Consultation for chronic rhinosinusitis with nasal polyps and asthma: clinical presentation, diagnostic work-up, and treatment options.

Chronic rhinosinusitis (CRS) is characterized by chronic inflammation of the sinonasal mucosa, affects over 12% of the US population, and costs over $20 billion annually. CRS can be divided into two major phenotypes based on whether nasal polyps are present (CRSwNP) or absent (CRSsNP). This grand rounds review will discuss the clinical approach to patients with CRSwNP, including typical presentations, work-up, and currently available treatment options. Tools that physicians can utilize to assess subjective sinonasal symptoms, as well as objective measures of disease, will be reviewed. Additional focus will be on recognizing clinical comorbidities commonly associated with CRSwNP, including asthma, bronchiectasis, allergic rhinitis, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Clinical outcomes can be improved by providing a comprehensive approach to evaluating (and managing) patients with CRSwNP.

Single cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the United States, but the actual roles that eosinophils play in CRSwNP remain largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue, we performed single cell RNA sequencing (scRNA-Seq) analysis of NP tissue. METHODS: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched before processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by Gene Ontology (geneontology.org) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry. RESULTS: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses), and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were downregulated and 354 genes upregulated in NP eosinophils compared to all PB eosinophils (>1.5-fold, Padj < .05). Upregulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling, and antiapoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue. CONCLUSIONS: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part by controlling inflammation and hyperproliferation of other cells.

Prevention of allergic reactions during oxaliplatin desensitization through inhibition of Bruton tyrosine kinase.

BACKGROUND: Acute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Breakthrough symptoms, including anaphylaxis, can still occur during RDD. OBJECTIVE: Our aim was to evaluate whether pretreatment with acalabrutinib, a Bruton tyrosine kinase inhibitor, can prevent anaphylaxis during RDD in a patient sensitized to oxaliplatin. METHODS: A 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his fifth cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib before and during RDD were reviewed, and the patient elected to proceed. RESULTS: With acalabrutinib taken before and during the RDD, the patient was able to tolerate oxaliplatin RDD without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient's positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% vs 0.98%) before the RDD but did protect against basopenia (0.74% vs 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% vs 2.38%) or polyclonal anti-human IgE antibody (0.08% vs 44.2%). CONCLUSIONS: Five doses of acalabrutinib, 100 mg, orally twice daily starting during the evening 2 days before and continuing through RDD allowed a sensitized patient to receive oxaliplatin successfully and safely.

IL-13 and IL-13-induced periostin levels are specifically decreased in patients following endoscopic sinus surgery for chronic rhinosinusitis.

BACKGROUND: Type 2 (T2) inflammation plays a pathogenic role in chronic rhinosinusitis (CRS). The effects of endoscopic sinus surgery (ESS) on T2 inflammation are unknown. OBJECTIVE: The aim of this study was to compare T2 inflammatory biomarkers from middle meatal (MM) mucus for distinguishing patients with CRS from CRS-free patients, identifying major phenotypes (CRS without nasal polyps [CRSsNP] and CRS with nasal polyps [CRSwNP]), assessing endotypic change, and establishing cross-sectional and longitudinal outcomes in patients undergoing ESS. METHODS: MM mucus samples were collected from patients with CRSsNP and patients with CRSwNP before and 6 to 12 months after ESS and compared with samples from CRS-free control patients. T2 biomarkers were evaluated both continuously and using threshold-based definitions of T2 endotype to identify relationships with patient-reported (based on the 22-Item Sinonasal Outcomes Test and Chronic Rhinosinusitis Patient-Reported Outcomes Measure) and clinician-reported (radiographic and endoscopic) severity. Linear mixed models were developed to analyze clinical variables associated with T2 biomarker levels. RESULTS: A total of 154 patients with CRS (89 with CRSsNP and 65 with CRSwNP) were enrolled, with a mean interval of 9 months between ESS and follow-up. An analysis of pre-ESS MM mucus samples revealed elevated levels of T2 mediators in patients with CRSwNP versus in patients with CRSsNP and CRS-free controls. Temporally stable correlations between levels of IL-13 and IL-5, levels of periostin and complement 5a, and levels of eosinophil cationic protein (ECP) and eotaxin-3 were observed. On this basis and on the basis of pathologic significance, levels of IL-13, periostin and ECP were further analyzed. After ESS, levels of IL-13 and periostin decreased significantly, whereas ECP levels remained unchanged. Across pre- and post-ESS evaluation, the T2 endotype was associated with radiographic severity but did not predict outcomes. CRSwNP status and African American race were associated with higher levels of IL-13 and periostin, whereas ECP level was higher in patients undergoing extensive surgery. CONCLUSION: ESS decreased levels of IL-13 and periostin in the middle meatus. T2 inflammation after ESS was correlated with patient- and clinician-reported severity across phenotypes. Pre-ESS T2 inflammation did not predict post-ESS outcomes.

