Pseudouridine is the most abundant RNA modification, yet except for a few well-studied cases, little is known about the modified positions and their function(s). Here, we develop Ψ-seq for ...transcriptome-wide quantitative mapping of pseudouridine. We validate Ψ-seq with spike-ins and de novo identification of previously reported positions and discover hundreds of unique sites in human and yeast mRNAs and snoRNAs. Perturbing pseudouridine synthases (PUS) uncovers which pseudouridine synthase modifies each site and their target sequence features. mRNA pseudouridinylation depends on both site-specific and snoRNA-guided pseudouridine synthases. Upon heat shock in yeast, Pus7p-mediated pseudouridylation is induced at >200 sites, and PUS7 deletion decreases the levels of otherwise pseudouridylated mRNA, suggesting a role in enhancing transcript stability. rRNA pseudouridine stoichiometries are conserved but reduced in cells from dyskeratosis congenita patients, where the PUS DKC1 is mutated. Our work identifies an enhanced, transcriptome-wide scope for pseudouridine and methods to dissect its underlying mechanisms and function.
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•Ψ-seq for high resolution, transcriptome-wide profiling of pseudouridine•Many distinct sites in mRNA; dynamically regulated in heat shock•Sites depend on conserved cognate pseudouridine synthases in yeast and human•Reduced rRNA and TERC pseudouridine in dyskeratosis congenita patients
Transcriptome-wide pseudouridine mapping reveals extensive, dynamic pseudouridylation of mRNA and noncoding RNA in yeast and human.
Clinical practice guideline: Tympanostomy tubes in children Rosenfeld, Richard M; Schwartz, Seth R; Pynnonen, Melissa A ...
Otolaryngology and head and neck surgery/Otolaryngology--head and neck surgery,
July 2013, Letnik:
149, Številka:
1 Suppl
Journal Article
Recenzirano
Odprti dostop
Insertion of tympanostomy tubes is the most common ambulatory surgery performed on children in the United States. Tympanostomy tubes are most often inserted because of persistent middle ear fluid, ...frequent ear infections, or ear infections that persist after antibiotic therapy. Despite the frequency of tympanostomy tube insertion, there are currently no clinical practice guidelines in the United States that address specific indications for surgery. This guideline is intended for any clinician involved in managing children, aged 6 months to 12 years, with tympanostomy tubes or being considered for tympanostomy tubes in any care setting, as an intervention for otitis media of any type.
The primary purpose of this clinical practice guideline is to provide clinicians with evidence-based recommendations on patient selection and surgical indications for and management of tympanostomy tubes in children. The development group broadly discussed indications for tube placement, perioperative management, care of children with indwelling tubes, and outcomes of tympanostomy tube surgery. Given the lack of current published guidance on surgical indications, the group focused on situations in which tube insertion would be optional, recommended, or not recommended. Additional emphasis was placed on opportunities for quality improvement, particularly regarding shared decision making and care of children with existing tubes. ACTION STATEMENTS: The development group made a strong recommendation that clinicians should prescribe topical antibiotic eardrops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea. The panel made recommendations that (1) clinicians should not perform tympanostomy tube insertion in children with a single episode of otitis media with effusion (OME) of less than 3 months' duration; (2) clinicians should obtain an age-appropriate hearing test if OME persists for 3 months or longer (chronic OME) or prior to surgery when a child becomes a candidate for tympanostomy tube insertion; (3) clinicians should offer bilateral tympanostomy tube insertion to children with bilateral OME for 3 months or longer (chronic OME) and documented hearing difficulties; (4) clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who did not receive tympanostomy tubes until the effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are suspected; (5) clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media (AOM) who do not have middle ear effusion in either ear at the time of assessment for tube candidacy; (6) clinicians should offer bilateral tympanostomy tube insertion to children with recurrent AOM who have unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy; (7) clinicians should determine if a child with recurrent AOM or with OME of any duration is at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors; (8) in the perioperative period, clinicians should educate caregivers of children with tympanostomy tubes regarding the expected duration of tube function, recommended follow-up schedule, and detection of complications; (9) clinicians should not encourage routine, prophylactic water precautions (use of earplugs, headbands; avoidance of swimming or water sports) for children with tympanostomy tubes. The development group provided the following options: (1) clinicians may perform tympanostomy tube insertion in children with unilateral or bilateral OME for 3 months or longer (chronic OME) and symptoms that are likely attributable to OME including, but not limited to, vestibular problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life and (2) clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is unlikely to resolve quickly as reflected by a type B (flat) tympanogram or persistence of effusion for 3 months or longer (chronic OME).
