Citations

Abstract Phosphomannomutase 2 (PMM2‐CDG) is the most common congenital disorder of N‐glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2‐CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2‐CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence‐based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2‐CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2‐CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2‐CDG patients.

Objective This update of a 2011 guideline developed by the American Academy of Otolaryngology–Head and Neck Surgery Foundation provides evidence‐based recommendations on the pre‐, intra‐, and postoperative care and management of children 1 to 18 years of age under consideration for tonsillectomy. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil, including its capsule, by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Tonsillectomy is one of the most common surgical procedures in the United States, with 289,000 ambulatory procedures performed annually in children <15 years of age based on the most recent published data. This guideline is intended for all clinicians in any setting who interact with children who may be candidates for tonsillectomy. Purpose The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing children under consideration for tonsillectomy and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to educate clinicians, patients, and/or caregivers regarding the indications for tonsillectomy and the natural history of recurrent throat infections. Additional goals include the following: optimizing the perioperative management of children undergoing tonsillectomy, emphasizing the need for evaluation and intervention in special populations, improving the counseling and education of families who are considering tonsillectomy for their children, highlighting the management options for patients with modifying factors, and reducing inappropriate or unnecessary variations in care. Children aged 1 to 18 years under consideration for tonsillectomy are the target patient for the guideline. For this guideline update, the American Academy of Otolaryngology–Head and Neck Surgery Foundation selected a panel representing the fields of nursing, anesthesiology, consumers, family medicine, infectious disease, otolaryngology–head and neck surgery, pediatrics, and sleep medicine. Key Action Statements The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should recommend watchful waiting for recurrent throat infection if there have been <7 episodes in the past year, <5 episodes per year in the past 2 years, or <3 episodes per year in the past 3 years. (2) Clinicians should administer a single intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. (3) Clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. The guideline update group made recommendations for the following KASs: (1) Clinicians should assess the child with recurrent throat infection who does not meet criteria in KAS 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergies/intolerance, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or history of >1 peritonsillar abscess. (2) Clinicians should ask caregivers of children with obstructive sleep‐disordered breathing and tonsillar hypertrophy about comorbid conditions that may improve after tonsillectomy, including growth retardation, poor school performance, enuresis, asthma, and behavioral problems. (3) Before performing tonsillectomy, the clinician should refer children with obstructive sleep‐disordered breathing for polysomnography if they are <2 years of age or if they exhibit any of the following: obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (4) The clinician should advocate for polysomnography prior to tonsillectomy for obstructive sleep‐disordered breathing in children without any of the comorbidities listed in KAS 5 for whom the need for tonsillectomy is uncertain or when there is discordance between the physical examination and the reported severity of oSDB. (5) Clinicians should recommend tonsillectomy for children with obstructive sleep apnea documented by overnight polysomnography. (6) Clinicians should counsel patients and caregivers and explain that obstructive sleep‐disordered breathing may persist or recur after tonsillectomy and may require further management. (7) The clinician should counsel patients and caregivers regarding the importance of managing posttonsillectomy pain as part of the perioperative education process and should reinforce this counseling at the time of surgery with reminders about the need to anticipate, reassess, and adequately treat pain after surgery. (8) Clinicians should arrange for overnight, inpatient monitoring of children after tonsillectomy if they are <3 years old or have severe obstructive sleep apnea (apnea‐hypopnea index ≥10 obstructive events/hour, oxygen saturation nadir <80%, or both). (9) Clinicians should follow up with patients and/or caregivers after tonsillectomy and document in the medical record the presence or absence of bleeding within 24 hours of surgery (primary bleeding) and bleeding occurring later than 24 hours after surgery (secondary bleeding). (10) Clinicians should determine their rate of primary and secondary posttonsillectomy bleeding at least annually. The guideline update group made a strong recommendation against 2 actions: (1) Clinicians should not administer or prescribe perioperative antibiotics to children undergoing tonsillectomy. (2) Clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years. The policy level for the recommendation about documenting recurrent throat infection was an option: (1) Clinicians may recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year, at least 5 episodes per year for 2 years, or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and ≥1 of the following: temperature >38.3°C (101°F), cervical adenopathy, tonsillar exudate, or positive test for group A beta‐hemolytic streptococcus. Differences from Prior Guideline (1) Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply. (2) There were 1 new clinical practice guideline, 26 new systematic reviews, and 13 new randomized controlled trials included in the current guideline update. (3) Inclusion of 2 consumer advocates on the guideline update group. (4) Changes to 5 KASs from the original guideline: KAS 1 (Watchful waiting for recurrent throat infection), KAS 3 (Tonsillectomy for recurrent infection with modifying factors), KAS 4 (Tonsillectomy for obstructive sleep‐disordered breathing), KAS 9 (Perioperative pain counseling), and KAS 10 (Perioperative antibiotics). (5) Seven new KASs: KAS 5 (Indications for polysomnography), KAS 6 (Additional recommendations for polysomnography), KAS 7 (Tonsillectomy for obstructive sleep apnea), KAS 12 (Inpatient monitoring for children after tonsillectomy), KAS 13 (Postoperative ibuprofen and acetaminophen), KAS 14 (Postoperative codeine), and KAS 15a (Outcome assessment for bleeding). (6) Addition of an algorithm outlining KASs. (7) Enhanced emphasis on patient and/or caregiver education and shared decision making.

