Extended-Release Calcifediol: A Data Journey From Phase 3 Studies to Real-world Evidence Highlights the Importance of Early Treatment of Secondary Hyperparathyroidism.

BACKGROUND: Early secondary hyperparathyroidism (SHPT) diagnosis and treatment are crucial to delay the progression of SHPT and related complications, in particular, cardiovascular events and bone fractures. Extended-release calcifediol (ERC) has been developed for the treatment of SHPT in patients with stage 3/4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI). SUMMARY: This review compares baseline characteristics and treatment responses of SHPT patients receiving ERC in Phase 3 studies with those treated with ERC in a real-world study. Mean ± standard deviation baseline parathyroid hormone (PTH) levels were 147 ± 56 pg/mL and 148 ± 64 pg/mL in the Phase 3 ERC cohorts, and 181 ± 98 pg/mL in the real-world study. Other baseline laboratory parameters were consistent between the clinical and real-world studies. ERC treatment increased 25-hydroxyvitamin D [25(OH)D] and significantly reduced PTH levels, regardless of baseline CKD stage, in all studies. In the pooled Phase 3 per-protocol populations, 74% of the ERC cohort were up-titrated to 60 µg/day after 12 weeks at 30 µg/day, 97% attained 25(OH)D levels ≥30 ng/mL, and 40% achieved ≥30% PTH reduction. Despite a much lower rate of uptitration in the real-world study, 70% of patients achieved 25(OH)D levels ≥30 ng/mL, and 40% had a ≥30% reduction in PTH. KEY MESSAGES: These data establish a 'continuum' of clinical and real-world evidence of ERC effectiveness for treating SHPT, irrespective of CKD stage, baseline PTH levels, and ERC dose. This evidence supports early treatment initiation with ERC, following diagnosis of SHPT, VDI, and stage 3 CKD, to delay SHPT progression.

Flying fast improves aerodynamic economy of heavier birds.

A paradox of avian long-distance migrations is that birds must greatly increase their body mass prior to departure, yet this is presumed to substantially increase their energy cost of flight. However, here we show that when homing pigeons flying in a flock are loaded with ventrally located weight, both their heart rate and estimated energy expenditure rise by a remarkably small amount. The net effect is that costs per unit time increase only slightly and per unit mass they decrease. We suggest that this is because these homing flights are relatively fast, and consequently flight costs associated with increases in body parasite drag dominate over those of weight support, leading to an improvement in mass-specific flight economy. We propose that the relatively small absolute aerodynamic penalty for carrying enlarged fuel stores and flight muscles during fast flight has helped to select for the evolution of long-distance migration.

How birds dissipate heat before, during and after flight.

Animal flight uses metabolic energy at a higher rate than any other mode of locomotion. A relatively small proportion of the metabolic energy is converted into mechanical power; the remainder is given off as heat. Effective heat dissipation is necessary to avoid hyperthermia. In this study, we measured surface temperatures in lovebirds (Agapornis personatus) using infrared thermography and used heat transfer modelling to calculate heat dissipation by convection, radiation and conduction, before, during and after flight. The total non-evaporative rate of heat dissipation in flying birds was 12× higher than before flight and 19× higher than after flight. During flight, heat was largely dissipated by forced convection, via the exposed ventral wing areas, resulting in lower surface temperatures compared with birds at rest. When perched, both before and after exercise, the head and trunk were the main areas involved in dissipating heat. The surface temperature of the legs increased with flight duration and remained high on landing, suggesting that there was an increase in the flow of warmer blood to this region during and after flight. The methodology developed in this study to investigate how birds thermoregulate during flight could be used in future studies to assess the impact of climate change on the behavioural ecology of birds, particularly those species undertaking migratory flights.

Evaluation of Therapies for Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney Disease.

