Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain.

Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain1-7. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.

Adverse events and labeling issues related to suspected sesame allergy reported in an online survey.

BACKGROUND: Allergen avoidance is critical for those with immunoglobulin E-mediated food allergy, but can only be successful with accurate product information. Although the Food and Drug Administration maintains the Center for Food Safety and Nutrition Adverse Event Reporting System to collect adverse event (AE) reports related to foods, there is substantial underreporting, and information regarding product labeling issues is limited. OBJECTIVE: The purpose of this study was to describe allergic reactions associated with accidental oral exposure to sesame and the role of product labeling. METHODS: A questionnaire was developed and disseminated to online communities focused on sesame allergy. The questionnaire included questions on clinical characteristics, treatments, outcomes, and labeling issues. RESULTS: A total of 360 clinical reactions related to sesame were reviewed in 327 individuals. Anaphylaxis occurred in 68.9% of reactions. Hospitalization occurred in 47.8% of events and epinephrine was administered in 36.4% of cases. Events involving a packaged food product occurred in 67.5% of AEs with only 43.8% of these using the term "sesame." An alternative name was noted in 46.0% of products that did not include "sesame" on labeling, most of which was "tahini." CONCLUSION: We determined considerable sesame food allergy morbidity, in part owing to inconsistent allergen labeling. Our findings support the development of a more rapid process for the Food and Drug Administration to update the major allergen list and formulation of an improved system for reporting AEs related to foods.

Forensic Discrimination of Differentially Sourced Animal Blood Using a Bottom-Up Proteomics Based MALDI MS Approach.

Recently published work has reported the development and application of a bottom-up proteomic approach to distinguish between human and animal blood (down to animal species level), by rapid screening using Matrix Assisted Laser Desorption Ionisation Mass Spectrometry (MALDI MS). In that study, it was additionally observed that intravenous animal blood exhibits different spectral profiles from blood collected within the animal chest cavity as well as from the diluted blood collected within packets of meat. In this follow-up study we explored the resulting hypothesis that, depending on how blood is shed or collected, protein biomarker profiles vary to the extent of systematically permitting a distinction between possible sources of blood (for example, flesh wound versus packaged meat). This intelligence may be important in reconstructing the dynamics of the crime. The combination of statistical analysis and tandem mass spectrometry has yielded additional animal blood markers as well as confirming the ability to correctly determine the animal species from which blood derived, regardless of the retailer selling it (amongst the five investigated). These data confirm the initial hypothesis and demonstrate the opportunity for the proteomics-MALDI combined approach to provide additional intelligence to the investigation of violent crimes when examining blood evidence.

Differences in oral food challenge reaction severity based on increasing age in a pediatric population.

BACKGROUND: Food allergy reactions range from mild to severe with differences in age appearing to be an important factor associated with reaction severity. OBJECTIVE: To define differences in oral food challenge (OFC) reaction severity in pediatric patients from infancy to adolescence using objective clinical outcomes and standardized reaction grading tools. METHODS: Retrospective review of all positive OFC results at 2 large institutions between September 2016 and February 2019. Reaction severity was defined by presence of cardiovascular, neurologic, lower respiratory, or laryngeal symptoms, epinephrine requirement, and grading using 2 established food allergy reaction scales. RESULTS: Infants and toddlers had fewer reactions involving cardiovascular, neurologic, lower respiratory, or laryngeal symptoms compared with older age groups. Epinephrine was also required less frequently during reactions in infants and toddlers, compared with older age groups. There was no difference in reaction severity in infants and toddlers based on clinical history of eczema. Increasing age was significantly correlated with increased epinephrine requirement (R2 = 0.12, P = .002), elevated Consortium of Food Allergy Research score (R2 = .012, P = .003), and approached significance for increased Practical Allergy score (R2 = .005, P = .05). History of asthma and sesame allergy were identified to be positively correlated with more severe reactions. CONCLUSION: Infants and young toddlers have less severe reactions during OFCs compared with older age groups supporting early food introduction practices. In children under 12 months of age, severe reactions are most rare calling into question screening practices using specific allergy testing before food introduction. Standardized reaction grading tools may be valuable instruments to categorize reaction severity during OFCs.

Men exhibit faster skeletal muscle tissue desaturation than women before and after a fatiguing handgrip.

