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This study introduces the prostate cancer linear energy transfer sensitivity index (PCLSI) as a novel method to predict relative biological effectiveness (RBE) in prostate cancer using linear energy transfer (LET) in proton therapy based on screening for DNA repair mutations.
Materials and Methods:
Five prostate cancer cell lines with DNA repair mutations known to cause sensitivity to LET and DNA repair inhibitors were examined using published data. Relative Du145 LET sensitivity data were leveraged to deduce the LET equivalent of olaparib doses. The PCLSI model was built using three of the prostate cancer cell lines (LNCaP, 22Rv1 and Du145) with DNA mutation frequency from patient cohorts. The PCLSI model was compared against two established RBE models, McNamara and McMahon, for LET-optimized prostate cancer treatment plans.
Results:
The PCLSI model relies on the presence of eight DNA repair mutations: AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, which are most likely to predict increased LET sensitivity and RBE in proton therapy. In the LET-optimized plan, the PCLSI model indicates that prostate cancer cells with these DNA repair mutations are more sensitive to increased LET than the McNamara and McMahon RBE models, with expected RBE increases ranging from 11%–33% at 2keV/µm.
Conclusions:
The PCLSI model predicts increasing RBE as a function of LET in the presence of certain genetic mutations. The integration of LET-optimized proton therapy and genetic mutation profiling could be a significant step toward the use of individualized medicine to improve outcomes using RBE escalation without the potential toxicity of physical dose escalation.
Three-dimensional (3D) food printing is a rapidly emerging technology offering unprecedented potential for customised food design and personalised nutrition. Here, we evaluate the technological advances in extrusion-based 3D food printing and its possibilities to promote healthy and sustainable eating. We consider the challenges in implementing the technology in real-world applications. We propose viable applications for 3D food printing in health care, health promotion and food waste upcycling. Finally, we outline future work on 3D food printing in food safety, acceptability and economics, ethics and regulations.
Fossil fishes are among the rarest in volcanic oceanic islands, their presence providing invaluable data for the understanding of more general (palaeo)biogeographical patterns and processes. Santa Maria Island (Azores Archipelago) is renowned for its palaeontological heritage, with representatives of several phyla, including the Chordata. We report on the fossil fishes, resulting in an increase in the number of Pliocene fishes from the Azores to 11 taxa: seven Chondrichthyes and at least four Actinopterygii. The genus Sparisoma is reported for the first time in the fossil record. The presence of fossil remains of the parrotfish Sparisoma cretense in Last Interglacial outcrops is significant, because it posits a setback for the theory that most of the present-day Azorean marine species colonized the area after the last glacial episode. Our multidisciplinary approach combines palaeontological data with ecological and published genetic data, offering an alternative interpretation. We suggest that most of the Azorean shallow-water subtropical and temperate marine species living in the archipelago during the Last Interglacial were not affected by the decrease in sea surface temperatures during the last glacial episode. We also predict low genetic diversity for fish species presently living in the Azores and ecologically associated with fine sediments, as a result of the remobilization and sediment transport to abyssal depths, during the Last Glacial episode; these are viewed as post-glacial colonizers or as ‘bottleneck’ survivors from the Last Glaciation.
The ‘deep sea’ encompasses a broad range of habitats that differ greatly in their assemblages and ecosystem functioning. Habitats may be described by a combination of environmental factors (e.g., depth, slope) and biotic factors (e.g., source of primary productivity). We review recent attempts to define deep-sea biogeographic provinces based on spatial and temporal variations in oceanographic conditions, and consider potential boundaries to distributional ranges, in particular habitats based on recent phylogeographic studies. We briefly discuss abiotic interactions in various habitats, noting the particular influence of local hydrodynamics. We consider competition and predation at whale falls and hydrothermal vents, discuss symbiotic interactions particularly with respect to deep-sea corals, which are particularly prevalent in submarine canyons and seamounts, and consider the difficulties of inferring processes from patterns.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Unlike most bird species, individual kingfisher species (Aves: Alcedinidae) are typically parasitized by only a single genus of louse (Alcedoffula, Alcedoecus, or Emersoniella). These louse genera are typically specific to a particular kingfisher subfamily. Specifically, Alcedoecus and Emersoniella parasitize Halcyoninae, whereas Alcedoffula parasitizes Alcedininae and Cerylinae. Although Emersoniella is geographically restricted to the Indo-Pacific region, Alcedoecus and Alcedoffula are geographically widespread. We used DNA sequences from two genes, the mitochondrial COI and nuclear EF-1α genes, to infer phylogenies for the two geographically widespread genera of kingfisher lice, Alcedoffula and Alcedoecus. These phylogenies included 47 kingfisher lice sampled from 11 of the 19 currently recognized genera of kingfishers. We compared louse phylogenies to host phylogenies to reconstruct their cophylogenetic history. Two distinct clades occur within Alcedoffula, one that infests Alcedininae and a second that infests Cerylinae. All species of Alcedoecus were found only on host species of the subfamily Halcyoninae. Cophylogenetic analysis indicated that Alcedoecus, as well as the clade of Alcedoffula occurring on Alcedininae, do not show evidence of cospeciation. In contrast, the clade of Alcedoffula occurring on Cerylinae showed strong evidence of cospeciation.
