Pneumococcal carriage, serotype distribution, and antimicrobial susceptibility in Papua New Guinean children vaccinated with PCV10 or PCV13 in a head-to-head trial.

BACKGROUND: Children in Papua New Guinea (PNG) are at high risk of pneumococcal infections. We investigated pneumococcal carriage rates, serotype distribution, and antimicrobial susceptibility in PNG children after vaccination with 10-valent or 13-valent pneumococcal conjugate vaccines (PCV10; PCV13). METHODS: Infants (N = 262) were randomized to receive 3 doses of PCV10 or PCV13 at 1-2-3 months of age, followed by pneumococcal polysaccharide vaccination (PPV) or no PPV at 9 months of age. Nasopharyngeal swabs (NPS) collected at ages 1, 4, 9, 10, 23 and 24 months were cultured using standard bacteriological procedures. Morphologically distinct Streptococcus pneumoniae colonies were serotyped by the Quellung reaction. Antimicrobial susceptibility was determined by Kirby-Bauer disc diffusion and minimum inhibitory concentration (MIC). RESULTS: S. pneumoniae was isolated from 883/1063 NPS collected at 1-23 months of age, including 820 serotypeable (64 different serotypes) and 144 non-serotypeable isolates. At age 23 months, 93.6% (95%CI 86.6-97.6%) of PCV10 recipients and 88.6% (95%CI 80.1-94.4%) of PCV13 recipients were pneumococcal carriers, with higher carriage of PCV10 serotypes by PCV10 recipients (19.8%, 95%CI 12.2-29.5) than PCV13 recipients (9.3%, 95%CI 4.1-17.3) (p = 0.049). There were no other statistically significant differences between PCV10 and PCV13 recipients and children receiving PPV or no PPV. Nearly half (45.6%) of carried pneumococci were non-susceptible to penicillin based on the meningitis breakpoint (MIC ≥ 0.12 µg/mL), but resistance was rare (1.1%) using the non-meningitis cut-off (MIC ≥ 8 µg/mL). Non-susceptibility to trimethoprim-sulfamethoxazole (SXT) was common: 23.2% of isolates showed intermediate resistance (MIC 1/19-2/38 µg/mL) and 16.9% full resistance (MIC ≥ 4/76 µg/mL). PCV serotypes 14 and 19A were commonly non-susceptible to both penicillin (14, 97%; 19A, 70%) and SXT (14, 97%; 19A, 87%). CONCLUSION: Even after PCV10 or PCV13 vaccination, children living in a high-risk setting such as PNG continue to experience high levels of pneumococcal colonization, including carriage of highly antimicrobial-resistant PCV serotypes. The study is registered with ClinicalTrials.gov (CTN NCT01619462).

Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study.

BACKGROUND: Serotype 24F is one of the emerging pneumococcal serotypes after the introduction of pneumococcal conjugate vaccine (PCV). We aimed to identify lineages driving the increase of serotype 24F in France and place these findings into a global context. METHODS: Whole-genome sequencing was performed on a collection of serotype 24F pneumococci from asymptomatic colonisation (n=229) and invasive disease (n=190) isolates among individuals younger than 18 years in France, from 2003 to 2018. To provide a global context, we included an additional collection of 24F isolates in the Global Pneumococcal Sequencing (GPS) project database for analysis. A Global Pneumococcal Sequence Cluster (GPSC) and a clonal complex (CC) were assigned to each genome. Phylogenetic, evolutionary, and spatiotemporal analysis were conducted using the same 24F collection and supplemented with a global collection of genomes belonging to the lineage of interest from the GPS project database (n=25 590). FINDINGS: Serotype 24F was identified in numerous countries mainly due to the clonal spread of three lineages: GPSC10 (CC230), GPSC16 (CC156), and GPSC206 (CC7701). GPSC10 was the only multidrug-resistant lineage. GPSC10 drove the increase in 24F in France and had high invasive disease potential. The international dataset of GPSC10 (n=888) revealed that this lineage expressed 16 other serotypes, with only six included in 13-valent PCV (PCV13). All serotype 24F isolates were clustered in a single clade within the GPSC10 phylogeny and long-range transmissions were detected from Europe to other continents. Spatiotemporal analysis showed GPSC10-24F took 3-5 years to spread across France and a rapid change of serotype composition from PCV13 serotype 19A to 24F during the introduction of PCV13 was observed in neighbouring country Spain. INTERPRETATION: Our work reveals that GPSC10 alone is a challenge for serotype-based vaccine strategy. More systematic investigation to identify lineages like GPSC10 will better inform and improve next-generation preventive strategies against pneumococcal diseases. FUNDING: Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention.

