significantly associated with improved overall survival, as did younger age, female sex, higher median income, lower comorbidity score, and earlier stage. Propensity score matched analysis confirmed the overall survival benefit associated with combined modality therapy. DISCUSSION: In this largest reported analysis of combined modality therapy for localized, inoperable intrahepatic cholangiocarcinoma, the addition of radiation to chemotherapy was associated with an improvement in overall survival. Three quarters of inoperable patients in the United States do not receive radiation. Survival remains relatively poor for all patients, and we enthusiastically support ongoing randomized trials seeking to incorporate radiotherapy as a possible means to improve outcomes.

Treating Opioid Dependence With Injectable Extended-Release Naltrexone (XR-NTX): Who Will Respond?

OBJECTIVES: Once-monthly intramuscular extended-release naltrexone (XR-NTX) has demonstrated efficacy for the prevention of relapse in opioid dependence, providing an alternative to agonist or partial agonist maintenance (ie, methadone and buprenorphine). The question remains, for whom is this unique treatment most efficacious and can patient-treatment matching factors be identified? METHODS: A moderator analysis was conducted on a previously reported 24-week, placebo-controlled, multisite, randomized controlled trial of XR-NTX (n = 126) versus placebo (n = 124) among recently detoxified opioid-dependent adults in Russia, which showed XR-NTX superior to placebo in proportion of opioid abstinent weeks. The moderator analysis examined a dichotomous indicator of good clinical response-achieving at least 90% of weeks abstinent over the 24-week trial. A series of logistic regression models were fit for this outcome as functions of treatment (XR-NTX vs placebo), each baseline moderator variable, and their interactions. The 25 baseline variables included demographics, clinical severity (Addiction Severity Index, SF-36, and Clinical Global Impression-Severity), functioning (EQ-5D), craving, and HIV serostatus (HIV+). RESULTS: More XR-NTX patients achieved 90% abstinence (64/126, 51%) versus placebo (39/124, 31%; P = 0.002). There were no significant interactions between baseline variables and treatment. There was a significant main effect of Clinical Global Impression-Severity score (P = 0.02), such that higher severity score was associated with a lower rate of Good Clinical Response. CONCLUSIONS: The absence of significant baseline by treatment interactions indicates that no patient-treatment matching variables could be identified. This suggests that XR-NTX was effective in promoting abstinence from opioids across a range of demographic and severity characteristics.

Channel-mediated lactate release by K⁺-stimulated astrocytes.

Excitatory synaptic transmission is accompanied by a local surge in interstitial lactate that occurs despite adequate oxygen availability, a puzzling phenomenon termed aerobic glycolysis. In addition to its role as an energy substrate, recent studies have shown that lactate modulates neuronal excitability acting through various targets, including NMDA receptors and G-protein-coupled receptors specific for lactate, but little is known about the cellular and molecular mechanisms responsible for the increase in interstitial lactate. Using a panel of genetically encoded fluorescence nanosensors for energy metabolites, we show here that mouse astrocytes in culture, in cortical slices, and in vivo maintain a steady-state reservoir of lactate. The reservoir was released to the extracellular space immediately after exposure of astrocytes to a physiological rise in extracellular K(+) or cell depolarization. Cell-attached patch-clamp analysis of cultured astrocytes revealed a 37 pS lactate-permeable ion channel activated by cell depolarization. The channel was modulated by lactate itself, resulting in a positive feedback loop for lactate release. A rapid fall in intracellular lactate levels was also observed in cortical astrocytes of anesthetized mice in response to local field stimulation. The existence of an astrocytic lactate reservoir and its quick mobilization via an ion channel in response to a neuronal cue provides fresh support to lactate roles in neuronal fueling and in gliotransmission.

Rapid response team activations within 24 hours of admission from the emergency department: an innovative approach for performance improvement.

