Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies.

INTRODUCTION: This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd. METHODS: Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized. RESULTS: The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years. CONCLUSIONS: In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit-risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all.

Depth as a driver of evolution and diversification of ancient squat lobsters (Decapoda, Galatheoidea, Phylladiorhynchus).

The exceptional hidden diversity included in the squat lobster genus Phylladiorhynchus and its wide bathymetric and geographic range make it an interesting group to thoroughly study its evolutionary history. Here we have analyzed the entire currently known species diversity of Phylladiorhynchus using an integrative approach that includes morphological and molecular characters. The aim was to establish whether depth range (bathymetry) has played a role in their morphological and molecular evolution and in their diversification pathways. Phylogenetic analyses recovered the genus as monophyletic and as the sister group of Coralliogalathea, conforming with current systematic hypotheses, although their placement in a monophyletic Galatheidae is doubted. All the analyzed species represent well-supported lineages, structured in ten clades, correlated in most part with the morphological phylogeny. The reconstruction of ancestral habitat showed that the most recent common ancestor of Phylladiorhynchus most likely lived in shallow water environments. The divergence time estimation analyses dated the origin of the genus back to the Upper Jurassic, preceding the origin of all the other galatheoid lineages. Morphological analyses suggested that species from deeper waters exhibit greater morphological divergences and lower genetic divergences in comparison to species from shallower waters. In Phylladiorhynchus, the colonization of deeper waters has taken place independently multiple times since the Lower-Cretaceous. Our reconstruction of ancestral habitat suggests that shallow water ancestors might show an acceleration in the molecular rate of evolution and a slowdown in the rates of morphological evolution in comparison to deep sea lineages. However, although lineages from shallow and deep sea habitats show slight differences in diversification trends, bathymetry does not significantly affect the diversification rate in Phylladiorhynchus according to our diversification analyses.

A novel integrative approach elucidates fine-scale dispersal patchiness in marine populations.

Dispersal is one of the main determining factors of population structure. In the marine habitat, well-connected populations with large numbers of reproducing individuals are common but even so population structure can exist on a small-scale. Variation in dispersal patterns between populations or over time is often associated to geographic distance or changing oceanographic barriers. Consequently, detecting structure and variation in dispersal on a fine-scale within marine populations still remains a challenge. Here we propose and use a novel approach of combining a clustering model, early-life history trait information from fish otoliths, spatial coordinates and genetic markers to detect very fine-scale dispersal patterns. We collected 1573 individuals (946 adults and 627 juveniles) of the black-faced blenny across a small-scale (2 km) coastline as well as at a larger-scale area (<50 kms). A total of 178 single nucleotide polymorphism markers were used to evaluate relatedness patterns within this well-connected population. In our clustering models we categorized SHORT-range dispersers to be potential local recruits based on their high relatedness within and low relatedness towards other spatial clusters. Local retention and/or dispersal of this potential local recruitment varied across the 2 km coastline with higher frequency of SHORT-range dispersers towards the southwest of the area for adults. An inverse pattern was found for juveniles, showing an increase of SHORT-range dispersers towards the northeast. As we rule out selective movement and mortality from one year to the next, this pattern reveals a complex but not full genetic mixing, and variability in coastal circulation is most likely the main driver of this fine-scale chaotic genetic patchiness within this otherwise homogeneous population. When focusing on the patterns within one recruitment season, we found large differences in temperatures (from approx. 17 °C to 25 °C) as well as pelagic larval duration (PLD) for juveniles from the beginning of the season and the end of the season. We were able to detect fine-scale differences in LONG-range juvenile dispersers, representing distant migrants, depending on whether they were born at the beginning of the season with a longer PLD, or at the end of the reproductive season. The ability to detect such fine-scale dispersal patchiness will aid in our understanding of the underlying mechanisms of population structuring and chaotic patchiness in a wide range of species even with high potential dispersal abilities.

