Hyperthyroidism Symptoms, Management, and Outcomes in Children and Adults Seeking Definitive Surgical Treatment.

OBJECTIVE: To identify the difference in presentation, time to treatment, and outcomes between hyperthyroid adults and children referred to surgical evaluation. BACKGROUND: There is little data on differences in presenting symptoms, time to treatment, and outcomes between adults and children presenting for thyroidectomy for Graves' disease. METHODS: We retrospectively reviewed records of patients with hyperthyroidism referred for thyroidectomy between January 2016 and April 2017. We divided our cohort into 2 groups based on age, children (age ≤18 years), and adults (age >18), and evaluated the difference in prevalence of symptoms, time from diagnosis, and initiation of antithyroid medications to surgery, and outcomes. RESULTS: We identified 38 patients (27 adults and 11 children) with data on hyperthyroidism symptoms referred for thyroidectomy. Relative to hyperthyroid adults, children with hyperthyroidism were more likely to present with hoarseness (55% vs 15%, P = 0.01) and difficulty concentrating (45% vs 7%, P = 0.01) at initial presentation. There was no statistically significant difference in prevalence of vision changes, exophthalmos, pretibial myxedema, palpitations, fatigue, temperature intolerance, dysphagia, tremors, or constitutional symptoms. A median of 15 months elapsed from diagnosis to thyroidectomy among adult and 6 months among pediatric patients. Adult and pediatric patients waited a median of 13 and 6 months from initiation of antithyroid medications to thyroidectomy, respectively. There was no significant difference in outcomes. CONCLUSIONS: Children with hyperthyroidism were more likely to present with hoarseness and difficulty concentrating than adults. Concentration and communication are critical skills in developing children, and early intervention with definitive therapy may improve such symptoms.

Single Gland, Ectopic Location: Adenomas are Common Causes of Primary Hyperparathyroidism in Children and Adolescents.

BACKGROUND: Primary hyperparathyroidism (PHPT) in children and adolescents is uncommon. Data-driven guidelines for management in pediatric patients are limited. METHODS: We performed a retrospective cohort analysis of all patients (1997-2017) with PHPT ≤ 21 years of age who underwent parathyroidectomy at three institutions. Clinical and demographic variables were analyzed. Primary operative outcome was cure (normocalcemia > 6 months after surgery); secondary outcome was operative success (intraoperative parathyroid hormone decrease of ≥ 50%). RESULTS: We identified 86 patients with a median age of 17 years (IQR: 14, 19); 64% (n = 55) were female. The mean preoperative serum calcium was 11.7 mg/dL, median parathyroid hormone (PTH) was 110 pg/mL, and median urine calcium was 4.1 mg/kg/24 h. Preoperatively, sestamibi scan localized in 41/71 patients (58%); neck ultrasound localized in 19/44 (43%). The most common pathology at surgery was a single ectopic parathyroid adenoma in 71% (n = 61). A high incidence of ectopic adenomas (25%, n = 22) was observed, most commonly intrathymic (n = 13), followed by tracheoesophageal groove (n = 5), carotid sheath (n = 2), and intrathyroidal (n = 2). Of 56 patients with retrievable data > 6 months postoperatively, cure was achieved in 55 of 56 patients (98%). One patient who presented to us with parathyromatosis require subsequent reoperation. CONCLUSION: In this multi-institutional series of PHPT in children and adolescents, the majority were sporadic PHPT and were due to a single adenoma. We observed a high incidence of ectopic parathyroid adenomas, most commonly intrathymic. Given the high risk for ectopic adenoma in pediatric patients, parathyroid surgery in children and adolescents should be performed by experienced surgeons.

Effect of Sickle Cell Anemia Therapies on the Natural History of Growth and Puberty Patterns.

