Pembrolizumab-Induced Vitiligo in Esophageal Squamous Cell Carcinoma Patient With Durable Complete Response.

Immune checkpoint inhibitors have emerged as a valuable therapeutic strategy in cancer treatment. Pembrolizumab is an inhibitor of programmed cell death protein 1 (PD-1) and its ligands 1 (PD-L1) and 2 (PD-L2). Disrupting the interaction between PD-L1 expressed on the cancer cell and PD-1 transmembrane protein on immune cells results in reactivation of T cell-mediated cellular immunity. This immune modulation has increased the risk of autoimmune adverse events, which can affect any organ system. Here, we present a case of delayed immune checkpoint inhibitor-induced vitiligo in a 74-year-old female with recurrent metastatic esophageal carcinoma who remains in remission more than five years after initiation of pembrolizumab.

Sex-linked genetic diversity and differentiation in a globally distributed avian species complex.

Sex chromosomes often bear distinct patterns of genetic variation due to unique patterns of inheritance and demography. The processes of mutation, recombination, genetic drift and selection also influence rates of evolution on sex chromosomes differently than autosomes. Measuring such differences provides information about how these processes shape genomic variation and their roles in the origin of species. To test hypotheses and predictions about patterns of autosomal and sex-linked genomic diversity and differentiation, we measured population genetic statistics within and between populations and subspecies of the barn swallow (Hirundo rustica) and performed explicit comparisons between autosomal and Z-linked genomic regions. We first tested for evidence of low Z-linked genetic diversity and high Z-linked population differentiation relative to autosomes, then for evidence that the Z chromosome bears greater ancestry information due to faster lineage sorting. Finally, we investigated geographical clines across hybrid zones for evidence that the Z chromosome is resistant to introgression due to selection against hybrids. We found evidence that the barn swallow mating system, demographic history and linked selection each contribute to low Z-linked diversity and high Z-linked differentiation. While incomplete lineage sorting is rampant across the genome, our results indicate faster sorting of ancestral polymorphism on the Z. Finally, hybrid zone analyses indicate barriers to introgression on the Z chromosome, suggesting that sex-linked traits are important in reproductive isolation, especially in migratory divide regions. Our study highlights how selection, gene flow and demography shape sex-linked genetic diversity and underlines the relevance of the Z chromosome in speciation.

Migratory divides coincide with reproductive barriers across replicated avian hybrid zones above the Tibetan Plateau.

Migratory divides are proposed to be catalysts for speciation across a diversity of taxa. However, it is difficult to test the relative contributions of migratory behaviour vs. other divergent traits to reproductive isolation. Comparing hybrid zones with and without migratory divides offers a rare opportunity to directly examine the contribution of divergent migratory behaviour to reproductive barriers. We show that across replicate sampling transects of two pairs of barn swallow (Hirundo rustica) subspecies, strong reproductive isolation coincided with a migratory divide spanning 20 degrees of latitude. A third subspecies pair exhibited no evidence for a migratory divide and hybridised extensively. Within migratory divides, overwintering habitats were associated with assortative mating, implicating a central contribution of divergent migratory behaviour to reproductive barriers. The remarkable geographic coincidence between migratory divides and genetic breaks supports a long-standing hypothesis that the Tibetan Plateau is a substantial barrier contributing to the diversity of Siberian avifauna.

Selection on multiple sexual signals in two Central and Eastern European populations of the barn swallow.