Introduction: Parathyroid hormone-lowering responses after administration of three different therapies capable of raising serum total 25-hydroxyvitamin D (25OHD) were evaluated in patients with secondary hyperparathyroidism (SHPT), vitamin D insufficiency (VDI), and stage 3 or 4 chronic kidney disease (CKD). Methods: Sixty-nine adult subjects with intact parathyroid hormone (iPTH) ≥85 and <500 pg/mL and VDI (25OHD <30 ng/mL) were randomized after ≥4-week washout to 2 months of open-label treatment with: (1) extended-release calcifediol (ERC) 60 µg/day; (2) immediate-release calcifediol (IRC) 266 µg/month; (3) high-dose cholecalciferol (HDC) 300,000 IU/month; or (4) paricalcitol plus low-dose cholecalciferol (PLDC) 1 or 2 µg and 800 IU/day, used as reference hormone replacement therapy. Serum 25OHD, calcium (Ca), phosphorus (P), plasma iPTH, and adverse events were monitored weekly. No clinically significant differences were observed at baseline between treatment groups. Results: Sixty-two subjects completed the study per protocol (PP; 14-17 per group). Mean (SD) 25OHD and iPTH at baseline were 20.6 (6.6) ng/mL and 144.8 (90) pg/mL, respectively. Mean 25OHD increased at end of treatment (EOT) to 82.9 (17.0) ng/mL with ERC (p < 0.001) and 30.8 (11.6) ng/mL with HDC (p < 0.05), but remained unchanged with IRC and PLDC. EOT 25OHD levels reached ≥30 ng/mL in all subjects treated with ERC and in 44% with HDC. All subjects attained EOT 25OHD levels ≥50 ng/mL with ERC versus none with other therapies. iPTH response rates at EOT (≥10, 20 or 30% below baseline) were similar for ERC and PLDC; rates for IRC and HDC were much lower. No significant changes from baseline were observed in ionized or corrected total Ca or P in any group. One episode of hypercalcemia (>10.3 mg/dL) occurred with PLDC. Hyperphosphatemia (>5.5 mg/dL) occurred once with ERC, eight times with HDC, 3 times with IRC, and twice with PLDC. Conclusion: ERC was highly effective in both raising serum 25OHD and decreasing iPTH in patients with SHPT, VDI, and stage 3 or 4 CKD. iPTH-lowering response rates with ERC were similar to daily PLDC, the reference therapy; rates with IRC or HDC were significantly lower. ERC is an attractive alternative to vitamin D hormone therapy in CKD patients.

Jackson Heart Study: Aggregate cardiovascular disease risk and auditory profiles.

Objectives: Evaluate the relationship between cardiovascular disease (CVD) risk factors and cochlear function in African Americans. Methods: Relationships between hearing loss, cochlear function, and CVD risk factors were assessed in a cross-sectional analysis of 1106 Jackson Heart Study participants. Hearing loss was defined as puretone average (PTA0.5,1,2,4) > 15 dB HL. Distortion product otoacoustic emissions (DPOAEs) were collected for f 2 = 1.0-8.0 kHz. Two amplitude averages were computed: DPOAElow (f 2 ≤ 4 kHz) and DPOAEhigh (f 2 ≥ 6 kHz). Based on major CVD risk factors (diabetes, current smoking, total cholesterol ≥240 mg/dL or treatment, and systolic blood pressure [BP]/diastolic BP ≥ 140/≥90 mmHg or treatment), four risk groups were created: 0, 1, 2, and ≥3 risk factors. Logistic regression estimated the odds of hearing loss and absent/reduced DPOAElow and DPOAEhigh by CVD risk status adjusting for age, sex, education, BMI, vertigo, and noise exposure. Results: With multivariable adjustment, diabetes was associated with hearing loss (OR = 1.48 [95% CI: 1.04-2.10]). However, there was not a statistically significant relationship between CVD risk factors (individually or for overall risk) and DPOAEs. Conclusion: Diabetes was associated with hearing loss. Neither individual CVD risk factors nor overall risk showed a relationship to cochlear dysfunction. Level of Evidence: 2b.

Factors in nephrologists' decision to treat pre-dialysis CKD patients with vitamin D insufficiency and SHPT: A discrete choice experiment.

