Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

The Nudging Effect of a Reminder Letter to Reduce Duplicated Medications: A Randomized Controlled Trial.

BACKGROUND: The increasing trend of multiple chronic conditions across the world has worsened the problem of medication duplication in health care systems without gatekeeping or referral requirement. Thus, to overcome this problem, a reminder letter has been developed in Taiwan to nudge patients to engage in medication management. OBJECTIVE: To evaluate the effect of reminder letter on reducing duplicated medications. RESEARCH DESIGN: A 2-arm randomized controlled trial design. SUBJECTS: Patients with duplicated medications in the first quarter of 2019. MEASURES: The Taiwanese single-payer National Health Insurance Administration identified the eligible patients for this study. A postal reminder letter regarding medication duplication was mailed to the patients in the study group, and no information was provided to the comparison group. Generalized estimation equation models with a difference-in-differences analysis were used to estimate the effects of the reminder letters. RESULTS: Each group included 11,000 patients. Those who had received the reminder letter were less likely to receive duplicated medications in the subsequent 2 quarters (postintervention 1: odds ratio [OR]=0.95, 95% CI=0.87-1.03; postintervention_2: OR=0.99, 95% CI=0.90-1.08) and had fewer days of duplicated medications (postintervention 1: ß=-0.115, P =0.015; postintervention 2 (ß=-0.091, P =0.089) than those who had not received the reminder letter, showing marginal but significant differences. CONCLUSIONS: A one-off reminder letter nudge could mildly decrease the occurrence of duplicated medications. Multiple nudges or nudges incorporating behavioral science insights may be further considered to improve medication safety in health systems without gatekeeping.

Quantitative and Multiplexed Chopper-Based Time-Gated Imaging for Bioanalysis on a Smartphone.

Smartphones are emerging platforms for point-of-care diagnostics (POCDs), where the on-board camera is, for example, used to image fluorescence. Many laboratory instruments are capable of time-gated (TG) photoluminescence (PL) measurements─an analytical method leveraged by multiple commercial assay kits. When paired with long-lived PL emitters such as luminescent lanthanide complexes (LLCs), time-gating eliminates background from sample autofluorescence and many other sources. This capability is amenable to minimally processed samples and would thus be useful for POCDs on a smartphone-based platform. Here, we report a double-chopper design for TG PL imaging using a portable, 3D-printed, smartphone-based device. The rotation speed, dimensions, and overlap of the chopper blades and gaps set the timing parameters, with delay times on the order of hundreds of microseconds to milliseconds. The device was capable of quantitative TG imaging of PL from terbium(III) and europium(III) LLCs, including rejection of short-lived PL background from serum and tissue phantoms, spectral and temporal multiplexing, a model time-gated Förster resonance energy transfer (TG-FRET) assay, and imaging of cells. As the first smartphone-based demonstrations of these important analytical capabilities, this work is an important foundation for developing POCD methods based on TG PL imaging.

Photoluminescent Nanoparticles for Chemical and Biological Analysis and Imaging.

Research related to the development and application of luminescent nanoparticles (LNPs) for chemical and biological analysis and imaging is flourishing. Novel materials and new applications continue to be reported after two decades of research. This review provides a comprehensive and heuristic overview of this field. It is targeted to both newcomers and experts who are interested in a critical assessment of LNP materials, their properties, strengths and weaknesses, and prospective applications. Numerous LNP materials are cataloged by fundamental descriptions of their chemical identities and physical morphology, quantitative photoluminescence (PL) properties, PL mechanisms, and surface chemistry. These materials include various semiconductor quantum dots, carbon nanotubes, graphene derivatives, carbon dots, nanodiamonds, luminescent metal nanoclusters, lanthanide-doped upconversion nanoparticles and downshifting nanoparticles, triplet-triplet annihilation nanoparticles, persistent-luminescence nanoparticles, conjugated polymer nanoparticles and semiconducting polymer dots, multi-nanoparticle assemblies, and doped and labeled nanoparticles, including but not limited to those based on polymers and silica. As an exercise in the critical assessment of LNP properties, these materials are ranked by several application-related functional criteria. Additional sections highlight recent examples of advances in chemical and biological analysis, point-of-care diagnostics, and cellular, tissue, and in vivo imaging and theranostics. These examples are drawn from the recent literature and organized by both LNP material and the particular properties that are leveraged to an advantage. Finally, a perspective on what comes next for the field is offered.

