Defining Medical Futility in Ethics, Law and Clinical Practice: An Exercise in Futility?

The debate as to the meaning of medical futility and what physicians should do in clinical practice dates back to the time of the writings of Hippocrates and Plato where it was said, "To attempt futile treatment is to display an ignorance that is allied to madness". In simpler times assertions regarding the obvious were sufficient to indicate what was thought "fitting" as a medical practitioner. In recent times, however, modern technology, professional values and power, patient autonomy, limited health care resources and societal expectations, make for a much more potent and potentially explosive mixture. In this article we argue that futility is a problem that will not go away, both because of increased health expectations and emerging technologies that keep making possible what was previously impossible. The problem of definition and its ramifications in terms of institutional policies is one in which the legal profession and its process (which often represents and reflects societal values) has a key role to play by way of critical reflection and appraisal

Confined placental mosaicism:Distribution of chromosomally abnormal cells over the term placenta

Objective: Non-invasive prenatal testing (NIPT) investigates placental DNA and may detect confined placental mosaicism (CPM). The aim of this study was to confirm CPM in the term placenta in cases with abnormal NIPT but normal follow-up cytogenetic studies of fetus and mother. Additionally we examined the distribution of abnormal cells over the placenta. Methods: Four chorionic villus (CV) biopsies from four placental quadrants were requested in cases where CPM was assumed. Both cell lineages of the CV, cytotrophoblast (CTB) and mesenchymal core (MC), were analyzed separately with SNP array. Results: The chromosome aberration was confirmed in 67 % of the placentas. Three quarters of the CTB and MC biopsies from these mosaic placentas were uniformly normal (57 %) or abnormal (20 %), and a minority showed mosaicism. Among 16 cases of CPM where first trimester CV were examined as well, 11 had chromosomally normal results during pregnancy. Discussion: Cytogenetic investigations of term placental biopsies suspected to be affected with CPM did not reveal the chromosome aberration in one third of the placentas. This is caused by the patchy pattern in which chromosomally abnormal cells are distributed over the placenta with the majority of the biopsies being uniformly normal. Further CPM research, including its clinical impact, requires the analysis of more than four biopsies to get insight into the extent of the affected part. Moreover, a subset of CPM type 1 and 3 seems to be only detectable with NIPT and not with first trimester CVS.</p

Linear ensemble-coding in midbrain superior colliculus specifies the saccade kinematics

Recently, we proposed an ensemble-coding scheme of the midbrain superior colliculus (SC) in which, during a saccade, each spike emitted by each recruited SC neuron contributes a fixed minivector to the gaze-control motor output. The size and direction of this ‘spike vector’ depend exclusively on a cell’s location within the SC motor map (Goossens and Van Opstal, in J Neurophysiol 95: 2326–2341, 2006). According to this simple scheme, the planned saccade trajectory results from instantaneous linear summation of all spike vectors across the motor map. In our simulations with this model, the brainstem saccade generator was simplified by a linear feedback system, rendering the total model (which has only three free parameters) essentially linear. Interestingly, when this scheme was applied to actually recorded spike trains from 139 saccade-related SC neurons, measured during thousands of eye movements to single visual targets, straight saccades resulted with the correct velocity profiles and nonlinear kinematic relations (‘main sequence properties– and ‘component stretching’) Hence, we concluded that the kinematic nonlinearity of saccades resides in the spatial-temporal distribution of SC activity, rather than in the brainstem burst generator. The latter is generally assumed in models of the saccadic system. Here we analyze how this behaviour might emerge from this simple scheme. In addition, we will show new experimental evidence in support of the proposed mechanism

Fetal fraction of cell-free DNA in noninvasive prenatal testing and adverse pregnancy outcomes:a nationwide retrospective cohort study of 56,110 pregnant women

Background: Noninvasive prenatal testing by cell-free DNA analysis is offered to pregnant women worldwide to screen for fetal aneuploidies. In noninvasive prenatal testing, the fetal fraction of cell-free DNA in the maternal circulation is measured as a quality control parameter. Given that fetal cell-free DNA originates from the placenta, the fetal fraction might also reflect placental health and maternal pregnancy adaptation. Objective: This study aimed to assess the association between the fetal fraction and adverse pregnancy outcomes. Study Design: We performed a retrospective cohort study of women with singleton pregnancies opting for noninvasive prenatal testing between June 2018 and June 2019 within the Dutch nationwide implementation study (Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing [TRIDENT]-2). Multivariable logistic regression analysis was used to assess associations between fetal fraction and adverse pregnancy outcomes. Fetal fraction was assessed as a continuous variable and as &lt;10th percentile, corresponding to a fetal fraction &lt;2.5%. Results: The cohort comprised 56,110 pregnancies. In the analysis of fetal fraction as a continuous variable, a decrease in fetal fraction was associated with increased risk of hypertensive disorders of pregnancy (adjusted odds ratio, 2.27 [95% confidence interval, 1.89–2.78]), small for gestational age neonates &lt;10th percentile (adjusted odds ratio, 1.37 [1.28–1.45]) and &lt;2.3rd percentile (adjusted odds ratio, 2.63 [1.96–3.57]), and spontaneous preterm birth from 24 to 37 weeks of gestation (adjusted odds ratio, 1.02 [1.01–1.03]). No association was found for fetal congenital anomalies (adjusted odds ratio, 1.02 [1.00–1.04]), stillbirth (adjusted odds ratio, 1.02 [0.96–1.08]), or neonatal death (adjusted odds ratio, 1.02 [0.96–1.08]). Similar associations were found for adverse pregnancy outcomes when fetal fraction was &lt;10th percentile. Conclusion: In early pregnancy, a low fetal fraction is associated with increased risk of adverse pregnancy outcomes. These findings can be used to expand the potential of noninvasive prenatal testing in the future, enabling the prediction of pregnancy complications and facilitating tailored pregnancy management through intensified monitoring or preventive measures.</p