Is the association between cognitive disease progression and atrial fibrillation modified by sex?

INTRODUCTION: It is unclear if sex differences exist in cognitive disease progression in mild cognitive impairment (MCI) and dementia associated with atrial fibrillation (AF). METHODS: Using a variety of statistical methods, we examined sex differences between AF and neuropsychological tests and cognitive disease progression, using the National Alzheimer's Coordinating Center data (N = 43,630). RESULTS: AF is associated with higher odds of dementia (odds ratio [OR] 3.00, 95% confidence interval [CI] [1.22, 7.37] in women and MCI in women (OR 3.43, 95% CI [1.55, 7.55]) versus men. Women with AF and normal baseline cognition had a higher risk of disease progression (hazard ratio [HR] 1.26, 95% CI [1.06, 1.50]) from normal to MCI and from MCI to vascular dementia (HR3.27, 95% CI [1.89, 5.65]) than men with AF or men and women without AF. DISCUSSION: AF was associated with more rapid progression to MCI and dementia in women, but more research is needed to confirm these findings.

Out-of-pocket expenses associated with pediatric heart transplantation.

INTRODUCTION: Heart transplantation in children is associated with high resource utilization. However, the financial burden on families and the association with patient and demographic factors remains unclear. This study aims to examine out-of-pocket expenses associated with pediatric heart transplantation. METHODS: An anonymous REDCap survey was distributed to caregivers of children who have undergone heart transplantation using social media, national organizations, and during clinic encounters from May through August 2022. RESULTS: There were a total of 146 respondents. The median monthly out-of-pocket expense was $250 (IQR $75-$500) and 20 respondents (13.7%) reported monthly expenses of >$1000. Families with commercial insurance reported significantly higher out-of-pocket expenses compared to those with government-sponsored insurance (median $350 vs. $100, p < .001). Families with government-sponsored insurance were most happy with their insurance coverage, followed by commercial insurance and then coverage through the Affordable Care Act (p < .001 for all pairwise comparisons). There was no statistically significant difference in overall transplant-related out-of-pocket expenses based on total household income (p = .222). Monthly out-of-pocket expense was not associated with the number of medications, type of immunosuppressants, or post-transplant complications including rejection, PTLD, or CAV (p = NS for all). Cardiac catheterizations and unplanned admissions were reported as the events that incurred the highest out-of-pocket expense. CONCLUSION: Families of children who have undergone heart transplantation can incur significant out-of-pocket expenses and strategies to mitigate this financial burden should be investigated.

Mechanistic and clinical updates in AERD: 2021-2022.