Objectives: Prior research has identified numerous genetic (including sex), education, health, and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find one model that best fits the observed data, risking interpretations that only the selected predictors are important. In reality, several predictor combinations may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates). In this study, we describe an alternative method, Information-Theoretic (IT) model averaging, and apply it to characterize a set of complex interactions in a longitudinal study on cognitive decline. Methods: Here, we used longitudinal cognitive data from 1256 late–middle aged adults from the Wisconsin Registry for Alzheimer’s Prevention study to examine the effects of sex, apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a set of models with different combinations of interactions among sex, APOE, literacy, and age. Results: For a list-learning test, model-averaged results showed better performance for women versus men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an association with cognitive performance in this age range (∼40–70 years). Conclusions: These results illustrate the utility of the IT approach and point to literacy as a potential modifier of cognitive decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work. (JINS, 2019, 25, 119–133)
Knowledge of the effects of burial depth and burial duration on seed viability and, consequently, seedbank persistence of Palmer amaranth (Amaranthus palmeri S. Watson) and waterhemp [Amaranthus tuberculatus (Moq.) J. D. Sauer] ecotypes can be used for the development of efficient weed management programs. This is of particular interest, given the great fecundity of both species and, consequently, their high seedbank replenishment potential. Seeds of both species collected from five different locations across the United States were investigated in seven states (sites) with different soil and climatic conditions. Seeds were placed at two depths (0 and 15 cm) for 3 yr. Each year, seeds were retrieved, and seed damage (shrunken, malformed, or broken) plus losses (deteriorated and futile germination) and viability were evaluated. Greater seed damage plus loss averaged across seed origin, burial depth, and year was recorded for lots tested at Illinois (51.3% and 51.8%) followed by Tennessee (40.5% and 45.1%) and Missouri (39.2% and 42%) for A. palmeri and A. tuberculatus, respectively. The site differences for seed persistence were probably due to higher volumetric water content at these sites. Rates of seed demise were directly proportional to burial depth (α=0.001), whereas the percentage of viable seeds recovered after 36 mo on the soil surface ranged from 4.1% to 4.3% compared with 5% to 5.3% at the 15-cm depth for A. palmeri and A. tuberculatus, respectively. Seed viability loss was greater in the seeds placed on the soil surface compared with the buried seeds. The greatest influences on seed viability were burial conditions and time and site-specific soil conditions, more so than geographical location. Thus, management of these weed species should focus on reducing seed shattering, enhancing seed removal from the soil surface, or adjusting tillage systems.
Objectives: Intraindividual cognitive variability (IICV) has been shown to differentiate between groups with normal cognition, mild cognitive impairment (MCI), and dementia. This study examined whether baseline IICV predicted subsequent mild to moderate cognitive impairment in a cognitively normal baseline sample. Methods: Participants with 4 waves of cognitive assessment were drawn from the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=684; 53.6(6.6) baseline age; 9.1(1.0) years follow-up; 70% female; 74.6% parental history of Alzheimer’s disease). The primary outcome was Wave 4 cognitive status (“cognitively normal” vs. “impaired”) determined by consensus conference; “impaired” included early MCI (n=109), clinical MCI (n=11), or dementia (n=1). Primary predictors included two IICV variables, each based on the standard deviation of a set of scores: “6 Factor IICV” and “4 Test IICV”. Each IICV variable was tested in a series of logistic regression models to determine whether IICV predicted cognitive status. In exploratory analyses, distribution-based cutoffs incorporating memory, executive function, and IICV patterns were used to create and test an MCI risk variable. Results: Results were similar for the IICV variables: higher IICV was associated with greater risk of subsequent impairment after covariate adjustment. After adjusting for memory and executive functioning scores contributing to IICV, IICV was not significant. The MCI risk variable also predicted risk of impairment. Conclusions: While IICV in middle-age predicts subsequent impairment, it is a weaker risk indicator than the memory and executive function scores contributing to its calculation. Exploratory analyses suggest potential to incorporate IICV patterns into risk assessment in clinical settings. (JINS, 2016, 22, 1016–1025)
There is a growing body of literature describing the characteristics of patients who plan for the end of life, but little research has examined how caregivers influence patients' advance care planning (ACP). The purpose of this study was to examine how patient and caregiver characteristics are associated with advance directive (AD) completion among patients diagnosed with a terminal illness. We defined AD completion as having completed a living will and/or identified a healthcare power of attorney.