Neural Basis of Somatosensory Spatial and Temporal Discrimination in Humans: The Role of Sensory Detection.

While detecting somatic stimuli from the external environment, an accurate determination of their spatial and temporal properties is essential for human behavior. Whether and how detection relates to human capacity for somatosensory spatial discrimination (SD) and temporal discrimination (TD) remains unclear. Here, participants underwent functional magnetic resonance imaging scanning when simply detecting vibrotactile stimuli of the leg, judging their location (SD), or deciding their number in time (TD). By conceptualizing tactile discrimination as consisting of detection and determination processes, we found that tactile detection elicited activation specifically involved in SD within the right inferior and superior parietal lobules, 2 regions previously implicated in the control of spatial attention. These 2 regions remained activated in the determination process, during which functional connectivity between these 2 regions predicted individual SD ability. In contrast, tactile detection produced little activation specifically related to TD. Participants' TD ability was implemented in brain regions implicated in coding temporal structures of somatic stimuli (primary somatosensory cortex) and time estimation (anterior cingulate, pre-supplementary motor area, and putamen). Together, our findings indicate a close link between somatosensory detection and SD (but not TD) at the neural level, which aids in explaining why we can promptly respond toward detected somatic stimuli.

Residential greenness and birth outcomes: Evaluating the mediation and interaction effects of particulate air pollution.

BACKGROUND: The few studies that examined the association between residential greenness and birth outcomes have produced inconsistent results, and the underlying mechanisms of these associations remain unclear. OBJECTIVES: We examined the mediation and interaction effects of particulate matter (PM) air pollution on the relationship between greenness exposure during the first and third trimesters of pregnancy and birth outcomes, including preterm birth (PTB), term low birth weight (TLBW), small for gestational age (SGA), birth weight (BW), and head circumference (HC). METHODS: We conducted a retrospective cohort study on 16,184 singleton live births between 2010 and 2012 in Taiwan. Residential greenness was estimated based on the normalized difference vegetation index (NDVI), and the PM information during the first and third trimesters was estimated through hybrid kriging land use regression and ordinary kriging interpolation methods. Multiple regression analyses were performed to evaluate the associations between greenness exposure and birth outcomes. We estimated the mediating effects of PM associated with greenness exposure on birth outcomes through causal mediation analyses. We also examined the potential multiplicative and additive interactions between greenness exposure and PM and their effects on birth outcomes. RESULTS: The first trimester NDVI exposure was associated with reduced risks for PTB, TLBW, and SGA, which had an adjusted OR (aOR) of 0.93 (95% CI: 0.89-0.97), 0.91 (95% CI: 0.83-0.99), and 0.95 (95% CI: 0.91-1.00), respectively, per 0.1 unit increase in multi-pollutant models. The causal mediation analysis showed that PM mediated approximately 5-19% of the association between first and third trimester greenness and PTB and mediated approximately 15-37% of the association between greenness and SGA. We identified multiplicative interactions in log scale between first trimester PM10 and NDVI exposure for SGA (aORinteraction = 0.92, p = 0.03) and HC (estimateinteraction = 1.47, p = 0.04). CONCLUSIONS: This study revealed beneficial associations between residential greenness and birth outcomes, including PTB, TLBW, and SGA. The associations were partly mediated by a reduction in exposure to PM air pollution. SUMMARY: The beneficial effects of greenness on PTB and SGA are partly mediated by a reduction in exposure to PM air pollution.

Effects of Positive and Negative Expectations on Human Pain Perception Engage Separate But Interrelated and Dependently Regulated Cerebral Mechanisms.

