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.

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.

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

Debate remains around anatomic origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of the 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 from two different human neurotypical donors, we identified 287 and 780 mosaic variants (MVs), respectively that were used to deconvolve clonal dynamics. Clonal spread and allelic fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted compared with resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome-transcriptome analysis at both a cell-type-specific and 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 MVs across 17 locations within one parietal lobe reveals restrictions of clonal spread in the anterior-posterior axis precedes that of 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.

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.

In depth investigation of the capabilities and limitations of combined proteomic-MALDI MS based approach for the forensic detection of blood.

For the past 7 years, Matrix Assisted Laser Desorption Ionisation Mass Spectrometry (MALDI MS) based methods have been developed and published for the forensic detection of blood in stains and fingermarks. However, in the view of adoption in an operational context, further investigation into the capabilities and limitations of this approach must be conducted. The refinement and testing of this approach must also be tailored to the requirements of the end users, enabling them to address the specific circumstances most encountered in a forensic scenario. The present study delves deeper into the assessment of the applicability of MALDI MS based strategy for the reliable and robust detection of human blood through: (i) a semi-qualitative assessment of the sensitivity of the method, (ii) a wider investigation of the compatibility of the method with the prior application of commonly used presumptive tests and (iii) assessment of the specificity of the method (when blood is present in mixture with other biofluids) and of its robustness, by assessing blood detection from a range of porous materials. The findings strengthen the evidence supporting the adoption of MALDI MS based approaches as a confirmatory test for the forensic detection of human blood in an operational context.

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.

Handgrip exercise induces sex-specific mean arterial pressure and oxygenation responses but similar performance fatigability.

Women exhibit an attenuated exercise pressor reflex (EPR) when compared to men. The influence of sex-specific mechanisms related to the EPR and performance fatigability remain to be fully elucidated. The purpose was to determine the impact of oxygenation and metabolic efficiency on sex-specific performance fatigability and increases in mean arterial pressure (MAP) resulting from a fatiguing isometric handgrip (IHG). Twenty-four adults volunteered to perform an IHG at 25% at maximal voluntary isometric contractions (MVICs). Pre- and posttest MVICs were conducted to quantify performance fatigability. MAP was collected at 3 timepoints. A near-infrared spectroscopy device was attached to the forearm to derive the following signals: oxy[haem], deoxy[haem], total[haem], and diff[haem]. These values were normalized and examined across time in 5% segments of time-to-task-failure. Metabolic efficiency was defined as the ratio force:deoxy[haem]. During the IHG, there was a decline in oxy[haem] for the men (b = -0.075), whereas the women demonstrated an increase (b = 0.117). For the men, the diff[haem] tracked the mean oxy[haem] response, but there was no change for the women. The men exhibited greater declines in metabolic efficiency, yet there were no sex differences in PF (46.6 ± 9.7% vs. 45.5 ± 14.2%). For relative MAP, the men (24.5 ± 15.1%) exhibited a greater (p = .03) increase than the women (11.0 ± 17.6%). These results indicated the EPR was more prominent for the men, perhaps due to differences in mechanical stimuli and a lack of ability to maintain metabolic efficiency. However, these physiological differences did not induce a sex difference in performance fatigability.

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.

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.

Diagnostic accuracy of optical coherence tomography for surgical margin assessment of feline injection-site sarcoma.

The invasive, locally aggressive nature of feline injection-site sarcomas (FISSs) poses a unique challenge for surgeons to obtain complete margins with surgical excision. Optical coherence tomography (OCT), an imaging technology that uses light waves to generate real-time views of tissue architecture, provides an emerging solution to this dilemma by allowing fast, high-resolution scanning of surgical margins. The purpose of this study was to use OCT to assess surgical margins of FISS and to evaluate the diagnostic accuracy of OCT for detecting residual cancer using six evaluators of varying experience. Five FISSs were imaged with OCT to create a training set of OCT images that were compared with histopathology. Next, 25 FISSs were imaged with OCT prior to histopathology. Six evaluators of varying experience participated in a training session on OCT imaging after which each of the evaluators was given a dataset that included OCT images and videos to score on a scale from cancerous to non-cancerous. Diagnostic accuracy statistics were calculated. The overall sensitivity and specificity for classification of OCT images by evaluators were 78.9% and 77.6%, respectively. Correct classification rate of OCT images was associated with experience, while individual sensitivities and specificities had more variation between experience groups. This study demonstrates the ability of evaluators to correctly classify OCT images with overall low levels of experience and training and also illustrates areas where increased training can improve accuracy of evaluators in interpretation of OCT surgical margin images.

Analysis of risk factors associated with complications following mandibulectomy and maxillectomy in dogs.