OBJECTIVES: Performance improvement programs in emergency medicine (EM) have evolved beyond peer reviews of referred cases and now encompass a large set of quality metrics that are measured proactively. However, peer review of cases continues to be an important element of performance improvement, and selection of cases tends to be driven by an ad hoc referral process based on concerns about problems with care in the emergency department (ED). In the past decade, there has been widespread hospital adoption of rapid response teams (RRTs) that respond to patients who decline clinically to reduce adverse outcomes. In an effort to cast a wider net, to take a more systematic approach, and to avoid "blind spots" from individual variability in criteria for referring cases, the institution instituted a new process for selecting cases for ED peer review based on RRT activations within 24 hours of admission from the ED. The hypothesis was that a formal process for review of these activation cases would increase the number of cases for peer review. METHODS: This was a prospective, observational study conducted from July 1, 2012, to June 30, 2013, at an urban, academic medical center with an EM residency program. A new automated monthly report was created, capturing all RRT activations within 24 hours of admission from the ED. All events were reviewed by three physicians from the ED performance improvement committee to examine for systems issues, individual provider issues, or both, that might yield opportunities for improvement. Cases with potential opportunities were reviewed by the full ED performance improvement committee. Cases were classified according to the indication for response team activation using the system outlined by the U.S. Agency for Healthcare Research and Quality. RESULTS: During the study period 61,814 patients were treated in the ED, and 13,067 were admitted to inpatient status. Thirty-two RRT activations within 24 hours of admission from the ED occurred among these admitted patients, representing 0.24% of admissions (95% confidence interval [CI] = 0.16% to 0.33%). Of the 32 cases, only one was also referred independently for ED performance improvement review via the traditional ad hoc process. During the same period of time, 85 cases were referred to the ED performance improvement committee via the traditional ad hoc referral process. Thus, the RRT cases added an additional 31 cases, or 36.5%, to the 85 cases reviewed in ED performance improvement. Of the 32 cases, two were determined by the performance improvement committee to have individual provider factors in their ED care, which contributed to the clinical decline triggering the response teams; none had system factors. Most of the response team activations were for neurologic changes (n = 13) and respiratory status changes (n = 12). In two cases there was long-term morbidity or mortality related to the team activation event; in neither of these cases were ED system or individual provider factors judged to have contributed. CONCLUSIONS: The review of RRT activations within 24 hours of admission from the ED significantly supplemented the typical ad hoc referral system for peer review of cases, highlighting cases that likely would not have received attention within the ED. This novel and unique case review process revealed opportunities for education and performance improvement. This and other systematic approaches to case detection may be useful adjuncts to traditional case referrals for review.

Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1.

Parkinson disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Although growing evidence indicates that endoplasmic reticulum (ER) stress is a hallmark of PD, its exact contribution to the disease process is not well understood. Here we report that developmental ablation of X-Box binding protein 1 (XBP1) in the nervous system, a key regulator of the unfolded protein response (UPR), protects dopaminergic neurons against a PD-inducing neurotoxin. This survival effect was associated with a preconditioning condition that resulted from induction of an adaptive ER stress response in dopaminergic neurons of the SNpc, but not in other brain regions. In contrast, silencing XBP1 in adult animals triggered chronic ER stress and dopaminergic neuron degeneration. Supporting this finding, gene therapy to deliver an active form of XBP1 provided neuroprotection and reduced striatal denervation in animals injected with 6-hydroxydopamine. Our results reveal a physiological role of the UPR in the maintenance of protein homeostasis in dopaminergic neurons that may help explain the differential neuronal vulnerability observed in PD.

Effects of polyunsaturated fatty acids from plant oils and algae on milk fat yield and composition are associated with mammary lipogenic and SREBF1 gene expression.