Variation in intensity and targets of sexual selection on multiple traits has been suggested to play a major role in promoting phenotypic differentiation between populations, although the divergence in selection may depend on year, local conditions or age. In this study, we quantified sexual selection for two putative sexual signals across two Central and East European barn swallow (Hirundo rustica rustica) populations from Czech Republic and Romania over multiple years. We then related these differences in selection to variation in sexual characters among barn swallow populations. Our results show that tail length and ventral coloration vary between populations, sexes, and age classes (first-time breeders vs. experienced birds). We found that selection on tail length was stronger in first-time breeders than in experienced birds and in males than in females in the Romanian population, while these differences between age groups and sexes were weak in Czech birds. We suggest that the populational difference in selection on tail length might be related to the differences in breeding conditions. Our results show that ventral coloration is darker (i.e., has lower brightness) in the Romanian than in the Czech population, and in experienced birds and males compared with first-time breeders and females, respectively. The sexual difference in ventral coloration may suggest sexual selection on this trait, which is supported by the significant directional selection of ventral coloration in first-time breeding males on laying date. However, after controlling for the confounding effect of wing length and tarsus length, the partial directional selection gradient on this trait turned nonsignificant, suggesting that the advantage of dark ventral coloration in early breeding birds is determined by the correlated traits of body size. These findings show that ventral coloration may be advantageous over the breeding season, but the underlying mechanism of this relationship is not clarified.

Dynamic changes in display architecture and function across environments revealed by a systems approach to animal communication.

Animal communication is often structurally complex and dynamic, with signaler and receiver behavior varying in response to multiple environmental factors. To date, studies assessing signal dynamics have mostly focused on the relationships between select signaling traits and receiver responses in a single environment. We use the wolf spider Schizocosa floridana to explore the relationships between courtship display form and function across two social contexts (female presence vs absence) and two light environments (light vs dark). We use traditional analytical methods to determine predictors of copulation success (i.e., signal function) and examine these predictors in a structural context by overlaying them on signal phenotype networks (Wilkins et al. 2015). This allows us to explore system design principles (degeneracy, redundancy, pluripotentiality), providing insight into hypotheses regarding complex signal evolution. We found that both social context and light environment affect courtship structure, although the predictors of mating success remain similar across light environments, suggesting system degeneracy. Contrastingly, the same display traits may serve different functions across social environments, suggesting pluripotentiality. Ultimately, our network approach uncovers a complexity in display structure and function that is missed by functional analyses alone, highlighting the importance of systems-based methodologies for understanding the dynamic nature of complex signals.

Genomic variation across two barn swallow hybrid zones reveals traits associated with divergence in sympatry and allopatry.

Hybrid zones are geographic regions where isolating barriers between divergent populations are challenged by admixture. Identifying factors that facilitate or inhibit hybridization in sympatry can illuminate the processes that maintain those reproductive barriers. We analysed patterns of hybridization and phenotypic variation across two newly discovered hybrid zones between three subspecies of barn swallow (Hirundo rustica). These subspecies differ in ventral coloration and wing length, traits that are targets of sexual and natural selection, respectively, and are associated with genome-wide differentiation in allopatry. We tested the hypothesis that the degree of divergence in these traits is associated with the extent of hybridization in secondary contact. We applied measures of population structure based on >23,000 SNPs to confirm that named subspecies correspond to distinct genomic clusters, and assessed coincidence between geographic clines for ancestry and phenotype. Although gene flow was ongoing across both hybrid zones and pairwise FST between subspecies was extremely low, we found striking differences in the extent of hybridization. In the more phenotypically differentiated subspecies pair, clines for ancestry, wing length and ventral coloration were steep and coincident, suggestive of strong isolation and, potentially, selection associated with phenotype. In the less phenotypically differentiated pair, gene flow and phenotypic variation occurred over a wide geographic span, indicative of weaker isolation. Traits associated with genome-wide differentiation in allopatry may thus also contribute to isolation in sympatry. We discuss potentially important additional roles for evolutionary history and ecology in shaping variation in the extent hybridization between closely related pairs of subspecies.

Atrioventricular block masked by posteroseptal bypass tract located in coronary sinus aneurysm.

Atrial fibrillation with concurrent ventricular preexcitation identifies a high-risk arrhythmic substrate and usually results in catheter ablation of the atrioventricular bypass tract. Electrocardiography can only approximate the anatomical location of an accessory pathway. Here we report a case where a bypass tract was localised to a coronary sinus aneurysm and antegrade atrioventricular conduction masked underlying atrioventricular nodal block.

