Fungus packs a punch in the gut.

The impact of intestinal fungi on host physiology and their mechanisms of interaction are incompletely understood. In a recent issue of Cell, Leonardi et al. (2022) showed that mucosal fungi induce intestinal Th17 cells to produce IL-22 and IL-17A. IL-22 acts on the gut epithelium to protect barrier integrity, whereas IL-17 acts on IL-17RA+ neurons to enhance sociability.

An amygdala circuit that suppresses social engagement.

Innate social behaviours, such as mating and fighting, are fundamental to animal reproduction and survival1. However, social engagements can also put an individual at risk2. Little is known about the neural mechanisms that enable appropriate risk assessment and the suppression of hazardous social interactions. Here we identify the posteromedial nucleus of the cortical amygdala (COApm) as a locus required for the suppression of male mating when a female mouse is unhealthy. Using anatomical tracing, functional imaging and circuit-level epistatic analyses, we show that suppression of mating with an unhealthy female is mediated by the COApm projections onto the glutamatergic population of the medial amygdalar nucleus (MEA). We further show that the role of the COApm-to-MEA connection in regulating male mating behaviour relies on the neuromodulator thyrotropin-releasing hormone (TRH). TRH is expressed in the COApm, whereas the TRH receptor (TRHR) is found in the postsynaptic MEA glutamatergic neurons. Manipulating neural activity of TRH-expressing neurons in the COApm modulated male mating behaviour. In the MEA, activation of the TRHR pathway by ligand infusion inhibited mating even towards healthy female mice, whereas genetic ablation of TRHR facilitated mating with unhealthy individuals. In summary, we reveal a neural pathway that relies on the neuromodulator TRH to modulate social interactions according to the health status of the reciprocating individual. Individuals must balance the cost of social interactions relative to the benefit, as deficits in the ability to select healthy mates may lead to the spread of disease.

LeFort III Versus Monobloc Frontofacial Advancement: A Comparative Analysis of Soft Tissue Changes.

INTRODUCTION: The LeFort III and monobloc are commonly used midface advancement procedures for patients with syndromic craniosynostosis with well characterized postoperative skeletal changes. However, the differential effects of these procedures on facial soft tissues are less understood. The purpose of this study was to critically analyze and compare the effects of these 2 procedures on the overlying soft tissues of the face. METHODS: Frontal and lateral preoperative and postoperative photographs of patients undergoing monobloc or LeFort III were retrospectively analyzed using ImageJ to measure soft tissue landmarks. Measurements included height of facial thirds, nasal length and width, intercanthal distance, and palpebral fissure height and width. Facial convexity was quantified by calculating the angle between sellion (radix), subnasale, and pogonion on lateral photographs. RESULTS: Twenty-five patients with an average age of 6.7 years (range 4.8-14.5) undergoing monobloc (n=12) and LeFort III (n=13) were identified retrospectively and analyzed preoperatively and 6.4±3.6 months postoperatively. Patients undergoing LeFort III had a greater average postoperative increase in facial convexity angle acuity (28.2°) than patients undergoing monobloc (17.8°, P =0.021). Patients in both groups experience postoperative increases in nasal width ( P <0.001) and decreases in palpebral fissure height ( P <0.001). CONCLUSIONS: Both subcranial LeFort III advancements and monobloc frontofacial advancements resulted in significant changes in the soft tissues. Patients undergoing LeFort III procedures achieved greater acuity of the facial convexity angle, likely because the nasion is not advanced with the LeFort III segment.

Eyeing Risks: A Critical Analysis of the Use of Periorbital Steroids in Fronto-orbital Advancement.