PURPOSE: The purpose was to test the hypothesis that sex and fatigue effect of the early phase of skeletal muscle tissue oxygenation (StO2, %) desaturation rate as well as that strength matched adults may exhibit similar responses. METHODS: Twenty-four adults visited the laboratory twice to quantify this early phase of desaturation during vascular occlusion tests (VOT) while in a rested state. The second visit included a sustained handgrip task at 25% of maximal muscular strength until task failure. At failure, a post-task VOT was initiated. Muscle desaturation was defined as StO2 and collected by a near-infrared spectroscopy device. The muscle size and adipose thickness were determined via ultrasonography. Linear regression was used to quantify the rates of desaturation during the VOTs as well as during the fatiguing handgrip. RESULTS: There were sex differences in the rate of desaturation pre- and post-handgrip, such that independent of fatigue, the men (p < 0.001) desaturated more rapidly than the women (pre: b = - 0.208 vs. - 0.123%∙s-1; post: - 0.079 vs. - 0.070%∙s-1). During the fatiguing handgrip, the transformed StO2 values indicated that the males desaturated more rapidly than the females (b = - 0.070 vs. - 0.015). The matched pairs exhibited the same responses as the total sample. CONCLUSION: Overall, muscle size and strength as well as adipose tissue were likely not the primary cause of the differences in rates of muscle desaturation. We hypothesized that differences in fiber type and mitochondria were the principle mechanisms provoking the differences in muscle oxygenation.

Influence of speaker's gender on speaker introductions at the 2018 ACVS Surgical Summit.

OBJECTIVE: To evaluate whether formality of introduction differed between male vs female speakers at the 2018 American College of Veterinary Surgeons (ACVS) scientific meeting and identify other variables that predisposed introducers or chairs to informal introduction. STUDY DESIGN: Observational study. SAMPLE POPULATION: Thirteen session chairs introducing 68 lectures (41 by females, 27 by males) by 63 speakers. METHODS: Observers recorded the session introducer, speaker, and whether speakers were introduced with a formal or informal title. Information evaluated included type of oral presentation; introducer gender, year, and country of graduation from veterinary school; speaker gender; whether the speaker was a resident; and speaker's year of graduation. RESULTS: Female speakers were introduced by their first name in 9 of 41 introductions compared to in 1 of 27 introductions for male speakers. This difference reached statistical significance when data independence was assumed (P = .043); however, this significance was narrowly lost when data clustering on session introducer was controlled for (P = .067). CONCLUSION: In this study, female speakers were more likely than male speakers to be introduced by their first and last names rather than with their professional title at a recent ACVS scientific meeting. IMPACT: Additional research is required to determine the effect of this type of subordinate language and gender bias in veterinary surgery.

Advances in atopic dermatitis in 2017.

This review encompasses relevant scientific and clinical advances in atopic dermatitis (AD) published in 2017. These include articles from the Journal of Allergy and Clinical Immunology, as well as other prominent publications that have contributed to the emerging field, on the microenvironment of the skin and molecular patterns guiding biologic treatment strategies. The most commonly questioned and explored themes of the year included the effect of the microbiome on AD development, as well as cell signaling and symptom severity. Topics also included the description of patient-specific molecular endotypes within the larger population with AD. All of these factors will create potential opportunities to guide personalized therapy with the broadening array of topical and systemic interventions currently available, as well as providing new insights to guide the development of novel molecularly targeted therapeutics. With recent US Food and Drug Administration approval of the first wave of new targeted therapies for AD, additional information exploring the safety profiles and long-term effects of these medications was also at the forefront in 2017.

When Your Kind Cannot Live Here: How Generic Language and Criminal Sanctions Shape Social Categorization.

Using generic language to describe groups (applying characteristics to entire categories) is ubiquitous and affects how children and adults categorize other people. Five-year-olds, 8-year-olds, and adults ( N = 190) learned about a novel social group that separated into two factions (citizens and noncitizens). Noncitizens were described in either generic or specific language. Later, the children and adults categorized individuals in two contexts: criminal (individuals labeled as noncitizens faced jail and deportation) and noncriminal (labeling had no consequences). Language genericity influenced decision making. Participants in the specific-language condition, but not those in the generic-language condition, reduced the rate at which they identified potential noncitizens when their judgments resulted in criminal penalties compared with when their judgments had no consequences. In addition, learning about noncitizens in specific language (vs. generic language) increased the amount of matching evidence participants needed to identify potential noncitizens (preponderance standard) and decreased participants' certainty in their judgments. Thus, generic language encourages children and adults to categorize individuals using a lower evidentiary standard regardless of negative consequences for presumed social-group membership.

