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OBJECTIVE Quantitative measurements of trigonocephaly can be used to characterize and track this phenotype, which is associated with metopic craniosynostosis. Traditionally, trigonocephaly metrics were extracted from CT scans; however, this method exposes patients to ionizing radiation. Three-dimensional optical scans are another option but are not routinely available in most outpatient settings. Recently, the authors developed semiautomated artificial intelligence algorithms that extract craniometric data from orthogonal 2D photographs. Although 2D photographs are safe, inexpensive, and straightforward to obtain, the accuracy of photograph-based craniometrics in comparison to CT and 3D optical scan correlates has not been established. In this study the authors compared the classification power of 2D photograph–based metrics of trigonocephaly with four CT-based metrics and one 3D optical scan–based metric in a heterogeneous series of patients who presented to an outpatient craniofacial clinic. METHODS In this study the authors performed retrospective craniometric analyses of patient 2D photographs, 3D optical scans, and CT scans. Imaging-derived craniometrics include the 2D photograph–based anterior arc angle (AAA2D-photo), anterior-posterior ratio (APR2D-photo), and anterior-middle ratio (AMR2D-photo); the CT-based anterior arc angle (AAACT), metopic index (MICT), endocranial-bifrontal angle (eBFACT), and interfrontal angle (IFACT); and the 3D optical scan–based anterior arc angle (AAA3D-optical). Receiver operating characteristics (ROCs) were used to identify craniometrics strongly descriptive of trigonocephaly. Interrater comparisons were made between paired trigonocephaly measurements obtained from photographs and either CT scans or 3D optical scans. RESULTS There were 13 photograph-based and CT-based pairs and 22 paired measurements from 2D photographs and 3D optical scans. AAA displayed the strongest classification capacity across all three imaging modalities. Significant agreement was observed between AAACT and AAA2D-photo (intraclass correlation coefficient [ICC] = 0.68 [95% CI 0.24–0.89], p = 0.0035), and AAA3D-optical and AAA2D-photo (ICC = 0.70 [95% CI 0.41–0.87], p < 0.0001). There was no significant correlation between APR2D-photo or AMR2D-photo and conventional CT-based metrics describing longitudinal width ratios (MICT). CONCLUSIONS Photograph-based craniometrics are powerful tools that can be used to quantify the severity of trigonocephaly and exhibit high concordance with standard measurements derived from CT scans and 3D optical scans. The authors developed and freely share a research-use application to calculate trigonocephaly metrics from 2D photographs. Given the availability of digital photography, lack of ionizing radiation, and low cost of photograph-based craniometric derivation, this technique may be useful to supplement routine ambulatory care and objectively track outcomes following treatment.

ImportanceGlaucoma can develop following cataract removal in children.ObjectiveTo assess the cumulative incidence of glaucoma-related adverse events (defined as glaucoma or glaucoma suspect) and factors associated with risk of these adverse events in the first 5 years after lensectomy prior to 13 years of age.Design, Setting, and ParticipantsThis cohort study used longitudinal registry data collected at enrollment and annually for 5 years from 45 institutional and 16 community sites. Participants were children aged 12 years or younger with at least 1 office visit after lensectomy from June 2012 to July 2015. Data were analyzed from February through December 2022.ExposuresUsual clinical care after lensectomy.Main Outcomes and MeasuresThe main outcomes were cumulative incidence of glaucoma-related adverse events and baseline factors associated with risk of these adverse events.ResultsThe study included 810 children (1049 eyes); 443 eyes of 321 children (55% female; mean [SD] age, 0.89 [1.97] years) were aphakic after lensectomy, and 606 eyes of 489 children (53% male; mean [SD] age, 5.65 [3.32] years) were pseudophakic. The 5-year cumulative incidence of glaucoma-related adverse events was 29% (95% CI, 25%-34%) in 443 eyes with aphakia and 7% (95% CI, 5%-9%) in 606 eyes with pseudophakia; 7% (95% CI, 5%-10%) of aphakic eyes and 3% (95% CI, 2%-5%) of pseudophakic eyes were diagnosed as glaucoma suspect. Among aphakic eyes, a higher risk for glaucoma-related adverse events was associated with 4 of 8 factors, including age less than 3 months (vs ≥3 months: adjusted hazard ratio [aHR], 2.88; 99% CI, 1.57-5.23), abnormal anterior segment (vs normal: aHR, 2.88; 99% CI, 1.56-5.30), intraoperative complications at time of lensectomy (vs none; aHR, 2.25; 99% CI, 1.04-4.87), and bilaterality (vs unilaterality: aHR, 1.88; 99% CI, 1.02-3.48). Neither of the 2 factors evaluated for pseudophakic eyes, laterality and anterior vitrectomy, were associated with risk of glaucoma-related adverse events.Conclusions and RelevanceIn this cohort study, glaucoma-related adverse events were common after cataract surgery in children; age less than 3 months at surgery was associated with elevated risk of the adverse events in aphakic eyes. Children with pseudophakia, who were older at surgery, less frequently developed a glaucoma-related adverse event within 5 years of lensectomy. The findings suggest that ongoing monitoring for the development of glaucoma is needed after lensectomy at any age.