Aspirin-exacerbated respiratory disease (AERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma and chronic rhinosinusitis with nasal polyposis. Works published in 2021-2022 confirmed the critical role of lipid mediator dysregulation and mast cell activation and expanded our understanding of basophils, macrophages, fibrin dysregulation, and the 15-lipoxygenase pathway in disease pathogenesis. Translational studies established inflammatory heterogeneity in the upper and lower airway at baseline and during aspirin-induced respiratory reactions. Clinical cohorts provided insights into the mechanistic actions of frequently utilized biologic therapies in AERD. These advances are already changing clinical care delivery and affecting patient outcomes. Despite this, further work is needed to improve clinical tools to reliably diagnose AERD and identify factors that could prevent development of the disease altogether. Additionally, the impact of inflammatory heterogeneity on clinical trajectories and the utility and safety of combination biologic and daily aspirin therapies remains unanswered.

Recent insights into the mechanisms of anaphylaxis.

Anaphylaxis is an acute life-threatening systemic allergic reaction that can have a wide range of clinical manifestations. The most common triggers for anaphylaxis include food, medication, and venom. What is curious regarding anaphylaxis is how so many different agents can induce a severe systemic clinical response but only in a select subgroup of patients. Over the past decade, several important advances have been made in understanding the underlying cellular and molecular mechanisms contributing to anaphylaxis, with mast cells (MCs) being an essential component. Classically, cross-linked immunoglobulin E (IgE) bound to its high- affinity receptor induces MC mediator release. However, toll-like, complement, or Mas-related G-protein-coupled receptors also activate mouse and human MCs. While anaphylaxis secondary to foods historically has been more extensively characterized clinically and mechanistically, more recent studies have shifted focus toward understanding drug-induced anaphylaxis. The focus of this review is to highlight recent basic science developments and compare what is currently known regarding anaphylaxis to food, medications, and venom.

A Decade of Clinical Advances in Chronic Rhinosinusitis: 2012-2022.

The field of chronic rhinosinusitis (CRS) is constantly evolving. In the past 10 years, key advancements in basic and translational research as well as clinical studies have improved our understanding and management of CRS. Notably, treatment options have expanded to include novel therapeutic drugs, devices, and surgical techniques. Assessments of patient symptoms and their impact on quality of life have become more standardized. Progress has also been made in both determining the true prevalence of CRS and recognizing comorbidities that can impact CRS severity. Practice guidelines have also shifted from expert opinion to more data-driven analyses. This review highlights major clinical advancements made in the field of CRS over the past 10 years as well as identifies current gaps in knowledge that can form the basis for new areas of study over the next decade.

Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP). OBJECTIVE: We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs). METHODS: OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface-cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP. RESULTS: Increased levels of OSM receptor ß chain (OSMRß), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRß in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRß and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP. CONCLUSIONS: OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.

The Joint Task Force on Practice Parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis.

These evidence-based guidelines support patients, clinicians, and other stakeholders in decisions about the use of intranasal corticosteroids (INCS), biologics, and aspirin therapy after desensitization (ATAD) for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). It is important to note that the current evidence on surgery for CRSwNP was not assessed for this guideline nor were management options other than INCS, biologics, and ATAD. The Allergy-Immunology Joint Task Force on Practice Parameters formed a multidisciplinary guideline panel balanced to include the views of multiple stakeholders and to minimize potential biases. Systematic reviews for each management option informed the guideline. The guideline panel used the Grading of Recommendations Assessment, Development and Evaluation approach to inform and develop recommendations. The guideline panel reached consensus on the following statements: (1) In people with CRSwNP, the guideline panel suggests INCS rather than no INCS (conditional recommendation, low certainty of evidence). (2) In people with CRSwNP, the guideline panel suggests biologics rather than no biologics (conditional recommendation, moderate certainty of evidence). (3) In people with aspirin (nonsteroidal anti-inflammatory drug)-exacerbated respiratory disease, the guideline panel suggests ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). The conditions for each recommendation are discussed in the guideline.

Repeat crossclamp after failed initial degenerative mitral valve repair is safe and successful.