Update on thyroid eye disease: Regional variations in prevalence, diagnosis, and management.

Thyroid eye disease (TED) is a rare disease that can lead to decreased quality of life, permanent disfigurement, and vision loss. Clinically, TED presents with exophthalmos, periorbital edema, extraocular muscle dysfunction, and eyelid retraction, and can lead to vision-threatening complications such as exposure to keratopathy and dysthyroid optic neuropathy (DON). Over the last several years, significant advancements have been made in the understanding of its pathophysiology as well as optimal management. Ethnic variations in the prevalence, clinical presentation, and risk of vision-threatening complications of TED are summarized, and risk factors associated with TED are discussed. Additionally, significant advances have been made in the management of TED. The management of TED traditionally included anti-inflammatory medications, orbital radiation therapy, orbital surgical decompression, and biologic therapies. Most recently, targeted therapies such as teprotumumab, an insulin-like growth factor-1 receptor antagonist, have been studied in the context of TED, with promising initial data. In this review, updates in the understanding and management of TED are presented with a focus on the international variations in presentation and management.

Variants of Streptococcus pneumoniae Serotype 14 from Papua New Guinea with the Potential to Be Mistyped and Escape Vaccine-Induced Protection.

Streptococcus pneumoniae (the pneumococcus) is a human pathogen of global importance, classified into serotypes based on the type of capsular polysaccharide produced. Serotyping of pneumococci is essential for disease surveillance and vaccine impact measurement. However, the accuracy of serotyping methods can be affected by previously undiscovered variants. Previous studies have identified variants of serotype 14, a highly invasive serotype included in all licensed vaccine formulations. However, the potential of these variants to influence serotyping accuracy and evade vaccine-induced protection has not been investigated. In this study, we screened 1,386 nasopharyngeal swabs from children hospitalized with acute respiratory infection in Papua New Guinea for pneumococci. Swabs containing pneumococci (n = 1,226) were serotyped by microarray to identify pneumococci with a divergent serotype 14 capsule locus. Three serotype 14 variants ('14-like') were isolated and characterized further. The serotyping results of these isolates using molecular methods varied depending on the method, with 3/3 typing as nontypeable (PneumoCaT), 3/3 typing as serotype 14 (seroBA), and 2/3 typing as serotype 14 (SeroCall and quantitative PCR). All three isolates were nontypeable by phenotypic methods (Quellung and latex agglutination), indicating the absence of capsule. Illumina and nanopore sequencing were employed to examine their capsule loci and revealed unique mutations. Lastly, when incubated with sera from vaccinated individuals, the 14-like isolates evaded serotype-specific opsonophagocytic killing. Our study highlights the need for phenotypic testing to validate serotyping data derived from molecular methods. The convergent evolution of capsule loss underscores the importance of studying pneumococcal population biology to monitor the emergence of pneumococci capable of vaccine escape, globally. IMPORTANCE Pneumococcus is a pathogen of major public health importance. Current vaccines have limited valency, targeting a subset (up to 20) of the more than 100 capsule types (serotypes). Precise serotyping methods are therefore essential to avoid mistyping, which can reduce the accuracy of data used to inform decisions around vaccine introduction and/or maintenance of national vaccination programs. In this study, we examine a variant of serotype 14 (14-like), a virulent serotype present in all currently licensed vaccine formulations. Although these 14-like pneumococci no longer produce a serotype 14 capsule, widely used molecular methods can mistype them as serotype 14. Importantly, we show that 14-like pneumococci can evade opsonophagocytic killing mediated by vaccination. Despite the high accuracy of molecular methods for serotyping, our study reemphasizes their limitations. This is particularly relevant in situations where nonvaccine type pneumococci (e.g., the 14-likes in this study) could potentially be misidentified as a vaccine type (e.g., serotype 14).

Distinct Streptococcus pneumoniae cause invasive disease in Papua New Guinea.