Fetal fraction of cell-free DNA in noninvasive prenatal testing and adverse pregnancy outcomes:a nationwide retrospective cohort study of 56,110 pregnant women

Background: Noninvasive prenatal testing by cell-free DNA analysis is offered to pregnant women worldwide to screen for fetal aneuploidies. In noninvasive prenatal testing, the fetal fraction of cell-free DNA in the maternal circulation is measured as a quality control parameter. Given that fetal cell-free DNA originates from the placenta, the fetal fraction might also reflect placental health and maternal pregnancy adaptation. Objective: This study aimed to assess the association between the fetal fraction and adverse pregnancy outcomes. Study Design: We performed a retrospective cohort study of women with singleton pregnancies opting for noninvasive prenatal testing between June 2018 and June 2019 within the Dutch nationwide implementation study (Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing [TRIDENT]-2). Multivariable logistic regression analysis was used to assess associations between fetal fraction and adverse pregnancy outcomes. Fetal fraction was assessed as a continuous variable and as &lt;10th percentile, corresponding to a fetal fraction &lt;2.5%. Results: The cohort comprised 56,110 pregnancies. In the analysis of fetal fraction as a continuous variable, a decrease in fetal fraction was associated with increased risk of hypertensive disorders of pregnancy (adjusted odds ratio, 2.27 [95% confidence interval, 1.89–2.78]), small for gestational age neonates &lt;10th percentile (adjusted odds ratio, 1.37 [1.28–1.45]) and &lt;2.3rd percentile (adjusted odds ratio, 2.63 [1.96–3.57]), and spontaneous preterm birth from 24 to 37 weeks of gestation (adjusted odds ratio, 1.02 [1.01–1.03]). No association was found for fetal congenital anomalies (adjusted odds ratio, 1.02 [1.00–1.04]), stillbirth (adjusted odds ratio, 1.02 [0.96–1.08]), or neonatal death (adjusted odds ratio, 1.02 [0.96–1.08]). Similar associations were found for adverse pregnancy outcomes when fetal fraction was &lt;10th percentile. Conclusion: In early pregnancy, a low fetal fraction is associated with increased risk of adverse pregnancy outcomes. These findings can be used to expand the potential of noninvasive prenatal testing in the future, enabling the prediction of pregnancy complications and facilitating tailored pregnancy management through intensified monitoring or preventive measures.</p

Double Dissociation of Format-Dependent and Number-Specific Neurons in Human Parietal Cortex

Based on neuroimaging methods, it is a commonly held view that numerical representation in the human parietal lobes is format independent. We used a transcranial magnetic stimulation adaptation paradigm to examine the existence of functionally segregated overlapping populations of neurons for different numerical formats and to reveal how numerical information is encoded and represented. Based on 2 experiments, we found that right parietal lobe stimulation showed a dissociation between digits and verbal numbers, whereas the left parietal lobe showed a double dissociation between the different numerical formats. Further analysis and modeling also excluded pre- or postrepresentational components as the source of the current effects. These results demonstrate that both parietal lobes are equipped with format-dependent neurons that encode quantity

Setting things straight: a comparison of measures of saccade trajectory deviation

In eye movements, saccade trajectory deviation has often been used as a physiological operationalization of visual attention, distraction, or the visual system’s prioritization of different sources of information. However, there are many ways to measure saccade trajectories and to quantify their deviation. This may lead to noncomparable results and poses the problem of choosing a method that will maximize statistical power. Using data from existing studies and from our own experiments, we used principal components analysis to carry out a systematic quantification of the relationships among eight different measures of saccade trajectory deviation and their power to detect the effects of experimental manipulations, as measured by standardized effect size. We concluded that (1) the saccade deviation measure is a good default measure of saccade trajectory deviation, because it is somewhat correlated with all other measures and shows relatively high effect sizes for two well-known experimental effects; (2) more generally, measures made relative to the position of the saccade target are more powerful; and (3) measures of deviation based on the early part of the saccade are made more stable when they are based on data from an eyetracker with a high sampling rate. Our recommendations may be of use to future eye movement researchers seeking to optimize the designs of their studies

Placental studies elucidate discrepancies between NIPT showing a structural chromosome aberration and a differently abnormal fetal karyotype

Objective: Placental cytogenetic studies may reveal the origin of discordant noninvasive prenatal testing (NIPT). We performed placental studies to elucidate discordances between NIPT showing a structural chromosome aberration and the fetus having a different chromosome aberration in three cases. Method: Diagnostic testing with genomic SNP microarray was performed in three cases with NIPT showing a duplication on 4q (case 1), a terminal deletion of 13q (case 2), and a terminal deletion of 15q (case 3). Placental studies involved SNP array analysis of cytotrophoblast and mesenchymal core of chorionic villi of four placental quadrants. Clinical follow-up was performed as well. Results: Amniotic fluid revealed a different structural chromosome aberration than predicted by NIPT: a terminal 2q deletion (case 1), a segmental uniparental isodisomy of 13q (case 2), and a terminal duplication of 15q and of 13q (case 3). Placental studies revealed the aberration detected with NIPT in the cytotrophoblast, whereas the fetal karyotype was confirmed in the placental mesenchymal core. Conclusion: Our study shows that targeted cytogenetic investigations for confirmation of NIPT showing a microscopically visible structural chromosome aberration should be avoided, since another aberration, even a submicroscopic one or one involving another chromosome, may be present in the fetus

Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing:Follow-up results of the TRIDENT-2 study

In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weigh