The DCDC2 deletion is not a risk factor for dyslexia.

Dyslexia is a specific impairment in learning to read and has strong heritability. An intronic deletion within the DCDC2 gene, with ~8% frequency in European populations, is increasingly used as a marker for dyslexia in neuroimaging and behavioral studies. At a mechanistic level, this deletion has been proposed to influence sensory processing capacity, and in particular sensitivity to visual coherent motion. Our re-assessment of the literature, however, did not reveal strong support for a role of this specific deletion in dyslexia. We also analyzed data from five distinct cohorts, enriched for individuals with dyslexia, and did not identify any signal indicative of associations for the DCDC2 deletion with reading-related measures, including in a combined sample analysis (N=526). We believe we conducted the first replication analysis for a proposed deletion effect on visual motion perception and found no association (N=445 siblings). We also report that the DCDC2 deletion has a frequency of 37.6% in a cohort representative of the general population recruited in Hong Kong (N=220). This figure, together with a lack of association between the deletion and reading abilities in this cohort, indicates the low likelihood of a direct deletion effect on reading skills. Therefore, on the basis of multiple strands of evidence, we conclude that the DCDC2 deletion is not a strong risk factor for dyslexia. Our analyses and literature re-evaluation are important for interpreting current developments within multidisciplinary studies of dyslexia and, more generally, contribute to current discussions about the importance of reproducibility in science.

Kinship analyses identify fish dispersal events on a temperate coastline.

Connectivity is crucial for the persistence and resilience of marine species, the establishment of networks of marine protected areas and the delineation of fishery management units. In the marine environment, understanding connectivity is still a major challenge, due to the technical difficulties of tracking larvae. Recently, parentage analysis has provided a means to address this question effectively. To be effective, this method requires limited adult movement and extensive sampling of parents, which is often not possible for marine species. An alternative approach that is less sensitive to constraints in parental movement and sampling could be the reconstruction of sibships. Here, we directly measure connectivity and larval dispersal in a temperate marine ecosystem through both analytical approaches. We use data from 178 single nucleotide polymorphism markers to perform parentage and sibship reconstruction of the black-faced blenny (Tripterygion delaisi) from an open coastline in the Mediterranean Sea. Parentage analysis revealed a decrease in dispersal success in the focal area over 1 km distance and approximately 6.5% of the juveniles were identified as self-recruits. Sibship reconstruction analysis found that, in general, full siblings did not recruit together to the same location, and that the largest distance between recruitment locations was much higher (11.5 km) than found for parent-offspring pairs (1.2 km). Direct measurements of dispersal are essential to understanding connectivity patterns in different marine habitats, and show the degree of self-replenishment and sustainability of populations of marine organisms. We demonstrate that sibship reconstruction allows direct measurements of dispersal and family structure in marine species while being more easily applied in those species for which the collection of the parental population is difficult or unfeasible.

SNP development from RNA-seq data in a nonmodel fish: how many individuals are needed for accurate allele frequency prediction?

Single nucleotide polymorphisms (SNPs) are rapidly becoming the marker of choice in population genetics due to a variety of advantages relative to other markers, including higher genomic density, data quality, reproducibility and genotyping efficiency, as well as ease of portability between laboratories. Advances in sequencing technology and methodologies to reduce genomic representation have made the isolation of SNPs feasible for nonmodel organisms. RNA-seq is one such technique for the discovery of SNPs and development of markers for large-scale genotyping. Here, we report the development of 192 validated SNP markers for parentage analysis in Tripterygion delaisi (the black-faced blenny), a small rocky-shore fish from the Mediterranean Sea. RNA-seq data for 15 individual samples were used for SNP discovery by applying a series of selection criteria. Genotypes were then collected from 1599 individuals from the same population with the resulting loci. Differences in heterozygosity and allele frequencies were found between the two data sets. Heterozygosity was lower, on average, in the population sample, and the mean difference between the frequencies of particular alleles in the two data sets was 0.135 ± 0.100. We used bootstrap resampling of the sequence data to predict appropriate sample sizes for SNP discovery. As cDNA library production is time-consuming and expensive, we suggest that using seven individuals for RNA sequencing reduces the probability of discarding highly informative SNP loci, due to lack of observed polymorphism, whereas use of more than 12 samples does not considerably improve prediction of true allele frequencies.