Little is known about the most important factors that inform a nephrologist's decision to treat (DTT) pre-dialysis chronic kidney disease (CKD) patients with vitamin D insufficiency (VDI) and secondary hyperparathyroidism (SHPT). The objective of this study was to identify such factors and their relative importance in the DTT with a vitamin D therapy. A web-based, adaptive design conjoint analysis discrete-choice survey was developed to study factors that informed the DTT among a sample of 200 nephrologists located throughout the United States. Based on literature review and clinician input, eight attributes were selected that could influence a provider's DTT: age, race, CKD stage, serum 25-hydroxyvitamin D (25D), parathyroid hormone (PTH), serum calcium (Ca), serum phosphorus (P), and history of comorbidities. Respondents were asked to select one patient profile most suitable for treatment from three profiles with varying attribute levels. Each attribute's relative importance score was computed using hierarchical-Bayesian statistics to measure the influence of each factor where higher scores represented greater DTT consideration. The pooled analysis revealed the four most important factors: serum 25D (31.4%), serum Ca (22.7%), plasma PTH (11.5%) levels, and history of comorbidities (8.5%). Age (8.2%), serum P (7.7%), CKD stage (5.7%), and race (4.4%) were relatively less important. Patients' 25D and Ca levels contributed to more than half of nephrologists' DTT, with the consideration of PTH levels being less of a factor. Further understanding of the driving forces behind the factors that inform the DTT may help to standardize the management of CKD patients with SHPT and VDI and improve outcomes.

REsCue trial: Randomized controlled clinical trial with extended-release calcifediol in symptomatic COVID-19 outpatients.

OBJECTIVES: This double-blind randomized controlled trial investigated raising serum 25-hydroxyvitamin D (25D) with extended-release calcifediol (ERC) on time to symptom resolution in patients with mild to moderate COVID-19. METHODS: COVID-19 outpatients received oral ERC (300 mcg on days 1-3 and 60 mcg on days 4-27) or placebo (NCT04551911). Symptoms were self-reported daily. Primary end points were raising 25D to ≥50 ng/mL and decreasing resolution time for five aggregated symptoms (three respiratory). RESULTS: In all, 171 patients were randomized, 160 treated and 134 (65 ERC, 69 placebo) retained. The average age was 43 y (range 18-71), 59% were women. The mean baseline 25D was 37 ± 1 (SE) ng/mL. In the full analysis set (FAS), 81% of patients in the ERC group achieved 25D levels of ≥50 ng/mL versus 15% in the placebo group (P < 0.0001). In the per-protocol (PP) population, mean 25D increased with ERC to 82 ± 4 (SE) ng/mL (P < 0.0001) by day 7; the placebo group trended lower. Symptom resolution time was unchanged in the FAS by ERC (hazard ratio [HR], 0.983; 95% confidence interval [CI], 0.695-1.390; P = 0.922). In the PP population, respiratory symptoms resolved 4 d faster when 25D was elevated above baseline level at both days 7 and 14 (median 6.5 versus 10.5 d; HR, 1.372; 95% CI, 0.945-1.991; P = 0.0962; Wilcoxon P = 0.0386). Symptoms resolved in both treatment groups to a similar extent by study end. Safety concerns including hypercalcemia were absent with ERC treatment. CONCLUSION: ERC safely raised serum 25D to ≥50 ng/mL in outpatients with COVID-19, possibly accelerating resolution of respiratory symptoms and mitigating the risk for pneumonia. These findings warrant further study.

Real-world assessment: effectiveness and safety of extended-release calcifediol and other vitamin D therapies for secondary hyperparathyroidism in CKD patients.

INTRODUCTION: Extended-release calcifediol (ERC), active vitamin D hormones and analogs (AVD) and nutritional vitamin D (NVD) are commonly used therapies for treating secondary hyperparathyroidism (SHPT) in adults with stage 3-4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI). Their effectiveness for increasing serum total 25-hydroxyvitamin D (25D) and reducing elevated plasma parathyroid hormone (PTH), the latter of which is associated with increased morbidity and mortality, has varied across controlled clinical trials. This study aimed to assess real-world experience of ERC and other vitamin D therapies in reducing PTH and increasing 25D. METHODS: Medical records of 376 adult patients with stage 3-4 CKD and a history of SHPT and VDI from 15 United States (US) nephrology clinics were reviewed for up to 1 year pre- and post-ERC, NVD or AVD initiation. Key study variables included patient demographics, concomitant usage of medications and laboratory data. The mean age of the study population was 69.5 years, with gender and racial distributions representative of the US CKD population. Enrolled patients were grouped by treatment into three cohorts: ERC (n = 174), AVD (n = 55) and NVD (n = 147), and mean baseline levels were similar for serum 25D (18.8-23.5 ng/mL), calcium (Ca: 9.1-9.3 mg/dL), phosphorus (P: 3.7-3.8 mg/dL) and estimated glomerular filtration rate (eGFR: 30.3-35.7 mL/min/1.73m2). Mean baseline PTH was 181.4 pg/mL for the ERC cohort versus 156.9 for the AVD cohort and 134.8 pg/mL (p < 0.001) for the NVD cohort. Mean follow-up during treatment ranged from 20.0 to 28.8 weeks. RESULTS: Serum 25D rose in all cohorts (p < 0.001) during treatment. ERC yielded the highest increase (p < 0.001) of 23.7 ± 1.6 ng/mL versus 9.7 ± 1.5 and 5.5 ± 1.3 ng/mL for NVD and AVD, respectively. PTH declined with ERC treatment by 34.1 ± 6.6 pg/mL (p < 0.001) but remained unchanged in the other two cohorts. Serum Ca increased 0.2 ± 0.1 pg/mL (p < 0.001) with AVD but remained otherwise stable. Serum alkaline phosphatase remained unchanged. CONCLUSIONS: Real-world clinical effectiveness and safety varied across the therapies under investigation, but only ERC effectively raised mean 25D (to well above 30 ng/mL) and reduced mean PTH levels without causing hypercalcemia.