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

Abstract Pre and post-licensure studies have supported the safety of the intranasally administered live, attenuated influenza vaccine (LAIV). The objective of this study was to measure changes to the nasal microbiome in subjects who received LAIV. We hypothesized that administration would result in only a transient alteration of the nasal microbiome. To test this hypothesis, we swabbed the anterior nares just before vaccination (Day 0), and on Day 7 and Day 28. We performed next-generation sequencing on amplified 16s rRNA genes. There was a significant increase in alpha diversity (Observed, CHAO, and ACE) from Days 0 to 7 (p = 0.02, 0.00, 0.01; respectively) and Days 0 to 28 (p = 0.05, 0.03, 0.05; respectively). When measuring differences in specific observed taxanomic units (OTUs), we identified a significant increase in Flavobacteriaceae and Enterobacteriaceae after vaccination. These data suggest that LAIV may increase the ability of these less abundant OTUs to establish a community niche and, therefore, could be clinically relevant. We have begun to investigate the second objective of this study, which is to correlate microbiome composition with mucosal immunity to influenza virus. To our knowledge, this is the first study to investigate LAIV-induced alterations to the human microbiome. These data may lead to a better understanding of the influences of the host microbiome on the response to vaccine, and perhaps infection.

Abstract We have previously demonstrated that inbred B10.T(6R) mice are resistant to Yesinia pestis (KIM5 strain) and resistance decreases with age. It has been shown that Y. pestis is cleared by neutrophil engulfment. We evaluate here the potential contribution of IL-1β, a proinflammatory cytokine important for neutrophil recruitment and activation. IL-1β levels were measured from spleens and sera collected 60 and 72 hour post infection from young (resistant) and middle-aged (susceptible) B10.T(6R) mice and control (susceptible) C57BL/6. Splenic IL-1β production was statistically higher in young B10.T(6R), compared with both middle-aged B10.T(6R) and C57BL/6 mice. Serum IL-1β levels were also moderately higher in young B10.T(6R) mice when compared to middle aged B10.T(6R) and C57BL/6 mice. IL-1β produced by Y. pestis-infected peritoneal-derived macrophages taken from uninfected young and middle-aged B10.T(6R) mice and C57BL/6 mice was measured at 2,4,8 and 24 hour. IL-1β levels were significantly elevated in peritoneal macrophages infected in vitro from young B10.T(6R) mice compared to decreased levels in both middle-aged B10.T(6R) and C57BL/6 derived peritoneal macrophages. These studies suggest a direct correlation between elevated IL-1β levels and resistance to Y. pestis infection observed in young B10.T(6R) mice.

Abstract We have identified in an extracellular segment of the alpha1 subunit of nicotinic acetylcholine receptor (AChR) of homologous muscle a 17-residue autoantigen that, without conjugation to a carrier, activates Th lymphocytes and induces production of autoantibodies that cause electrophysiologic signs of experimental autoimmune myasthenia gravis. A panel of overlapping synthetic peptides revealed two T cell epitopes, one encompassed by residues 121-136 and the other by 129-145. Residues 129 (glutamic acid) and 130 (isoleucine) were implicated in a pathogenic B cell epitope. Peptide 129-145 (Glu-Ile-Ile-Val-Thr-His-Phe-Pro-Phe-Asp-Glu-Gln-Asn-Cys-Ser-Met-Lys, a conserved sequence in rat and human AChR) induced autoantibody production in 76% of rats. All seropositive rats had evidence of experimental autoimmune myasthenia gravis; five of five tested had electrophysiologic signs, and all had loss of immunochemically measured autologous muscle AChR. Analogues of 129-145, with single residues substituted by alanine, revealed phenylalanine 135, phenylalanine 137, and glutamic acid 139 as most important determinants of Ag/MHC-II/TCR interactions; phenylalanine 137 is critical for T cell activation. B cells were the major MHC-II-positive cell type to which the self-peptide 129-145 bound in a population of nonimmune splenic cells. More efficient processing and presentation of the Th cell epitope by an expanded population of immune B cells selected by specifically binding another epitope of the same peptide would greatly amplify the production of autoantibodies. Peptide autoantigens of this type could plausibly perpetuate the autoantibody response in myasthenia gravis, and are a rational target for strategies aimed at Ag-specific therapeutic intervention.