This update of a 2004 guideline codeveloped by the American Academy of Otolaryngology-Head and Neck Surgery Foundation, the American Academy of Pediatrics, and the American Academy of Family ...Physicians, provides evidence-based recommendations to manage otitis media with effusion (OME), defined as the presence of fluid in the middle ear without signs or symptoms of acute ear infection. Changes from the prior guideline include consumer advocates added to the update group, evidence from 4 new clinical practice guidelines, 20 new systematic reviews, and 49 randomized control trials, enhanced emphasis on patient education and shared decision making, a new algorithm to clarify action statement relationships, and new and expanded recommendations for the diagnosis and management of OME.
The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing OME and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to improve diagnostic accuracy, identify children who are most susceptible to developmental sequelae from OME, and educate clinicians and patients regarding the favorable natural history of most OME and the clinical benefits for medical therapy (eg, steroids, antihistamines, decongestants). Additional goals relate to OME surveillance, hearing and language evaluation, and management of OME detected by newborn screening. The target patient for the guideline is a child aged 2 months through 12 years with OME, with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae. The guideline is intended for all clinicians who are likely to diagnose and manage children with OME, and it applies to any setting in which OME would be identified, monitored, or managed. This guideline, however, does not apply to patients <2 months or >12 years old.
The update group made strong recommendations that clinicians (1) should document the presence of middle ear effusion with pneumatic otoscopy when diagnosing OME in a child; (2) should perform pneumatic otoscopy to assess for OME in a child with otalgia, hearing loss, or both; (3) should obtain tympanometry in children with suspected OME for whom the diagnosis is uncertain after performing (or attempting) pneumatic otoscopy; (4) should manage the child with OME who is not at risk with watchful waiting for 3 months from the date of effusion onset (if known) or 3 months from the date of diagnosis (if onset is unknown); (5) should recommend against using intranasal or systemic steroids for treating OME; (6) should recommend against using systemic antibiotics for treating OME; and (7) should recommend against using antihistamines, decongestants, or both for treating OME.The update group made recommendations that clinicians (1) should document in the medical record counseling of parents of infants with OME who fail a newborn screening regarding the importance of follow-up to ensure that hearing is normal when OME resolves and to exclude an underlying sensorineural hearing loss; (2) should determine if a child with OME is at increased risk for speech, language, or learning problems from middle ear effusion because of baseline sensory, physical, cognitive, or behavioral factors; (3) should evaluate at-risk children for OME at the time of diagnosis of an at-risk condition and at 12 to 18 months of age (if diagnosed as being at risk prior to this time); (4) should not routinely screen children for OME who are not at risk and do not have symptoms that may be attributable to OME, such as hearing difficulties, balance (vestibular) problems, poor school performance, behavioral problems, or ear discomfort; (5) should educate children with OME and their families regarding the natural history of OME, need for follow-up, and the possible sequelae; (6) should obtain an age-appropriate hearing test if OME persists for 3 months or longer OR for OME of any duration in an at-risk child; (7) should counsel families of children with bilateral OME and documented hearing loss about the potential impact on speech and language development; (8) should reevaluate, at 3- to 6-month intervals, children with chronic OME until the effusion is no longer present, significant hearing loss is identified, or structural abnormalities of the eardrum or middle ear are suspected; (9) should recommend tympanostomy tubes when surgery is performed for OME in a child <4 years old; adenoidectomy should not be performed unless a distinct indication exists (nasal obstruction, chronic adenoiditis); (10) should recommend tympanostomy tubes, adenoidectomy, or both when surgery is performed for OME in a child ≥4 years old; and (11) should document resolution of OME, improved hearing, or improved quality of life when managing a child with OME.