Objective: Surgical risk and long-term outcomes when re-crossclamp is required during degenerative mitral valve repair are unknown. We examined the outcomes of patients who required re-crossclamp for mitral valve reintervention. Methods: Adults undergoing mitral valve repair for degenerative mitral valve disease at a single center from 2007 to 2021 who required more than 1 crossclamp for mitral valve reintervention were included. Outcomes including major morbidity and 30-day mortality were collected. Kaplan-Meier analysis characterized survival and freedom from recurrent mitral regurgitation. Results: A total of 69 patients required re-crossclamp for mitral valve reintervention. Of those, 72% (n = 50) underwent successful re-repair and the remaining underwent mitral valve replacement (28%, n = 19). Major morbidity occurred in 23% (n = 16). There was no 30-day mortality, and median long-term survival was 10.9 years for those undergoing re-repair and 7.2 years for those undergoing replacement (P = .79). Midterm echocardiography follow-up was available for 67% (33/50) of patients who were successfully re-repaired with a median follow-up of 20 (interquartile range, 7-37) months. At late follow-up, 90% of patients had mild or less mitral regurgitation. Of those re-repaired, 2 patients later required mitral valve reintervention. Conclusions: Patients requiring re-crossclamp for residual mitral regurgitation had low perioperative morbidity and no mortality. Most patients underwent successful re-repair (vs mitral valve replacement) with excellent valve function and long-term survival. In the event of unsatisfactory repair at the time of mitral valve repair, attempt at re-repair is safe and successful with the appropriate valvar anatomy.

Topical corticosteroids for chronic rhinosinusitis with nasal polyposis: GRADE systematic review and network meta-analysis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with a significant disease burden. The optimal use of and administration route for intranasal corticosteroids (INCS) when managing CRSwNP are unclear. OBJECTIVE: We systematically synthesized the evidence addressing INCS for CRSwNP. METHODS: We searched studies archived in Medline, Embase, and Central from database inception until September 1, 2021, for randomized controlled trials comparing INCS using any delivery method to placebo or other INCS administration types. Paired reviewers screened records, abstracted data, and rated risk of bias (CLARITY revision of Cochrane Risk of Bias version 1 tool) independently and in duplicate. We synthesized the evidence for each outcome using random effects network meta-analyses. We critically appraised the evidence following the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) approach. RESULTS: We analyzed 61 randomized controlled trials (7176 participants, 8 interventions). Sinusitis-related quality of life might improve with INCS rinse (mean difference [MD] -6.83, 95% confidence interval [CI] -11.94 to -1.71) and exhalation delivery system (EDS) (MD -7.86, 95% CI -14.64 to -1.08) compared to placebo (both low certainty evidence). Nasal obstruction symptoms are likely improved when receiving INCS via stent/dressing (MD -0.31, 95% CI -0.54 to -0.08), spray (MD -0.51, 95% CI -0.61 to -0.41), and EDS (MD -0.35, 95% CI -0.51 to -0.18) (all moderate to high certainty) compared to placebo. We found no important differences in adverse effects among interventions (moderate certainty for INCS spray, very low to low certainty for others). CONCLUSIONS: Multiple delivery forms of INCS are viable therapeutic options for CRSwNP, resulting in improvement of patient-important outcomes. INCS via stent, spray, and EDS appear to be beneficial across the widest range of considered outcomes.

Retinoic acid promotes fibrinolysis and may regulate polyp formation.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. OBJECTIVES: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. METHODS: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. RESULTS: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01). CONCLUSIONS: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.

A Grounded Theory Approach to Navigating Infertility Care During U.S. Military Service.