Abstract A synthetic gene encoding the 210 N-terminal residues of the alpha-subunit of the nicotinic acetylcholine receptor (AChR) of human skeletal muscle was cloned into an inducible expression plasmid to produce a fusion protein in high yield in Escherichia coli. Like native human AChR, the recombinant human alpha 1-210 protein induced AChR-binding, AChR-modulating, and AChR-blocking autoantibodies in rats when injected once intradermally as an emulsion in CFA, with Bordetella pertussis vaccine as supplementary adjuvant. The minimum dose of recombinant protein required to induce biochemical signs of experimental autoimmune myasthenia gravis (EAMG) with 100% incidence was 2.2 micrograms. With 6.6 to 22 micrograms, serum levels of autoantibodies were persistent, and clinically apparent EAMG lasted more than a month. Clinical, electrophysiological, and biochemical indices of EAMG induced by doses of 66 micrograms or more were more uniformly severe and persistent, with 33% fatality. Rats receiving a control extract of E. coli containing plasmid without the alpha 1-210 codon insert, with adjuvants, did not develop autoantibodies or signs of EAMG. This highly reproducible new model of EAMG induced by a recombinant human autoantigen should be valuable for testing Ag-specific immunotherapeutic strategies that might be applicable to treating acquired myasthenia gravis in humans.

Abstract This study reports the synthesis of a disulfide-looped peptide corresponding to residues 125-147 (Cys 128-Cys 142) of the nicotinic acetylcholine receptor (AChR) of human skeletal muscle, H alpha 125-147 (Lys-Ser-Tyr-Cys-Glu-Ile-Ile-Val-Thr-His-Phe-Pro-Phe-Asp-Glu-Gln- Asn-Cys-Ser-Nle-Lys Leu-Gly), and a nondisulfide-looped analogue, H alpha 125-147(S) (Lys-Ser-Tyr-Ser-Glu-Ile-Ile-Val-Thr-His-Phe-Pro-Phe-Asp-Glu- Gln-Asn-Cys-Ser-Nle-Lys-Leu-Gly), in which the amino acid Cys 128 was replaced with serine. Both peptides induced antigen-specific helper T cell responses, as evidenced in vitro by lymph node cell proliferation and in vivo by production of anti-AChR antibodies. Rats immunized with 100 micrograms of either synthetic peptide, without conjugation to a carrier, produced anti-peptide antibodies which bound to native AChR in immunoprecipitation assays and induced modulation of membrane-bound AChR from cultured human myotubes. Both peptides also induced electrophysiologic and biochemical signs of experimental autoimmune myasthenia gravis. Thus, region 125-147 of the AChR alpha-subunit is at least partly exposed extracellularly in human muscle and contains one or more autoantigenic sites capable of stimulating T cells and B cells. Disulfide-linkage between residues Cys 128 and Cys 142 is not essential for myasthenogenicity.

AbstractBackgroundCytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is increasingly performed for peritoneal surface malignancies but remains associated with significant morbidity. Scant research is available regarding the impact of insurance status on postoperative outcomes.MethodsPatients undergoing CRS/HIPEC between 2000 and 2017 at 12 participating sites in the US HIPEC Collaborative were identified. Univariate and multivariate analyses were used to compare the baseline characteristics, operative variables, and postoperative outcomes of patients with government, private, or no insurance.ResultsAmong 2268 patients, 699 (30.8%) had government insurance, 1453 (64.0%) had private, and 116 (5.1%) were uninsured. Patients with government insurance were older, more likely to be non‐white, and comorbid (p < 0.05). Patients with government (OR: 2.25, CI: 1.50−3.36, p < 0.001) and private (OR: 1.69, CI: 1.15−2.49, p = 0.008) insurance had an increased risk of complications on univariate analysis. There was no independent relationship on multivariate analysis. An American Society of Anesthesiologists score of 3 or 4, peritoneal carcinomatosis index score >15, completeness of cytoreduction score >1, and nonhome discharge were factors independently associated with a postoperative complication.ConclusionWhile there were differences in postoperative outcomes between the three insurance groups on univariate analysis, there was no independent association between insurance status and postoperative complications after CRS/HIPEC.