The differential mechanism of action of vamorolone compared to traditional corticosteroid anti-inflammatory drugs is attributed to the loss of gene transcriptional activities associated with ...glucocorticoid response element binding and activation, potent antagonist activity for the mineralocorticoid receptor, superior membrane stabilization properties, and retention of the distinct NFκB inhibitory (anti-inflammatory) activities 3,5–7). Safety endpoints (linear growth, body mass index) are also compared with data from a 12-month trial of daily prednisone (0.75 mg/kg group) in similar-aged boys with DMD 17. Methods Ethics statement All studies had appropriate approvals by ethics committees or institutional review boards, as required by the 11 participating international academic clinical recruitment sites: (Duke University, Durham, NC, US; Alberta Children’s Hospital, Calgary, AB, Canada; Nemours Children’s Hospital, Orlando, FL, US; John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Queen Silvia Children’s Hospital, Gothenburg, Sweden; Schneider Children’s Medical Center, Tel Aviv University, Petah Tikvah, Israel; Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, VIC, Australia; The Children’s Hospital at Westmead, Sydney, NSW, Australia; University of Texas Southwestern Medical Center, Dallas, TX, US; Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, US; University of California Davis, Davis, CA, US). ...the total duration of corticosteroid treatment was longer than 18 months for most participants.
Clinical practice guideline: Allergic rhinitis Seidman, Michael D; Gurgel, Richard K; Lin, Sandra Y ...
Otolaryngology-head and neck surgery,
02/2015, Letnik:
152, Številka:
1 Suppl
Journal Article
Recenzirano
Allergic rhinitis (AR) is one of the most common diseases affecting adults. It is the most common chronic disease in children in the United States today and the fifth most common chronic disease in ...the United States overall. AR is estimated to affect nearly 1 in every 6 Americans and generates $2 to $5 billion in direct health expenditures annually. It can impair quality of life and, through loss of work and school attendance, is responsible for as much as $2 to $4 billion in lost productivity annually. Not surprisingly, myriad diagnostic tests and treatments are used in managing this disorder, yet there is considerable variation in their use. This clinical practice guideline was undertaken to optimize the care of patients with AR by addressing quality improvement opportunities through an evaluation of the available evidence and an assessment of the harm-benefit balance of various diagnostic and management options.
The primary purpose of this guideline is to address quality improvement opportunities for all clinicians, in any setting, who are likely to manage patients with AR as well as to optimize patient care, promote effective diagnosis and therapy, and reduce harmful or unnecessary variations in care. The guideline is intended to be applicable for both pediatric and adult patients with AR. Children under the age of 2 years were excluded from the clinical practice guideline because rhinitis in this population may be different than in older patients and is not informed by the same evidence base. The guideline is intended to focus on a limited number of quality improvement opportunities deemed most important by the working group and is not intended to be a comprehensive reference for diagnosing and managing AR. The recommendations outlined in the guideline are not intended to represent the standard of care for patient management, nor are the recommendations intended to limit treatment or care provided to individual patients.