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.

Extended-Release Calcifediol Effectively Raises Serum Total 25-Hydroxyvitamin D Even in Overweight Nondialysis Chronic Kidney Disease Patients with Secondary Hyperparathyroidism.

INTRODUCTION: Obesity increases the risk of vitamin D insufficiency, which exacerbates secondary hyperparathyroidism in chronic kidney disease. Recent studies suggest that serum total 25-hydroxyvitamin D (25OHD) levels of ≥50 ng/mL are necessary to produce significant reductions in elevated parathyroid hormone levels in nondialysis patients. Data from real-world and randomized controlled trials (RCTs) involving these patients were examined for (1) relationships between vitamin D treatments and the achieved levels of serum 25OHD and between serum 25OHD and body weight (BW)/body mass index (BMI); and (2) the impact of BW/BMI on achieving serum 25OHD levels ≥50 ng/mL with extended-release calcifediol (ERC) treatment or vitamin D supplementation (cholecalciferol or ergocalciferol). METHODS: Data obtained from nondialysis patients participating in two real-world studies, one conducted in Europe (Study 1) and the other (Study 2) in the USA, and in two US RCTs (Studies 3 and 4) were analyzed for serum 25OHD outcomes after treatment with ERC, vitamin D supplements, or placebo. RESULTS: More than 50% of subjects treated with vitamin D supplements in both real-world studies (Studies 1 and 2) failed to achieve serum 25OHD levels ≥30 ng/mL, a level widely viewed by nephrologists as the threshold of adequacy; only 7.3-7.5% of subjects achieved levels ≥50 ng/mL. Data from the European study (Study 1) showed that serum 25OHD levels had significant and nearly identical inverse relationships with BW and BMI, indicating that high BW or BMI thwarts the ability of vitamin D supplements to raise serum 25OHD. One RCT (Study 3) showed that 8 weeks of ERC treatment (60 µg/day) raised serum 25OHD levels to ≥30 and 50 ng/mL in all subjects, regardless of BW, while cholecalciferol (300,000 IU/month) raised serum 25OHD to these thresholds in 56% and 0% of subjects, respectively. The other RCT (Study 4) showed that ERC treatment (30 or 60 µg/day) successfully raised mean serum 25OHD levels to at least 50 ng/mL for subjects in all BW categories, whereas no increases were observed with placebo treatment. CONCLUSION: Real-world studies conducted in Europe and USA in nondialysis patients (Studies 1 and 2) showed that vitamin D supplements (cholecalciferol or ergocalciferol) were unreliable in raising serum total 25OHD to targets of 30 or 50 ng/mL. In contrast, ERC was demonstrated to be effective in one real-world study (Study 2) and two RCTs (Studies 3 and 4) conducted in US nondialysis patients in raising serum 25OHD to these targeted levels irrespective of BW.

Central Auditory Processing and the Relationship to Perceived Hearing Difficulty: The Jackson Heart Study.