OBJECTIVE: To evaluate the outcomes associated with two techniques of periorbital steroid administration in bilateral fronto-orbital advancement (FOA). DESIGN: Multi-institutional retrospective chart review. SETTING: Two high volume, tertiary US craniofacial centers. PATIENTS, PARTICIPANTS: Patients who underwent FOA between 2012 and 2021. INTERVENTIONS: Patients were divided into three cohorts based on method of steroid administration. Groups GEL and INJ represent those who received steroids in the form of triamcinolone soaked gelfoam or direct injection of dilute triamcinolone to the frontal/periorbital region, respectively. Group NON did not receive any periorbital steroids. MAIN OUTCOME MEASURE(S): Peri-operative outcomes including hospital length of stay and complications were evaluated based on method of periorbital steroid administration. Variables predictive of infectious complications were assessed using stepwise logistic regression. RESULTS: Four hundred and twelve patients were included in our sample (INJ:249, GEL:87, NON:76). Patients in the INJ group had a higher ASA class (P < .001) while patients in the NON group were significantly more likely to be syndromic (P < .001) and have multisuture craniosynostosis (P < .001). Rate of infectious complications for each cohort were NON: 2.6%, INJ: 4.4%, and GEL: 10.3%. There was no significant difference between groups in hospital length of stay (P = .654) or rate of post-operative infectious complications (P = .061). Increased ASA class (P = .021), increased length of stay (P = .016), and increased intraoperative narcotics (P = .011) were independent predictors of infectious complications. CONCLUSIONS: We identified a dose-dependent relationship between periorbital steroids and rate of postoperative infections, with key contributions from ASA class, hospital length of stay, and dose of intraoperative narcotics.

Toxidrome of an Easily Obtainable Nootropic: A Case Report of Phenibut Intoxication and Withdrawal Delirium.

PURPOSE/BACKGROUND: Phenibut (4-amino-3-phenyl-butyric acid) is a structural analog of GABA with central nervous system depressant and anxiolytic properties, developed in the former Soviet Union for anxiety, insomnia, and alcohol withdrawal. Its primary mechanism of action is believed to be a GABA-B receptor agonist-with high affinity at the α 2 δ subunit-containing voltage-dependent calcium channels and therefore gabapentinoid activity-as well as, to a lesser extent, GABA-A agonist activity. While not approved or regulated by the FDA, phenibut is easily obtainable online, where it is marketed as a nootropic, or cognitive enhancer. However, phenibut can lead to problems related to intoxication, dependency, and withdrawal, similar to other sedatives. METHODS/PROCEDURES: We present a case of phenibut intoxication and withdrawal delirium that provided diagnostic and management challenges because of a patient that was initially not forthcoming about his phenibut use which resulted in five presentations to the hospital including two admissions. FINDINGS/RESULTS: Initial differential including adrenergic, serotonergic or anticholinergic toxidrome based on clinical picture and history reported at that time, however phenibut use of 50 g daily was eventually revealed, an amount exceeding the highest reported cases in our review of the English literature. IMPLICATIONS/CONCLUSIONS: High-dose phenibut intoxication and withdrawal can appear as dramatic and dangerous as high-dose sedative withdrawal, however given its specified receptor affinity and binding profile we found that a pharmacotherapeutic approach targeting GABA-B, GABA-A, and gabapentenoid receptors were effective in stabilizing this patient, eventually leading to the patient's full and sustained recovery.

Patient Factors Affect Ergonomic Strain of Endoscopists During Colonoscopy.

INTRODUCTION: Endoscopic procedures place a great deal of muscular strain on providers, especially over the span of their careers. In this study we quantitatively analyzed the effects of patient factors such as age, body mass index, and sex on the ergonomics of endoscopists performing colonoscopies. METHODS: Surface electromyography (sEMG) was used to measure ergonomic strain of physicians while performing colonoscopies in several key muscle groups. The percent of the maximum voluntary contraction (%MVC) was used as a measure of muscular strain. Data was then analyzed based on the patient characteristics above. RESULTS: Endoscopists performing colonoscopies on female patients (n = 47) experienced significantly higher ergonomic strain in their right trapezius and right posterior forearm muscle groups when compared to colonoscopies performed on males (n = 35) (%MVC R-trapezius: Male: 8.2; Female: 8.9; p = 0.048); (%MVC R-posterior forearm: Male: 10.4; Female: 11.6; p = 0.0006). Operators experienced greater strain in the same muscle groups when performing colonoscopies on patients with BMI ≤ 25 (n = 25) when compared to patients with BMI > 25 (n = 57) (%MVC R-trapezius: BMI < 25: 9.7; BMI ≥ 25: 8.2; p = 0.0002); (%MVC R-posterior forearm: BMI < 25: 11.9; BMI ≥ 25: 10.8; p = 0.0001). CONCLUSION: Physicians experienced greater ergonomic strain when performing colonoscopies on female patients and on patients with a BMI < 25. We believe that these factors potentially impact the tortuosity of the colon and therefore influence the difficulty of navigating the endoscope. These results may aid physicians in gauging the anticipated difficulty of colonoscopies based on patient factors. Increased awareness of their posturing and ergonomics during challenging cases will alleviate musculoskeletal injuries in the long run.