The development group made a strong recommendation that clinicians recommend intranasal steroids for patients with a clinical diagnosis of AR whose symptoms affect their quality of life. The development group also made a strong recommendation that clinicians recommend oral second-generation/less sedating antihistamines for patients with AR and primary complaints of sneezing and itching. The panel made the following recommendations: (1) Clinicians should make the clinical diagnosis of AR when patients present with a history and physical examination consistent with an allergic cause and 1 or more of the following symptoms: nasal congestion, runny nose, itchy nose, or sneezing. Findings of AR consistent with an allergic cause include, but are not limited to, clear rhinorrhea, nasal congestion, pale discoloration of the nasal mucosa, and red and watery eyes. (2) Clinicians should perform and interpret, or refer to a clinician who can perform and interpret, specific IgE (skin or blood) allergy testing for patients with a clinical diagnosis of AR who do not respond to empiric treatment, or when the diagnosis is uncertain, or when knowledge of the specific causative allergen is needed to target therapy. (3) Clinicians should assess patients with a clinical diagnosis of AR for, and document in the medical record, the presence of associated conditions such as asthma, atopic dermatitis, sleep-disordered breathing, conjunctivitis, rhinosinusitis, and otitis media. (4) Clinicians should offer, or refer to a clinician who can offer, immunotherapy (sublingual or subcutaneous) for patients with AR who have inadequate response to symptoms with pharmacologic therapy with or without environmental controls. The panel recommended against (1) clinicians routinely performing sinonasal imaging in patients presenting with symptoms consistent with a diagnosis of AR and (2) clinicians offering oral leukotriene receptor antagonists as primary therapy for patients with AR. The panel group made the following options: (1) Clinicians may advise avoidance of known allergens or may advise environmental controls (ie, removal of pets; the use of air filtration systems, bed covers, and acaricides chemical agents formulated to kill dust mites) in patients with AR who have identified allergens that correlate with clinical symptoms. (2) Clinicians may offer intranasal antihistamines for patients with seasonal, perennial, or episodic AR. (3) Clinicians may offer combination pharmacologic therapy in patients with AR who have inadequate response to pharmacologic monotherapy. (4) Clinicians may offer, or refer to a surgeon who can offer, inferior turbinate reduction in patients with AR with nasal airway obstruction and enlarged inferior turbinates who have failed medical management. (5) Clinicians may offer acupuncture, or refer to a clinician who can offer acupuncture, for patients with AR who are interested in nonpharmacologic therapy. The development group provided no recommendation regarding the use of herbal therapy for patients with AR.
Objective
To compare differences in opioid prescription, health care utilization, and costs among patients with low back pain (LBP) who saw a physical therapist (PT) at the first point of care, at ...any time during the episode or not at all.
Data Sources
Commercial health insurance claims data, 2009–2013.
Study Design
Retrospective analyses using two‐stage residual inclusion instrumental variable models to estimate rates for opioid prescriptions, imaging services, emergency department visits, hospitalization, and health care costs.
Data Extraction
Patients aged 18–64 years with a new primary diagnosis of LBP, living in the northwest United States, were observed over a 1‐year period.
Principal Findings
Compared to patients who saw a PT later or never, patients who saw a PT first had lower probability of having an opioid prescription (89.4 percent), any advanced imaging services (27.9 percent), and an Emergency Department visit (14.7 percent), yet 19.3 percent higher probability of hospitalization (all p < .001). These patients also had significantly lower out‐of‐pocket costs, and costs appeared to shift away from outpatient and pharmacy toward provider settings.
Conclusions
When LBP patients saw a PT first, there was lower utilization of high‐cost medical services as well as lower opioid use, and cost shifts reflecting the change in utilization.
Understanding the extinction of
and origins of
and
in South Africa has been hampered by the perceived complex geological context of hominin fossils, poor chronological resolution, and a lack of ...well-preserved early
specimens. We describe, date, and contextualize the discovery of two hominin crania from Drimolen Main Quarry in South Africa. At ~2.04 million to 1.95 million years old, DNH 152 represents the earliest definitive occurrence of
, and DNH 134 represents the earliest occurrence of a cranium with clear affinities to
These crania also show that
,
, and
were contemporaneous at ~2 million years ago. This high taxonomic diversity is also reflected in non-hominin species and provides evidence of endemic evolution and dispersal during a period of climatic variability.
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We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa ...multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.
To study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD).
An open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with ...DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity.
Oral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy.
Daily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study.
This study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.
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