Cross-Reactive Sensor Array for Metal Ion Sensing Based on Fluorescent SAMs\ud

Fluorescent self assembled monolayers (SAMs) on glass were previouslydeveloped in our group as new sensing materials for metal ions. These fluorescent SAMs arecomprised by fluorophores and small molecules sequentially deposited on a monolayer onglass. The preorganization provided by the surface avoids the need for complex receptordesign, allowing for a combinatorial approach to sensing systems based on small molecules.Now we show the fabrication of an effective microarray for the screening of metal ions andthe properties of the sensing SAMs. A collection of fluorescent sensing SAMs wasgenerated by combinatorial methods and immobilized on the glass surfaces of a custom-made 140 well microtiter-plate. The resulting libraries are easily measured and show variedresponses to a series cations such as Cu2+ , Co2+ , Pb2+ , Ca2+ and Zn2+ . These surfaces are notdesigned to complex selectively a unique analyte but rather they are intended to producefingerprint type responses to a range of analytes by less specific interactions. The unselectiveresponses of the library to the presence of different cations generate a characteristic patternfor each analyte, a “finger print” response.\u

The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Abstract: Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making

What do Future Hospice Patients Expect of Hospice Care : Expectations of Patients in the Palliative Phase Who Might be in Need of Hospice Care in the Future: A Qualitative Exploration

Introduction: Hospice care (HC) in the Netherlands is available for patients with life expectancies <3 months. Little is known about expectations of patients who might be in need of HC. This study aims to gain insight into expectations of patients regarding HC in order to ameliorate HC to become driven by patient needs. Design: A generic qualitative study, using semistructured interviews and thematic analysis, is performed in the Netherlands from January to June 2018. A purposeful sample of 13 participants was drawn. Results: Participants expected hospice admission only when the burden became unbearable and a home death cannot be reached. Participants expected a homely atmosphere, where one can continue the life lived at home as much as possible. Participants supposed empathic professional caregivers, capable of providing appropriate care. The general practitioner is expected to stay involved in the care process due to the mutual trust. Medical and daily care are required to be provided by competent professionals, where volunteers are expected to provide supportive care. All caregivers are supposed to provide a listening ear and “being there” for participants. Social care and spiritual care are generally projected to be private matters, unless it is requested. Conclusions: Patients in the palliative phase who might be in need of HC have specific expectations. Perceptions of HC in the public domain should be nuanced in response to these expectations, and information provision on HC should be improved. Then, expectations could be met to make HC more driven by patient needs and future oriented

What do Future Hospice Patients Expect of Hospice Care : Expectations of Patients in the Palliative Phase Who Might be in Need of Hospice Care in the Future: A Qualitative Exploration

Introduction: Hospice care (HC) in the Netherlands is available for patients with life expectancies <3 months. Little is known about expectations of patients who might be in need of HC. This study aims to gain insight into expectations of patients regarding HC in order to ameliorate HC to become driven by patient needs. Design: A generic qualitative study, using semistructured interviews and thematic analysis, is performed in the Netherlands from January to June 2018. A purposeful sample of 13 participants was drawn. Results: Participants expected hospice admission only when the burden became unbearable and a home death cannot be reached. Participants expected a homely atmosphere, where one can continue the life lived at home as much as possible. Participants supposed empathic professional caregivers, capable of providing appropriate care. The general practitioner is expected to stay involved in the care process due to the mutual trust. Medical and daily care are required to be provided by competent professionals, where volunteers are expected to provide supportive care. All caregivers are supposed to provide a listening ear and “being there” for participants. Social care and spiritual care are generally projected to be private matters, unless it is requested. Conclusions: Patients in the palliative phase who might be in need of HC have specific expectations. Perceptions of HC in the public domain should be nuanced in response to these expectations, and information provision on HC should be improved. Then, expectations could be met to make HC more driven by patient needs and future oriented