Method:
A convenience sample of 206 caregiver–patient dyads was included in the study. All patients were diagnosed with an advanced life-limiting illness. Trained research nurses administered surveys to collect information on patient and caregiver demographics (i.e., age, sex, race, education, marital status, and individual annual income) and patients' diagnoses and completion of AD. Multivariate logistic regression was employed to model predictors for patients' AD completion.
Results:
Over half of our patient sample (59%) completed an AD. Patients who were older, diagnosed with amyotrophic lateral sclerosis, and with a caregiver who was Caucasian or declined to report an income level were more likely to have an AD in place.
Significance of results:
Our results suggest that both patient and caregiver characteristics may influence patients' decisions to complete an AD at the end of life. When possible, caregivers should be included in advance care planning for patients who are terminally ill.
The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer’s disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimer’s Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aβ42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aβ and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aβ42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aβ burden, that is, increased PiB-PET binding or reduced CSF Aβ42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aβ-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD. (JINS, 2015, 21, 841–850)
from
Part II
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State space methods for clinical data
By
L. H. Lehman, Massachusetts Institute of Technology,
M. J. Johnson, Massachusetts Institute of Technology,
S. Nemati, Harvard University,
R. P. Adams, Harvard University,
R. G. Mark, Massachusetts Institute of Technology
The time series of vital signs, such as heart rate (HR) and blood pressure (BP), can exhibit complex dynamic behaviors as a result of internally and externally induced changes in the state of the underlying control systems (Peng et al. 1995; Ivanov et al. 1999; Costa et al. 2002). For instance, time series of BP can exhibit oscillations on the order of seconds (e.g., due to the variations in sympathovagal balance), to minutes (e.g., as a consequence of fever, blood loss, or behavioral factors), to hours (e.g., due to humoral variations, sleep-wake cycle, or circadian effects) (Mancia 2012; Parati et al. 2013). A question of interest is whether “similar” dynamical patterns can be automatically identified across a heterogeneous patient cohort, and be used for prognosis of patients' health and progress.
In this work, we present a Bayesian nonparametric switching Markov processes framework with conditionally linear dynamics to learn phenotypic dynamic behaviors from vital sign time series of a patient cohort, and use the learned dynamics to characterize the changing physiological states of patients for critical-care bed-side monitoring (Lehman et al. 2012, 2013, 2014a; Nemati 2012). We assume that although the underlying dynamical system may be nonlinear and nonstationary and the stochastic noise components can be non-Gaussian, the dynamics can be approximated by a collection of linear dynamical systems (Nemati 2012; Nemati et al. 2012). Each such linear “dynamic” (or mode) is a time-dependent rule that describes how the future state of the system evolves from its current state, centered around a given system equilibrium point. Therefore, an ideal algorithm would be able to identify time series segments that follow a “similar” dynamic, and would switch to a different mode upon a change in the state of the underlying system.
We explore several variants of the Bayesian nonparametric approach to discovery of shared dynamics among patients via switching Markov processes: hierarchical Dirichlet process (HDP) autoregressive hidden Markov model (HDP-AR-HMM) (Teh et al. 2006; Fox et al. 2008), an explicit-duration HDP-based hidden semi-Markov model (HDP-AR-HSMM) (Johnson & Willsky 2013a), and the beta process autoregressive HMM (BP-AR-HMM) (Fox 2009; Fox et al. 2009, 2014).
Communication may be an influential determinant of inequality of access to, engagement with and benefit from psychiatric services.
Aims
To review the evidence on interventions designed to improve therapeutic communications between Black and minority ethnic patients and clinicians who provide care in psychiatric services.
Method
Systematic review and evidence synthesis (PROSPERO registration: CRD42011001661). Data sources included the published and the ‘grey’ literature. A survey of experts and a consultation with patients and carers all contributed to the evidence synthesis, interpretation and recommendations.