INTRODUCTION: In this study, we aimed to understand how active duty service members and their partners navigate the infertility care process within the Military Health System (MHS) while managing a military career. MATERIALS AND METHODS: We obtained Institutional Review Board approval to employ a qualitative design using grounded theory methods. We recruited participants using purposive sampling, followed by theoretical sampling. We derived data from demographic questionnaires and semi-structured interviews. Consistent with grounded theory methods, we began analysis with line-by-line coding and moved to focused coding. We employed constant comparative analysis throughout the process to name, categorize, and conceptualize data and relationships. RESULTS: The participants included 28 patients, five partners, nine health care providers, and two military leaders. The infertility care process began with active duty service members and their partners recognizing the desire to have a child and discovering infertility, followed by deciding to seek infertility care. The experience was temporally bound within the context of the military environment. We identified the following themes, which described facilitators and barriers to accessing care: Duty station location, career stage, military versus the civilian cost of services, command climate, and policy. These facilitators and barriers varied widely across the Department of Defense (DoD), which resulted in fragmented and inconsistent care cycles, contributed to emotional and physical stress, and created tension between career progression and family formation. CONCLUSIONS: Understanding how military couples perceive and manage demands of infertility care may enhance access to care, decrease patient costs, improve outcomes, result in better support for military couples who experience infertility, and ultimately improve the health and military readiness of our armed forces. The results support the need for action by providers, policy makers, and military leaders to develop effective infertility treatment programs and policies in the DoD.

Efficacy of an oral CRTH2 antagonist (AZD1981) in the treatment of chronic rhinosinusitis with nasal polyps in adults: A randomized controlled clinical trial.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease of the upper airways. AZD1981 is a selective antagonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 and other type 2 cells, including innate lymphoid cells type 2, eosinophils, and basophils. OBJECTIVE: To evaluate the efficacy of AZD1981 in reducing nasal polyp size when added to intranasal corticosteroids in adult patients with CRSwNP. METHODS: Eighty-one subjects (18-70 years of age) with CRSwNP were recruited and screened for trial eligibility from allergy and otolaryngology clinics from a single tertiary care site between June 2016 and August 2019. Eligible patients were randomized in a double-blind fashion to receive either AZD1981 (n = 22) or placebo (n = 21) orally three times a day for 12 weeks, added to intranasal corticosteroids. The primary endpoint was a change in nasal polyp score (NPS) at 12 weeks. Secondary endpoints included improvement in sinus computed tomography using Lund Mackay scoring, symptoms using visual analog scale, quality of life using Sino Nasal Outcome Test-22, and the Brief Smell Identification Test. RESULTS: Forty-three patients met the inclusion criteria and were enrolled. At 12 weeks, there was no difference in NPS change in the AZD1981 arm (mean 0, standard error 0.34, n = 15) compared with placebo (mean 0.20, standard error 0.36, n = 17); mean difference -0.20 (95% confidence interval: -1.21, 0.81; p = .69). No significant differences were observed for Lund Mackay score, symptoms, quality of life, or smell test. AZD1981 was well tolerated except for one case of hypersensitivity reaction. CONCLUSION: In patients with CRSwNP, the addition of AZD1981 to intranasal corticosteroids did not change nasal polyp size, radiographic scores, symptoms, or disease-specific quality of life.

Effects of Exercise Frequency and Intensity on Reducing Depressive Symptoms in Older Adults With Insomnia: A Pilot Randomized Controlled Trial.