A combinatiorial approach to surface-confined cation sensors in water

A novel material for sensing cations in water via fluorescence spectroscopy is presented. The material consists of a glass substrate functionalized with a series of fluorescent self-assembled monolayers. Parallel modification with pairs of fluorophore-binding molecules of monolayers formed on glass yield a library of sensitive glass substrates. Measurements of the changes in fluorescence intensity of the layers upon addition of aqueous solutions of Cu2+, Co2+, Ca2+ and Pb2+ confirmed the ability of the monolayer library to produce a fingerprint response for separate analytes with a high reproducibility. This new protocol for fabrication of sensitive probes in glass is suitable for array fabrication in small size substrates. Additionally, the covalent attachment of the fluorophore moieties to the monolayer allows monitoring of the integrity of the monolayer in time in contact with solutions. To the best of our knowledge this is the first example of sensing of cations in water by a self-assembled monolayer on glass

Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Cytochrome P-450 2D6 and 2C19 polymorphisms and consumption of care in psychiatric practice

Background: Cytochrome P-450 2D6 (CYP2D6) and 2C19 (CYP2C19) are known to contain functional polymorphisms that can alter the metabolic rate of many antidepressants (AD) and antipsychotics (AP). Individuals with no metabolic activity and with increased activity may be at risk for an unsatisfactory drug response. Objectives: Aim of this study was to assess the influence of CYP2D6 and CYP2C19 phenotypes on the consumption of care in psychiatric patients. Methods: The study was conducted in a psychiatric hospital in the Netherlands, including all admissions from July 2001 until July 2010, of patients genotyped for (at least) the CYP2D6 ∗3 ∗4 and gene multiplication and CYP2C19 ∗2. Patients were classified as poor metabolizers (PM), ultrarapid metabolizers (UM), intermediate metabolizers (IM) and extensive metabolizers (EM). To study the consumption of care, several outcome measures were calculated for PM and UM and compared to EM. Results: 7377 admissions were analyzed, belonging to 3859 unique patients. The total duration of hospital stays with AP and/or AD treatment was longer for CYP2D6 UM than for CYP2D6 EM (66 versus 48 days,

Use of preventive medication and supplements in general practice in patients in their last year of life: a Retrospective cohort study

Background: Several preventive medications and supplements become inappropriate in the last phase of life due to increased risk of adverse events caused by changed pharmacokinetics, drug-drug interactions, and changed care goals. Information on these preventive medication and supplements use in patients with a life-limiting illness in the home-care setting is limited. The primary aim of this study was to assess the use of four different groups of preventive drugs and supplements, which are inappropriate in adult patients with a life-limiting illness, living at home in the last year of life. The secondary aims were to assess reasons for discontinuing these drugs as documented in the general practitioners’ patient file and whether these reasons affected the time between medication discontinuation and death. Methods: We performed a retrospective cohort study using the routine primary care database of the Julius General Practitioners’ Network of the University Medical Centre Utrecht, a database consisting of routine care data from GPs from the city of Utrecht and its vicinity. Patients in the homecare setting with a life-limiting illness, diagnosed at least one year before death, were included. Descriptive analyses were used to describe the study population and the frequency of starting, using, and discontinuing medication and supplements in the last year of life. Results: A total of 458 of 666 included patients (69%) used at least one preventive drug in the last year of life. Vitamins were used by 36% of the patients, followed with 35% using cholesterol-lowering medication, 24% using calcium supplements and 9% using bisphosphonates. Bisphosphonates were discontinued by 70% of the users, calcium supplements by 61%, vitamins by 56% and cholesterol-lowering medication by 48% of the users, with a median interval between day of discontinuation and death of 119, 60, 110 and, 65 days, respectively. The median time between medication or supplement discontinuation and death was longest in patients with side effects and who had medication reviews. Conclusion: Many patients in their last phase of life in the home-care setting use inappropriate medication and supplements. Timely medication review may contribute to optimise medication use in the last year of life