Quadriceps tendon autograft has similar clinical outcomes when compared to hamstring tendon and bone-patellar tendon-bone autografts for revision ACL reconstruction: a systematic review and meta-analysis.

PURPOSE: Research regarding revision anterior cruciate ligament reconstruction (RACLR) with quadriceps tendon (QT) autografts is lacking. The purpose of this study was to perform a systematic review and meta-analysis of RACLR with QT and compare its patient outcomes to RACLR with hamstring tendon (HT) and bone-patellar tendon-bone (BTB) autografts. METHODS: Adhering to PRISMA guidelines, a search for studies using QT in RACLR was performed within PubMed, Scopus, and CINAHL from database date of inception through December 26, 2022. Primary outcomes sought included: failure rate, Lysholm scores, International Knee Documentation Committee (IKDC) scores, IKDC grades, arthrometric knee side-to-side differences (STSD), pivot shift grade, donor site morbidity, return to sport, visual analog scale (VAS) pain scores. RESULTS: Nine studies were included consisting of 606 RACLR: 349 QT, 169 HT, and 88 BTB. Overall failure rates were 7.6% QT, 13.3% HT, and 8.7% BTB. Mean weighted Lysholm scores were 85.8 ± 3.8 QT, 82.5 ± 3.8 HT and 86.6 ± 4.5 BTB. IKDC average scores were 82.3 ± 1.6 QT, 80.1 ± 1.7 HT, and 81.7 ± 5.5BTB. Combined rates of IKDC A/B grades were 88.4% and 80.0% for QT and HT, respectively. VAS average scores were 0.9 ± 1.1 QT, 1.4 ± 0.2 HT, and 0.7 ± 0.8 for BTB. Side-to-side difference was reported for QT and HT with average values of 1.7 ± 0.6 mm and 2.1 ± 0.5 mm, respectively. Grade 0 or 1 pivot shifts were reported in 96.2% of QT patients and 91.3% of HT. Donor site morbidity, only reported for QT and HT, was 14.6 ± 9.7% and 23.6 ± 14.1%, respectively. QT resulted in a mean Tegner score of 5.9 ± 1.5 versus HT 5.7 ± 1.5. Rate of return to pivoting sports was 38.0% QT, 48.6% HT, and 76.9% BTB. Across all outcomes, there was no significant difference when comparing QT to HT, QT to BTB, and QT compared to HT and BTB combined. CONCLUSIONS: RACLR with QT yields satisfactory patient reported outcomes, satisfactory improvement in knee laxity, expected return to sport rates, and has an overall 7.6% failure rate. Outcomes are comparative to those of HT and BTB making it an acceptable graft choice for RACLR. Surgeons should consider using QT autograft for RACLR, especially when other autografts are unavailable. LEVEL OF EVIDENCE: IV.

Understanding the patient experience of Classic Galactosemia in pediatric and adult patients: increased disease burden, challenges with daily living, and how they evolve over time.

BACKGROUND: Classic Galactosemia (CG) is a rare, autosomal recessive condition. Newborn screening and a timely galactose-restricted diet can resolve acute symptoms and decrease fatalities, but significant chronic, progressive morbidities remain and significantly impact daily life. The objective of this study was to better understand the burden of disease in children and adults with CGs and describe how morbidities evolve over time. METHODS: A total of 49 individuals with CG from the United States (US) were included in the qualitative surveys (13 adults [9 self-reported] and 36 pediatric patients). Fifteen follow-up interviews were conducted with 5 adults and 10 caregivers, discussing 17 individuals with CG overall (2 caregivers each discussed 2 children). RESULTS: Qualitative survey and interview data demonstrated the substantial burden of CG. Difficulties in a wide range of functions were experienced, which included: speech articulation; language and communication; cognition, memory and learning; emotions; and social interactions. Most difficulties appeared in childhood and persisted or worsened with age. Most adults did not live independently. Others lived semi-independently and experienced many daily challenges and required support. Caregivers also described the burden of caring for someone with CG and spoke about the impact this has on their day-to-day life, work, and relationships. CONCLUSIONS: These findings demonstrate the pronounced and persistent burden of disease encountered by individuals with CG, and that the condition has a significant impact on the quality of life of caregivers.

Non-uniform temporal scaling of developmental processes in the mammalian cortex.