As pediatric patients with sickle cell anemia (SCA) have impaired growth and puberty patterns, we studied the effect of disease-modifying therapies on growth and puberty patterns for patients with SCA receiving hydroxyurea (HU), transfusions, or no therapy. We performed a retrospective study of children with SCA in whom anthropometric measurements and therapy type were recorded. Penalized smoothing splines were fitted to estimate growth curves and growth velocity, and linear mixed models were used to examine differences across treatment groups. Across group analyses were divided into early childhood (4.0 to 7.9 y) and peripubertal (8.0 to 12.0 y). We analyzed growth data on 157 SCA patients. From 8.0 to 12.0 years, girls on transfusion therapy were significantly taller than girls on HU (range, 5.7 to 7.2 cm; P-value range 0.002 to 0.01). From 10.0 to 12.0 years, boys on transfusion therapy were significantly taller than boys on HU (range, 4.1 to 9.4 cm; P-value range <0.0001 to 0.04). In addition, boys on transfusion therapy had an earlier peak height velocity as compared with boys on either HU or no therapy. In conclusion, children receiving transfusions tended to be taller than children on HU or no therapy. Children on HU did not demonstrate superior growth pattern when compared with children on no therapy in the peripubertal years.

Hyperandrogenism and Hypokalemic Thyrotoxic Periodic Paralysis in a North American Adolescent Girl.

We present a unique case of hypokalemic thyrotoxic periodic paralysis (TPP) in an adolescent girl in North America. TPP is a rare but dangerous complication seen in thyrotoxic patients characterized by hypokalemia and acute proximal symmetric lower-extremity weakness. It is an especially rare phenomenon in pediatrics, with roughly 20 case reports described in adolescents worldwide; the majority are male. Our patient is a 14-year-old Asian girl with biochemical hyperandrogenism and known Graves disease who presented with an acute episode of lower-extremity weakness after eating a carbohydrate-rich meal. Laboratory workup revealed hypokalemia, hypomagnesemia, an undetectable thyrotropin, and hyperthyroxinemia. Electrolyte derangements responded well to supplementation, and the muscle weakness resolved with electrolyte normalization. Following improvement in thyroid function, the patient underwent thyroidectomy for definitive management of Graves disease. As TPP is potentially exacerbated by higher androgen and insulin levels, we suspect that with increasing rates of obesity and polycystic ovary syndrome, the incidence of TPP among adolescents may increase. It is therefore critically important that there is awareness and recognition of this serious diagnosis among all health care providers.

Global Health Disparities in Childhood Rickets.

Nutritional rickets is a global health problem reflecting both historical and contemporary health disparities arising from racial, ethnic, environmental, and geopolitical circumstances. It primarily affects marginalized populations and can contribute to long-term morbidity. Deficits in bone health in childhood may also contribute to osteomalacia/osteoporosis. Solutions require a global public health approach.

Evaluation and management of pediatric thyroid nodules and thyroid cancer at a single institution after adoption of the American Thyroid Association 2015 guidelines.

OBJECTIVES: The study purpose is to correlate clinical findings with rates of differentiated thyroid cancer (DTC) in a cohort of children presenting with thyroid nodules at a single institution since the adoption of the 2015 American Thyroid Association (ATA) Guidelines Task Force on Pediatric Thyroid Cancer. METHODS: Clinical, radiographic, and cytopathologic findings were retrospectively analyzed in a pediatric cohort (≤19 years) identified with ICD-10 codes for thyroid nodules and thyroid cancer from January 2017 until May 2021. RESULTS: We analyzed 183 patients with thyroid nodules. The mean patient age was 14 years (interquartile range 11-16) with a female (79.2 %) and white Caucasian (78.1 %) predominance. The overall DTC in our pediatric patient cohort was 12.6 % (23 out of 183). Most of the malignant nodules measured from 1-4 cm (65.2 %) with TI-RADS score of ≥4 (69.6 %). Among the fine-needle aspiration results (n=49), the highest frequency of DTC was within the malignant category (16.33 %), followed by suspicious for malignancy (6.12 %), then atypia or follicular lesion of undetermined significance (8.16 %), and lastly follicular lesion or neoplasm and benign with 4.08 % and 2.04 % respectively. Of the forty-four thyroid nodules that underwent surgical intervention, pathology was remarkable for 19 papillary thyroid carcinoma (43.18 %) and 4 follicular thyroid carcinoma (9.09 %). CONCLUSIONS: Based on the analysis of our pediatric cohort in the southeast region at a single institution, adoption of the 2015 ATA guidelines could lead to an increased accuracy in detecting DTC while reducing the number of patients requiring interventions, such as FNA biopsy and/or surgeries. Further, based on our small cohort, it would be reasonable for thyroid nodules 1 cm or less to be monitored clinically with physical exam and ultrasonography, with further therapeutic or diagnostic intervention considered based on concerning features or parental shared decision making.