OBJECTIVE: There are limited population-based studies of central auditory processing (CAP). We aimed to determine the relationship between CAP measures and perceived hearing difficulty (PHD) despite normal pure-tone audiometry in an African-American population. STUDY DESIGN: Cross-sectional. SETTING: Jackson Heart Study (JHS), Jackson, MS. SUBJECTS: Participants of an African-American cohort (26% men; age 54.2, standard deviations [SD] 9.2) who self-reported hearing difficulty despite normal hearing sensitivity defined as audiometric pure-tone average (PTA-4: average of 500, 1000, 2000, and 4000 Hz) less than or equal to 25 dBHL (n = 911) or across all tested frequencies (PT-AF: 250-8000 Hz) less than or equal to 25 dBHL (n = 516). METHODS: The Quick Speech-in-Noise (QuickSIN) and Dichotic Digits, Double Pairs (DDT2) tests were used to assess CAP. Logistic regression was used to examine the association between measures of CAP and PHD; adjusted for age, sex, education, and pure tone audiogram. RESULTS: PHD was present in 251 (28%) and 137 (27%) of participants using the PTA-4 and PT-AF models, respectively. Fully adjusted regression models revealed that each one-point increase in QuickSIN increased the odds of reporting PHD by 13.7% (odds ratio [OR] 1.14, p < 0.01, 95% CI: 1.08, 1.19) using the PTA-4 model and 15.0% (OR 1.15, p < 0.01, 95% CI: 1.08, 1.23) using the PT-AF model. For DDT2 testing, each 1% reduction in score, increased the odds of reporting PHD by 7.7% (OR 0.92, p < 0.01, 95% CI: 0.88, 0.97) in a fully adjusted PTA-4 model and 6.6% (OR 0.93, p = 0.04, 95% CI: 0.87, 0.99) in the PT-AF model. CONCLUSION: CAP deficits were associated with increased odds of PHD in normal hearing participants within the JHS cohort.

Clinical Practice Guideline: Tympanostomy Tubes in Children (Update).

OBJECTIVE: 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. All these conditions are encompassed by the term otitis media (middle ear inflammation). This guideline update provides evidence-based recommendations for patient selection and surgical indications for managing tympanostomy tubes in children. The guideline is intended for any clinician involved in managing children aged 6 months to 12 years with tympanostomy tubes or children being considered for tympanostomy tubes in any care setting as an intervention for otitis media of any type. The target audience includes specialists, primary care clinicians, and allied health professionals. PURPOSE: The purpose of this clinical practice guideline update is to reassess and update recommendations in the prior guideline from 2013 and to provide clinicians with trustworthy, evidence-based recommendations on patient selection and surgical indications for managing tympanostomy tubes in children. In planning the content of the updated guideline, the guideline update group (GUG) affirmed and included all the original key action statements (KASs), based on external review and GUG assessment of the original recommendations. The guideline update was supplemented with new research evidence and expanded profiles that addressed quality improvement and implementation issues. The group also discussed and prioritized the need for new recommendations based on gaps in the initial guideline or new evidence that would warrant and support KASs. The GUG further sought to bring greater coherence to the guideline recommendations by displaying relationships in a new flowchart to facilitate clinical decision making. Last, knowledge gaps were identified to guide future research. METHODS: In developing this update, the methods outlined in the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline Development Manual, Third Edition: A Quality-Driven Approach for Translating Evidence Into Action" were followed explicitly. The GUG was convened with representation from the disciplines of otolaryngology-head and neck surgery, otology, pediatrics, audiology, anesthesiology, family medicine, advanced practice nursing, speech-language pathology, and consumer advocacy. ACTION STATEMENTS: The GUG made strong recommendations for the following KASs: (14) clinicians should prescribe topical antibiotic ear drops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea; (16) the surgeon or designee should examine the ears of a child within 3 months of tympanostomy tube insertion AND should educate families regarding the need for routine, periodic follow-up to examine the ears until the tubes extrude.The GUG made recommendations for the following KASs: (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, from the date of onset (if known) or from the date of diagnosis (if onset is unknown); (2) clinicians should obtain a hearing evaluation if OME persists for 3 months or longer 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 AND documented hearing difficulties; (5) clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who do 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; (6) clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media who do not have middle ear effusion in either ear at the time of assessment for tube candidacy; (7) clinicians should offer bilateral tympanostomy tube insertion in children with recurrent acute otitis media who have unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy; (8) clinicians should determine if a child with recurrent acute otitis media 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; (10) the clinician should not place long-term tubes as initial surgery for children who meet criteria for tube insertion unless there is a specific reason based on an anticipated need for prolonged middle ear ventilation beyond that of a short-term tube; (12) 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; (13) clinicians should not routinely prescribe postoperative antibiotic ear drops after tympanostomy tube placement; (15) clinicians should not encourage routine, prophylactic water precautions (use of earplugs or headbands, avoidance of swimming or water sports) for children with tympanostomy tubes.The GUG offered the following KASs as options: (4) 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, all or in part, to OME that include, but are not limited to, balance (vestibular) problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life; (9) clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is likely to persist as reflected by a type B (flat) tympanogram or a documented effusion for 3 months or longer; (11) clinicians may perform adenoidectomy as an adjunct to tympanostomy tube insertion for children with symptoms directly related to the adenoids (adenoid infection or nasal obstruction) OR in children aged 4 years or older to potentially reduce future incidence of recurrent otitis media or the need for repeat tube insertion.