The time that it takes the brain to develop is highly variable across animals. Although staging systems equate major developmental milestones between mammalian species, it remains unclear how distinct processes of cortical development scale within these timeframes. Here, we compare the timing of cortical development in two mammals of similar size but different developmental pace: eutherian mice and marsupial fat-tailed dunnarts. Our results reveal that the temporal relationship between cell birth and laminar specification aligns to equivalent stages between these species, but that migration and axon extension do not scale uniformly according to the developmental stages, and are relatively more advanced in dunnarts. We identify a lack of basal intermediate progenitor cells in dunnarts that likely contributes in part to this timing difference. These findings demonstrate temporal limitations and differential plasticity of cortical developmental processes between similarly sized Therians and provide insight into subtle temporal changes that may have contributed to the early diversification of the mammalian brain.

Clade-specific forebrain cytoarchitectures of the extinct Tasmanian tiger.

The thylacine, or Tasmanian tiger, is the largest of modern-day carnivorous marsupials and was hunted to extinction by European settlers in Australia. Its physical resemblance to eutherian wolves is a striking example of evolutionary convergence to similar ecological niches. However, whether the neuroanatomical organization of the thylacine brain resembles that of canids and how it compares with other mammals remain unknown due to the scarcity of available samples. Here, we gained access to a century-old hematoxylin-stained histological series of a thylacine brain, digitalized it at high resolution, and compared its forebrain cellular architecture with 34 extant species of monotremes, marsupials, and eutherians. Phylogenetically informed comparisons of cortical folding, regional volumes, and cell sizes and densities across cortical areas and layers provide evidence against brain convergences with canids, instead demonstrating features typical of marsupials, and more specifically Dasyuridae, along with traits that scale similarly with brain size across mammals. Enlarged olfactory, limbic, and neocortical areas suggest a small-prey predator and/or scavenging lifestyle, similar to extant quolls and Tasmanian devils. These findings are consistent with a nonuniformity of trait convergences, with brain traits clustering more with phylogeny and head/body traits with lifestyle. By making this resource publicly available as rapid web-accessible, hierarchically organized, multiresolution images for perpetuity, we anticipate that additional comparative insights might arise from detailed studies of the thylacine brain and encourage researchers and curators to share, annotate, and preserve understudied material of outstanding biological relevance.

Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living.

BACKGROUND: Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, converting to an aberrant and toxic metabolite, galactitol. Newborn screening and timely galactose-restricted diet can resolve acute symptoms and decrease fatalities. However, despite this, significant chronic, progressive morbidities remain which have a real impact upon daily life. To better understand the burden of disease, 20 in-depth qualitative interviews were undertaken with adult patients (n = 12), and their caregivers (n = 8), enrolled in the ACTION-Galactosemia trial, part of a clinical program designed to investigate the safety and efficacy of AT-007 (govorestat) in reducing toxic galactitol and long-term clinical outcomes in Classic Galactosemia. RESULTS: Interviews revealed the substantial burden of Classic Galactosemia on patients and families. Most adults were not able to live independently, and all required support with day-to-day activities. Short- and long-term memory difficulties and tremors were identified as the most frequently experienced and challenging symptoms. Other difficulties such as fine motor skills and slow/slurred speech contribute to the significant impact on daily activities, affecting ability to communicate and interact with others. Symptoms were first noticed in early childhood and worsened with age. Classic Galactosemia impacted all areas of daily functioning and quality of life, leading to social isolation, anxiety, anger/frustration and depression. This demonstrates the significant burden of disease and challenges associated with Classic Galactosemia. CONCLUSIONS: The impact on both patients and caregivers underscores the severity of the unmet medical need and the importance of pharmacological intervention to halt or prevent disease progression. Any treatment that could reduce symptoms or slow functional decline would ease the burden of this condition on patients and caregivers.

COVID-19 modifications of offseason and preseason training for NFL athletes are associated with increased risk of regular season injuries.

OBJECTIVES: COVID-19 altered National Football League (NFL) player and team training during the 2020 offseason. All preseason games were cancelled resulting in absence of game play before the first week of the regular season. Thus, concerns exist regarding injury susceptibility of players during regular season games. The purpose of this study was to evaluate and compare injury rates during the 2020 NFL season versus injury rates from the unaffected 2017-2019 seasons. We hypothesized there would be an increased injury rate and an increased rate of season ending injuries during the modified 2020 season. METHODS: The NFL's public injury database was queried to identify players placed on the injury lists throughout the 2017-2020 seasons. All players listed as "out" and on the injured reserve due to physical injury were included in the data set. For further stratification, injury incidence was separated based on position. Time missed due to COVID-19 illness was not included. Injury rates were expressed as injuries per 1000 athlete exposures (AE). RESULTS: Overall, 893 individual players missed games due to injury during the 2020 NFL regular season compared to an average of 743 over the 2017-2019 seasons. Defensive players at all positions had a statistically significant increase in injury incidence from an average of 7.54 to 10.20 injuries per 1000 AE. Defensive backs were most affected with a 46% increase in players injured. There was no statistically significant difference in season ending injuries for any position. CONCLUSIONS: The COVID-19 stricken 2020 NFL regular season saw an increased rate and incidence of injuries. Specifically, defensive players had a higher incidence of injury overall with defensive backs experiencing the greatest increase in injury rates.