Streptococcus pneumoniae is a key contributor to childhood morbidity and mortality in Papua New Guinea (PNG). For the first time, whole genome sequencing of 174 isolates has enabled detailed characterisation of diverse S. pneumoniae causing invasive disease in young children in PNG, 1989-2014. This study captures the baseline S. pneumoniae population prior to the introduction of 13-valent pneumococcal conjugate vaccine (PCV13) into the national childhood immunisation programme in 2014. Relationships amongst lineages, serotypes and antimicrobial resistance traits were characterised, and the population was viewed in the context of a global collection of isolates. The analyses highlighted adiverse S. pneumoniae population associated with invasive disease in PNG, with 45 unique Global Pneumococcal Sequence Clusters (GPSCs) observed amongst the 174 isolates reflecting multiple lineages observed in PNG that have not been identified in other geographic locations. The majority of isolates were from children with meningitis, of which 52% (n=72) expressed non-PCV13 serotypes. Over a third of isolates were predicted to be resistant to at least one antimicrobial. PCV13 serotype isolates had 10.1 times the odds of being multidrug-resistant (MDR) compared to non-vaccine serotype isolates, and no isolates with GPSCs unique to PNG were MDR. Serotype 2 was the most commonly identified serotype; we identified a highly clonal cluster of serotype 2 isolates unique to PNG, and a distinct second cluster indicative of long-distance transmission. Ongoing surveillance, including whole-genome sequencing, is needed to ascertain the impact of the national PCV13 programme upon the S. pneumoniae population, including serotype replacement and antimicrobial resistance traits.

Bilateral Paraneoplastic Orbital Myositis Associated With Malignant Melanoma and Multiple Myeloma.

Paraneoplastic extraocular muscle enlargement has been reported in a small number of patients with cancers including breast or lymphoma, usually presenting with bilateral multiple muscle involvement. Such myositis may be autoimmune. Furthermore, orbital inflammation is a recognized complication of immune-modulation therapy used to treat melanoma, such as ipilimumab. Extraorbital myositis has been described in myeloma, and polymyositis in melanoma. We present a case of bilateral, asymmetrical extraocular muscle enlargement with spontaneous resolution in a patient with simultaneous new diagnoses of metastatic malignant melanoma and multiple myeloma. A similar episode 7 months before diagnosis also resolved spontaneously. The authors believe this to be the first reported case of paraneoplastic orbital myositis associated with multiple myeloma or untreated malignant melanoma.

Anterior approach ptosis surgery: comparison of absorbable polyglactin sutures and non-absorbable polyester sutures. Does Vicryl stand the test of time?

PURPOSE: To determine whether the long-term success of ptosis surgery is influenced by the use of absorbable or non-absorbable sutures to advance the levator aponeurosis onto the tarsal plate. METHODS: Multi-centre retrospective comparative study of re-operation rates in primary anterior approach ptosis surgery using absorbable polyglactin sutures (Vicryl) and non-absorbable polyester sutures (Ethibond). The Medisoft audit tool was used to identify all patients who underwent primary ptosis surgery for aponeurotic ptosis, performed by five oculoplastic consultants within a 7-year period, across two NHS Ophthalmology departments. The electronic patient records were reviewed for each patient. Basic demographics, suture material, and post-operative complications were recorded. All patients requiring repeat surgery between the study dates and the present day were recorded, allowing a minimum postoperative period of 3 years and 10 months. Re-operation rates in surgery using absorbable Vicryl sutures and non-absorbable Ethibond sutures were compared using Fisher's exact test. RESULTS: Four hundred and fifty-five operations in 330 patients were performed within the study period that met the inclusion and exclusion criteria. Fifty-seven percent of the patients were female, with an average age of 68.8 years. One hundred and sixty-nine operations in 128 patients were performed using absorbable Vicryl sutures. Of these, 22 (13.0%) required repeat operations. Two hundred and eighty-six operations in 202 patients were performed using non-absorbable Ethibond sutures. Of these, 17 (5.9%) required repeat operations. The two-tailed P-value was 0.0143. CONCLUSION: The use of non-absorbable Ethibond sutures to advance the levator aponeurosis onto the tarsal plate in primary ptosis surgery is associated with improved long-term success and reduced need for secondary surgery.

Lack of effectiveness of 13-valent pneumococcal conjugate vaccination against pneumococcal carriage density in Papua New Guinean infants.