Improving Equitable Access to Continuous Glucose Monitors for Alabama's Children with Type 1 Diabetes: A Quality Improvement Project.

Background: Continuous glucose monitors (CGMs) are a tool that can reduce the burden of self-monitoring of glucose values in children and adults with type 1 diabetes (T1D), are associated with improved glycemic control, and are associated with reduced fear of hypoglycemia. Unfortunately, disparities in access to CGM exist and rates of CGM access in Alabama in 2019 were below national averages. We aimed to increase CGM access and reduce disparities in access by race, insurance status, and high-risk diabetes status. Methods: Stakeholder input identified barriers to CGM access and defined the existing process. Process changes were implemented and studied for effect. Data were collected from the electronic health record to track rates of CGM access in patients aged 2 years and above with T1D for >3 months. Results: For the eligible population, rates of CGM access increased from a baseline of 50% to 82%. Rates for CGM access in patients with high-risk T1D increased from 34% to 85%. Disparity in CGM access for non-Hispanic Whites and non-Hispanic Blacks decreased from 18% to 6%. Disparity in CGM access for privately insured and Medicaid-insured patients decreased from 38% to 12%. Conclusions: Targeted quality improvement projects using stakeholder input can increase access to diabetes technology while reducing disparities. As technology advances, concerted efforts are needed to ensure equitable access to evolving therapies for all patients with T1D.

Outpatient parathyroidectomy in the pediatric population: An 18-year experience.

BACKGROUND: Parathyroidectomy for primary hyperparathyroidism (pHPT) is safely performed in the outpatient setting in the adult population. However, concern that children and adolescents have higher complication rates and are unable to recognize and communicate symptoms of hypocalcemia has limited same-day discharges in the pediatric population. METHODS: Nineteen patients aged 8-18 years (14.1 ± 0.7) underwent outpatient parathyroidectomy for pHPT by a single high-volume endocrine surgeon from 2002-2020. Patient demographics, disease, operations, and complications were reviewed. RESULTS: Sixteen of 19 patients were symptomatic with fatigue (62.5%), joint pain (37.5%) and nephrolithiasis (18.7%) most common. Mean preoperative Ca and PTH were 11.7 ± 0.3 mg/dL and 102.3 ± 11.8pg/mL, respectively. Ten of 19 had a single adenoma and 9 had multigland hyperplasia including one MEN1 and one MEN2A patient. We performed 11 four-gland explorations, 8 unilateral parathyroidectomies; including 9 transcervical thymectomies, 1 total thyroidectomy, and 1 bilateral central neck dissection. Mean 6-month postoperative Ca and PTH levels were 9.5 ± 0.3 mg/dL (range 7.3-10.3) and 29±5.0pg/mL (range 6.3-77), respectively. One patient developed permanent hypoparathyroidism and 1 had temporary hypocalcemia. No temporary or permanent hoarseness, unplanned same-day admission, wound complications, or Emergency Department visits occurred. CONCLUSION: Outpatient parathyroidectomy can be safely and effectively performed in pediatric patients with primary HPT. LEVEL OF EVIDENCE: Treatment Study, Level III.

Intraoperative parathyroid hormone measurement facilitates outpatient thyroidectomy in children.

INTRODUCTION: We hypothesize that intraoperative parathyroid hormone (ioPTH) measurement after a total thyroidectomy predicts children at risk for hypoparathyroidism and allow for outpatient procedure. METHODS: Between 2015 and 2019, we reviewed all patients under the age of 21 undergoing a thyroidectomy (total or lobectomy). Based on the ioPTH concentration, the patients were treated by the following protocol: a) PTH ≥20 pg/mL: no treatment; b) PTH = 10-19 pg/mL: 1000 mg calcium orally TID; c) PTH = 5-9 pg/mL: calcitriol 250 µg orally BID plus 1000 mg calcium orally TID; or d) PTH <5 pg/mL calcitriol 500 µg orally BID plus 1000 mg calcium orally TID. RESULTS: Fifty-two patients were included with a median age of 16 (range 6-21 years). Thirty-two patients (62%) had normal PTH (≥10 pg/mL) while 20 (38%) had low PTH levels (<10 pg/mL). Of those patients with low PTH, 60% had normalization of levels within 2 weeks of surgery. CONCLUSIONS: Thyroid surgery in children can be performed as an outpatient procedure. The ioPTH measurements and a protocol to treat patients with low PTH assists in safe discharge.