Permanent genetic resources added to molecular ecology resources database 1 April 2012 - 31 May 2012.

This article documents the addition of 123 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Brenthis ino, Cichla orinocensis, Cichla temensis, Epinephelus striatus, Gobio gobio, Liocarcinus depurator, Macrolophus pygmaeus, Monilinia vaccinii-corymbosi, Pelochelys cantorii, Philotrypesis josephi, Romanogobio vladykovi, Takydromus luyeanus and Takydromus viridipunctatus. These loci were cross-tested on the following species: Cichla intermedia, Cichla ocellaris, Cichla pinima, Epinephelus acanthistius, Gobio carpathicus, Gobio obtusirostris, Gobio sp. 1, Gobio volgensis, Macrolophus costalis, Macrolophus melanotoma, Macrolophus pygmaeus, Romanogobio albipinnatus, Romanogobio banaticus, Romanogobio belingi, Romanogobio kesslerii, Romanogobio parvus, Romanogobio pentatrichus, Romanogobio uranoscopus, Takydromus formosanus, Takydromus hsuehshanesis and Takydromus stejnegeri.

Matching genetics with oceanography: directional gene flow in a Mediterranean fish species.

Genetic connectivity and geographic fragmentation are two opposing mechanisms determining the population structure of species. While the first homogenizes the genetic background across populations the second one allows their differentiation. Therefore, knowledge of processes affecting dispersal of marine organisms is crucial to understand their genetic distribution patterns and for the effective management of their populations. In this study, we use genetic analyses of eleven microsatellites in combination with oceanographic satellite and dispersal simulation data to determine distribution patterns for Serranus cabrilla, a ubiquitous demersal broadcast spawner, in the Mediterranean Sea. Pairwise population F(ST) values ranged between -0.003 and 0.135. Two genetically distinct clusters were identified, with a clear division located between the oceanographic discontinuities at the Ibiza Channel (IC) and the Almeria-Oran Front (AOF), revealing an admixed population in between. The Balearic Front (BF) also appeared to dictate population structure. Directional gene flow on the Spanish coast was observed as S. cabrilla dispersed from west to east over the AOF, from north to south on the IC and from south of the IC towards the Balearic Islands. Correlations between genetic and oceanographic data were highly significant. Seasonal changes in current patterns and the relationship between ocean circulation patterns and spawning season may also play an important role in population structure around oceanographic fronts.

Contactless and continuous monitoring of heart rate based on photoplethysmography on a mattress.

This paper reports a novel contactless monitoring method to record photoplethysmogram (PPG) on a mattress for the continuous measurement of heart rate (HR). PPGs were obtained from subjects' fingers and backs with and without making a direct contact between the PPG sensor and their skin when they rested in a supine position on the mattress. Electrocardiograms (ECGs) were measured from the subjects' limbs for reference. Clear PPG waveforms were obtained from the subjects' backs. Beat-to-beat HR derived from contactless PPG measurement was comparable to those measured from contact PPG and ECG measurements. Thus we found that contactless PPG could be captured from the subjects' backs and it was sufficient to provide accurate HR measurements. This contactless monitoring of PPG has the potential to reduce obstruction in sleep and provide clinical evaluation in sleep study.

Contactless recording of photoplethysmogram on a sleeping bed.