Executive Summary of Clinical Practice Guideline on Tympanostomy Tubes in Children (Update).

OBJECTIVE: This executive summary of the guideline update provides evidence-based recommendations for patient selection and surgical indications for managing tympanostomy tubes in children. The summary and guideline are intended for any clinician involved in managing children aged 6 months to 12 years with tympanostomy tubes or children being considered for tympanostomy tubes in any care setting as an intervention for otitis media of any type. The target audience includes specialists, primary care clinicians, and allied health professionals. PURPOSE: The purpose of this executive summary is to provide a succinct overview for clinicians of the key action statements (recommendations), summary tables, and patient decision aids from the update of the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline: Tympanostomy Tubes in Children (Update)." The new guideline updates recommendations in the prior guideline from 2013 and provides clinicians with trustworthy, evidence-based recommendations on patient selection and surgical indications for managing tympanostomy tubes in children. This summary is not intended to substitute for the full guideline, and clinicians are encouraged to read the full guideline before implementing the recommended actions. METHODS: The guideline on which this summary is based was developed using methods outlined in the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline Development Manual, Third Edition: A Quality-Driven Approach for Translating Evidence Into Action," which were followed explicitly. The guideline update group represented the disciplines of otolaryngology-head and neck surgery, otology, pediatrics, audiology, anesthesiology, family medicine, advanced practice nursing, speech-language pathology, and consumer advocacy. ACTION STATEMENTS: Strong recommendations were made for the following key action statements: (14) Clinicians should prescribe topical antibiotic ear drops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea. (16) The surgeon or designee should examine the ears of a child within 3 months of tympanostomy tube insertion AND should educate families regarding the need for routine, periodic follow-up to examine the ears until the tubes extrude.Recommendations were made for the following key action statements: (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, from the date of onset (if known) or from the date of diagnosis (if onset is unknown). (2) Clinicians should obtain a hearing evaluation if OME persists for 3 months or longer 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 AND documented hearing difficulties. (5) Clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who do 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. (6) Clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media (AOM) who do not have middle ear effusion (MEE) in either ear at the time of assessment for tube candidacy. (7) Clinicians should offer bilateral tympanostomy tube insertion in children with recurrent AOM who have unilateral or bilateral MEE at the time of assessment for tube candidacy. (8) 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. (10) The clinician should not place long-term tubes as initial surgery for children who meet criteria for tube insertion unless there is a specific reason based on an anticipated need for prolonged middle ear ventilation beyond that of a short-term tube. (12) 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. (13) Clinicians should not routinely prescribe postoperative antibiotic ear drops after tympanostomy tube placement. (15) Clinicians should not encourage routine, prophylactic water precautions (use of earplugs or headbands, avoidance of swimming or water sports) for children with tympanostomy tubes.Options were offered from the following key action statements: (4) 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, all or in part, to OME that include, but are not limited to, balance (vestibular) problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life. (9) Clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is likely to persist as reflected by a type B (flat) tympanogram or a documented effusion for 3 months or longer. (11) Clinicians may perform adenoidectomy as an adjunct to tympanostomy tube insertion for children with symptoms directly related to the adenoids (adenoid infection or nasal obstruction) OR in children aged 4 years or older to potentially reduce future incidence of recurrent otitis media or the need for repeat tube insertion.

Real-World Assessment: Clinical Effectiveness and Safety of Extended-Release Calcifediol.