The main aim of the present study was to examine the effects of long-term supplementing diets with saturated or unprotected polyunsaturated fatty acids from two different plant oils rich in either n-3 or n-6 fatty acids (FAs) plus docosahexaenoic acid (DHA)-rich algae on mammary gene expression and milk fat composition in lactating dairy cows. Gene expression was determined from mammary tissue and milk epithelial cells. Eighteen primiparous German Holstein dairy cows in mid-lactation were randomly assigned into three dietary treatments that consist of silage-based diets supplemented with rumen-stable fractionated palm fat (SAT; 3.1% of the basal diet dry matter, DM), or a mixture of linseed oil (2.7% of the basal diet DM) plus DHA-rich algae (LINA; 0.4% of the basal diet DM) or a mixture of sunflower oil (2.7% of the basal diet DM) plus DHA-rich algae (SUNA; 0.4% of the basal diet DM), for a period of 10 weeks. At the end of the experimental period, the cows were slaughtered and mammary tissues were collected to study the gene expression of lipogenic enzymes. During the last week, the milk yield and composition were determined, and milk was collected for FA measurements and the isolation of milk purified mammary epithelial cells (MECs). Supplementation with plant oils and DHA-rich algae resulted in milk fat depression (MFD; yield and percentage). The secretion of de novo FAs in the milk was reduced, whereas the secretion of trans-10,cis-12-CLA and DHA were increased. These changes in FA secretions were associated in mammary tissue with a joint down-regulation of mammary lipogenic enzyme gene expression (stearoyl-CoA desaturase, SCD1; FA synthase, FASN) and expression of the regulatory element binding transcription factor (SREBF1), whereas no effect was observed on lipoprotein lipase (LPL) and glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM). A positive relationship between mammary SCD1 and SREBF1 mRNA abundances was observed, suggesting a similar regulation for these genes. Such data on mammary gene expression in lactating cows presenting MFD contribute to strengthen the molecular mechanisms that govern milk fat synthesis in the mammary glands. In purified MEC, the dietary treatments had no effect on gene expressions. Differences between mammary tissue and milk purified MEC gene expression were attributed to the effect of lipid supplements on the number of milk purified MEC and its RNA quality, which are determinant factors for the analysis of gene expression using milk cells.

Acanthosis nigricans identifies youth at high risk for metabolic abnormalities.

OBJECTIVE: To determine the prevalence of abnormal glucose homeostasis and cardiovascular risk factors in youth with acanthosis nigricans (AN). STUDY DESIGN: Youth (8-14 years) were recruited from community pediatric offices. Each subject underwent a questionnaire, a targeted physical examination, and an oral glucose tolerance test. RESULTS: Subjects (n = 236) with AN of the neck (AN+) (60% Hispanic, 30% African American, 54% female, body mass index [BMI] z-score 2.3 kg/m(2)) and 51 youth without AN (65% Hispanic, 22% African American, 37% female, BMI z-score 2.1 kg/m(2)) completed the study. Twenty-nine percent of the AN+ group had abnormal glucose homeostasis, 27% had systolic blood pressure > 95th percentile, and 50% had high-density lipoprotein-cholesterol < or =5th percentile. Once corrected for sex, puberty, maternal education, and BMI z-score, AN remained significantly associated with insulin resistance and abnormal glucose homeostasis. For youth in the AN+ group, homeostasis model assessment of insulin resistance, female sex, and positive glutamic acid decarboxylase antibodies remained significantly and independently associated with impaired glucose tolerance. CONCLUSIONS: Youth in the AN+ group had severe insulin resistance, and more than 1 in 4 already had abnormal glucose homeostasis. AN identified a high-risk population, for whom appropriate interventions have the potential to attenuate or even prevent the development of diabetes and further metabolic abnormalities.

An enantioselective double Diels-Alder approach to the tetracyclic framework of colombiasin A.

The complex tetracyclic carbon skeleton of colombiasin A is conveniently accessed through an enantioselective intermolecular Diels-Alder-sulfoxide elimination-intramolecular Diels-Alder (DA-E-IMDA) sequence.