This paper reports a novel contactless monitoring method to record reflective mode photoplethysmogram (PPG) on a sleeping bed for heart rate (HR) estimation. The electrocardiogram (ECG) and pulse transit time (PTT) were also measured in this study. ECG was measured from subjects' limbs whilst PPG was obtained from their right index fingers and their backs with and without direct contact between the PPG sensor and the subjects' skin respectively. Clear PPG waveforms were obtained from the subjects' backs even though the sensor was not directly attached to their skin. Beat-to-beat HRs derived from the back PPGs were closely correlated with those measured from the finger PPGs and ECGs. Thus we found that contactless PPG could be captured from the subjects' backs to determine HR accurately.

Impedance cardiography for cuffless and non-invasive measurement of systolic blood pressure.

In this study, we have used impedance cardiography to determine blood pressure (BP) cufflessly and non-invasively. We have devised a new parameter, QdZ [the duration measured from the foot of electrocardiogram (ECG) Q wave to the peak of impedance cardiogram (ICG)], for this purpose. Twenty-two subjects performed four minutes of treadmill exercise such that systolic BP (SBP) was increased significantly. We found that SBP was closely correlated with QdZ (R(2)=0.65) demonstrating the potential application of ICG to cuffless and non-invasive BP measurement.

Tissue characterization using terahertz pulsed imaging in reflection geometry.

Terahertz pulsed imaging (TPI) is a non-ionizing and non-destructive imaging technique that has been recently used to study a wide range of biological materials. The severe attenuation of terahertz radiation in samples with high water content means that biological samples need to be very thin if they are to be measured in transmission geometry. To overcome this limitation, samples could be measured in reflection geometry and this is the most feasible way in which TPI could be performed in a clinical setting. In this study, we therefore used TPI in reflection geometry to characterize the terahertz properties of several organ samples freshly harvested from laboratory rats. We observed differences in the measured time domain responses and determined the frequency-dependent optical properties to characterize the samples further. We found statistically significant differences between the tissue types. These results show that TPI has the potential to accurately differentiate between tissue types non-invasively.

Phylogeography of the European spiny lobster (Palinurus elephas): Influence of current oceanographical features and historical processes.

The European spiny lobster (Palinurus elephas) is a suitable model organism to study the effects of past history and current oceanographic processes on the genetic diversity and population structure of marine species with a long-lived larval phase. A portion of the COI gene was sequenced in 227 individuals from 11 localities, covering most of the present distribution of the species. Divergence was found between Atlantic and Mediterranean regions, which could be explained by restricted gene flow between populations. Moreover, a principal component analysis detected differences within basins. The existence of genetic differentiation between Brittany and Ireland-Scotland populations could be accounted for by the large effect of the Gulf Stream, while mesoscale processes suffered by the incoming Atlantic waters could be responsible of genetic differentiation within the Mediterranean. Furthermore, historical processes could be responsible for a reduction on the overall genetic variability of P. elephas. The haplotypic distribution found in P. elephas, with the presence of one abundant haplotype and a large number of closely related haplotypes, is typical of species experiencing reduction in variability and subsequent expansions. Climatic fluctuations related to glacial cycles could explain the present level of variability and nucleotide diversity found. Interestingly, these glacial events do not seem to have the same impact in other species of the same genus. Our results indicate that recent glacial events could have had a lower impact on Palinurus mauritanicus, a congeneric species that presents an overlapping distribution area but is found in cooler waters than P. elephas.

Population structure within and between subspecies of the Mediterranean triplefin fish Tripterygion delaisi revealed by highly polymorphic microsatellite loci.