Procedure to decouple reflectance and down-shifting effects in luminescent down-shifting enhanced photovoltaics.

The down-shifting (DS) process is a purely optical approach used to improve the short-wavelength response of a solar cell by shifting high-energy photons to the visible range, which can be more efficiently absorbed by the solar cell. In addition to the DS effect, coupling a DS layer to the top surface of a solar cell results in a change in surface reflectance. The two effects are intermixed and therefore, usually reported as a single effect. Here we propose a procedure to decouple the two effects. Analytical equations are derived to decouple the two effects, that consider the experimentally measured quantum efficiency of the solar cell with and without the DS layer, in addition to transfer matrix simulations of the parasitic absorption in the device structure. In this work, an overall degradation of 0.46 mA/cm2 is observed when adding a DS layer composed of silicon nanocrystals embedded in a quartz matrix to a silicon solar cell of 11% baseline efficiency. To fully understand the contribution from each effect, the surface reflectance and DS effects are decoupled and quantified using the described procedure. We observe an enhancement of 0.27 mA/cm2 in short-circuit current density due to the DS effect, while the surface reflectance effect leads to a degradation of 0.73 mA/cm2 in short-circuit current density.

An experimental study on the impact of clinical interruptions on simulated trainee performances of central venous catheterization.

BACKGROUND: Interruptions are common in the healthcare setting. This experimental study compares the effects of interruptions on simulated performances of central venous catheterization during a highly versus minimally complex portion of the task. METHODS: Twenty-six residents were assigned to interruptions during tasks that are (1) highly complex: establishing ultrasound-guided venous access (experimental group, n = 15) or (2) minimally complex: skin cleansing (control group, n = 11). Primary outcomes were (a) performance scores at three time points measured with a validated checklist, (b) time spent on the respective tasks, and (c) number of attempts to establish venous access. RESULTS: Repeated measure analyses of variances of performance scores over time indicated no main effect of time or group. The interaction between time and group was significant: F (2, 44) = 4.28, p = 0.02, and partial eta2 = 0.16, indicating a large effect size. The experimental group scores decreased steadily over time, while the control group scores increased with time. The experimental group required longer to access the vein (148 s; interquartile range (IQR) 60 to 361 vs. 44 s; IQR 27 to 133 s; p = 0.034). Median number of attempts to establish venous access was higher in the experimental group (2, IQR 1-7 vs. 1, IQR 1-2; p = 0.03). CONCLUSIONS: Interruptions during a highly complex task resulted in a consistent decrement in performance scores, longer time required to perform the task, and a higher number of venous access attempts than interruptions during a minimally complex tasks. We recommend avoiding interrupting trainees performing bedside procedures.

The maintenance of phenotypic divergence through sexual selection: An experimental study in barn swallows Hirundo rustica.

Previous studies have shown that sexual signals can rapidly diverge among closely related species. However, we lack experimental studies to demonstrate that differences in trait-associated reproductive performance maintain sexual trait differences between closely related populations, in support for a role of sexual selection in speciation. Populations of Northern Hemisphere distributed barn swallows Hirundo rustica are closely related, yet differ in two plumage-based traits: ventral color and length of the outermost tail feathers (streamers). Here we provide experimental evidence that manipulations of these traits result in different reproductive consequences in two subspecies of barn swallow: (H. r. erythrogaster in North America and H. r. transitiva in the East Mediterranean). Experimental results in Colorado, USA, demonstrate that males with (1) darkened ventral coloration and (2) shortened streamers gained paternity between two successive reproductive bouts. In contrast, exaggeration of both traits improved reproductive performance within H. r. transitiva in Israel: males with a combination treatment of darkened ventral coloration and elongated streamers gained paternity between two successive reproductive bouts. Collectively, these experimental results fill an important gap in our understanding for how divergent sexual selection maintains phenotype differentiation in closely related populations, an important aspect of the speciation process.