Long-term aesthetic and photogrammetric outcomes in non-syndromic unicoronal synostosis: comparison of fronto-orbital distraction osteogenesis and fronto-orbital advancement and remodeling.

BACKGROUND: Fronto-orbital advancement and remodeling (FOAR) is among the most common surgical approaches for unicoronal craniosynostosis (UCS), although some data demonstrate failure to achieve long-term aesthetic normalcy, leading some to seek alternative treatment paradigms such as fronto-orbital distraction osteogenesis (FODO). This study compares long-term aesthetic outcomes of patients with UCS treated with FOAR and FODO. METHODS: Twenty patients (four males) with non-syndromic UCS presenting to our institution and undergoing distraction were compared to a matched cohort of 20 patients (six males) undergoing FOAR. Clinical photographs and ImageJ were used to quantify periorbital anatomy including palpebral fissures, pupil-to-brow distance (PTB), and margin-reflex distance (MRD1) in pixels. Whitaker classification was blindly assigned by craniofacial surgeons. RESULTS: Photogrammetric analysis and Mann-Whitney U tests demonstrated significantly improved postoperative symmetry in distraction patients for palpebral width (p = 0.020), MRD1 (p = 0.045), and canthal tilt (p = 0.010). Average Whitaker classification scores between FOAR (1.94) and distraction (1.79) cohorts were similar (p = 0.374). CONCLUSIONS: UCS patients demonstrated significant postoperative improvements in periorbital symmetry, with distraction patients demonstrating superior results in palpebral width and canthal tilt. FOAR and FODO patients achieved similar Whitaker classification scores. These cohorts will be followed until craniofacial maturity prior to making any definitive conclusions.

Spinal pseudomeningocele closure: capsulofascial interposition technique.

INTRODUCTION: The development of a spinal pseudomeningocele is a complication of dural repair or reconstruction that carries significant morbidity for pediatric patients. In addition to cerebrospinal fluid (CSF) hypotension and positional headaches, CSF leaking into the extradural space increases the risk for incisional breakdown, meningitis, and cosmetic deformity. Spinal pseudomeningocele management is challenging, and reported techniques range from local wound revisions/exploration to shunt placement for permanent CSF diversion. METHODS: At our institution, we have recently implemented a multidisciplinary approach of capsulofascial interposition for the surgical repair of the symptomatic spinal pseudomeningocele with a combined neurosurgery-plastic surgery team. To our knowledge, this technique has not previously been characterized, and we describe the technical aspects of this surgery here. RESULTS: Among 10 patients treated with this technique, none required reoperation or developed infections following pseudomeningocele closure; 2 patients received postoperative transfusions; and 2 patients underwent CSF diversion procedures. CONCLUSION: We propose that this capsulofascial interposition technique should be employed in the surgical treatment of symptomatic spinal pseudomeningoceles.

Spring forces and calvarial thickness predict cephalic index changes following spring-mediated cranioplasty for sagittal craniosynostosis.