A single institution experience with papillary thyroid cancer: Are outcomes better at comprehensive cancer centers?

INTRODUCTION: Papillary thyroid cancer (PTC) is the most common form of thyroid cancer. Although the survival rate is excellent, recurrence is as high as 20%. The mainstay of therapy is thyroidectomy and lymph node dissection based on risk factors. Data from other cancers suggest that surgical outcomes are most optimal at comprehensive cancer centers. We hypothesize that patients with PTC who had their initial operation at a comprehensive cancer center would have a better oncologic outcome. METHODS: We utilized an IRB-approved cancer care registry database of patients with thyroid cancer who were seen at our institution between 2000 and 2018. Patient records were updated with cancer-specific outcomes including recurrence and need for re-intervention. Clinical and surgical outcomes were then compared between patients who had their initial operation at a comprehensive cancer center (CCC group, n = 503) versus those who did not (non-CCC group, n = 72). RESULTS: Mean patient age was 49 ± 16 years and 70% were female. Average tumor size was 1.6 ± 1.6 cm. There was no difference in tumor size, age, gender or race between groups. Pre-operative ultrasound was more frequently performed at the CCC (89%) than at non-CCC's (51%, p < 0.001). CCC patients were more likely to undergo initial total thyroidectomies compared to non-CCC patients (76% vs. 21%, p < 0.001). Positive surgical margins were more frequently found in patients at non-CCC's (19%) than at the CCC (9.7%, p = 0.016). Finally, CCC patients had a significantly lower cancer recurrence rate (5.0% vs. 37.5%, p < 0.001). Therefore, the need for additional cancer operations was much greater in patients who had initial thyroid surgery at non-CCC (31.9% vs. 1.4%, p < 0.001). CONCLUSIONS: Patients with PTC who have their initial thyroidectomy at non-CCC have higher recurrence rates, higher rates of positive tumor margins on pathology, and increased need for additional operations. These data suggest that patients who have their initial procedure at a CCC for PTC have better long-term outcomes.

Outpatient thyroidectomy in the pediatric population.

Preoperative optimization and patient education have allowed for the transition of thyroid surgery to the outpatient setting over the last few decades. Performing these operations in the outpatient setting has proven to be cost-effective and safe in the adult population. The purpose of this study is to evaluate the safety and efficacy of outpatient thyroid surgery in the pediatric population. A retrospective review from December 2015 to February 2019 of patients under the age of 18 years of age undergoing thyroidectomy performed by two endocrine surgeons at a large academic was performed. There were 55 consecutive operations performed in 51 patients for thyroid pathology, two were excluded as they were inpatient procedures. Cases were reviewed for complications, unplanned same-day admission, 30-day admission, unplanned reoperation, and death. Mean age was 15 ± 0.3 years (range 9-18 years), 79% of the patients were female. Operations were performed for Graves' disease (n = 29), thyroid cancer (n = 9), thyroid nodule (n = 6), multinodular goiter (n = 4), Hashimoto's disease (n = 3), and toxic adenoma (n = 2). Operations performed included: total thyroidectomy (n = 36), thyroid lobectomy (n = 13), total thyroidectomy with lymph node dissection (n = 2), and lateral neck dissection (n = 2). All patients were discharged home within 6 h after completion of the operation. Five (9.4%) patients had transient hypoparathyroidism, with parathyroid hormone levels <10 pg/mL immediately postoperatively. One patient (1.9%) developed a postoperative hematoma on postoperative day six and required reoperation and readmission. Two patients (3.8%) had permanent hypoparathyroidism and one had transient hoarseness (1.9%). There were otherwise no readmissions or ED visits. In conclusion, outpatient thyroid surgery is safe and effective for pediatric patients.

A hybrid functional nanomaterial: POSS functionalized carbon nanofiber.

A hybrid functional nanomaterial was synthesized by functionalizing carbon nanofibers (CNF) with polyhedral oligomeric silsesquioxane (POSS). The reaction between CNF and the amine group of ocataminophenyl POSS was achieved using carbodiimide chemistry. The CNF-POSS hybrids were designed to increase the reactivity of CNF without affecting its inherent properties. The reactive amine groups of CNF-POSS were further modified with an oligomer of polyimide polymer to improve the interaction with the polymer matrix, thus forming a nanocomposite with enhanced multifunctional properties. Functionalization was characterized using thermal gravimetric analysis (TGA), x-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM).