Disease burden in people with cystic fibrosis heterozygous for F508del and a minimal function mutation.

BACKGROUND: People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation. METHODS: People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity. RESULTS: 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort. CONCLUSIONS: People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.

Surgical Management of Proximal Fifth Metatarsal Fractures in Elite Athletes: A Systematic Review.

BACKGROUND: As a result of the high physical demand in sport, elite athletes are particularly prone to fifth metatarsal fractures. These injuries are typically managed surgically to avoid high rates of delayed union and allow for quicker return to play (RTP). PURPOSE: To review studies showing clinical and radiographic outcomes, RTP rates, and complication rates after different surgical treatment modalities for fifth metatarsal fractures exclusively in elite-level athletes. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic search was conducted within the PubMed, Scopus, and Cochrane databases from January 2000 to January 2020. Inclusion criteria consisted of clinical outcome studies after operative management of fifth metatarsal fractures in elite athletes. Exclusion criteria consisted of nonoperative management, high school or recreational-level athletic participation, nonclinical studies, expert opinions, and case series with <5 patients. RESULTS: A total of 12 studies met inclusion and exclusion criteria, comprising 280 fifth metatarsal fractures treated surgically. Intramedullary screw fixation was the most common fixation construct (47.9%), and some form of intraoperative adjunctive treatment (calcaneal autograft, iliac crest bone graft, bone marrow aspirate concentrate, demineralized bone matrix) was used in 67% of cases. Radiographic union was achieved in 96.7% of fractures regardless of surgical construct used. The overall mean time to union was 9.19 weeks, with RTP at a mean of 11.15 weeks. The overall reported complication rate was 22.5%, with varying severity of complications. Refracture rates were comparable between the different surgical constructs used, and the overall refracture rate was 8.6%. CONCLUSION: Elite athletes appeared to have a high rate of union and reliably returned to the same level of competition after surgical management of fifth metatarsal fractures, irrespective of surgical construct used. Despite this, the overall complication rate was >20%. Specific recommendations for optimal surgical management could not be made based on the heterogeneity of the included studies.

Combining Multiplex Fluorescence in situ Hybridization with Fluorescent Immunohistochemistry on Fresh Frozen or Fixed Mouse Brain Sections.

Fluorescent in situ hybridization (FISH) is a molecular technique that identifies the presence and spatial distribution of specific RNA transcripts within cells. Neurochemical phenotyping of functionally identified neurons usually requires concurrent labelling with multiple antibodies (targeting protein) using immunohistochemistry (IHC) and optimization of in situ hybridization (targeting RNA), in tandem. A "neurochemical signature" to characterize particular neurons may be achieved however complicating factors include the need to verify FISH and IHC targets before combining the methods, and the limited number of RNAs and proteins that may be targeted simultaneously within the same tissue section. Here we describe a protocol, using both fresh frozen and fixed mouse brain preparations, which detects multiple mRNAs and proteins in the same brain section using RNAscope FISH followed by fluorescence immunostaining, respectively. We use the combined method to describe the expression pattern of low abundance mRNAs (e.g., galanin receptor 1) and high abundance mRNAs (e.g., glycine transporter 2), in immunohistochemically identified brainstem nuclei. Key considerations for protein labelling downstream of the FISH assay extend beyond tissue preparation and optimization of FISH probe labelling. For example, we found that antibody binding and labelling specificity can be detrimentally affected by the protease step within the FISH probe assay. Proteases catalyze hydrolytic cleavage of peptide bonds, facilitating FISH probe entry into cells, however they may also digest the protein targeted by the subsequent IHC assay, producing off target binding. The subcellular location of the targeted protein is another factor contributing to IHC success following FISH probe assay. We observed IHC specificity to be retained when the targeted protein is membrane bound, whereas IHC targeting cytoplasmic protein required extensive troubleshooting. Finally, we found handling of slide-mounted fixed frozen tissue more challenging than fresh frozen tissue, however IHC quality was overall better with fixed frozen tissue, when combined with RNAscope.