BACKGROUND: Papua New Guinea (PNG) introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in 2014, with administration at 1, 2, and 3 months of age. PCV13 has reduced or eliminated carriage of vaccine types in populations with low pneumococcal carriage prevalence, carriage density and serotype diversity. This study investigated PCV13 impact on serotype-specific pneumococcal carriage prevalence, density, and serotype diversity in PNG infants, who have some of the highest reported rates of pneumococcal carriage and disease in the world. METHODS: Nasopharyngeal swabs were collected at 1, 4 and 9 months of age from PCV13-vaccinated infants (n = 57) and age-/season-matched, unvaccinated infants (at approximately 1 month, n = 53; 4 months, n = 57; 9 months, n = 52). Serotype-specific pneumococcal carriage density and antimicrobial resistance genes were identified by qPCR and microarray. RESULTS: Pneumococci were present in 89% of swabs, with 60 different serotypes and four non-encapsulated variants detected. Multiple serotype carriage was common (47% of swabs). Vaccine type carriage prevalence was similar between PCV13-vaccinated and unvaccinated infants at 4 and 9 months of age. The prevalence of non-vaccine type carriage was also similar between cohorts, with non-vaccine types present in three-quarters of samples (from both vaccinated and unvaccinated infants) by 4 months of age. The median pneumococcal carriage density was high and similar at each age group (~7.0 log10genome equivalents/mL). PCV13 had no effect on overall pneumococcal carriage density, vaccine type density, non-vaccine type density, or the prevalence of antimicrobial resistance genes. CONCLUSION: PNG infants experience dense and diverse pneumococcal colonisation with concurrent serotypes from 1 month of age. PCV13 had no impact on pneumococcal carriage density, even for vaccine serotypes. The low prevalence of vaccine serotypes, high pneumococcal carriage density and abundance of non-vaccine serotypes likely contribute to the lack of PCV13 impact on carriage in PNG infants. Indirect effects of the infant PCV programs are likely to be limited in PNG. Alternative vaccines with broader coverage should be considered.

PCV10 elicits Protein D IgG responses in Papua New Guinean children but has no impact on NTHi carriage in the first two years of life.

BACKGROUND: Nasopharyngeal colonisation with nontypeable Haemophilus influenzae (NTHi) is associated with development of infections including pneumonia and otitis media. The 10-valent pneumococcal conjugate vaccine (PCV10) uses NTHi Protein D (PD) as a carrier. Papua New Guinean children have exceptionally early and dense NTHi carriage, and high rates of NTHi-associated disease. Vaccination with PCV10 could potentially reduce NTHi carriage and disease in this population by inducing a NTHi PD immune response. METHODS: Serum and nasopharyngeal swabs were collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age. Children received PCV10 (n = 55) or PCV13 (not containing NTHi PD) (n = 46) at 1, 2 and 3 months of age. NTHi carriage density was measured in swabs by qPCR. Serum PD-IgG levels were measured by bead-based immunoassay. RESULTS: Papua New Guinean children did naturally develop PD-IgG antibodies whose levels were increased at 4 months of age with PCV10 vaccination at 1-2-3 months. Despite this, most children were colonised with NTHi by 4 months of age (~95%) regardless of being vaccinated with PCV10 or PCV13, and PCV10 had no impact on NTHi carriage density. CONCLUSION: Early vaccination of infants with PCV10 elicited a robust PD antibody response but this had no impact on NTHi carriage. TRIAL REGISTRATION: ClinicalTrials.gov CTN NCT01619462.

Clinical challenges of thyroid eye disease in HIV-positive patients on highly active antiretroviral therapy.

BACKGROUND: Graves' disease (GD) as an immune reconstitution inflammatory syndrome during highly active antiretroviral therapy (HAART) for HIV has previously been reported. However, clinical challenges associated with HIV in the context of thyroid eye disease (TED) are not as well-characterized. OBJECTIVE: To determine the frequency of coexisting HIV and TED, describe TED presentation and course in the context of HIV, and evaluate management difficulties as well as potential solutions. METHODS: Cross-sectional study of all patients with coexisting GD and HIV at University Hospitals Birmingham (2003-2014). Retrospective case note review to identify TED with particular reference to HAART regimen, CD4+ T-cell count, HIV viral load, and TED activity and severity. RESULTS: Of 783 subjects with GD and 1186 with HIV, 11 were identified with both GD and HIV. Of these, three had clinical features of TED; each was of Afro-Caribbean origin, was in their fourth decade, and initially presented with undetectable CD4 T cells and high HIV viral loads. All went on to develop GD >3 years after commencing HAART, with normal CD4 count and undetectable viral load at the time of GD diagnosis. The full spectrum of TED was represented, with two subjects requiring orbital decompression surgery. DISCUSSION: TED in the context of HIV is uncommon. Many challenges exist in such patients, particularly HAART drug interactions with antithyroid and immunosuppressant medications. To better understand TED in HIV and to counsel patients with this copathology most effectively, future multicenter surveillance is required.