A rapid assessment approach for public health decision-making related to the prevention of malaria during pregnancy

Objective: To develop a rapid field assessment methodology to address the burden of malaria during pregnancy and the options for intervening within the existing antenatal care system in Kenya. Methods: Surveys consisting of questionnaires, sampling of blood for parasitaemia and anaemia, and birth outcome assessment were conducted in antenatal clinics, delivery units, and in the community in Ksumu and Mombasa, Kenya. Findings: T he ratges of maternal anaemia and severe anaemia, were, resctively, 79 cent and 8 cent in Kisumu, and 95 cent and 24 cent in Mombasa. The rates of placental parasitaemia were 27 cent and 24 cent and the ratges of low birth weight were 18 cent and 24 cent in Kisumu and Mombasa, respectively. Women with placental parasitaemia had a higher incidence of low birth wight compared with women without placental parasitaemai in both Kisumu (28 cent vs 16 cent,P=0.0004) and Mombasa (42 cent vs 20 cent, P=0.004). A total of 95 cent and 98 cent for women in Kisumu and Mombasa, respectively, reported attending an antenatal clinic during their previous pregnancy. Conclusion: This metodology can be used by ministries of health to collect data for decision-making regarding malaria control during pregnancy: it can also privide a baseline measurement on which to evaluate subsequent interventions

Polymorphism in the gene encoding the Pfs48/45 antigen of Plasmodium falciparum. XI. Asembo Bay Cohort Project.

We have investigated the genetic diversity of the gene encoding the transmission-blocking vaccine antigen Pfs48/45 of Plasmodium falciparum parasites from western Kenya and compared it with parasite populations from Thailand, India, and Venezuela. We report 44 complete new sequences. Overall, the antigen is less polymorphic as compared with other pre-erythrocytic and blood stage antigens. Contrary to other P. falciparum antigens, the number of synonymous substitutions per synonymous site exceeds the number of non-synonymous substitutions per non-synonymous site. We have found that the Pfs48/45 gene of Kenyan parasites is more polymorphic than parasites from other geographic origins. Our analysis reveals that positive natural selection is involved in the maintenance of the observed polymorphism. No evidence of intragenic recombination was found. F(st) values reveal high levels of gene flow between India and Thailand, however, there are strong constraints in gene flow among Kenyan, Southeast Asian, and Venezuelan parasites. No alleles could be linked to a specific geographic region. The results of this study suggest that this gametocyte antigen, like other asexual blood stage antigens, is under selection pressure.

Lack of effect of respiratory syncytial virus infection on theophylline disposition in children.

Conflicting reports raise a question about decreased plasma clearance (Clp) of theophylline in man during viral infections. Thus a dilemma exists concerning requisite dose adjustments. We examined this issue by retrospectively evaluating theophylline Clp in children infected with respiratory syncytial virus (RSV). Two pharmacokinetic approaches were applied to a one-compartment open model to fit theophylline concentrations during 83 hospitalizations of 76 children, 6 to 48 months of age, who received intravenous theophylline therapy and were tested for RSV infection. Iterative linear regression analyses of all theophylline data were used to estimate apparent volume of distribution, elimination rate constant, plasma half-life, and Clp in 39 of the hospitalizations. When insufficient data were available to distinguish apparent volume of distribution and elimination rate constant (n = 44), steady-state estimates of Clp were calculated. An age-matched and percentile body weight-matched cohort design presented RSV as the primary covariate. Theophylline Clp was similar in 29 matched RSV-infected and -uninfected pairs (1.32 +/- 0.14 and 1.25 +/- 0.05 ml/kg per minute, respectively), as were other pharmacokinetic values. Unexpectedly, a significant, inverse linear relationship was found for Clp and percentile body weight. Additionally, children born prematurely and hospitalized in the neonatal intensive care unit had significantly higher theophylline Clp; this did not affect findings regarding RSV infection. Theophylline Clp was not decreased in RSV-infected children. Current theophylline dosing recommendations for young children infected with RSV should not be altered, but careful monitoring of plasma theophylline levels should be continued.