A Standardized Order-Set Improves Variability in Opioid Discharge Prescribing Patterns After Surgical Fixation of Pediatric Supracondylar Humerus Fractures.

OBJECTIVE: To evaluate institutional opioid prescribing patterns following percutaneous fixation of pediatric supracondylar humerus fractures before and after implementation of a standardized discharge order set. DESIGN: A retrospective review of patients who underwent closed reduction and percutaneous skeletal fixation of a Type II or III supracondylar humerus fracture in 2017 (prior to pain protocol implementation) and again in 2019 (after pain protocol implementation) SETTING: Single Tertiary Care Children's Hospital PARTICIPANTS: In total, 106 patients met inclusion criteria between years 2017 (n = 49) and 2019 (n = 57). Exclusion criteria included miscoded patients, open fractures, patients who presented with vascular injury or nerve palsy, polytrauma patients with multiple fractures in the same upper extremity, and supracondylar humerus fractures that underwent an open procedure. RESULTS: There were no significant differences between inpatient pain scores (p = 0.91) and MDE prescribed (p = 0.75) between the 2 cohorts. In 2017, large variability was noted in day supply of opioids (0-11.4 days) and MDE (0-8.45 mg/kg), with significant differences between prescribing patterns of junior and senior level residents (mean day supply of opioids (p = 0.045), mean MDE prescribed on discharge (p = 0.001)). After implementation of a standardized opioid discharge order set, there was a tenfold increase in the number of patients discharged without an opioid prescription (2017: 4%, 2019: 44%). Additionally, any discrepancies between prescribing practices of junior and senior level residents were eliminated (mean day supply of opioids (p = 0.65), mean MDE prescribed on discharge (p = 0.69)). CONCLUSIONS: The introduction of a standardized post-operative opioid discharge order set led to a 10-fold increase in the number of patients discharged without an opioid prescription. Additionally, the order set decreased the variability in the prescribing patterns of discharge opioid medications without change in pain control. The resident prescribing variability based upon level of experience resolved with the use of the order set.

Analysis of Mechanically Activated Ion Channels at the Cell-Substrate Interface: Combining Pillar Arrays and Whole-Cell Patch-Clamp.

Ionic currents can be evoked by mechanical inputs applied directly at the cell-substrate interface. These ionic currents are mediated by mechanically activated ion channels, where the open probability increases with increasing mechanical input. In order to study mechanically activated ion channels directly at the interface between cells and their environment, we have developed a technique to simultaneously monitor ion channel activity whilst stimuli are applied via displacement of cell-substrate contacts. This technique utilizes whole-cell patch-clamp electrophysiology and elastomeric pillar arrays, it is quantitative and appropriate for studying channels that respond to stimuli that are propagated to an adherent cell via the physical substrate. The mammalian channels PIEZO1, PIEZO2 have been shown to be activated by substrate deflections, using this technique. In addition, TRPV4 mediated currents can be evoked by substrate deflections, in contrast to alternate stimulation methods such as membrane stretch or cellular indentation. The deflections applied at cell-substrate points mimic the magnitude of physical stimuli that impact cells in situ.

Pediatric Obstructive Sleep Apnea and Asthma: Clinical Implications.

Obstructive sleep apnea (OSA) and asthma are common conditions in children with preventable long-term consequences. There is significant overlap in symptomatology and pathophysiology for pediatric OSA and asthma. Recent evidence supports clear associations between the two diseases; however, causality has not been demonstrated. Regardless, it is important to recognize the overlap and evaluate for the other condition when one is present. For example, in patients with severe OSA, clinical evaluation for asthma should be considered, including history for typical asthma symptoms and spirometry. For patients with severe or poorly controlled asthma, OSA should be considered as a complicating condition. Clinical history for OSA as well as pediatric sleep questionnaires may be helpful tools in evaluation of the child with severe asthma. To decrease long-term consequences from asthma and OSA in children, clinicians should consider the relationship between these two diseases. [Pediatr Ann. 2017;46(9):e332-e335.].

Pediatric Obstructive Sleep Apnea in High-Risk Populations: Clinical Implications.

Certain common medical conditions are associated with a higher risk of pediatric obstructive sleep apnea (OSA). A lower threshold for screening is therefore indicated for such patient cohorts. In this article, we briefly discuss the high prevalence of OSA in children born prematurely, and in those with Down syndrome, craniofacial disorders, and neuromuscular disorders. Primary care providers should have an increased index of suspicion for OSA in these children, considering the neurocognitive disability that occurs in these high-risk groups when OSA is left untreated. [Pediatr Ann. 2017;46(9):e336-e339.].