Expectations substantially influence pain perception, but the relationship between positive and negative expectations remains unclear. Recent evidence indicates that the integration between pain-related expectations and prediction errors is crucial for pain perception, which suggests that aversive prediction error-associated regions, such as the anterior insular cortex (aIC) and rostral anterior cingulate cortex (rACC), may play a pivotal role in expectation-induced pain modulation and help to delineate the relationship between positive and negative expectations. In a stimulus expectancy paradigm combining fMRI in healthy volunteers of both sexes, we found that, although positive and negative expectations respectively engaged the right aIC and right rACC to modulate pain, their associated activations and pain rating changes were significantly correlated. When positive and negative expectations modulated pain, the right aIC and rACC exhibited opposite coupling with periaqueductal gray (PAG) and the mismatch between actual and expected pain respectively modulated their coupling with PAG and thalamus across individuals. Participants' certainty about expectations predicted the extent of pain modulation, with positive expectations involving connectivity between aIC and hippocampus, a region regulating anxiety, and negative expectations engaging connectivity between rACC and lateral orbitofrontal cortex, a region reflecting outcome value and certainty. Interestingly, the strength of these certainty-related connectivities was also significantly associated between positive and negative expectations. These findings suggest that aversive prediction-error-related regions interact with pain-processing circuits to underlie stimulus expectancy effects on pain, with positive and negative expectations engaging dissociable but interrelated neural responses that are dependently regulated by individual certainty about expectations.SIGNIFICANCE STATEMENT Positive and negative expectations substantially influence pain perception, but their relationship remains unclear. Using fMRI in a stimulus expectancy paradigm, we found that, although positive and negative expectations engaged separate brain regions encoding the mismatch between actual and expected pain and involved opposite functional connectivities with the descending pain modulatory system, they produced significantly correlated pain rating changes and brain activation. Moreover, participants' certainty about expectations predicted the magnitude of both types of pain modulation, with the underlying functional connectivities significantly correlated between positive and negative expectations. These findings advance current understanding about cognitive modulation of pain, suggesting that both types of pain modulation engage different aversive prediction error signals but are dependently regulated by individual certainty about expectations.

Gestational risk factors and childhood cancers: A cohort study in Taiwan.

Gestational risk factors such as birth weight, gestational age and parity have been repeatedly found to be related to pediatric cancers, but few reports have emerged from Asian countries. Here we report on demographic and gestational factors in a Taiwanese cohort. Our study included all children born in Taiwan 2004-2014 for whom there was a birth record (n = 2,079,037), of which 1900 children had been diagnosed with cancer prior to age 12. We conducted multivariable hazard regression to examine associations between demographic and gestational factors with cancer. Greater parity (family with 2+ older children) was related to acute myeloid leukemia [Hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.31, 3.55), central nervous system tumors (HR = 1.67, CI: 1.13, 2.48) and neuroblastoma (HR = 1.67, CI: 1.07, 2.63). Hepatoblastoma cases had a higher risk of low birth weight (<2,500 g; HR = 3.01, CI: 1.85, 4.91), very preterm birth (<33 weeks gestation; HR = 13.71, CI: 7.45, 25.23), plural pregnancies (HR = 2.37, CI: 1.10, 5.14) and both small (HR = 2.13, CI: 1.23, 3.67) and large (HR = 1.83, CI: 1.01, 3.32) for gestational age. Germ cell tumors were more common among children born in rural areas (HR = 1.63, CI: 1.02, 2.60). Despite that Taiwan has lower rates of both high and low birthweight compared to other developed nations, we observed several similar associations to those reported in Western Countries. Further research should examine unique exposures in Taiwan that may be contributing to higher incidence of certain cancer types.

Quality of life of breast cancer survivors following breast-conserving therapy versus mastectomy: a multicenter study in Taiwan.

BACKGROUND: Breast cancer is the most common female malignancy worldwide. The aim of this study was to investigate the influence of surgical procedures and quality-of-care (QoC) on quality-of-life (QoL) among breast cancer survivors who underwent breast-conserving therapy (BCT) or mastectomy, and to identify provider- and patient-related factors pertaining to QoL. METHOD: In this cross-sectional study, structured-questionnaires were distributed among breast cancer survivors in 19 hospitals. QoL was evaluated using the European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30) and the breast cancer specific module (EORTC QLQ-BR23). QoC is indicated by adherence to the core measures stipulated for the treatment of breast cancer. Multiple regression and hierarchical linear modeling were used for multivariate analysis. RESULTS: A total of 544 female survivors of Stage 0-III breast cancer were included, among whom 217 (39.9%) underwent BCT and 327 (60.1%) underwent mastectomy. Surgical modality does not appear to have a notable impact on any QoL domains except body image; i.e. patients who underwent BCT reported better body image (diff = 11.20, P < 0.001), particularly at 1-5 years after the initial treatment. Independent factors including age, education, employment, marital status, income, chemotherapy, duration since treatment, recurrence status, primary hospital accreditation level and location all appear to be correlated to QoL. CONCLUSION: Patients with breast cancer should be informed of differences in QoL when discussing treatment options. Furthermore, physicians should recognize that the impact of surgical treatment modality on QoL may vary according to patients' sociodemographic and clinical characteristics.