OBJECTIVE: To provide information about complication rates and the risk factors for complications with mandibulectomy and maxillectomy procedures in dogs. ANIMALS: 459 client-owned dogs that underwent a mandibulectomy or maxillectomy between January 1, 2007, and January 1, 2018. PROCEDURES: Inclusion criteria included a complete medical record that contained an anesthesia record, surgical report, available histopathology results, and results of CBC and serum biochemical analysis before surgery. A minimum follow-up of 90 days after surgery was required. RESULTS: 271 complications occurred in 171 of 459 (37.3%) dogs. Eighteen complications were not given a severity description. Of the remaining 253 complications, most were considered minor (157/253 [62.1%]). Multivariable logistic regression analysis revealed that only increased surgical time had a significant (OR, 1.36; 95% CI, 1.12 to 1.54) association with the occurrence of ≥ 1 complication. For each additional hour of surgery, the odds of complications increased by 36%. Preoperative radiation therapy or chemotherapy increased the odds of incisional dehiscence or oral fistula formation (OR, 3.0; 95% CI, 1.3 to 7.2). Additionally, undergoing maxillectomy, compared with mandibulectomy, increased the odds of incisional dehiscence or oral fistula formation (OR, 1.8; 95% CI, 1.1 to 3.1). Two hundred forty-four of 271 (90.0%) complications occurred in the perioperative period (0 to 3 months after surgery). CONCLUSIONS AND CLINICAL RELEVANCE: Compared with mandibulectomy, performing maxillectomy increased the risk for incisional dehiscence or oral fistula formation. Mandibulectomy and maxillectomy had a moderate risk for a complication.

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.

"MALDI-CSI": A proposed method for the tandem detection of human blood and DNA typing from enhanced fingermarks.

Matrix Assisted Laser Desorption Ionization Mass Spectrometry Profiling and Imaging (MALDI MSP and MALDI MSI), in combination with bottom up proteomics, have proven to successfully detect and map blood-derived peptide signatures in blood fingermarks, with high specificity and compatibility with a number of blood enhancement techniques (BET). In the present study, the application of MALDI MSP and MSI to blood marks has been investigated further. In particular, the MALDI based detection and visualisation of blood has been explored in tandem with DNA typing. This investigation has been undertaken in a scenario simulating blood fingermarks on painted walls. In the present study, two sets of marks were analysed with each set comprising of a depletion series of four marks deposited on a surface treated to simulate painted walls: Set I - developed with Ninhydrin (NIN) and Set II- developed with Acid Black-1 (AB-1). For both sets, the application of MALDI MSP was successful in detecting haem and human specific haemoglobin peptide markers. MALDI MSI also provided molecular images by visualising haem on the ridge pattern enhanced by BET. The feasibility of successful and subsequent DNA profiling from the recovered fingermarks was also assessed for marks that had undergone enzymatic in situ digestion and MALDI MSI; it was observed that in 73% of the samples analysed, a DNA profile suitable for comparison was obtained. Based on these results, a possible operational workflow has been proposed incorporating the use of a MALDI MS based approach as a confirmatory test for human blood enabling subsequent DNA typing.

Pre-validation of a MALDI MS proteomics-based method for the reliable detection of blood and blood provenance.

The reliable identification of blood, as well as the determination of its origin (human or animal) is of great importance in a forensic investigation. Whilst presumptive tests are rapid and deployed in situ, their very nature requires confirmatory tests to be performed remotely. However, only serological tests can determine blood provenance. The present study improves on a previously devised Matrix Assisted Laser Desorption Ionisation Mass Spectrometry (MALDI MS)-proteomics based method for the reliable detection of blood by enabling the determination of blood provenance. The overall protocol was developed to be more specific than presumptive tests and faster/easier than the gold standard liquid chromatography (LC) MS/MS analysis. This is considered a pre-validation study that has investigated stains and fingermarks made in blood, other biofluids and substances that can elicit a false-positive response to colorimetric or presumptive tests, in a blind fashion. Stains and marks were either untreated or enhanced with a range of presumptive tests. Human and animal blood were correctly discriminated from other biofluids and non-biofluid related matrices; animal species determination was also possible within the system investigated. The procedure is compatible with the prior application of presumptive tests. The refined strategy resulting from iterative improvements through a trial and error study of 56 samples was applied to a final set of 13 blind samples. This final study yielded 12/13 correct identifications with the 13th sample being correctly identified as animal blood but with no species attribution. This body of work will contribute towards the validation of MALDI MS based methods and deployment in violent crimes involving bloodshed.

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.

Adherence to follow-up recommendations for dogs with apocrine gland anal sac adenocarcinoma: A multicentre retrospective study.

Progressive disease is common following anal sacculectomy for apocrine gland anal sac adenocarcinoma (AGASACA); additional therapy may prolong survival. Adherence to medical recommendations influences therapeutic success in humans. The purpose of this study was to assess the adherence to follow-up recommendations in dogs with AGASACA. Medical records of patients that underwent anal sacculectomy for AGASACA, with or without iliosacral lymphadenectomy, between July 2015 and July 2018, were reviewed at eight referral institutions to assess post-operative recommendations and owner adherence to recommendations. One hundred and seventy-four dogs were included, of which 162 underwent unilateral anal sacculectomy, 12 underwent bilateral anal sacculectomy and 39 underwent concurrent iliosacral lymphadenectomy. Seventy-six owners (44%) received recommendations for staging at the time of discharge, histopathology results or at the first follow-up visit. One hundred and forty owners (80%) received recommendations for treatment following the initial surgery. Fifty of seventy-six (66%) owners pursued at least one staging recommendation and 69 of 140 (49%) owners pursued some kind of adjuvant treatment recommendation. Overall, 16 of 76 (21%) were adherent to staging recommendations with 20 adherent for the first year following surgery (26%). Forty-seven of 140 (34%) were adherent to treatment recommendations with 54 (39%) adherent for the first year. Owners that were adherent to restaging recommendations at 1 year following surgery were significantly more likely to pursue treatment for progressive disease (P = .014). Further work is required to assess owner motivation and evaluate strategies to improve adherence, given the potential impact on patient treatment.