Immunogenicity, safety, and efficacy of a tetravalent dengue vaccine in children and adolescents: an analysis by age group.

BACKGROUND: Dengue is an increasing threat to global health. This exploratory analysis evaluated the immunogenicity, safety, and vaccine efficacy (VE) of a live-attenuated tetravalent dengue vaccine (TAK-003) in participants enrolled in the phase 3 DEN-301 trial (NCT02747927), stratified by baseline age (4-5 years; 6-11 years; or 12-16 years). METHODS: Participants were randomized 2:1 to receive 2 doses of TAK-003, administered 3 months apart, or placebo. Dengue serostatus was evaluated at enrolment. VE against virologically-confirmed dengue (VCD) and hospitalized VCD; immunogenicity (geometric mean titers; GMTs); and safety were evaluated per age group through ∼4 years post-vaccination. RESULTS: VE against VCD across serotypes was 43.5% (95% confidence interval: 25.3%, 57.3%) for 4-5 year-olds; 63.5% (56.9%, 69.1%) for 6-11 year-olds, and 67.7% (57.8%, 75.2%) for 12-16 year-olds. VE against hospitalized VCD was 63.8% (21.1%, 83.4%), 85.1% (77.1%, 90.3%), and 89.7% (77.9%, 95.2%), for the three age groups, respectively. GMTs remained elevated against all four serotypes for ∼4 years post-vaccination, with no evident differences across age groups. No clear differences in safety by age were identified. CONCLUSIONS: This exploratory analysis shows TAK-003 was efficacious in dengue prevention across age groups in children and adolescents 4-16 years of age living in dengue endemic areas. Relatively lower VE in 4-5 year-olds was potentially confounded by causative serotype distribution, small sample size, and VE by serotype, and should be considered in benefit-risk evaluations in this age group.

Dual transcriptional characterization of spinach and Peronospora effusa during resistant and susceptible race-cultivar interactions.

BACKGROUND: Spinach downy mildew, caused by the obligate oomycete pathogen, Peronospora effusa remains a major concern for spinach production. Disease control is predominantly based on development of resistant spinach cultivars. However, new races and novel isolates of the pathogen continue to emerge and overcome cultivar resistance. Currently there are 20 known races of P. effusa. Here we characterized the transcriptomes of spinach, Spinacia oleracea, and P. effusa during disease progression using the spinach cultivar Viroflay, the near isogenic lines NIL1 and NIL3, and P. effusa races, R13 and R19, at 24 h post inoculation and 6 days post inoculation. A total of 54 samples were collected and subjected to sequencing and transcriptomic analysis. RESULTS: Differentially expressed gene (DEG) analysis in resistant spinach interactions of R13-NIL1 and R19-NIL3 revealed spinach DEGs from protein kinase-like and P-loop containing families, which have roles in plant defense. The homologous plant defense genes included but were not limited to, receptor-like protein kinases (Spiol0281C06495, Spiol06Chr21559 and Spiol06Chr24027), a BAK1 homolog (Spiol0223C05961), genes with leucine rich repeat motifs (Spiol04Chr08771, Spiol04Chr01972, Spiol05Chr26812, Spiol04Chr11049, Spiol0084S08137, Spiol03Chr20299) and ABC-transporters (Spiol02Chr28975, Spiol06Chr22112, Spiol06Chr03998 and Spiol04Chr09723). Additionally, analysis of the expression of eight homologous to previously reported downy mildew resistance genes revealed that some are differentially expressed during resistant reactions but not during susceptible reactions. Examination of P. effusa gene expression during infection of susceptible cultivars identified expressed genes present in R19 or R13 including predicted RxLR and Crinkler effector genes that may be responsible for race-specific virulence on NIL1 or NIL3 spinach hosts, respectively. CONCLUSIONS: These findings deliver foundational insight to gene expression in both spinach and P. effusa during susceptible and resistant interactions and provide a library of candidate genes for further exploration and functional analysis. Such resources will be beneficial to spinach breeding efforts for disease resistance in addition to better understanding the virulence mechanisms of this obligate pathogen.