Objective This update of a 2011 guideline developed by the American Academy of Otolaryngology–Head and Neck Surgery Foundation provides evidence‐based recommendations on the pre‐, intra‐, and postoperative care and management of children 1 to 18 years of age under consideration for tonsillectomy. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil, including its capsule, by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Tonsillectomy is one of the most common surgical procedures in the United States, with 289,000 ambulatory procedures performed annually in children <15 years of age, based on the most recent published data. This guideline is intended for all clinicians in any setting who interact with children who may be candidates for tonsillectomy. Purpose The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing children under consideration for tonsillectomy and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to educate clinicians, patients, and/or caregivers regarding the indications for tonsillectomy and the natural history of recurrent throat infections. Additional goals include the following: optimizing the perioperative management of children undergoing tonsillectomy, emphasizing the need for evaluation and intervention in special populations, improving the counseling and education of families who are considering tonsillectomy for their children, highlighting the management options for patients with modifying factors, and reducing inappropriate or unnecessary variations in care. Children aged 1 to 18 years under consideration for tonsillectomy are the target patient for the guideline. For this guideline update, the American Academy of Otolaryngology–Head and Neck Surgery Foundation selected a panel representing the fields of nursing, anesthesiology, consumers, family medicine, infectious disease, otolaryngology–head and neck surgery, pediatrics, and sleep medicine. Key Action Statements The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should recommend watchful waiting for recurrent throat infection if there have been <7 episodes in the past year, <5 episodes per year in the past 2 years, or <3 episodes per year in the past 3 years. (2) Clinicians should administer a single intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. (3) Clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. The guideline update group made recommendations for the following KASs: (1) Clinicians should assess the child with recurrent throat infection who does not meet criteria in KAS 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergies/intolerance, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or history of >1 peritonsillar abscess. (2) Clinicians should ask caregivers of children with obstructive sleep‐disordered breathing and tonsillar hypertrophy about comorbid conditions that may improve after tonsillectomy, including growth retardation, poor school performance, enuresis, asthma, and behavioral problems. (3) Before performing tonsillectomy, the clinician should refer children with obstructive sleep‐disordered breathing for polysomnography if they are <2 years of age or if they exhibit any of the following: obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (4) The clinician should advocate for polysomnography prior to tonsillectomy for obstructive sleep‐disordered breathing in children without any of the comorbidities listed in KAS 5 for whom the need for tonsillectomy is uncertain or when there is discordance between the physical examination and the reported severity of obstructive sleep‐disordered breathing. (5) Clinicians should recommend tonsillectomy for children with obstructive sleep apnea documented by overnight polysomnography. (6) Clinicians should counsel patients and caregivers and explain that obstructive sleep‐disordered breathing may persist or recur after tonsillectomy and may require further management. (7) The clinician should counsel patients and caregivers regarding the importance of managing posttonsillectomy pain as part of the perioperative education process and should reinforce this counseling at the time of surgery with reminders about the need to anticipate, reassess, and adequately treat pain after surgery. (8) Clinicians should arrange for overnight, inpatient monitoring of children after tonsillectomy if they are <3 years old or have severe obstructive sleep apnea (apnea‐hypopnea index ≥10 obstructive events/hour, oxygen saturation nadir <80%, or both). (9) Clinicians should follow up with patients and/or caregivers after tonsillectomy and document in the medical record the presence or absence of bleeding within 24 hours of surgery (primary bleeding) and bleeding occurring later than 24 hours after surgery (secondary bleeding). (10) Clinicians should determine their rate of primary and secondary posttonsillectomy bleeding at least annually. The guideline update group made a strong recommendation against 2 actions: (1) Clinicians should not administer or prescribe perioperative antibiotics to children undergoing tonsillectomy. (2) Clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years. The policy level for the recommendation about documenting recurrent throat infection was an option : (1) Clinicians may recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year, at least 5 episodes per year for 2 years, or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and ≥1 of the following: temperature >38.3°C (101°F), cervical adenopathy, tonsillar exudate, or positive test for group A beta‐hemolytic streptococcus. Differences from Prior Guideline Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply. There were 1 new clinical practice guideline, 26 new systematic reviews, and 13 new randomized controlled trials included in the current guideline update. Inclusion of 2 consumer advocates on the guideline update group. Changes to 5 KASs from the original guideline: KAS 1 (Watchful waiting for recurrent throat infection), KAS 3 (Tonsillectomy for recurrent infection with modifying factors), KAS 4 (Tonsillectomy for obstructive sleep‐disordered breathing), KAS 9 (Perioperative pain counseling), and KAS 10 (Perioperative antibiotics). Seven new KASs: KAS 5 (Indications for polysomnography), KAS 6 (Additional recommendations for polysomnography), KAS 7 (Tonsillectomy for obstructive sleep apnea), KAS 12 (Inpatient monitoring for children after tonsillectomy), KAS 13 (Postoperative ibuprofen and acetaminophen), KAS 14 (Postoperative codeine), and KAS 15a (Outcome assessment for bleeding). Addition of an algorithm outlining KASs. Enhanced emphasis on patient and/or caregiver education and shared decision making.

Abstract Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Abstract Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.

Abstract Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.