BACKGROUND: Variables interacting to predict outcomes following spring-mediated cranioplasty (SMC) for non-syndromic craniosynostosis, including spring parameters and calvarial thickness, are poorly understood. This study assessed interactions between spring parameters and calvarial thickness to predict changes in cephalic index (CI) following SMC. METHODS: Patients undergoing SMC for non-syndromic sagittal craniosynostosis at our institution between 2014 and 2021 were included. Calvarial thickness was determined from patient preoperative CTs using Materalise Mimics at 27 points in relation to the sagittal suture. Linear mixed effects models were used to determine interactions between anterior, middle, and posterior calvarial thickness with spring force and length. RESULTS: Sixty-nine patients undergoing surgery at mean age 3.7 months were included in this study. Stronger posterior spring force interacted with thinner posterior calvarial thickness to predict greater changes in CI at 3 months postoperatively (p = 0.022). When evaluating spring force and calvarial thickness set distances from the sagittal suture, stronger posterior spring force interacted with thinner posterior calvarial thickness 5 mm (p = 0.043) and 10 mm (p = 0.036) from the sagittal suture to predict changes in CI. Interactions between spring parameters and calvarial thickness in the anterior and middle positions did not significantly predict changes in CI. CONCLUSIONS: Stronger posterior spring force interacted with thinner posterior calvaria to predict greater changes in CI 3 months following SMC for non-syndromic sagittal craniosynostosis. These results suggest dynamic interactions between several variables may impact outcomes following SMC.

Real Face Analysis of Masculinity-Femininity, Facial Ratios, and Attractiveness.

BACKGROUND: Previous studies have evaluated the influence of facial features in determining male and female sex using prototypical renderings or artificially altered faces in relatively small sample sizes. Using a large set of human photographs and raters, this study hypothesized that certain anatomic facial ratios are associated with perceptions of masculinity/femininity, can interact to predict sex, and are associated with ratings of attractiveness differently in males and females. METHODS: Ratings of masculinity-femininity and binary self-identification (male or female) were compared with facial anatomic ratios from 827 frontal facial photographs. Ratios were used to characterize facial feature relativity, where higher ratio scores indicated relatively more facial feature representation. RESULTS: Femininity was associated with prominent middle third ratio, nose length, lip vermillion height, eye height, and eye width ratios; masculinity was associated with prominence of the upper and lower facial thirds, nose width, chin height, and philtrum height ratios (all P < 0.01). Subgroup analysis demonstrated many of these relationships persisted when evaluating masculinity in females and femininity in males. Misgendering in males was associated with greater middle third ratio and upper lip ratio, whereas misgendering in females was associated with increased nose width ratio. CONCLUSIONS: This study demonstrates associations of femininity with increased horizontal middle third representation, and masculinity was associated with increased upper and lower horizontal representation. These facial ratios interact to predict male and female sex, which could have implications for optimizing facial feminization/masculinization outcomes and building algorithms for artificial intelligence analysis of faces.

Visual Attention, Bias, and Social Dispositions Toward People With Facial Anomalies: A Prospective Study With Eye-Tracking Technology.

BACKGROUND: Facial attractiveness influences our perceptions of others, with beautiful faces reaping societal rewards and anomalous faces encountering penalties. The purpose of this study was to determine associations of visual attention with bias and social dispositions toward people with facial anomalies. METHODS: Sixty subjects completed tests evaluating implicit bias, explicit bias, and social dispositions before viewing publicly available images of preoperative and postoperative patients with hemifacial microsomia. Eye-tracking was used to register visual fixations. RESULTS: Participants with higher implicit bias scores fixated significantly less on the cheek and ear region preoperatively (P = 0.004). Participants with higher scores in empathic concern and perspective taking fixated more on the forehead and orbit preoperatively (P = 0.045) and nose and lips (P = 0.027) preoperativel. CONCLUSIONS: Participants with higher levels of implicit bias spent less visual attention on anomalous facial anatomy, whereas participants with higher levels of empathic concern and perspective taking spent more visual attention on normal facial anatomy. Levels of bias and social dispositions such as empathy may predict layperson gaze patterns toward those with facial anomalies and provide insights to neural mechanisms underlying the "anomalous is bad" paradigm.

