Context: The absence of classical symptoms and signs of hyperthyroidism often results in delayed diagnosis and treatment. Objectives: The objective of the study was to determine the prevalence of symptoms and signs of hyperthyroidism according to patients’ age and gender as well as severity and type of hyperthyroidism. Design, Participants and Setting: This was a cross-sectional study of 3049 consecutive patients with hyperthyroidism presenting to a single secondary/tertiary care clinic. Main Outcome Measures: Calculation of adjusted odds ratios for presence/absence of symptoms/signs of hyperthyroidism simultaneously analyzing the influence of patients’ age/gender, disease etiology/severity, symptom duration, and smoking. Results: The majority of patients older than 61 yr had two or more symptoms. The lowest proportion of subjects reporting five or more symptoms was found in those older than 61 yr. Increasing age was associated with reduced adjusted odds ratio for the presence of most classical symptoms except for weight loss and shortness of breath, independent of disease severity. Those with more severe hyperthyroidism and smokers had increased odds ratios for most symptoms. Older age, higher serum free T₄ concentrations at diagnosis, male gender, and toxic nodular hyperthyroidism were independently associated with risk of atrial fibrillation. Signs of ophthalmopathy were associated with increasing age, smoking, longer symptom duration, and female gender. Conclusions: Classical symptoms and signs of hyperthyroidism are significantly less prevalent in older patients and more prevalent in smokers and subjects with higher free T₄ concentrations. We propose a lower threshold for performing thyroid function tests in patients older than 60 yr, especially in those presenting with atrial fibrillation, weight loss, or shortness of breath.

Objective To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. Design Retrospective cohort study. Setting The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. Participants Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. Exposure TSH concentration in patients with hypothyroidism. Main outcome measures Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. Results 162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH 10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). Conclusions In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

Context: Hyperthyroidism is common, but opinions regarding optimal therapy with antithyroid drugs or radioiodine (131-I) differ. There are no randomized trials comparing these options in terms of mortality. Objective: The aim of the study was to determine whether mortality associated with hyperthyroidism varies with treatment administered or other factors. Design, Setting, and Patients: We conducted a prospective observational population-based study of 1036 subjects aged ≥ 40 years presenting to a single specialist clinic from 1989–2003 with a first episode of hyperthyroidism who were followed until June 2012. Interventions: Antithyroid drugs or radioiodine (131-I) were administered. Main Outcome Measures: We compared causes of death with age-, sex-, and period-specific mortality in England and Wales and used within-cohort analysis of influence of treatment modality, outcome, disease etiology, severity and control, and comorbidities. Results: In 12 868 person-years of follow-up, 334 died vs 290.6 expected (standardized mortality ratio [SMR], 1.15 [95% confidence interval (CI),1.03–1.28]; P = .01). Increased all-cause mortality largely reflected increased circulatory deaths (SMR, 1.20 [95% CI, 1.01–1.43]; P = .04). All-cause mortality was increased for the person-years accumulated during thionamide treatment (SMR, 1.30 [95% CI, 1.05–1.61]; P = .02) and after 131-I not associated with hypothyroidism (SMR, 1.24 [95% CI, 1.04–1.46]; P = .01) but not during T₄ replacement for 131-I-induced hypothyroidism (SMR, 0.98 [95% CI, 0.82–1.18]; P = .85). Within-cohort analysis comparing mortality during thionamide treatment showed a similar hazard ratio (HR) for all-cause mortality when 131-I did not result in hypothyroidism (HR, 0.95 [95% CI, 0.70–1.29]), but reduced mortality with 131-I-induced hypothyroidism (HR, 0.70 [95% CI, 0.51–0.96]). Reduced mortality associated with hypothyroidism was seen only in those without significant comorbidities and not in those with other serious diseases. Atrial fibrillation at presentation (P = .02) and an increment of 10 pmol/L in serial free T₄ concentration during follow-up (P = .009) were independently associated with mortality. Conclusions: Among hyperthyroid subjects aged 40 years or older, mortality was increased during periods of thionamide treatment and after radioiodine not resulting in hypothyroidism, but not during follow-up after radioiodine-induced hypothyroidism. Independent associations of mortality with atrial fibrillation and incomplete biochemical control during treatment indicate potential causative links with poor outcome.