Multimodal signalling in the North American barn swallow: a phenotype network approach.

Complex signals, involving multiple components within and across modalities, are common in animal communication. However, decomposing complex signals into traits and their interactions remains a fundamental challenge for studies of phenotype evolution. We apply a novel phenotype network approach for studying complex signal evolution in the North American barn swallow (Hirundo rustica erythrogaster). We integrate model testing with correlation-based phenotype networks to infer the contributions of female mate choice and male-male competition to the evolution of barn swallow communication. Overall, the best predictors of mate choice were distinct from those for competition, while moderate functional overlap suggests males and females use some of the same traits to assess potential mates and rivals. We interpret model results in the context of a network of traits, and suggest this approach allows researchers a more nuanced view of trait clustering patterns that informs new hypotheses about the evolution of communication systems.

Does the sex of a simulated patient affect CPR?

INTRODUCTION: While males and females are equally at risk of sudden cardiac arrest (SCA), females are less likely to be resuscitated. Cardiopulmonary Resuscitation (CPR) may be inhibited by socio-cultural norms about exposing female victims' chests. Empirically confirming this hypothesis is limited by lack of patient simulators modeling realistic female physiques. A commercially-available patient simulator was transformed to evaluate how physical attributes of a patient's sex might influence lay participants who were asked to resuscitate a female versus a male during simulated cardiac arrest. METHODS: Sixty-nine participants consented to be in the study. Participants were randomly assigned to provide CPR and defibrillation as instructed by a commercially-available automated external defibrillator on a patient simulator presented as either a male or female experiencing cardiac arrest. RESULTS: Rescuers removed significantly more clothing from the male than the female, with men removing less clothing from the female. More rescuers' initial hand placements for CPR were centered between the female's breasts compared to the male, on which placement was distributed across the chest towards the nipples. DISCUSSION: While rescuers had better hand placement for CPR on the female, both men and women rescuers were reluctant to remove the female's clothing, with men significantly more hesitant. Reticence to remove clothing was often articulated relative to social norms during structured interviews. We suggest that using only male simulators will not allow trainees to experience social differences associated with the care of a female simulated patient. Realistic female patient simulators are needed.

New approaches to the treatment of biofilm-related infections.

Bacteria causing chronic infections predominately grow as surface-attached, sessile communities known as biofilms. Biofilm-related infections including cystic fibrosis lung infection, chronic and recurrent otitis media, chronic wounds and implant- and catheter-associated infections, are a significant cause of morbidity and mortality and financial cost. Chronic biofilm-based infections are recalcitrant to conventional antibiotic therapy and are often unperturbed by host immune responses such as phagocytosis, despite a sustained presence of host inflammation. The diagnosis of clinically important biofilm infections is often difficult as Koch's postulates are rarely met. If treatment is required, surgical removal of the infected implant, or debridement of wound or bone, is the most efficient means of eradicating a clinically significant biofilm. New approaches to treatment are under investigation.

Reconstructing past changes in locus-specific recombination rates.

BACKGROUND: Recombination rates vary at the level of the species, population and individual. Now recognized as a transient feature of the genome, recombination rates at a given locus can change markedly over time. Existing inferential methods, predominantly based on linkage disequilibrium patterns, return a long-term average estimate of past recombination rates. Such estimates can be misleading, but no analytical framework to infer recombination rates that have changed over time is currently available. RESULTS: We apply coalescent modeling in conjunction with a suite of summary statistics to show that the recombination history of a locus can be reconstructed from a time series of genetic samples. More usefully, we describe a new method, based on n-tuple dataset subsampling, to infer past changes in recombination rate from DNA sequences taken at a single time point. This subsampling strategy can correctly assign simulated loci to constant, increasing and decreasing recombination models with an accuracy of 84%. CONCLUSIONS: While providing an important stepping-stone to determining past recombination rates, n-tuple subsampling still exhibits a moderate error rate. Theoretical limitations indicated by coalescent theory suggest that highly accurate inference of past recombination rates will remain challenging. Nevertheless, we show for the first time that reconstructing historic recombination rates is possible in principle.