Machine Learning in Metopic Craniosynostosis: Does Phenotypic Severity Predict Long-Term Esthetic Outcome?

BACKGROUND: There have been few longitudinal studies assessing the effect of preoperative phenotypic severity on long-term esthetic outcomes in metopic craniosynostosis. This study evaluates the relationship between metopic severity and long-term esthetic outcomes using interfrontal angle (IFA) and CranioRate, a novel metopic synostosis severity measure. METHODS: Patients with metopic craniosynostosis who underwent bifrontal orbital advancement and remodeling between 2012 and 2017 were reviewed. Preoperative computed tomography head scans were analyzed for IFA and CranioRate, a machine learning algorithm which generates quantitative severity ratings including metopic severity score (MSS) and cranial morphology deviation (CMD). Long-term esthetic outcomes were assessed by craniofacial surgeons using blinded 3-rater esthetic grading of clinical photos. Raters assessed Whitaker score and the presence of temporal hollowing, lateral orbital retrusion, frontal bone irregularities and/or "any visible irregularities." RESULTS: Preoperative scans were performed at a mean age of 7.7±3.4 months, with average MSS of 6/10, CMD of 200/300, and IFA of 116.8±13.8 degrees. Patients underwent bifrontal orbital advancement and remodeling at mean 9.9±3.1 months. The average time from operation to esthetic assessment was 5.4±1.0 years. Pearson correlation revealed a significant negative correlation between MSS and age at computed tomography ( r =-0.451, P =0.004) and IFA ( r =-0.371, P =0.034) and between IFA and age at surgery ( r =-0.383, P =0.018). In multinomial logistic regression, preoperative MSS was the only independent predictor of visible irregularities (odds ratio=2.18, B =0.780, P =0.024) and preoperative IFA alone significantly predicted Whitaker score, with more acute IFA predicting worse Whitaker score (odds ratio=0.928, B =-0.074, P =0.928). CONCLUSIONS: More severe preoperative phenotypes of metopic craniosynostosis were associated with worse esthetic dysmorphology. Objective measures of preoperative metopic severity predicted long-term esthetic outcomes.

Geospatial and Socioeconomic Factors Interact to Predict Management and Outcomes in Cleft Lip and Palate Surgery: A Single Institution Study of 740 Patients.

OBJECTIVE: Determine interactions between geospatial and socioeconomic factors influencing cleft lip and/or cleft palate (CL/P) management and outcomes. DESIGN: Retrospective review and outcomes analysis (n = 740). SETTING: Urban academic tertiary care center. PATIENTS: 740 patients undergoing primary (CL/P) surgery from 2009 to 2019. MAIN OUTCOMES MEASURES: Prenatal evaluation by plastic surgery, nasoalveolar molding, cleft lip adhesion, and age at CL/P surgery. RESULTS: Prenatal evaluation by plastic surgery was predicted by the interaction between higher patient median block group income and shorter patient distance from the care center (OR = 1.07, p = 0.022). Nasoalveolar molding was also predicted by the interaction between higher patient median block group income and shorter distance from the care center (OR = 1.28, p = 0.016), whereas cleft lip adhesion was predicted by higher patient median block group income alone (OR = 0.41, p < 0.001). Lower patient median block group income predicted later age at cleft lip (ß = -67.25, p = 0.011) and cleft palate (ß = -46.35, p = 0.050) repair surgery. CONCLUSIONS: Distance from the care center and lower median income by block group interacted to significantly predict prenatal evaluation by plastic surgery and nasoalveolar molding for patients with CL/P at a large, urban, tertiary care center. Patients living farthest from the care center who received prenatal evaluation by plastic surgery or who underwent nasoalveolar molding had higher median block group income. Future work will determine mechanisms perpetuating these barriers to care.

Disability Caused by Cleft Lip and Palate: A Systematic Review and Critical Valuation Appraisal.