INTRODUCTION: The safety and efficacy of extended-release calcifediol (ERC) as a treatment for secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI) has been demonstrated in prospective randomized clinical trials (RCTs). ERC (Rayaldee®) was approved by the Food and Drug Administration in 2016 on the basis of these prospective RCTs. The current retrospective study assessed the postlaunch data available with respect to ERC's efficacy and safety in increasing serum 25-hydroxyvitamin D (25D) and reducing parathyroid hormone (PTH) in the indicated population. MATERIALS AND METHODS: Medical records of 174 patients who met study criteria from 15 geographically representative United States nephrology clinics were reviewed for 1 year before and after initiation of ERC treatment. Enrolled subjects had ages ≥18 years, stage 3 or 4 CKD, and a history of SHPT and VDI. Key study variables included patient demographics, medication usage, and laboratory results, including serial 25D and PTH determinations. RESULTS: The enrolled subjects had a mean age of 69.0 years, gender and racial distributions representative of the indicated population, and were balanced for CKD stage. Most (98%) received 30 mcg of ERC/day during the course of treatment (mean follow-up: 24 weeks). Baseline 25D and PTH levels averaged 20.3 ± 0.7 (standard error) ng/mL and 181 ± 7.4 pg/mL, respectively. ERC treatment raised 25D by 23.7 ± 1.6 ng/mL (p < 0.001) and decreased PTH by 34.1 ± 6.6 pg/mL (p < 0.001) with nominal changes of 0.1 mg/dL (p > 0.05) in serum calcium (Ca) and phosphorus (P) levels. DISCUSSION/CONCLUSION: Analysis of postlaunch data confirmed ERC's effectiveness in increasing serum 25D and reducing PTH levels without statistically significant or notable impact on serum Ca and P levels. A significant percentage of these subjects achieved 25D levels ≥30 mg/mL and PTH levels which decreased by at least 30% from baseline. Dose titration to 60 mcgs was rarely prescribed. Closer patient monitoring and appropriate dose titration may have led to a higher percentage of subjects achieving an increase in 25D levels to at least 50 ng/mL and a reduction in PTH levels of at least 30%.

Association Between Cardiometabolic Factors and Dizziness in African Americans: The Jackson Heart Study.

BACKGROUND: Balance dysfunction is a complex, disabling health condition that can present with multiple phenotypes and etiologies. Data regarding prevalence, characterization of dizziness, or associated factors is limited, especially in an African American population. PURPOSE: The aim of the study is to characterize balance dysfunction presentation and prevalence in an African American cohort, and balance dysfunction relationship to cardiometabolic factors. RESEARCH DESIGN: The study design is descriptive, cross sectional analysis. STUDY SAMPLE: The study sample consist of N = 1,314, participants in the Jackson Heart Study (JHS). DATA COLLECTION AND ANALYSIS: JHS participants were presented an initial Hearing health screening questionnaire (N = 1,314). Of these, 317 participants reported dizziness and completed a follow-up Dizziness History Questionnaire. Descriptive analysis was used to compare differences in the cohorts' social-demographic characteristics and cardiometabolic variables to the 997 participants who did not report dizziness on the initial screening questionnaire. Based on questionnaire responses, participants were grouped into dizziness profiles (orthostatic, migraine, and vestibular) to further examine differences in cardiometabolic markers as related to different profiles of dizziness. Logistical regression models were adjusted for age, sex, education, reported noise exposure, and hearing sensitivity. RESULTS: Participants that reported any dizziness were slightly older and predominantly women. Other significant complaints in the dizzy versus nondizzy cohort included hearing loss, tinnitus, and a history of noise exposure (p < 0.001). Participants that reported any dizziness had significantly higher prevalence of hypertension, blood pressure medication use, and higher body mass index (BMI). Individuals with symptoms alluding to an orthostatic or migraine etiology had significant differences in prevalence of hypertension, blood pressure medication use, and BMI (p < 0.001). Alternatively, cardiometabolic variables were not significantly related to the report of dizziness symptoms consistent with vestibular profiles. CONCLUSION: Dizziness among African Americans is comparable to the general population with regards to age and sex distribution, accordingly to previously published estimates. Participants with dizziness symptoms appear to have significant differences in BMI and blood pressure regulation, especially with associated orthostatic or migraine type profiles; this relationship does not appear to be conserved in participants who present with vestibular etiology symptoms.