Although F(ST) values are widely used to elucidate population relationships, in some cases, when employing highly polymorphic loci, they should be regarded with caution, particularly when subspecies are under consideration. Tripterygion delaisi presents two subspecies that were investigated here, using 10 microsatellite loci. A Bayesian approach allowed us to clearly identify both subspecies as two different evolutionary significant units. However, low F(ST) values were found between subspecies as a consequence of the large number of alleles per locus, while homoplasy could be disregarded as indicated by the standardized genetic distance G'(ST). Heterozygosity saturation was observed in highly polymorphic loci containing more than 15 alleles, and this threshold was used to define two loci pools. The less variable loci pool revealed higher genetic variance between subspecies, while the more variable pool showed higher genetic variance between populations. Furthermore, higher differentiation was also observed between populations using G'(ST) with the more variable loci. Nonetheless, a more reliable population structure within subspecies was obtained when all loci were included in the analyses. In T. d. xanthosoma, isolation by distance was detected between the eight analysed populations, and six genetically homogeneous clusters were inferred by Bayesian analyses that are in accordance with F(ST) values. The neighbourhood-size method also indicated rather small dispersal capabilities. In conclusion, in fish with limited adult and larval dispersal capabilities, continuous rocky habitat seems to allow contact between populations and prevent genetic differentiation, while large discontinuities of sand or deep-water channels seems to reduce gene flow.

Effect of brine discharge from a desalination plant on macrobenthic communities in the NW Mediterranean.

This paper examines the possible effects of discharges from a desalination plant on the macrobenthic community inhabiting the sandy substratum off the coast of Blanes in Spain (NW Mediterranean) using multivariate and univariate analyses. Two controls and one putatively impacted location were selected and visual censuses were carried out 12 times before and 12 times after the plant had begun operating. No significant variations attributable to the brine discharges from the desalination plant were found. The failure to record any impact may be explained by the high natural variability that is a characteristic feature of bottoms of this type and also by the rapid dilution undergone by the hypersaline brine upon leaving the discharge pipe.

Large-scale species-richness gradients in the Atlantic Ocean.

The increase in species richness from the poles to the Equator has been observed in numerous terrestrial and aquatic taxa. A number of different hypotheses have been put forward as explanations for this trend, e.g. area and energy availability. However, whether these hypotheses apply to large spatial scales in marine environments remains unclear. The present study shows a clear latitudinal gradient from high to low latitude (from 80 degrees N to 70 degrees S) in marine species richness for 6643 species (fishes and invertebrates) in 10 different taxa dwelling in benthic and pelagic habitats on both sides of the Atlantic. The patterns in benthic taxa are strongly influenced by coastal hydrographic processes, with marked peaks and troughs, and consequently the gradients are not symmetric along both Atlantic sides. Pelagic taxa show a plateau-shaped distribution and the influence from coastal events on gradients could not be demonstrated. The relationships between species richness and different environmental factors indicate that area size does not explain the latitudinal pattern in benthic species richness on a large spatial scale. Sea-surface temperature (positive relationship) is the best predictor of this pattern for benthic species, and nitrate concentration (negative relationship) is the best predictor for pelagic species. The results call into question the existence of a single primary cause that would explain the pattern in marine species richness on a large spatial scale.

Localization of brief sounds: effects of level and background noise.

Listeners show systematic errors in vertical-plane localization of wide-band sounds when tested with brief-duration stimuli at high intensities, but long-duration sounds at any comfortable level do not produce such errors. Improvements in high-level sound localization associated with increased stimulus duration might result from temporal integration or from adaptation that might allow reliable processing of later portions of the stimulus. Free-field localization judgments were obtained for clicks and for 3- and 100-ms noise bursts presented at sensation levels from 30 to 55 dB. For the brief (clicks and 3-ms) stimuli, listeners showed compression of elevation judgments and increased rates and unusual patterns of front/back confusion at sensation levels higher than 40-45 dB. At lower sensation levels, brief sounds were localized accurately. The localization task was repeated using 3-ms noise burst targets in a background of spatially diffuse, wide-band noise intended to pre-adapt the system prior to the target onset. For high-level targets, the addition of background noise afforded mild release from the elevation compression effect. Finally, a train of identical, high-level, 3-ms bursts was found to be localized more accurately than a single burst. These results support the adaptation hypothesis.