Correlation between Cosyntropin Stimulation Study and Disease Severity in Children with Fluid- and Catecholamine-Refractory Shock in the Pediatric and Cardiovascular Intensive Care Unit.

BACKGROUND: The cosyntropin stimulation study (CSS) measures the patient's ability to adequately mount a cortisol response. Clinically, CSS results may not be used to guide hydrocortisone use. The objective of this study was to examine how the CSS results are associated with clinical parameters, mortality/disease severity, and use of glucocorticoids in pediatric patients with catecholamine- and fluid-resistant shock. METHODS: This was a retrospective cohort study of patients who had a CSS during 2009-2014 in the intensive care unit at a children's hospital. Data collected included clinical variables, mortality, biochemical studies, and glucocorticoid use. PRISM III scores were used to determine the association between CSS results and disease severity. Adequate response to cosyntropin was defined as peak cortisol of 18 µg/dL or higher. RESULTS: Of the 76 patients that underwent CSS, 68 (89%) had an adequate response to cosyntropin. There was a positive correlation between peak cortisol and PRISM III score (r = 0.45, r2 = 0.2). Glucocorticoid was administered in 52/76 (68%) despite several patients with normal CSS results. CONCLUSIONS: Sicker patients were more likely to have an adequate response to CSS. Clinically, glucocorticoid supplementation was not based on CSS results. Further prospective studies are needed to elucidate if CSS is a valuable clinical tool.

Shedding light on hypovitaminosis D and rickets.

The recent resurgence of the ancient disease of vitamin D deficiency rickets and the widespread presence of hypovitaminosis D across the age spectrum pose significant challenges for today's clinicians. Furthermore, new research into previously unsuspected actions of vitamin D in multiple cell systems offer the possibility that vitamin D will play an increasingly important role in our understanding of a wide variety of disease states.

Response to sorafenib in a pediatric patient with papillary thyroid carcinoma with diffuse nodular pulmonary disease requiring mechanical ventilation.

BACKGROUND: Papillary thyroid cancer (PTC) presents with local and distant metastases more frequently in children than in adults. However, hypoxemia secondary to pulmonary metastases has not been reported in the literature. Sorafenib is a small-molecule multikinase inhibitor used in radioactive iodine ((131)I)-refractive papillary thyroid carcinoma. PATIENT FINDINGS: An eight-year-old boy presented with fever and hypoxemia and was found to have H1N1 viral pneumonia requiring mechanical ventilation and antiviral and glucocorticoid treatment. After initial improvement, he was readmitted one month later because of persistent hypoxemia. A high-resolution computed tomography of the chest and neck revealed multiple 1-4 mm nodules and necrotic lymph nodes on the right side of the neck. Left lung wedge resection and right deep cervical node biopsies were consistent with PTC. He underwent a total thyroidectomy with a central neck node dissection and postoperatively required prolonged mechanical ventilation. Due to the inability to be weaned from mechanical ventilation, treatment with sorafenib 200 mg daily (10 mg/kg/day, 250 mg/m(2)) was initiated. Eight days thereafter, ventilation support was discontinued and the child was extubated. However, he failed extubation secondary to supraglottic edema, and seven days later tracheostomy was performed. The dosage of sorafenib was increased to 200 mg twice daily (20 mg/kg/day, 500 mg/m(2)). After 52 days of therapy, a repeat computed tomography scan showed reduction in the lung nodule size to 1-2 mm. He underwent (131)I therapy 87 days after sorafenib was started. A post-treatment scan showed extensive uptake throughout the lungs and thyroid bed, supraclavicular nodes, and cervical nodes. CONCLUSIONS: This is the first reported case of a pediatric patient with respiratory failure possibly secondary to diffuse micronodular PTC requiring mechanical ventilation and subsequent delay in definitive therapy. Sorafenib could be considered for gap therapy when (131)I therapy cannot be administered in a timely manner. Treatment with this multikinase inhibitor does not seem to adversely affect the uptake of (131)I in radiation-naïve patients.