Classification of orbital fractures using the AO/ASIF system in a population surveillance cohort of traumatic optic neuropathy.

PURPOSE: In our prospective nationwide surveillance study of traumatic optic neuropathy (TON) in the United Kingdom, the prevalence of orbital fractures was found to be 39% (47/121). The prevalence of skull fractures was 7.4% (9/121). This study aims to identify the association of craniofacial-orbital fractures with the severity of visual loss. METHODS: TON patients who sustained orbital fractures were identified prospectively by population-based active surveillance through the British Ophthalmic Surveillance Unit over a 2-year period. Available CT scans were classified by a head and neck radiologist according to the Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation (AO/ASIF) scheme: the face was divided into 4 units; fractures in each unit were graded according to displacement (A-C) and severity (1.1-3.3). Correlation between severity of craniofacial orbital fractures and visual acuity as well as number of fractured units and visual acuity were evaluated. RESULTS: Twelve of the 25 patients (48%) with imaging available had adequate high resolution craniofacial CT imaging for review and classification using the AO/ASIF system (i.e. 48 classifiable units). Three of 48 (6%) units were undisplaced (grade A), 18 of 48 (29%) units were minimally displaced (grade B), and 4 of 48 (8%) units had largely displaced (grade C) fractures. Twenty-three units (47.9%) had no fractures; 5 patients had radiological evidence of optic canal fractures. Poor visual acuities positively correlated with severity of fractures graded using the AO/ASIF classification (Spearman's rho = 0.95, p = 0.05) and number of fractured units (Spearman's rho = 1.0, p < 0.0001). CONCLUSION: AO/ASIF classification system provides a uniform method in the assessment of orbital fractures which correlates with visual outcome in TON.

A 2-year prospective surveillance of pediatric traumatic optic neuropathy in the United Kingdom.

BACKGROUND: To report epidemiologic data on traumatic optic neuropathy (TON) in patients less than 18 years of age in the United Kingdom acquired by prospective population-based active surveillance through the British Ophthalmic Surveillance Unit. METHODS: Data were obtained from incident and 6-month follow-up questionnaires sent to reporting ophthalmologists over a period of 2 years. Main outcome measures were demographic data, clinical and visual function at presentation and follow-up, investigations, and treatments used. RESULTS: A total of 26 cases (21 males) were identified; follow-up data were available for 23 (88%). Minimum estimated annual incidence was 0.99 cases per million. Leading causes of TON included 6 sports injuries (23%), 5 falls (19%), and 4 traffic accidents (16%). Presenting best-corrected visual acuity was ≤ 6/60 in 15 cases (58%), with no light perception in 7 cases (27%). Associated injuries were as follows: nonpenetrating injuries, 8 (31%); adnexal injuries, 3 (11.5%); orbital fractures, 5 (19%); skull fractures, 3 (12%); intracranial bleeding, 1 (4%). Fourteen (54%) received no treatment, and 9 (35%) were treated with steroids. Final visual acuity improved in 7 of 21 patients (33%), with 13 of 23 (56%) achieving final visual acuity ≤ 6/60, 10 of whom (43%) had no light perception. Baseline visual acuity was associated with last follow-up visual acuity (P = 0.03), but treatment and improvement of visual acuity by at least 3 lines were not associated. Treatment was more common in children with poor presenting vision (P = 0.03). CONCLUSIONS: The incidence, natural history, poor presenting visual acuity, and male prevalence of TON in children appear similar to adults in adults in the UK.

Investigation of standard care versus sham Reiki placebo versus actual Reiki therapy to enhance comfort and well-being in a chemotherapy infusion center.