Sibling composition, executive function, and children's thinking about mental diversity.

Prior investigations of relations between sibling composition and theory of mind have focused almost exclusively on false belief understanding in children 6 years of age and younger. The current work expands previous research by examining whether sibling composition predicts 4- to 11-year-olds' (N=192) more advanced mental state reasoning on interpretive theory of mind tasks. Even when controlling for age and executive function, children with a greater number of older siblings or with more same-sex siblings demonstrated stronger knowledge in both their predictions and explanations that people with different past experiences can have diverse interpretations of ambiguous stimuli. These data provide some of the first documentation of sibling constellations that predict individual differences in theory of mind during middle childhood.

Comparison of Pneumoperitoneum Volumes in Lift Laparoscopy With Variable Lift Locations and Tensile Forces.

OBJECTIVE: Evaluate the effect of peritoneal lift location and tensile force on peritoneal volume. STUDY DESIGN: Complete randomized block design. ANIMALS: Eleven fresh canine cadavers. METHODS: Cadavers underwent abdominal computed tomography (CT) scans after each treatment; 1) no lift, 2) umbilical lift with 15% body weight (BW) tension, 3) umbilical lift with 20% BW, 4) umbilical lift with 25% BW, 5) caudal lift with 15% BW, and 6) both umbilical and caudal lift with 15% BW shared equally between devices (dual lift). Isobaric pneumoperitoneal volume, instrument working distances, and transverse measures were calculated and normalized for each dog and compared across treatments. RESULTS: Increasing tensile force created a correspondingly larger pneumoperitoneal volume for the umbilical lift (0.34-0.40 total abdominal volume). Dual lifting created a larger pneumoperitoneal volume than either location alone at the same tension (0.39 total abdominal volume). Increasing lift tensions increased working distances, except to caudal abdominal structures. Increasing lift tensions at the umbilical location reduced the transverse diameter of the abdomen at the level of the kidney (0.92-0.86 total abdominal volume) and increased the transverse diameter at the midperitoneum (1.0-1.05 total abdominal volume). CONCLUSIONS: Larger isobaric penumoperitoneal volumes are produced with increased tensile force, or with dual lifting at lower force. A caudal lift leads to a small pneumoperitoneal volume but equivalent working space to caudal abdominal structures. Using an umbilical lift with moderate tensile force is preferable, providing good visualization and working space. Caudal lifting may be utilized to access caudal abdominal structures.

Long digital extensor tendon mineralization and cranial cruciate ligament rupture in a dog.

OBJECTIVE: To report clinical and histopathologic features of long digital extensor (LDE) tendon mineralization with concurrent cranial cruciate ligament (CCL) rupture in a dog. STUDY DESIGN: Case report. ANIMAL: 1.5-year-old, male castrated, English bulldog mix weighing 31.5 kg. METHODS: Pre- and postoperative orthogonal radiographs, arthroscopic evaluation, arthrotomy with en bloc surgical excision, and histopathologic analysis of the excised LDE tendon. RESULTS: There was radiographic evidence of mineralization in the region of the proximal LDE and stifle instability suggestive of CCL rupture. Arthroscopy, and subsequent arthrotomy, showed complete tearing of the CCL and an intact but grossly thickened LDE. No evidence of avulsion or bony proliferation associated with the LDE was appreciated. Tibial plateau leveling osteotomy (TPLO) and tenectomy of the LDE returned the dog to normal weight-bearing. No evidence of ectopic mineralization in the affected limb or similar clinical signs in the contralateral limb have been observed in 12 months follow-up. CONCLUSIONS: LDE tenectomy followed by stabilization of the stifle by TPLO resulted in a functional outcome. Mineralization without concurrent avulsion of the LDE has not been reported in dogs; however, posterolateral tendon injury in people has been linked to knee instability and cruciate ligament rupture.