A novel CASR mutation associated with neonatal severe hyperparathyroidism transmitted as an autosomal recessive disorder.

BACKGROUND: Neonatal severe primary hyperparathyroidism (NSHPT, MIM 239200) is most often an isolated disorder that is due to biallelic inactivating mutations in the CASR, the gene encoding the calcium sensing receptor; NSHPT is inherited from parents with familial hypocalciuric hypercalcemia, each of whom has one mutated CASR allele. OBJECTIVES: To report clinical and genetic findings in a brother and sister with NSHPT due to a novel mutation in the CASR transmitted as an autosomal recessive trait and to examine the functional effect of the mutation. SUBJECTS AND METHODS: A brother and sister with marked hypercalcemia due to NSHPT were identified; the boy also had craniosynostosis requiring surgical repair. The genotyping of the CASR in both children and their parents who were eucalcemic and normophosphatemic was undertaken. In order to examine the significance of the variant CASR identified, the CASR variant was expressed in vitro and examined by three computer computational programs [PolyPhen2, MutationTaster, Sorting Intolerant From Tolerant (SIFT)] designed to evaluate the effect of a nucleotide variant on the structure and likely functional consequence upon the protein product. RESULTS: A sequence variant in the CASR was identified [G>T point mutation at nucleotide c.2303 in exon 7 (c.2303G>T) resulting in the replacement of glycine by valine at codon 768 (p.Gly768Val)]. Two copies of this CASR variant were present in the genome of the siblings while a single copy of the CASR variant was present in both of the clinically and biochemically normal parents, a pattern of transmission consistent with autosomal recessive inheritance of NSHPT in this family. When expressed in HEK293 cells in vitro, the novel Gly768Val variant did not interfere with protein generation or migration to the cell membrane in vitro. The analysis of the functional effect of the Gly768Val CASR variant by the PolyPhen2, MutationTaster, and Sorting Intolerant From Tolerant computer programs revealed that this mutation was very likely to be deleterious. CONCLUSION: The NSHPT associated with biallelic Gly768Val mutations of the CASR in two siblings with severe hypercalcemia and hyperparathyroidism and their clinically and biochemically normal heterozygous parents was transmitted as an autosomal recessive disorder in this family.

Positive prolactin response to bromocriptine in 2 patients with cabergoline-resistant prolactinomas.

OBJECTIVE: To describe a positive prolactin response to bromocriptine treatment in 2 patients with cabergoline-resistant prolactinomas. METHODS: We report the patients' clinical presentations, laboratory test results, imaging findings, and clinical courses. RESULTS: Patient 1 had a 5-mm pituitary microadenoma that was initially diagnosed at age 30 years. After initial diagnosis, she was treated with transvaginal bromocriptine for 9 years and then subsequently went untreated for 2 years. After developing symptoms of amenorrhea, decreased libido, and hyperprolactinemia, oral cabergoline, 0.5 mg twice weekly, was initiated. Her prolactin concentration remained elevated at 80 ng/mL while taking cabergoline. Her prolactin concentration decreased to 13 ng/mL after her regimen was switched to bromocriptine, 5 mg daily. Patient 2 had a 17-mm pituitary macroadenoma that was initially diagnosed at age 15 years. Oral cabergoline was started at 0.5 mg twice weekly and increased to 1 mg 3 times weekly when prolactin levels continued to rise to 340 ng/mL over 18 months. After visual field defects developed, transsphenoidal surgery was performed. One year after surgery, magnetic resonance imaging showed a 6- to 7-mm pituitary adenoma, and there was a gradual rise in serum prolactin. Her serum prolactin concentration continued to rise to 212 ng/mL with increasing tumor size over 3 years. Cabergoline was discontinued and oral bromocriptine was initiated at a dosage of 10 mg daily. After 4.5 months of bromocriptine therapy, her serum prolactin concentration decreased to 133 ng/mL. However, after 2 months, the macroadenoma continued to increase in size and a visual field defect developed, so another transsphenoidal operation was performed. CONCLUSIONS: Although cabergoline is generally preferred to bromocriptine for the treatment of patients with prolactinomas because of its better tolerance profile and greater effectiveness, in patients with cabergoline-resistant prolactinomas, a bromocriptine trial should be considered a safe, relatively inexpensive, and well-tolerated alternative.