Effect of charged amino acid side chain length on lateral cross-strand interactions between carboxylate-containing residues and lysine analogues in a ß-hairpin.

ß-Sheets are one of the fundamental three-dimensional building blocks for protein structures. Oppositely charged amino acids are frequently observed directly across one another in antiparallel sheet structures, suggesting the importance of cross-strand ion pairing interactions. Despite the apparent electrostatic nature of ion pairing interactions, the charged amino acids Asp, Glu, Arg, Lys have different numbers of hydrophobic methylenes linking the charged functionality to the backbone. Accordingly, the effect of charged amino acid side chain length on cross-strand ion pairing interactions at lateral non-hydrogen bonded positions was investigated in a ß-hairpin motif. The negatively charged residues with a carboxylate (Asp, Glu, Aad in increasing length) were incorporated at position 4, and the positively charged residues with an ammonium (Dap, Dab, Orn, Lys in increasing length) were incorporated at position 9. The fraction folded population and folding free energy were derived from the chemical shift deviation data. Double mutant cycle analysis was used to determine the interaction energy for the potential lateral ion pairs. Only the Asp/Glu-Dap interactions with shorter side chains and the Aad-Orn/Lys interactions with longer side chains exhibited stabilizing energetics, mostly relying on electrostatics and hydrophobics, respectively. This suggested the need for length matching of the interacting residues to stabilize the ß-hairpin motif. A survey of a nonredundant protein structure database revealed that the statistical sheet pair propensity followed the trend Asp-Lys < Glu-Lys, also implying the need for length matching of the oppositely charged residues.

Effect of charged amino acid side chain length at non-hydrogen bonded strand positions on ß-hairpin stability.

ß-Sheets have been implicated in various neurological disorders, and ∼20% of protein residues adopt a sheet conformation. Therefore, studies on the structural origin of sheet stability can provide fundamental knowledge with potential biomedical applications. Oppositely charged amino acids are frequently observed across one another in antiparallel ß-sheets. Interestingly, the side chains of natural charged amino acids Asp, Glu, Arg, Lys have different numbers of hydrophobic methylenes linking the backbone to the hydrophilic charged functionalities. To explore the inherent effect of charged amino acid side chain length on antiparallel sheets, the stability of a designed hairpin motif containing charged amino acids with varying side chain lengths at non-hydrogen bonded positions was studied. Peptides with the guest position on the N-terminal strand and the C-terminal strand were investigated by NMR methods. The charged amino acids (Xaa) included negatively charged residues with a carboxylate group (Asp, Glu, Aad in increasing length), positively charged residues with an ammonium group (Dap, Dab, Orn, Lys in increasing length), and positively charged residues with a guanidinium group (Agp, Agb, Arg, Agh in increasing length). The fraction folded and folding free energy for each peptide were derived from the chemical shift deviation data. The stability of the peptides with the charged residues at the N-terminal guest position followed the trends: Asp > Glu > Aad, Dap < Dab < Orn ∼ Lys, and Agb < Arg < Agh < Agp. The stability of the peptides with the charged residues at the C-terminal guest position followed the trends: Asp < Glu < Aad, Dap ∼ Dab < Orn ∼ Lys, and Agb < Arg ∼ Agp < Agh. These trends were rationalized by thermodynamic sheet propensity and cross-strand interactions.

Spectrotemporal characterization of photoluminescent silicon nanocrystals and their energy transfer to dyes.