PURPOSE/OBJECTIVES: To determine whether provision of Reiki therapy during outpatient chemotherapy is associated with increased comfort and well-being. DESIGN: Double-blind, randomized clinical controlled trial. SETTING: Outpatient chemotherapy center. SAMPLE: 189 participants were randomized to actual Reiki, sham Reiki placebo, or standard care. METHODS: Patients receiving chemotherapy were randomly placed into one of three groups. Patients received either standard care, a placebo, or an actual Reiki therapy treatment. A demographic tool and pre- and post-tests were given before and after chemotherapy infusion. MAIN RESEARCH VARIABLES: Reiki therapy, sham Reiki placebo therapy, standard care, and self-reported levels of comfort and well-being pre- and postintervention. FINDINGS: Although Reiki therapy was statistically significant in raising the comfort and well-being of patients post-therapy, the sham Reiki placebo also was statistically significant. Patients in the standard care group did not experience changes in comfort and well-being during their infusion session. CONCLUSIONS: The findings indicate that the presence of an RN providing one-on-one support during chemotherapy was influential in raising comfort and well-being levels, with or without an attempted healing energy field. IMPLICATIONS FOR NURSING: An attempt by clinic nurses to provide more designated one-to-one presence and support for patients while receiving their chemotherapy infusions could increase patient comfort and well-being.

Drainage of the maxillary sinus: a comparative anatomy study in humans and goats.

OBJECTIVE: The maxillary sinuses are the most frequently infected paranasal sinuses in humans. It has been suggested that infection occurs relatively commonly in the maxillary sinuses owing to the position of their ostia high on their superomedial walls, which may be suboptimal for natural drainage. This may represent evolutionary lag, whereby the ostia remained in a quadrupedal position as bipedal humans evolved from their primate ancestors. This study examined the hypothesis that drainage of the maxillary sinus is optimal in the quadrupedal position. DESIGN: The drainage of the human maxillary sinus and an analogous quadruped, the goat, was examined and compared in the upright, quadrupedal, and intermediate positions. SETTING: Department of Anatomy, King's College London. METHODS: Cadaveric human and goat maxillary sinuses were filled with saline in each position and the volume at which saline overflowed through the ostia was noted. MAIN OUTCOME MEASURE: Volume at which spontaneous drainage occurred through ostia. RESULTS: The volume of saline instilled before drainage was maximal in the upright position and reduced with each increase in anterior tilt, with drainage occurring most easily at 90° for both human and goat sinuses. Drainage was significantly better in the quadrupedal head position than upright in both species (p < .01). CONCLUSIONS: This study demonstrated that human maxillary sinuses exhibit better passive drainage through their ostia when tilted anteriorly to mimic a quadrupedal head position. This may be an example of an evolutionary lag phenomenon and could be one etiologic factor in the prevalence of maxillary sinusitis in humans.

Intraoperative floppy iris syndrome associated with risperidone intake.

PURPOSE: Intraoperative floppy iris syndrome (IFIS) has been strongly associated with intake of selective a1 adrenergic blockers, particularly tamsulosin. Intraoperative floppy iris syndrome has also been linked to the use of other drugs with some a antagonist activity. METHODS: We identified patients on long-term treatment with the antipsychotic agent risperidone who showed typical features of IFIS during cataract surgery. RESULTS: We report 3 eyes in 2 patients taking risperidone in which typical features of IFIS were noted during cataract surgery. CONCLUSIONS: Risperidone is a widely prescribed drug in psychiatric practice and has a-blocking actions as well as strong affinity for serotonin 2A receptors. Ophthalmologists should be aware of the possible association with IFIS when performing cataract surgery on patients taking risperidone.

Regulation of the response to Nodal-mediated mesoderm induction by Xrel3.

The Xenopus egg has a yolk-laden vegetal hemisphere juxtaposed to a darkly pigmented animal hemisphere. Mesoderm is derived from the marginal zone, located at the interface between the two hemispheres. The vegetal-most cells become endoderm and release TGF-beta-related factors, including the Xenopus Nodal related (Xnr) proteins, which diffuse to induce the marginal zone to form mesoderm. The remaining animal cells become ectoderm, but our understanding of the mechanisms that limit the response to induction is incomplete. In this study, we provide evidence to suggest that Xrel3, a member of the Rel/NF-kappaB family, plays a role in defining the boundary separating induced from uninduced cells by regulating Xnr-responsive gene transcription. Ectopic Xrel3 expressed in prospective mesoderm caused repression of mesoderm-specific genes resulting in loss-of-function phenotypes that were rescued by co-expression of Xnr2. Depletion of Xrel3 from embryos with antisense morpholinos increased Xnr-dependent transcription, broadened expression of the pan-mesoderm marker Xbra and sensitized animal cells to mesoderm induction by Xnr2. We propose that an additional component to the mechanism that differentiates the ectoderm from the mesoderm involves regulation of nodal-dependent gene transcription by Xrel3.