Morphology, behavior, and phylogenomics of Oxytoxum lohmannii, Dinoflagellata.

Dinoflagellates are an abundant and diverse group of protists representing a wealth of unique biology and ecology. While many dinoflagellates are photosynthetic or mixotrophic, many taxa are heterotrophs, often with complex feeding strategies. Compared to their photosynthetic counterparts, heterotrophic dinoflagellates remain understudied, as they are difficult to culture. One exception, a long-cultured isolate originally classified as Amphidinium but recently reclassified as Oxytoxum, has been the subject of a number of feeding, growth, and chemosensory studies. This lineage was recently determined to be closely related to Prorocentrum using phylogenetics of ribosomal RNA gene sequences, but the exact nature of this relationship remains unresolved. Using transcriptomes sequenced from culture and three single cells from the environment, we produce a robust phylogeny of 242 genes, revealing Oxytoxum is likely sister to the Prorocentrum clade, rather than nested within it. Molecular investigations uncover evidence of a reduced, nonphotosynthetic plastid and proteorhodopsin, a photoactive proton pump acquired horizontally from bacteria. We describe the ultrastructure of O. lohmannii, including densely packed trichocysts, and a new type of mucocyst. We observe that O. lohmannii feeds preferentially on cryptophytes using myzocytosis, but can also feed on various phytoflagellates using conventional phagocytosis. O. lohmannii is amenable to culture, providing an opportunity to better study heterotrophic dinoflagellate biology and feeding ecology.

Ecological correlates of species' roles in highly invaded seed dispersal networks.

Ecosystems with a mix of native and introduced species are increasing globally as extinction and introduction rates rise, resulting in novel species interactions. While species interactions are highly vulnerable to disturbance, little is known about the roles that introduced species play in novel interaction networks and what processes underlie such roles. Studying one of the most extreme cases of human-modified ecosystems, the island of O'ahu, Hawaii, we show that introduced species there shape the structure of seed dispersal networks to a greater extent than native species. Although both neutral and niche-based processes influenced network structure, niche-based processes played a larger role, despite theory predicting neutral processes to be predominantly important for islands. In fact, ecological correlates of species' roles (morphology, behavior, abundance) were largely similar to those in native-dominated networks. However, the most important ecological correlates varied with spatial scale and trophic level, highlighting the importance of examining these factors separately to unravel processes determining species contributions to network structure. Although introduced species integrate into interaction networks more deeply than previously thought, by examining the mechanistic basis of species' roles we can use traits to identify species that can be removed from (or added to) a system to improve crucial ecosystem functions, such as seed dispersal.

Transmission of Spinach Downy Mildew via Seed and Infested Leaf Debris.

Spinach downy mildew, caused by the obligate oomycete pathogen Peronospora effusa, is a worldwide constraint on spinach production. The role of airborne sporangia in the disease cycle of P. effusa is well established, but the role of the sexual oospores in the epidemiology of P. effusa is less clear and has been a major challenge to examine experimentally. To evaluate seed transmission of spinach downy mildew via oospores in this study, isolated glass chambers were employed in two independent experiments to grow out oospore-infested spinach seed and noninfested seeds mixed with oospore-infested crop debris. Downy mildew diseased spinach plants were observed 37 and 34 days after planting in the two isolator experiments, respectively, in the chambers that contained one of two oospore-infested seed lots or seeds coated with oospore-infested leaves. Spinach plants in isolated glass chambers initiated from seeds without oospores did not show downy mildew symptoms. Similar findings were obtained using the same seed lot samples in a third experiment conducted in a growth chamber. In direct grow out tests to examine oospore infection on seedlings performed in a containment greenhouse with oospore-infested seed of two different cultivars, characteristic Peronospora sporangiophores were observed growing from a seedling of each cultivar. The frequency of seedlings developing symptoms from 82 of these oospore-infested seed indicated that approximately 2.4% of seedlings from infested seed developed symptoms, and 0.55% of seedlings from total seeds assayed developed symptoms. The results provide evidence that oospores can serve as a source of inoculum for downy mildew and provide further evidence of direct seed transmission of the downy mildew pathogen to seedlings in spinach via seedborne oospores.

Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection.

BACKGROUND: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection. METHODS: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-µg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection. RESULTS: TAK-426 at 10-µg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection. CONCLUSIONS: These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations. CLINICAL TRIALS REGISTRATION: NCT03343626.

Recovery from alcohol among urban Alaska Native and American Indian people.

Alaska Native and American Indian (ANAI) people experience dramatic alcohol-related health disparities compared to the general US population. Although the majority of ANAI people reside in urban settings (>70%), data are sparse on alcohol abstinence among urban ANAI people with alcohol use disorder (AUD). We conducted a qualitative study using a phenomenological approach to examine the experiences of 20 urban ANAI adults recovering from AUD. Participants' narratives had their own unique dimensions but shared a clear, interrelated trajectory of pre-alcohol recovery, a turning point, and ongoing alcohol recovery. All participants reported a combination of external and internal motivation to stop using alcohol.

Ancestral Chromosomes for Family Peronosporaceae Inferred from a Telomere-to-Telomere Genome Assembly of Peronospora effusa.

Downy mildew disease of spinach, caused by the oomycete Peronospora effusa, causes major losses to spinach production. In this study, the 17 chromosomes of P. effusa were assembled telomere-to-telomere, using Pacific Biosciences high-fidelity reads. Of these, 16 chromosomes are complete and gapless; chromosome 15 contains one gap bridging the nucleolus organizer region. This is the first telomere-to-telomere genome assembly for an oomycete. Putative centromeric regions were identified on all chromosomes. This new assembly enables a reevaluation of the genomic composition of Peronospora spp.; the assembly was almost double the size and contained more repeat sequences than previously reported for any Peronospora species. Genome fragments consistently underrepresented in six previously reported assemblies of P. effusa typically encoded repeats. Some genes annotated as encoding effectors were organized into multigene clusters on several chromosomes. Putative effectors were annotated on 16 of the 17 chromosomes. The intergenic distances between annotated genes were consistent with compartmentalization of the genome into gene-dense and gene-sparse regions. Genes encoding putative effectors were enriched in gene-sparse regions. The near-gapless assembly revealed apparent horizontal gene transfer from Ascomycete fungi. Gene order was highly conserved between P. effusa and the genetically oriented assembly of the oomycete Bremia lactucae; high levels of synteny were also detected with Phytophthora sojae. Extensive synteny between phylogenetically distant species suggests that many other oomycete species may have similar chromosome organization. Therefore, this assembly provides the foundation for genomic analyses of diverse oomycetes.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Mechanisms underlying interaction frequencies and robustness in a novel seed dispersal network: lessons for restoration.

As human-caused extinctions and invasions accumulate across the planet, understanding the processes governing ecological functions mediated by species interactions, and anticipating the effect of species loss on such functions become increasingly urgent. In seed dispersal networks, the mechanisms that influence interaction frequencies may also influence the capacity of a species to switch to alternative partners (rewiring), influencing network robustness. Studying seed dispersal interactions in novel ecosystems on O'ahu island, Hawai'i, we test whether the same mechanisms defining interaction frequencies can regulate rewiring and increase network robustness to simulated species extinctions. We found that spatial and temporal overlaps were the primary mechanisms underlying interaction frequencies, and the loss of the more connected species affected networks to a greater extent. Further, rewiring increased network robustness, and morphological matching and spatial and temporal overlaps between partners were more influential on network robustness than species abundances. We argue that to achieve self-sustaining ecosystems, restoration initiatives can consider optimal morphological matching and spatial and temporal overlaps between consumers and resources to maximize chances of native plant dispersal. Specifically, restoration initiatives may benefit from replacing invasive species with native species possessing characteristics that promote frequent interactions and increase the probability of rewiring (such as long fruiting periods, small seeds and broad distributions).