Silicon nanocrystals (SiNCs) are a promising material for applications in bioanalysis and imaging. Compared to other types of semiconductor nanocrystals, the development and characterization of energy transfer (ET) configurations with SiNCs has been far more limited, resulting in an equally limited understanding of this process and its SiNC-specific nuances. Here, we present a systematic and detailed study of ET between SiNCs and dyes. A combination of spectroelectrophoresis and time-gated and time-resolved photoluminescence measurements were used to characterize the photophysical properties of ensembles of SiNCs and gain insight into how these properties varied as a function of nanocrystal size. ET between SiNC donors and a series of non-fluorescent Black Hole Quencher (BHQ) dyes and fluorescent sulfo-Cyanine 5.5 dye acceptors was evaluated in terms of spectral properties, wavelength-resolved efficiencies, trends with spectral overlap integral, and differences between two methods of BHQ association with the SiNCs. The overall results were consistent with a Förster resonance energy transfer (FRET) mechanism where the polydispersity of the SiNCs had a significant impact on the observed ET: the choice of wavelength and timing parameters were important, and ensemble measurements represented an average of heterogeneous ET behaviors. Prospective advantages and disadvantages of SiNCs as ET donors are discussed. This study serves as a foundation for the continued and optimized development of ET configurations with SiNCs.

A Dendrimer-Based Time-Gated Concentric FRET Configuration for Multiplexed Sensing.

Förster resonance energy transfer (FRET) is widely used for the development of biological probes and sensors. In this context, the norm for multiplexed detection is deployment of multiple probes, each a discrete donor-acceptor pair. Concentric FRET (cFRET) probes enable multiplexed sensing with a single vector but, to date, have only been developed around semiconductor quantum dots, which may limit the scope of biological applications for such probes. Here, we demonstrate that dendrimers labeled with a luminescent terbium complex (Tb) are a viable and advantageous alternative platform for cFRET probes. Polyamidoamine dendrimers were functionalized with Tb, biotin, NeutrAvidin, and three types of dye-labeled oligonucleotide probes to establish a network of competitive and sequential Tb-to-dye and dye-to-dye FRET pathways. These probes were characterized physically and photophysically, and a time-gated multiplexed assay for DNA targets was demonstrated. The time-gating offered by the Tb allowed the rejection of background autofluorescence from serum. More broadly, this dendrimer-based architecture shows that cFRET is a general concept and is an important step toward a new generation of probes for biological sensing.

Why is hypercalciuria absent at diagnosis in some children with ATP6V1B1 mutation?

We try to explain why hypercalciuria is absent at diagnosis in some children with an ATP6V1B1 mutation. A 5-month-old girl presented with distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Direct sequencing of the ATP6V1B1 genes disclosed a new homozygous mutation (452 delT) in exon 13. In particular, an absence of hypercalciuria and a normal level of parathyroid hormones were noted. After alkaline therapy, the signs of nephrocalcinosis improved on ultrasound during follow-up. After a review of the literature regarding patients with ATP6V1B1 gene mutations, a young age seemed to be an important factor for normocalciuria. The probable mechanism of normocalciuria and a dynamic mode of calcium excretion in patients with dRTA is proposed. The determinant factors include the degree of systemic acidosis, urine pH, genetic polymorphisms, age, dietary factors, and volume status. Low sodium intake may be a major determinant of normocalciuria in these patients. It is suggested that hypercalciuria is usually absent at diagnosis of dRTA in young infants. Blood pH, plasma bicarbonate concentration, urinary citrate levels, and growth catch-up may be better indicators of adequate alkali therapy in normocalciuric children. Volume contraction, low salt content in infant formula, and alkaline urine in young infants are likely to account for the increased calcium reabsorption.

Preparation and Characterization of Quantum Dot-Peptide Conjugates Based on Polyhistidine Tags.

Quantum dots (QDs) offer bright and robust photoluminescence among several other advantages in comparison to fluorescent dyes. In order to leverage the advantageous properties of QDs for applications in bioanalysis and imaging, simple and reliable methods for bioconjugation are required. One such method for conjugating peptides to QDs is the use of polyhistidine tags, which spontaneously bind to the surface of QDs. We describe protocols for assembling polyhistidine-tagged peptides to QDs and for characterizing the resultant QD-peptide conjugates. The latter include both electrophoretic and FRET-based protocols for confirming successful peptide assembly, estimating the maximum peptide loading capacity, and measuring the assembly kinetics. Sensors for protease activity and intracellular delivery are briefly noted as prospective applications of QD-peptide conjugates.

Concentric FRET: a review of the emerging concept, theory, and applications.