OBJECTIVE: Measuring disability as a concept of impaired global function enables beneficiaries of treatment, the impact of treatment, and targets of health system investment to be rigorously assessed. Measures of disability are not well established for cleft lip and palate. This study aims to systematically review disability weight (DW) studies pertaining to orofacial clefts (OFCs) and identify methodological strengths and shortcomings of each approach. DESIGN: Systematic literature review of studies that met the following criteria: (1) peer-reviewed publication, (2) focus on disability valuation, (3) mention orofacial clefts, and (4) publication January 2001-December 2021. SETTING: None. PATIENTS/PARTICIPANTS: None. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Disability weight method of valuation and the value itself. RESULTS: The final search strategy yielded 1,067 studies. Seven manuscripts were ultimately included for data extraction. The disability weights used in our studies, including those newly generated or taken from the Global Burden of Disease Studies (GBD), ranged widely for isolated cleft lip (0.0-0.100) and cleft palate with or without cleft lip (0.0-0.269). The GBD studies limited their consideration of cleft sequelae informing disability weights to impact on appearance and speech-related concerns, while other studies accounted for comorbidities such as pain and social stigma. CONCLUSIONS: Current measures of cleft disability are sparse, inadequately reflect the comprehensive impact of an OFC on function and socialization, and are limited in detail or supporting evidence. Use of a comprehensive health state description in evaluating disability weights offers a realistic means of accurately representing the diverse sequelae of an OFC.

Sociodemographic Disparities in Craniosynostosis: A Systematic Review.

OBJECTIVE: Given the consequences of delayed treatment and diagnosis of craniosynostosis, this study reviews the literature on sociodemographic risk factors and disparities associated with delayed craniosynostosis treatment. DESIGN: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search of PubMed/Medline and Embase was performed by two independent reviewers. Included studies discussed craniosynostosis health disparities. Demographic characteristics and outcomes were analyzed. SETTING: Not applicable. PATIENTS: Patients with craniosynostosis. INTERVENTIONS: Standard surgical intervention for craniosynostosis. RESULTS: Our literature search yielded 273 studies, of which 18 were included for analysis. Included studies represented data from 31 256 U.S. patients with craniosynostosis. Sixty percent of patients (n = 16 510) were White, 13.8% were Hispanic/Latino, 6.2% were Black/African American, 1.3% were Asian, 0.3% were American Indian or Alaska Native, and 0.1% were Native Hawaiian or Pacific Islander. Average age at surgery was 6.36 months for White patients, 10.63 months for Black patients, and 9.18 months for Hispanic patients. Minority racial and/or ethnic status was a risk factor for delayed presentation, and increased incidence of open surgery, complication rates, hospital charges, operative time, anesthesia duration, and hospital length of stay. Government-funded health insurance was associated with delayed intervention and increased complications. CONCLUSIONS: Minority craniosynostosis patients experience delays in intervention and increased complication rates. Our findings highlight the importance of expedited and equitable referrals, screenings, and treatment, and the need for a standardized approach to investigating longitudinal demographic and outcomes data in this population.

Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial.

BACKGROUND: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma. METHODS: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110. FINDINGS: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]). INTERPRETATION: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. FUNDING: Novartis.

Safety and efficacy of nivolumab plus ipilimumab in patients with advanced renal cell carcinoma with brain metastases: CheckMate 920.

BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here. METHODS: Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others. RESULTS: After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable). CONCLUSIONS: In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.

Making the Diagnosis in Sagittal Craniosynostosis-It's Height, Not Length, That Matters.