Results
Twenty-one studies were included in our analysis. The trials showed benefits mainly for depressive symptoms, experiences of care, knowledge, stigma, adherence to prescribed medication, insight and alliance. The effect sizes were smaller for better-quality trials (range of d 0.18–0.75) than for moderate- or lower-quality studies (range of d 0.18–4.3). The review found only two studies offering weak economic evidence.
Conclusions
Culturally adapted psychotherapies, and ethnographic and motivational assessment leading to psychotherapies were effective and favoured by patients and carers. Further trials are needed from outside of the UK and USA, as are economic evaluations and studies of routine psychiatric care practices.
Antibiograms have effectively improved antibiotic prescribing in acute-care settings; however, their effectiveness in skilled nursing facilities (SNFs) is currently unknown.
Objective.
To develop SNF-specific antibiograms and identify opportunities to improve antibiotic prescribing.
Design and Setting.
Cross-sectional and pretest-posttest study among residents of 3 Maryland SNFs.
Methods.
Antibiograms were created using clinical culture data from a 6-month period in each SNF. We also used admission clinical culture data from the acute care facility primarily associated with each SNF for transferred residents. We manually collected all data from medical charts, and antibiograms were created using WHONET software. We then used a pretest-posttest study to evaluate the effectiveness of an antibiogram on changing antibiotic prescribing practices in a single SNF. Appropriate empirical antibiotic therapy was defined as an empirical antibiotic choice that sufficiently covered the infecting organism, considering antibiotic susceptibilities.
Results.
We reviewed 839 patient charts from SNF and acute care facilities. During the initial assessment period, 85% of initial antibiotic use in the SNFs was empirical, and thus only 15% of initial antibiotics were based on culture results. Fluoroquinolones were the most frequently used empirical antibiotics, accounting for 54.5% of initial prescribing instances. Among patients with available culture data, only 35% of empirical antibiotic prescribing was determined to be appropriate. In the single SNF in which we evaluated antibiogram effectiveness, prevalence of appropriate antibiotic prescribing increased from 32% to 45% after antibiogram implementation; however, this was not statistically significant (P = .32).
Conclusions.
Implementation of antibiograms may be effective in improving empirical antibiotic prescribing in SNFs.
The relative influence of amyloid burden, neuronal structure and function, and prior cognitive performance on prospective memory decline among asymptomatic late middle-aged individuals at risk for Alzheimer's disease (AD) is currently unknown. We investigated this using longitudinal cognitive data from 122 middle-aged adults (21 “Decliners” and 101 “Stables”) enrolled in the Wisconsin Registry for Alzheimer's Prevention who underwent multimodality neuroimaging [11C-Pittsburgh Compound B (PiB), 18F-fluorodeoxyglucose (FDG), and structural/functional magnetic resonance imaging (fMRI)] 5.7 ± 1.4 years (range = 2.9–8.9) after their baseline cognitive assessment. Covariate-adjusted regression analyses revealed that the only imaging measure that significantly distinguished Decliners from Stables (p = .027) was a Neuronal Function composite derived from FDG and fMRI. In contrast, several cognitive measures, especially those that tap episodic memory, significantly distinguished the groups (p's<.05). Complementary receiver operating characteristic curve analyses identified the Brief Visuospatial Memory Test-Revised (BVMT-R) Total (.82 ± .05, p < .001), the BVMT-R Delayed Recall (.73 ± .06, p = .001), and the Reading subtest from the Wide-Range Achievement Test-III (.72 ± .06, p = .002) as the top three measures that best discriminated the groups. These findings suggest that early memory test performance might serve a more clinically pivotal role in forecasting future cognitive course than is currently presumed. (JINS, 2014, 20, 1–12)
The natural history of congenital lower urinary tract obstruction (LUTO) is highly variable and dependent on the gender, severity, duration, and age of onset of the obstruction. Outcome is measured in terms of postnatal survival and is dependent on two factors: pulmonary development and renal function. Complete urethral obstruction or significant restriction of urethral flow results in accumulation of urine within the fetal bladder, leading to marked distention. Prolonged obstruction results in smooth muscle hypertrophy and hyperplasia within the bladder wall, and eventual impairment of contractile capacity as well as compliance and elasticity. Histological studies indicate a progressive dilatation of the distal to proximal renal tubules associated with development of peritubular and interstitial fibrosis. Component of the prenatal evaluation is the serial analysis of fetal urine, obtained by vesicocentesis. More recent studies were designed to focus on the long-term outcomes of children with specific documented urethral obstructions.