Concentric Förster resonance energy transfer (cFRET) is an emerging concept for single-vector multiplexed bioanalysis and imaging. It features a network of competitive and sequential energy transfer pathways, which, to date, has been assembled with a central semiconductor quantum dot (QD) and biomolecular linkers to multiple copies of multiple types of concentrically-arranged fluorescent dyes. In this review, we provide a first-hand account of the concept and development of cFRET, starting from its place in the broader context of FRET probes and assemblies. Topics of discussion include materials for cFRET, with a focus on the enabling properties of QDs and the ideal properties of nominal acceptor dyes; characterization and analysis of cFRET configurations via photoluminescence intensity, emission ratio, lifetime, and photobleaching measurements; semi-empirical modeling to determine the rates and efficiencies of competitive and sequential FRET pathways from overall quenching efficiencies; and archetypical examples of cFRET configurations and their application in bioanalysis and imaging. Most of the latter examples demonstrate multiplexed detection of protease activity or nucleic acid targets. Examples of atypical and cFRET-like configurations are also discussed, including those that utilize time-gated FRET relays and charge-transfer quenching. We conclude with a perspective on challenges and directions for future research with cFRET. Although still emerging as a method, many exciting opportunities in bioanalysis, imaging, and beyond are envisioned for cFRET.

Insight into Patients' Experiences of Cancer Care in Taiwan: An Instrument Translation and Cross-Cultural Adaptation Study.

Background: Since Taiwan launched the Cancer Prevention Act in 2003, several prevention strategies and early detection programs have been implemented to reduce the incidence, morbidity and mortality rates of cancer. However, most of the programs have concentrated on healthcare providers. Evaluations from the patient's perspective have been lacking. Thus, in this study a cancer patient experience questionnaire was developed in the Taiwanese context and a preliminary nationwide investigation was conducted on the status of cancer care from the patient's perspective. Methods: An extensive literature review was first conducted to collect information on the existing instruments used to measure the cancer patient's experience. Thereafter, a multidisciplinary expert panel was convened to select an optimal instrument based on the IOM's six domains for evaluating patient-centered care. The European Organisation for Research and Treatment of Cancer (EORTC) translation procedure was applied to the questionnaire for cross-cultural adaptation. A nationwide field test was then implemented at certificated cancer care hospitals. Results: Fifteen questionnaires were collected for the literature review. The expert panel selected the National Cancer Patient Experience Survey based on the IOM's recommendations. After cross-cultural translation of the questionnaire, a total of 4000 questionnaires were administered in 19 certificated cancer care hospitals and two major cancer patient associations, with 1010 being returned (25.25% response rate). Most of the respondents were middle-aged, and 70% were female. The respondents reported they had a good experience with cancer care, except for "Home care and support" and "Finding out what was wrong with you". Stratified analysis was conducted, with the results showing that the cancer patients' experiences varied depending on their sociodemographic and cancer-related characteristics. Conclusions: A Taiwanese version of the cancer patient experience survey questionnaire was developed. Its results showed that the cancer patient's experiences varied, depending on the patient's age, cancer type, and cancer history. This study can be used as a basis to establish a patient-centered care model for cancer care in Taiwan.

Impact of Targeted Therapy on the Quality of End-of-Life Care for Patients With Non-Small-Cell Lung Cancer: A Population-Based Study in Taiwan.

CONTEXT: Targeted therapies with epidermal growth factor receptor tyrosine kinase inhibitors have been widely used in the treatment of advanced non-small-cell lung cancer (NSCLC). However, little research has focused on the use of targeted therapies at the end of life (EOL). OBJECTIVES: This study investigated the determinants of receiving targeted therapy during the last month of life and how targeted therapies affect the quality of EOL care. METHODS: We conducted a retrospective population-based study using a cancer registry and National Health Insurance claims data among 42,678 Taiwanese NSCLC decedents in 2005-2012. Propensity score matching and generalized linear mixed models were used to estimate associations. RESULTS: We identified 3439 (21.3%) NSCLC patients who received targeted therapy within 30 days of death. Younger age, adenocarcinoma histology, postdiagnosis survival exceeding six months, and later year of death were associated with receiving targeted agents at EOL. The odds increased when patients were treated by pulmonologists or oncologists or in district hospitals or facilities with a higher case volume. Patients who were prescribed targeted therapy near death were significantly more likely to undergo aggressive EOL care (odds ratio = 2.35, 95% CI = 1.83-3.02) including multiple emergency department visits, hospitalization exceeding 14 days, admission to intensive care units, use of intubation and mechanical ventilation, cardiopulmonary resuscitation, and late hospice referrals. CONCLUSIONS: Targeted therapy at EOL should be considered a quality-of-care indicator. Guidance in the cessation of targeted therapy and the ongoing monitoring of practice initiatives are warranted. The decision-making processes associated with EOL care also require further investigation.