INTRODUCTION: This study assesses the diagnostic reliability of a novel photogrammetric measurement to distinguish sagittal craniosynostosis (SS) from control and false positive cases (SNS). METHODS: Head CTs from 2014-2020 were reviewed for patients with sagittal synostosis (SS, n = 177), presumed sagittal synostosis with normal imaging (SNS, n = 30), and controls (n = 100). Using preoperative clinical photographs and CTs, a measurement reflecting the anterior-posterior location of the vertex was measured using an angle drawn between the cranial vertex, nasion, and opisthocranion (VNO) in profile view, with the head in a neutral position. RESULTS: Mean age at pre-operative head CT was 9.5 months for the SS cohort, 4.2 months for the SNS cohort, and 8.9 months for controls (p = .327). Mean age at pre-operative clinical photograph was 9.5 months for the SS cohort and 4.2 months for the SNS cohort (p = .149). Pearson correlations revealed no significant association between age and VNO angle. The average VNO angle measured on clinical photographs was 54.7° ± 3.8° for the SS group, 43.1° ± 2.2° for the SNS group, and 41.1° ± 3.7° for controls (p < .001). Receiver operating characteristic (ROC) analysis yielded a cut-off of ≥ 50° to identify SS. Diagnostic sensitivity and specificity were 96.6% and 99.2%, respectively. Three-rater analysis yielded an average ICC of 0.742 (p = .004). CONCLUSIONS: Measurement of the VNO angle is a reliable screening tool to diagnose sagittal craniosynostosis, with an angle of 50° or more suggesting suture synostosis. This method relies on the relationship between the anterior displacement of the vertex and occipital bulleting to approach the diagnostic accuracy of CT imaging.

Cadaveric Bone Allografting for Severe Mandibular Hypoplasia With Alleviation of Upper Airway Obstruction in Goldenhar Syndrome.

ABSTRACT: Severe congenital mandibular hypoplasia may cause significant upper airway obstruction, often necessitating immediate tracheostomy. Recent surgical advances have demonstrated early intervention with mandibular distraction osteogenesis over tracheostomy may yield desirable aesthetic and functional outcomes. Here we present a case of bilateral mandibular hypoplasia, severe on the right and mild on the left, secondary to Goldenhar syndrome yielding significant tongue-based upper airway obstruction that was surgically corrected with mandibular bone allograft reconstruction of the right condyle, ramus, and posterior half of the mandibular body. Postoperative polysomnography revealed significantly improved obstructive apnea and computed tomography demonstrated adequate placement of the bone allograft to overcorrect the affected hemi-mandible. To the authors' knowledge, this is the first report of immediate mandibular allografting alleviating tongue-based upper airway obstruction secondary to mandibular hypoplasia in an infant. Mandibular bone allografting may be a favorable alternative to immediate tracheostomy with delayed surgical intervention, though long-term follow up is needed to assess graft durability and maintenance of airway patency.

Associations of Facial Proportionality, Attractiveness, and Character Traits.

BACKGROUND: Facial proportionality and symmetry are positively associated with perceived levels of facial attractiveness. OBJECTIVE: The aims of this study were to confirm and extend the association of proportionality with perceived levels of attractiveness and character traits and determine differences in attractiveness and character ratings between "anomalous" and "typical" faces using a large dataset. METHODS: Ratings of 597 unique individuals from the Chicago Face Database were used. A formula was developed as a proxy of relative horizontal proportionality, where a proportionality score of "0" indicated perfect proportionality and more negative scores indicated less proportionality. Faces were categorized as "anomalous" or "typical" by 2 independent reviewers based on physical features. RESULTS: Across the ratings for all faces, Spearman correlations revealed greater proportionality was associated with attractiveness ( ρ = 0.292, P < 0.001) and trustworthiness ( ρ = 0.193, P < 0.001), while lesser proportionality was associated with impressions of anger (ρ = 0.132, P = 0.001), dominance (ρ = 0.259, P < 0.001), and threateningness ( ρ = 0.234, P < 0.001). Mann-Whitney U tests revealed the typical cohort had significantly higher levels of proportionality (-13.98 versus -15.14, P = 0.030) and ratings of attractiveness (3.39 versus 2.99, P < 0.001) and trustworthiness (3.48 versus 3.35, P < 0.001). CONCLUSIONS: This study demonstrated that facial proportionality is not only significantly associated with higher ratings of attractiveness, but also associated with judgements of trustworthiness. Proportionality plays a role in evoking negative attributions of personality characteristics to people with facial anomalies.