Early Detection of the Spinach Downy Mildew Pathogen in Leaves by Recombinase Polymerase Amplification.

Downy mildew of spinach, caused by Peronospora effusa, is a major economic threat to both organic and conventional spinach production. Symptomatic spinach leaves are unmarketable and spinach with latent infections are problematic because symptoms can develop postharvest. Therefore, early detection methods for P. effusa could help producers identify infection before visible symptoms appear. Recombinase polymerase amplification (RPA) provides sensitive and specific detection of pathogen DNA and is a rapid, field-applicable method that does not require advanced technical knowledge or equipment-heavy DNA extraction. Here, we used comparative genomics to identify a unique region of the P. effusa mitochondrial genome to develop an RPA assay for the early detection of P. effusa in spinach leaves. In tandem, we established a TaqMan quantitative PCR (qPCR) assay and used this assay to validate the P. effusa specificity of the locus across Peronospora spp. and to compare assay performance. Neither the TaqMan qPCR nor the RPA showed cross reactivity with the closely related beet downy mildew pathogen, P. schachtii. TaqMan qPCR and RPA have detection thresholds of 100 and 900 fg of DNA, respectively. Both assays could detect P. effusa in presymptomatic leaves, with RPA-based detection occurring as early as 5 days before the appearance of symptoms and TaqMan qPCR-based detection occurring after 24 h of plant exposure to airborne spores. Implementation of the RPA detection method could provide real-time information for point-of-care management strategies at field sites.

Cultural efficacy as a novel component of understanding linkages between culture and mental health in Indigenous communities.

We used a novel measure of cultural efficacy to examine empirical pathways between enculturation, efficacy, and two wellbeing outcomes. Cultural factors are not consistently linked to better wellbeing in the academic literature despite widespread understanding of these processes in Indigenous communities. Healing pathways is a community-based participatory study with eight reservations/reserves in the upper Midwest and Canada. This study uses data collected in 2017-2018 (n = 453, 58.1% women, mean age = 26.3 years) and structural equation modeling to test the relationships between enculturation, cultural efficacy, and mental health. The direct effect of enculturation on anxiety was positive. The indirect effect of enculturation via cultural efficacy was negatively associated with anxiety and positively associated with positive mental health. Cultural efficacy is an important linking variable through which the protective effects of culture manifest. The complex nature of culture must be met with innovative measures and deep understanding of Indigenous peoples to fully capture the protective role of culture.

Adaptation without Specialization Early in a Host Shift.

AbstractStudents of speciation debate the role of performance trade-offs across different environments early in speciation. We tested for early performance trade-offs with a host shift experiment using a member of the Enchenopa binotata species complex of treehoppers (Hemiptera: Membracidae). In this clade of plant-feeding insects, different species live on different host plants and exhibit strong behavioral and physiological host specialization. After five generations, the experimental host shifts resulted either in no adaptation or in adaptation without specialization. The latter result was more likely in sympatry; in allopatry, populations on novel host plants were more likely to become extinct. We conclude that in the early stages of speciation, adaptation to novel host plants does not necessarily bring about performance trade-offs on ancestral environments. Adaptation may be facilitated rather than hindered by gene flow, which prevents extinction. Additional causes of specialization and assortative mating may be required if colonization of novel environments is to result in speciation.

Spiritual connectedness through prayer as a mediator of the relationship between Indigenous language use and positive mental health.

OBJECTIVE: The objective of this study is to understand how Indigenous language and spirituality revitalization efforts may affect mental health within Indigenous communities. Although Indigenous communities experience disproportionate rates of mental health problems, research supporting language and spirituality's role in improving mental health is under-researched and poorly understood. METHOD: Data for this study are from a Community-based Participatory Research Project involving five Anishinaabe tribes in Minnesota and Wisconsin. Participants were sampled from clinic records of adults with a diagnosis of type 2 diabetes, living on or near the reservation, and self-identifying as American Indian (mean age = 46.3; n = 191). RESULT: Structural equation modeling illustrates that language use in the home is associated with positive mental health through spiritual connectedness. CONCLUSION: Results support tribal community expressions of the positive effects of cultural involvement for Indigenous wellbeing, and improve what is known about the interconnectedness of language and spirituality. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Sec-Delivered Effector 1 (SDE1) of 'Candidatus Liberibacter asiaticus' Promotes Citrus Huanglongbing.