Evolutionary divergence in acoustic signals: causes and consequences.

Acoustic signals mediate mate choice, resource defense, and species recognition in a broad range of taxa. It has been proposed, therefore, that divergence in acoustic signals plays a key role in speciation. Nonetheless, the processes driving divergence of acoustic traits and their consequences in terms of speciation are poorly understood. A review of empirical and comparative studies reveals strong support for a role of sexual selection in acoustic divergence, but the possible concomitant influences of ecological context are rarely examined. We summarize a conceptual framework for testing the relative significance of both adaptive and neutral mechanisms leading to acoustic divergence, predictions for cases where these processes lead to speciation, and how their relative importance plays out over evolutionary time.

Positive carotenoid balance correlates with greater reproductive performance in a wild bird.

BACKGROUND: Carotenoids can confer somatic and reproductive benefits, but most evidence is from captive animal experimentation or single time-point sampling. Another perhaps more informative means by which to assess physiological contributions to animal performance is by tracking an individual's ability to increase or sustain carotenoids or other health-related molecules over time, as these are likely to be temporally variable. METHODOLOGY/PRINCIPAL FINDINGS: In a field study of North American barn swallows (Hirundo rustica erythrogaster), we analyzed within-individual changes in carotenoid concentrations by repeatedly sampling the carotenoid profiles of individuals over the course of the breeding season. Our results demonstrate that carotenoid concentrations of individuals are temporally dynamic and that season-long balance of these molecules, rather than single time-point samples, predict reproductive performance. This was true even when controlling for two important variables associated with reproductive outcomes: (1) timing of breeding and (2) sexually selected plumage coloration, which is itself positively correlated with and concomitantly changes with circulating carotenoid concentrations. CONCLUSIONS/SIGNIFICANCE: While reproduction itself is purported to impose health stress on organisms, these data suggest that free-ranging, high-quality individuals can mitigate such costs, by one or several genetic, environmental (diet), or physiological mechanisms. Moreover, the temporal variations in both health-linked physiological measures and morphological traits we uncover here merit further examination in other species, especially when goals include the estimation of signal information content or the costs of trait expression.

Influence of albumin supplementation on tacrolimus and cyclosporine therapy early after liver transplantation.

Liver transplant recipients administered gelatin (GEL) rather than human albumin solution (HAS) can become profoundly hypoalbuminemic in the early postoperative period and often have hepatic dysfunction at this time. The combined effect of these two abnormalities could be an increase in the unbound (active) concentration of low-extraction highly albumin-bound drugs, such as tacrolimus (TAC). This may increase the efficacy and/or toxicity of such drugs. We prospectively compared the clinical outcome of 69 de novo liver transplant recipients randomized primarily to TAC or cyclosporine (CYA) and secondarily to HAS or GEL therapy during the first 14 days after liver transplantation. Antipyrine clearance on the 7th postoperative day was used as a measure of liver metabolic function. Serum albumin levels were significantly lower in both GEL arms than HAS arms during the first 14 days (P <.001). Although antipyrine clearance was similar in all four trial arms, it was intermediate between that found in historic healthy controls and patients with cirrhosis (P <.0001). Serum creatinine concentrations were significantly greater in the TAC plus GEL arm than the other three arms (P <.001). The linearized treated acute rejection rate was significantly greater in the TAC plus HAS arm than the other three arms (relative risk, 2.02; 95% confidence interval, 1.07 to 3.78; P =.03). These data indicate that excess nephrotoxicity can occur with TAC in liver transplant recipients with impaired hepatic metabolism who are administered GEL. In addition, supplementary albumin may reduce the efficacy of TAC in liver transplant recipients at a time when the risk for rejection is greatest.