Background: Detecting antibody responses during and after SARS-CoV-2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect. Methods: We systemically developed an ELISA assay, optimising different antigens and amplification steps, in serum and saliva from symptomatic and asymptomatic SARS-CoV-2-infected subjects. Results: Using trimeric spike glycoprotein, rather than nucleocapsid enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti-spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti-spike, but not nucleocapsid, IgG, IgA and IgM antibody responses were readily detectable in saliva from non-hospitalized symptomatic and asymptomatic individuals. Antibody responses in saliva and serum were largely independent of each other and symptom reporting. Conclusions: Detecting antibody responses in both saliva and serum is optimal for determining virus exposure and understanding immune responses after SARS-CoV-2 infection. Funding: This work was funded by the University of Birmingham, the National Institute for Health Research (UK), the NIH National Institute for Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation and the University of Southampton.

Severe iodine deficiency during pregnancy has been associated with pregnancy/neonatal loss, and adverse pregnancy outcomes; however, the impact of mild–to–moderate iodine insufficiency, though prevalent in pregnancy, is not well-documented. We assessed whether mild iodine deficiency during pregnancy was associated with pregnancy/infant loss, or with other adverse pregnancy outcomes. We used samples and data from the Avon Longitudinal Study of Parents and Children (ALSPAC), from 3140 singleton pregnancies and from a further 42 women with pregnancy/infant loss. The group was classified as mildly-to-moderately iodine deficient with a median urinary iodine concentration of 95.3 µg/L (IQR 57.0–153.0; median urinary iodine-to-creatinine ratio (UI/Creat) 124 µg/g, IQR 82–198). The likelihood of pregnancy/infant loss was not different across four UI/Creat groups (250 µg/g). The incidence of pre-eclampsia, non-proteinuric gestational hypertension, gestational diabetes, glycosuria, anaemia, post-partum haemorrhage, preterm delivery, mode of delivery, being small for gestational age, and large for gestational age did not differ significantly among UI/Creat groups, nor were there any significant differences in the median UI/Creat. We conclude that maternal iodine status was not associated with adverse pregnancy outcomes in a mildly-to-moderately iodine-deficient pregnant population. However, in view of the low number of women with pregnancy/infant loss in our study, further research is required.

Background: Real-world evidence (RWE) plays an increasingly important role within global regulatory and reimbursement processes. RWE generation can be enhanced by the collection and use of patient-reported outcomes (PROs), which can provide valuable information on the effectiveness, safety, and tolerability of health interventions from the patient perspective. This systematic review aims to examine and summarise the available PRO-specific recommendations and guidance for RWE generation. Methods and findings: Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and websites of selected organisations were systematically searched to identify relevant publications. 1,249 articles were screened of which 7 papers met the eligibility criteria and were included in the review. The included publications provided PRO-specific recommendations to facilitate the use of PROs for RWE generation and these were extracted and grouped into eight major categories. These included: (1) instrument selection, (2) participation and engagement, (3) burden to health care professionals and patients, (4) stakeholder collaboration, (5) education and training, (6) PRO implementation process, (7) data collection and management, and (8) data analysis and presentation of results. The main limitation of the study was the potential exclusion of relevant publications, due to poor indexing of the databases and websites searched. Conclusions: PROs may provide valuable and crucial patient input in RWE generation. Whilst valuable insights can be gained from guidance for use of PROs in clinical care, there is a lack of international guidance specific to RWE generation in the context of use for regulatory decision-making, reimbursement, and health policy. Clear and appropriate evidence-based guidance is required to maximise the potential benefits of implementing PROs for RWE generation. Unique aspects between PRO guidance for clinical care and other purposes should be differentiated. The needs of various stakeholder groups (including patients, health care professionals, regulators, payers, and industry) should be considered when developing future guidelines.