Sec-delivered effector 1 (SDE1) from the huanglongbing (HLB)-associated bacterium 'Candidatus Liberibacter asiaticus' was previously characterized as an inhibitor of defense-related, papain-like cysteine proteases in vitro and in planta. Here, we investigated the contributions of SDE1 to HLB progression. We found that SDE1 expression in the model plant Arabidopsis thaliana caused severe yellowing in mature leaves, reminiscent of both 'Ca. L. asiaticus' infection symptoms and accelerated leaf senescence. Induction of senescence signatures was also observed in the SDE1-expressing A. thaliana lines. These signatures were apparent in older leaves but not in seedlings, suggesting an age-associated effect. Furthermore, independent lines of transgenic Citrus paradisi (L.) Macfadyen (Duncan grapefruit) that express SDE1 exhibited hypersusceptibility to 'Ca. L. asiaticus'. Similar to A. thaliana, transgenic citrus expressing SDE1 showed altered expression of senescence-associated genes, but only after infection with 'Ca. L. asiaticus'. These findings suggest that SDE1 is a virulence factor that contributes to HLB progression, likely by inducing premature or accelerated senescence in citrus. This work provides new insight into HLB pathogenesis.[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Major transitions in dinoflagellate evolution unveiled by phylotranscriptomics.

Dinoflagellates are key species in marine environments, but they remain poorly understood in part because of their large, complex genomes, unique molecular biology, and unresolved in-group relationships. We created a taxonomically representative dataset of dinoflagellate transcriptomes and used this to infer a strongly supported phylogeny to map major morphological and molecular transitions in dinoflagellate evolution. Our results show an early-branching position of Noctiluca, monophyly of thecate (plate-bearing) dinoflagellates, and paraphyly of athecate ones. This represents unambiguous phylogenetic evidence for a single origin of the group's cellulosic theca, which we show coincided with a radiation of cellulases implicated in cell division. By integrating dinoflagellate molecular, fossil, and biogeochemical evidence, we propose a revised model for the evolution of thecal tabulations and suggest that the late acquisition of dinosterol in the group is inconsistent with dinoflagellates being the source of this biomarker in pre-Mesozoic strata. Three distantly related, fundamentally nonphotosynthetic dinoflagellates, Noctiluca, Oxyrrhis, and Dinophysis, contain cryptic plastidial metabolisms and lack alternative cytosolic pathways, suggesting that all free-living dinoflagellates are metabolically dependent on plastids. This finding led us to propose general mechanisms of dependency on plastid organelles in eukaryotes that have lost photosynthesis; it also suggests that the evolutionary origin of bioluminescence in nonphotosynthetic dinoflagellates may be linked to plastidic tetrapyrrole biosynthesis. Finally, we use our phylogenetic framework to show that dinoflagellate nuclei have recruited DNA-binding proteins in three distinct evolutionary waves, which included two independent acquisitions of bacterial histone-like proteins.

Contrasting effects of high-intensity photosynthetically active radiation on two bloom-forming dinoflagellates.