Pulmonary Vasculopathy Associated with FIGF Gene Mutation.

Vascular endothelial growth factor (VEGF)-D is capable of inducing angiogenesis and lymphangiogenesis through signaling via VEGF receptor (VEGFR)-2 and VEGFR-3, respectively. Mutations in the FIGF (c-fos-induced growth factor) gene encoding VEGF-D have not been reported previously. We describe a young male with a hemizygous mutation in the X-chromosome gene FIGF (c.352 G>A) associated with early childhood respiratory deficiency. Histologically, lungs showed ectatic pulmonary arteries and pulmonary veins. The mutation resulted in a substitution of valine to methionine at residue 118 of the VEGF-D protein. The resultant mutant protein had increased dimerization, induced elevated VEGFR-2 signaling, and caused aberrant angiogenesis in vivo. Our observations characterize a new subtype of congenital diffuse lung disease, provide a histological correlate, and support a critical role for VEGF-D in lung vascular development and homeostasis.

An update on childhood urticaria and angioedema.

PURPOSE OF REVIEW: The present review serves to address urticaria - both acute and chronic - as well as the differential diagnosis of urticarial syndromes in the pediatric population. We also wish to update the reader on progress in the pathophysiology, diagnosis and treatment of urticaria. RECENT FINDINGS: Acute and chronic urticaria represent syndromes caused by a variety of triggers. Recent literature continues to describe subtypes of urticaria that may be differentially responsive to particular therapies. Recent associations highlight the need to fully evaluate patients for allergic and infectious triggers of urticaria. It is important to distinguish idiopathic urticaria from related conditions such as anaphylaxis, systemic conditions and autoimmune urticaria. Although antihistamines remain a cornerstone of therapy, particular urticaria subtypes may also respond to novel therapies such as omalizumab. Chronic urticaria has a significant impact on a patient's quality of life. SUMMARY: Urticaria is a common condition. Our understanding of distinct urticaria subtypes differentially responsive to targeted therapies continues to increase. Due to the myriad of triggers that may cause urticaria, careful individualized patient assessment is necessary to exclude potential etiologies prior to a diagnosis of idiopathic urticaria.

Integrating medical and psychological health care for children with atopic dermatitis.

OBJECTIVE: To present descriptive data from a hospital-based interdisciplinary program that provides integrated medical and psychological health-care for children with atopic dermatitis (AD). METHODS: Clinical records were reviewed for 69 children seen in our program to examine parent-reported AD-related presenting concerns, as well as common problems and interventions addressed during family visits with the program psychologist. RESULTS: The most common presenting concerns included child itching and scratching and associated sleep problems. Parent initial request for a meeting with the program psychologist was not related to child disease severity, but was associated with child sleep problems and parent emotional and practical challenges in managing the child's condition. CONCLUSIONS: Results support the need for, acceptance of, and feasibility of providing integrated care for children with AD and their families. Changes to our clinical model based on study findings are discussed.

Development of a preliminary questionnaire to assess parental response to children's food allergies.

BACKGROUND: Food allergy affects up to 8% of children. Unintentional exposure may result in minor to potentially fatal episodes. Management of allergies depends on strict allergen avoidance and emergency preparedness. The demands of allergy management and concerns for the child's safety may place parents at risk of developing emotional distress or difficulties in coping. OBJECTIVE: To develop a brief condition-specific measure to evaluate parental adjustment to and coping with children's food allergy. METHODS: A total of 221 parents of children 18 year or younger with food allergy were recruited from a private allergy practice and local food allergy support groups. Parents completed an 18-item questionnaire, the Food Allergy Parent Questionnaire (FAPQ), that assessed parental coping with a child's food allergy and questions related to their child's food allergy diagnosis and course. RESULTS: Factor analysis of the items on the FAPQ suggested 4 factors that accounted for 53.6% of the variance: parental anxiety/distress, psychosocial impact of allergies, parental coping/competence, and family support. Medical variables (greater number of food allergies, positive history of anaphylaxis) were associated with higher scores on the anxiety/distress and psychosocial impact subscales. Internal consistency was good for the anxiety/distress and psychosocial impact subscales (Cronbach alpha = .80 and .77, respectively) but lower for the parental coping/competence and family support subscales (alpha = .57 and .32, respectively). CONCLUSIONS: Although further psychometric data for the FAPQ is needed, preliminary findings suggest that the measure may be useful in screening for parental anxiety, perceived impact of food allergies, level of family support, and coping skills.