Squamous cell carcinoma of the colon: evaluation of treatment modalities and survival.

BACKGROUND: Squamous cell carcinoma of the colon (CSCC) is a rare subtype of colon cancer. This study aimed to evaluate treatment strategies and overall survival (OS). METHODS: Using the Surveillance, Epidemiology, and End Results program database from 2008 to 2019, patients aged 18 years with CSCC were identified. Treatment strategies and OS were summarized using the Kaplan-Meier analysis and the log-rank test. Adjusted Cox proportional hazards regression model ratios were calculated to evaluate the effect of confounding variables. RESULTS: After exclusions, 153 patients met the inclusion criteria. The most common treatment modalities included surgery alone (52.1%), surgery and adjuvant chemotherapy (12.9%), and no treatment (26.4%). Kaplan-Meier analysis revealed that patients who underwent surgery and adjuvant chemotherapy had significant improvements in OS (log-rank P = .002). Cox regression analysis revealed tumor grade (hazard ratio [HR], 2.12; 95% CI, 1.17-3.86) and receipt of chemotherapy (HR, 2.66; 95% CI, 1.23-5.76) as the only factors associated with improvements in OS. CONCLUSION: Patients who underwent surgery in combination with chemotherapy had better OS than those who underwent surgery alone. Tumor grade and receipt of chemotherapy were independently associated with OS.

Development and extensive sequencing of a broadly-consented Genome in a Bottle matched tumor-normal pair.

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first to be explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from thirteen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, and Hi-C, and karyotyping. These data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. We expect these data to facilitate innovation for whole genome measurement technologies, de novo assembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic mutations. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.

Crizanlizumab in sickle cell disease.

Vaso-occlusion in sickle cell disease (SCD) leads to a myriad of manifestations driving morbidity and mortality in patients with SCD. Increased leucocyte adhesion and P-selectin expression on platelets and endothelial cells is an inciting event that leads to obstruction of microcirculation by adhesion with rigid sickled red blood cells. Crizanlizumab is a first-in-class monoclonal antibody that inhibits P-selectin and has been shown to decrease the frequency of vaso-occlusive pain crises in patients with SCD in clinical trials. The role of crizanlizumab in other manifestations of SCD still needs further investigation.

There are more than 100,000 people in the USA living with sickle cell anemia, which is a form of the inherited blood disorder, sickle cell disease. Patients with sickle cell anemia are typically diagnosed through newborn screening programs. They are also diagnosed during times of vaso-occlusive pain crisis, where patients present with severe pain without an obvious cause, and also through hemolytic anemia, a disorder in which red blood cells are destroyed faster than they can be made. While children typically survive into adulthood, the life expectancy of those with sickle cell remains shorter secondary to the after-effects of chronic sickling, where the hemoglobin inside red blood cells sticks or clumps together, causing the cell to become fragile. The associated complications of chronic sickling include pulmonary hypertension (high blood pressure in the arteries of the lung and the right side of the heart), heart failure, stroke, liver dysfunction and splenic infarction, where the blood flow to the spleen is compromised. Crizanlizumab is a new therapy targeting P-selectin, a protein that blocks interaction with p-selectin glycoprotein ligand, and has shown promise in reducing vaso-occlusive crises.

Fasciotomy on a female patient with acquired factor VIII: A case report and literature review of management.

Key Clinical Message: Acquired factor VIII inhibitors can be a rare cause of extensive intramuscular bleeding requiring fasciotomy. The subsequent postoperative period requires close monitoring due to high risk of fatal blood loss. Abstract: Acquired factor VIII inhibitors are a rare cause of often extensive bleeding and subsequently large hematomas. This disorder's overall mortality can reach 38%, largely due to immunosuppression and subsequent infections or an underlying cause such as malignancy. The patient in this case study presented with a hematoma and extensive ecchymosis of the hand and forearm, which continued to progress, precipitating compartment syndrome of the hand and forearm and ultimately requiring fasciotomy. The combination of factors led to significant blood loss in the postoperative period requiring major fluid resuscitation and intensive care unit (ICU) level care. Due to this disorder's rarity and overall mortality, we present this case report with a literature review for management of acquired hemophilia in the setting of urgent fasciotomy.