Differences in the outcomes of adjuvant chemotherapy for colon cancer prescribed by physicians in different disciplines: a population-based study in Taiwan.

OBJECTIVES: One feature unique to the Taiwanese healthcare system is the ability of physicians other than oncologists to prescribe systemic chemotherapy. This study investigated whether the care paths implemented by oncologists and non-oncologists differ with regard to patient outcomes. SETTING: Data from the Taiwan Cancer Registry and National Health Insurance Database were linked to identify patients with colon cancer who underwent colectomy as first treatment within 3 months of diagnosis and adjuvant chemotherapy between 2005 and 2009. PARTICIPANTS AND METHODS: Postoperative patients who underwent adjuvant chemotherapy were included in this study. The exclusion criteria included patients with stage IV disease, a positive surgical margin and early disease recurrence. Among the patients presenting with multiple primary cancers, we also excluded patients who were diagnosed with colon cancer but for whom this was not the first primary cancer. The variables included sex, age, comorbidities, disease stage, chemotherapy cycle and changes in treatment regimen as well as the specialty of treatment providers and their case volume. Cox regression models and Kaplan-Meier analysis were used to examine differences in outcomes in the matched cohorts. RESULTS: We examined 3534 patients who were prescribed adjuvant chemotherapy by physicians from different disciplines. In terms of 5-year disease-free survival, no significant difference was observed between the groups of oncologists or surgeons among patients with stage II (90.02%vs88.99%) or stage III (77.64%vs79.99%) diseases. Patients who were subjected to changes in their chemotherapy regimens presented recurrence rates higher than those who were not. CONCLUSIONS: The discipline of practitioners is seldom taken into account in most series. This is the first study to provide empirical evidence demonstrating that the outcomes of patients with colon cancer do not depend on the treatment path, as long as the selection criteria for adjuvant chemotherapy is appropriate. Further study will be required before making any further conclusions.

Study of urinary 2-{[2-(acetylamino-2-carboxyethyl]sulfanyl}butanedioic acid, a mercapturic acid of rats treated with maleic acid.

Maleic anhydride was reported illegally adulterated into starch to prepare traditional foods for decades in Taiwan. Maleic acid (MA), hydrolyzed from maleic anhydride, could cause kidney damages to animals. The potential health effects due to long-term MA exposures through food consumption have been of great concerns. Assessment of the dietary MA exposures could be very difficult and complicated. One of the alternatives is to analyze an MA-specific biomarker to assess the daily total MA intake. Therefore, this paper aimed to study the mercapturic acid of MA, 2-{[2-(acetylamino)-2-carboxyethyl]sulfanyl}butanedioic acid (MAMA), with our newly-developed isotope-dilution online solid-phase extraction liquid chromatography tandem mass spectrometry (ID-SPE-LC-MS/MS) method. MAMA was first synthesized, purified, and characterized with NMR to reveal two diastereomers and used for developing the analytical method. The method was validated to reveal excellent sensitivity with a LOD at 16.3ng/mL and a LOQ at 20.6ng/mL and used to analyze MAMA in urine samples collected from Sprague-Dawley rats treated with a single dose of 0mg/kg, 6mg/kg, and 60mg/kg (n=5) of MA through gavage. Our results show dose-dependent increases in urinary MAMA contents, and 70% MAMA was excreted within 12h with no gender differences (p>0.05). A half life of urinary MAMA was estimated at 6.8h for rat. The formation of urinary MAMA validates it as a chemically-specific biomarker for current MA exposure. Future study of MA metabolism in vivo will elucidate mechanisms of MAMA formation, and analysis of this marker in epidemiology studies could help to shed light on the causal effects of MA on human.