While light limitation can inhibit bloom formation in dinoflagellates, the potential for high-intensity photosynthetically active radiation (PAR) to inhibit blooms by causing stress or damage has not been well-studied. We measured the effects of high-intensity PAR on the bloom-forming dinoflagellates Alexandrium fundyense and Heterocapsa rotundata. Various physiological parameters (photosynthetic efficiency Fv /Fm , cell permeability, dimethylsulfoniopropionate [DMSP], cell volume, and chlorophyll-a content) were measured before and after exposure to high-intensity natural sunlight in short-term light stress experiments. In addition, photosynthesis-irradiance (P-E) responses were compared for cells grown at different light levels to assess the capacity for photophysiological acclimation in each species. Experiments revealed distinct species-specific responses to high PAR. While high light decreased Fv /Fm in both species, A. fundyense showed little additional evidence of light stress in short-term experiments, although increased membrane permeability and intracellular DMSP indicated a response to handling. P-E responses further indicated a high light-adapted species with Chl-a inversely proportional to growth irradiance and no evidence of photoinhibition; reduced maximum per-cell photosynthesis rates suggest a trade-off between photoprotection and C fixation in high light-acclimated cells. Heterocapsa rotundata cells, in contrast, swelled in response to high light and sometimes lysed in short-term experiments, releasing DMSP. P-E responses confirmed a low light-adapted species with high photosynthetic efficiencies associated with trade-offs in the form of substantial photoinhibition and a lack of plasticity in Chl-a content. These contrasting responses illustrate that high light constrains dinoflagellate community composition through species-specific stress effects, with consequences for bloom formation and ecological interactions within the plankton.

Remodeling of Rectal Innervation After Pullthrough Surgery for Hirschsprung Disease: Relevance to Criteria for the Determination of Retained Transition Zone.

BACKGROUND: After pullthrough surgery for Hirschsprung disease (HSCR), Glut1-positive submucosal nerve hypertrophy is used to diagnose retained transition zone in the neorectum. We hypothesized that pelvic nerves, severed during pullthrough surgery, sprout into the neorectum to mimic transition zone. METHODS: The density (nerves/100x field) and maximum diameter of Glut1-positive submucosal nerves were measured in biopsies and redo resections from 20 patients with post-pullthrough obstructive symptoms. Their original and/or redo resections excluded unequivocal features of transition zone (myenteric hypoganglionosis or partial circumferential aganglionosis) in 17. Postoperative values were compared with control data from 28 cadaveric and 6 surgical non-HSCR specimens, and 14 primary HSCR resections. When possible, nerves were tracked from attached native pelvic soft tissue or aganglionic rectal cuff into the pulled-through colon. RESULTS: Glut1-positive submucosal nerves were not present in the 11 colons of non-HSCR infants less than 1 year of age, except sparsely in the rectum. In 17 older non-HSCR controls, occasional Glut1-positive nerves were observed in prerectal colon and were larger and more numerous in the rectum. In redo resections, Glut1-positive submucosal innervation in post-pullthrough specimens did not differ significantly from age-appropriate non-HSCR rectal controls and pelvic Glut1-positive nerves were never observed to penetrate the pulled-through colon. However, the density and caliber of Glut1-positive nerves in the neorectums were significantly greater than expected based on the prerectal location from which the pulled-through bowel originated. CONCLUSIONS: Submucosal innervation in post-pullthrough specimens does not support the hypothesis that native pelvic nerves innervate the neorectum, but suggests remodeling occurs to establish the age-appropriate density and caliber of rectal Glut1-positive innervation. The latter should not be interpreted as transition zone pullthrough in a rectal biopsy from a previously done pullthrough.

Human papillomavirus infection mediates response and outcome of vulvar squamous cell carcinomas treated with radiation therapy.