Background: The effects of exercise frequency and intensity on alleviating depressive symptoms in older adults with insomnia are unclear. Purpose: The purpose of this study was to investigate the influence of different exercise frequencies and intensities on prescribed aerobic-type physical activity (i.e., 75 min of vigorous-intensity exercise or 150 min of moderate-intensity exercise weekly) for reducing depressive symptoms in older adults living with insomnia, as recommended by the WHO. Design: This study is a randomized, controlled, assessor-blinded trial. Setting: This study is conducted at a single research site in Hong Kong. Participants: This study includes older adults aged 50 years or above with depressive symptoms and insomnia. Intervention: Participants were randomly assigned in a 1:1:1:1:1 ratio to the following groups: attention control (CON), moderate walking once weekly (MOD × 1/week), moderate walking thrice weekly (MOD × 3/week), vigorous walking once weekly (VIG × 1/week), and vigorous walking thrice weekly (VIG × 3/week). The total weekly exercise volumes among the walking groups were matched to the minimum recommended physical activity volume. Measurements: Depression, anxiety, self-perceived sleep quality, insomnia severity, actigraphy-assessed 7-day sleep data, 7-day sleep diary, cardiorespiratory fitness, adherence, and habitual physical activity were examined at baseline and after 12 weeks of intervention. Results: Both MOD × 3/week and VIG × 3/week groups demonstrated reduced depression (Hospital Anxiety and Depression Scale [HADS] - Depression: MOD × 3/wk: -68.6%; VIG × 3/week: -67.4%) and anxiety levels (HADS - Anxiety: MOD × 3/week: -54.3%; VIG × 3/week: -59.8%) compared with CON (both p < 0.01). Self-perceived sleep quality was improved in MOD × 3/week (-31.4% of the Pittsburgh Sleep Quality Index [PSQI]), VIG × 1/week (-34.1% of PSQI), and VIG × 3/week (-38.3% of PSQI), but not in MOD × 1/week, when compared with CON (p < 0.05). No serious adverse events were observed in this study. Conclusion: The effects of walking training on reducing depressive symptoms appeared to be dependent on exercise frequency. Our findings suggest that three sessions of walking per week at either moderate or vigorous-intensity effectively alleviate depressive symptoms in older adults with insomnia. Additional research is needed to further verify the effects of exercise frequency on depression. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04354922].

Evaluation of multinodular goiter and primary hyperparathyroidism leads to a diagnosis of AL amyloidosis.

BACKGROUND: Amyloid goiter, defined as excess amyloid within the thyroid gland in such quantities that it produces a clinically apparent goiter, is a very rare manifestation of systemic amyloidosis with cases commonly seen in the setting of Amyloid A (AA) amyloidosis. Amyloid goiter as the primary clinical manifestation secondary to Amyloid light chain (AL) amyloidosis is very rare. We present a case of AL amyloidosis with initial manifestation as goiter with amyloid deposition in the thyroid and the parathyroid gland. CASE PRESENTATION: A 73 year old male presented with goiter and compressive symptoms of dysphagia and hoarseness. Laboratory workup revealed normal thyroid function, nephrotic range proteinuria, elevated serum calcium level with an elevated parathyroid hormone level (PTH) consistent with primary hyperparathyroidism. Thyroid ultrasound showed an asymmetric goiter with three dominant nodules. Cervical computed tomography revealed a goiter with substernal extension and deviation of the trachea. Fine needle aspiration was unsatisfactory. There was also evidence of osteoporosis and hypercalciuria with negative Sestamibi scan for parathyroid adenoma. The patient underwent a total thyroidectomy and one gland parathyroidectomy. Pathology revealed benign thyroid parenchyma with diffuse amyloid deposition in the thyroid and parathyroid gland that stained apple green birefringence under polarized light on Congo Red stain. Immunochemical staining detected AL amyloid deposition of the lambda type. Bone marrow biopsy revealed an excess monoclonal lambda light chain of plasma cells consistent with a diagnosis of AL amyloidosis secondary to multiple myeloma affecting the kidney, thyroid, parathyroid gland, and heart. He was treated with 4 cycles of chemotherapy with a decrease in the M spike and light chains with a plan to pursue a bone marrow transplant. CONCLUSION: Amyloid goiter as the primary clinical manifestation secondary to AL amyloidosis with deposition in the thyroid and parathyroid gland is rare. The top differential for amyloid deposits in the thyroid includes systemic amyloidosis or medullary thyroid carcinoma. The definitive diagnosis lies in the histopathology of the thyroid tissue. To diagnose systemic amyloidosis as the etiology for a goiter, a solid understanding of the causes of systemic amyloidosis coupled with a thorough evaluation of the patient's history and laboratory data is necessary.

Quality of life after long-term biochemical control of acromegaly.

PURPOSE: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis). METHODS: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). RESULTS: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD. CONCLUSION: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control.