Stroke risk in African Americans with subclinical auditory dysfuntion evidenced by Distortion Product Otoacoustic Emissions: the Jackson heart study.

Objective: Distortion product otoacoustic emissions (DPOAEs) are sensitive to early indices of cochlear pathology. Pathology to the cochlea is in part mediated by ischaemic related mechanisms. We propose that DPOAEs may provide an objective measure of cardiovascular risk.Design: Cross-sectional.Study sample: The relationships between stroke risk and DPOAEs of 1,107 individuals from the Jackson Heart Study (JHS), an all-African-American cohort, were assessed. Linear regression models were used for analysis among all participants and delimited to normal hearing, defined as either a pure-tone threshold average of 500, 1000, 2000, and 4000 Hz (PTA4) ≤ 25 dBHL or pure-tone thresholds for all individual tested frequencies for each ear (500, 1000, 2000, 4000, and 8000 Hz) ≤ 25 dBHL.Results: We observed a significant inverse relationship between DPOAE amplitudes and stroke risk scores in the pooled cohort and in the subgroups with normal hearing defined by pure tone thresholds. Participants in the high-risk group had significantly lower DPOAE amplitudes than those in the low stroke risk group.Conclusions: Our results indicate that auditory dysfunction as measured by DPOAEs are related to stroke risk. Further prospective studies are needed to determine if DPOAEs could be used as a predictive tool for cardiovascular disease.

Relationship of Overall Cardiovascular Health and Hearing Loss in The Jackson Heart Study Population.

OBJECTIVES: To evaluate the relationships among the overall cardiovascular health scoring tool, Life's Simple 7 (LS7), and hearing in an African-American cardiovascular study cohort. METHODS: Using the Jackson Heart Study's cohort of African Americans, the relationships between the LS7 scoring metric and hearing of 1314 individuals were assessed. Standard audiometric data was collected and hearing loss was defined as a four-frequency average of 500, 1000, 2000, and 4000 Hz greater than 25 dBHL (PTA4). Measures of reported tinnitus and dizziness were also collected. The LS7 scoring tool, which consists of seven individual categories (abstinence from smoking, body mass index, physical activity, healthy diet, total cholesterol <200 mg/dL, normotension, and absence of diabetes mellitus), was used as measure of overall cardiovascular health. Each category of the LS7 was broken down into poor, intermediate, and ideal subgroups as in accordance with the American Heart Association Strategic Planning Task Force and Statistics Committee. Unadjusted and adjusted gamma regression and logistic regression models were constructed for determining relationships between LS7 and hearing loss. RESULTS: Higher total LS7 scores (per 1-unit increase) were associated with lower PTA4 in gamma regression analyses (RR = 0.942, 95% CI, 0.926-0.958, P < .001). This held true even after adjustments for age, sex, education, and history of noise exposure. Using logistic regression analyses to compare LS7 scores to presence of hearing loss, tinnitus, and vertigo; only hearing loss showed a statically significant relationship after adjustments for age, sex, education, and history of noise exposure. CONCLUSIONS: This study shows a significant, graded association between higher life's simple seven scores and lower incidence of hearing loss. LEVEL OF EVIDENCE: 2b. Laryngoscope, 2019.

Tackling the Tibetan Plateau in a down suit: insights into thermoregulation by bar-headed geese during migration.

Birds migrating through extreme environments can experience a range of challenges while meeting the demands of flight, including highly variable ambient temperatures, humidity and oxygen levels. However, there has been limited research into avian thermoregulation during migration in extreme environments. This study aimed to investigate the effect of flight performance and high altitude on body temperature (Tb) of free-flying bar-headed geese (Anser indicus), a species that completes a high-altitude trans-Himalayan migration through very cold, hypoxic environments. We measured abdominal Tb, along with altitude (via changes in barometric pressure), heart rate and body acceleration of bar-headed geese during their migration across the Tibetan Plateau. Bar-headed geese vary the circadian rhythm of Tb in response to migration, with peak daily Tb during daytime hours outside of migration but early in the morning or overnight during migration, reflecting changes in body acceleration. However, during flight, changes in Tb were not consistent with changes in flight performance (as measured by heart rate or rate of ascent) or altitude. Overall, our results suggest that bar-headed geese are able to thermoregulate during high-altitude migration, maintaining Tb within a relatively narrow range despite appreciable variation in flight intensity and environmental conditions.