PURPOSE: Human papillomavirus (HPV) is implicated as a causative factor in vulvar squamous cell carcinoma (VSCC). This study evaluates if p16-positivity, a surrogate for HPV, predicts for better response rates to chemoradiation therapy and survival. MATERIALS AND METHODS: We conducted a retrospective chart review of women treated with neoadjuvant or definitive chemoradiation (CRT) therapy from 2000 to 2016 for VSCC. p16 stain-positivity was defined as diffuse strong "block" immunoreactivity within invasive tumor. RESULTS: Seventy-three women with median follow-up of 13.4 months were analyzed. Thirty-three (45.2%) had p16+ tumors. Median age was 73 years (range: 37-89); with p16+ tumors, the median age was 60 years vs 73 years for women with p16- tumors (p < 0.001). The distribution of tumor size and stage by p16-status were similar. The complete clinical response (cCR) rate for p16+ tumors was 63.6% vs 35.0% for p16- tumors (p = 0.014). The pathologic complete response (pCR) rate for women treated neoadjuvantly was 53.8% vs 31.4% for p16+ vs p16-, respectively (p = 0.067). The combined complete response (cCR orpCR [CCR]) rate was 63.6% for p16+ and 30.0% for p16- (p = 0.004). Two-year vulvar control (VC) for women with p16+ tumors was 75.5% vs. 49.5% for p16- (p = 0.008). In women with p16+ tumors who achieved CCR, 2-year VC was 92.3% vs 52.1% for CIR (p = 0.009). For p16- tumors, 2-year VC was 67.3% vs 41.1% for CCR and CIR (p = 0.072). No woman with a p16+ tumor developed distant metastases vs. 7 with p16- tumor (p = 0.013). OS was not statistically different between p16+ cohorts, but was improved for p16- patients with CR vs CIR, 72.9% vs 18.8% (p = 0.026). CONCLUSIONS: p16-positive tumors appear to have better clinical and pathologic response rates and clinical outcomes.

Exchange equilibria of carboxylate-terminated ligands at PbS nanocrystal surfaces.

Ligand exchange reactions are commonly used to alter the surface chemistry of metal chalcogenide quantum dots; however, a lack of quantifiable data for these processes limits the rational functionalization of nanomaterials. Here, we quantify the X-type ligand exchange reaction between carboxylate-terminated ligands on PbS quantum dots via1H NMR spectroscopy. Using spectroscopic handles of both the native and exchange ligand, bound and free forms of each have been quantified as a function of exchange ligand concentration. We find that the equilibrium constants for the reaction between oleate-capped PbS quantum dots and undec-10-enoic acid are 2.23 ± 0.50 and 2.14 ± 0.42 for sets of nanocrystals prepared by two different synthetic methods. X-ray photoelectron, absorbance, and emission spectroscopies indicate that the carboxylate exchange reaction does not alter the lead ion coverage of the nanocrystal surface. The quantitative equilibrium constant determined herein can be used to improve control over partial ligand exchange reactions on PbS nanocrystals.

A case series of atypical features of patients with biopsy-proven isolated IgG4-related hypophysitis and normal serum IgG4 levels.

BACKGROUND: IgG4-related hypophysitis is a rare clinical entity that forms part of an emerging group of multi-organ IgG4-related fibrosclerotic systemic diseases. The rare prevalence of the disease, presenting features that overlap with other sellar pathologies, and variable imaging features can make preoperative identification challenging. PURPOSE AND METHODS: We report three cases of isolated IgG4-related hypophysitis with atypical clinical and imaging features that mimicked those of pituitary apoplexy and other sellar lesions. Additionally, we review the literature of IgG4-related hypophysitis to provide context for individual patient data described herein. RESULTS: All patients presented with symptoms that mimicked those of pituitary apoplexy and visual disturbance, and MRI findings suggestive of pituitary macroadenoma, Rathke's cleft cyst and craniopharyngioma. The clinical presentation warranted surgical decompression, resulting in rapid symptomatic improvement. Preoperative high-dose followed by postoperative low-dose glucocorticoid replacement therapy was administered in all cases. Histopathology showed dense infiltrate of IgG4 cells. Post-operative follow-up monitoring for 12-26 months revealed normal serum IgG4 levels with no other organ involvement, while endocrinological testing revealed persistent pituitary hormone deficiencies. CONCLUSIONS: Our cases highlight the importance of considering IgG4-related hypophysitis in the differential diagnosis of solid and cystic sellar lesions presenting acutely with pituitary apoplexy symptoms. Existing diagnostic criteria may not be sufficiently precise to permit rapid and reliable identification, or avoidance of surgery in the acute setting. In contrast to other reports of the natural history of this condition, despite the severity of presenting features, the disease in our cases was pituitary-restricted with normal serum IgG4 levels.