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Background: Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA., Methods: Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables., Results: Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs., Conclusions: Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages., (© 2024. The Author(s).)

Background: Major thermal injury induces a complex pathophysiological state characterized by burn shock and hypercatabolism. Steroids are used to modulate these post-injury responses. However, the effects of steroids on acute post-burn outcomes remain unclear., Methods: In this study of 52 thermally injured adult patients (median total burn surface area 42%, 33 males and 19 females), the effects of corticosteroid and oxandrolone on mortality, multi-organ failure (MOF), and sepsis were assessed individually. Clinical data were collected at days 1, 3, 7, and 14 post-injury., Results: Twenty-two (42%) and 34 (65%) burns patients received corticosteroids and oxandrolone within the same cohort, respectively. Following separate analysis for each steroid, corticosteroid use was associated with increased odds of in-hospital mortality (OR 3.25, 95% CI: 1.32-8•00), MOF (OR 2.36, 95% CI: 1.00-1.55), and sepsis (OR 5.95, 95% CI: 2.53-14.00). Days alive (HR 0.32, 95% CI: 0.18-0.60) and sepsis-free days (HR 0.54, 95% CI: 0.37-0.80) were lower among corticosteroid-treated patients. Oxandrolone use was associated with reduced odds of 28-day mortality (OR 0.11, 95% CI: 0.04-0.30), in-hospital mortality (OR 0.19, 95% CI: 0.08-0.43), and sepsis (OR 0.24, 95% CI: 0.08-0.69). Days alive, at 28 days (HR 6.42, 95% CI: 2.77-14.9) and in-hospital (HR 3.30, 95% CI: 1.93-5.63), were higher among the oxandrolone-treated group. However, oxandrolone was associated with increased MOF odds (OR 7.90, 95% CI: 2.89-21.60) and reduced MOF-free days (HR 0.23, 95% CI: 0.11-0.50)., Conclusion: Steroid therapies following major thermal injury may significantly affect patient prognosis. Oxandrolone was associated with better outcomes except for MOF. Adverse effects of corticosteroids and oxandrolone should be considered when managing burn patients., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2022. The Author(s).)

Background: This study evaluates the utility of arterial blood gas (ABG) parameters and chest radiography in predicting intubation need in patients with burn injuries with suspected inhalation injury., Methods: Patients with suspected inhalation injury admitted to a single centre, Burn Intensive Care Unit, between April 4th 2016 and July 5th 2019, were included. Admission ABG parameters and chest radiograph opacification were compared with whether the patient received an appropriate intubation: defined as intubation for a duration of over 48 h. Area under the receiver operator characteristic curve was calculated (AUROC)., Results: Eighty-nine patients were included. The majority (84%; n = 75) were intubated, of which 81% (n = 61) received appropriate intubations. pH had an AUROC of 0.88 and a pH of <7.30 had an 80% sensitivity and specificity for detecting appropriate intubation. P/F ratio had an AUROC of 0.81 and a P/F ratio of <40 had a 70% sensitivity and specificity for appropriate intubation. Chest radiograph opacification had poor utility in this regard (AUROC = 0.69). Adding pH and P/F ratio to the ABA criteria improved their sensitivity in detecting appropriate intubations (sensitivity: ABA + pH + P/F = 0.97 vs ABA = 0.86; p = 0.013), without altering their specificity., Conclusions: In patients suspected inhalation injury, pH and P/F ratio were good predictors for appropriate intubations. Incorporating the parameters into the ABA criteria improved their clinical utility., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Strict isolation of vulnerable individuals has been a strategy implemented by authorities to protect people from COVID-19. Our objective was to investigate health-related quality of life (HRQoL), uncertainty and coping behaviours in solid organ transplant (SOT) recipients during the COVID-19 pandemic. A cross-sectional survey of adult SOT recipients undergoing follow-up at our institution was performed. Perceived health status, uncertainty and coping strategies were assessed using the EQ-5D-5L, Short-form Mishel Uncertainty in Illness Scale (SF-MUIS) and Brief Cope, respectively. Interactions with COVID-19 risk perception, access to health care, demographic and clinical variables were assessed. The survey was completed by 826 of 3839 (21.5%) invited participants. Overall, low levels of uncertainty in illness were reported, and acceptance was the major coping strategy (92%). Coping by acceptance, feeling protected, self-perceived susceptibility to COVID-19 were associated with lower levels of uncertainty. Health status index scores were significantly lower for those with mental health illness, compromised access to health care, a perceived high risk of severe COVID-19 infection and higher levels of uncertainty. A history of mental health illness, risk perceptions, restricted healthcare access, uncertainty and coping strategies was associated with poorer HRQoL in SOT recipients during strict isolation. These findings may allow identification of strategies to improve HRQoL in SOT recipients during the pandemic., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Introduction: Hyperthyroidism is a common condition affecting up to 3% of the UK population. Treatment improves symptoms and reduces the risk of atrial fibrillation and stroke that contribute to increased mortality. The most common symptom is weight loss, which is reversed during treatment. However, the weight regain may be excessive, contributing to increased risk of obesity. Current treatment options include antithyroid drugs, radioiodine and thyroidectomy. Whether there are differences in either weight change or the long-term cardiometabolic risk between the three treatments is unclear., Methods and Analysis: The study will establish the natural history of weight change in hyperthyroidism, investigate the risk of obesity and risks of cardiometabolic conditions and death relative to the treatment. The data on patients diagnosed with hyperthyroidism between 1 January 1996 and 31 December 2015 will come from Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office of National Statistics Death Registry. The weight changes will be modelled using a flexible joint modelling, accounting for mortality. Obesity prevalence in the general population will be sourced from Health Survey for England and compared with the post-treatment prevalence of obesity in patients with hyperthyroidism. The incidence and time-to-event of major adverse cardiovascular events, other cardiometabolic outcomes and mortality will be compared between the treatments using the inverse propensity weighting model. Incidence rate ratios of outcomes will be modelled with Poisson regression. Time to event will be analysed using Cox proportional hazards model. A competing risks approach will be adopted to estimate comparative incidences to allow for the impact of mortality., Ethics and Dissemination: The study will bring new knowledge on the risk of developing obesity, cardiometabolic morbidity and mortality following treatment for hyperthyroidism to inform clinical practice and public health policies. The results will be disseminated via open-access peer-reviewed publications and directly to the patients and public groups (Independent Scientific Advisory Committee protocol approval #20&#95;000185)., Competing Interests: Competing interests: KRA has served as a paid consultant, providing unrelated methodological advice to Abbvie, Amaris, Allergan, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Creativ-Ceutical, GSK, ICON/Oxford Outcomes, Ipsen, Janssen, Eli Lilly, Merck, NICE, Novartis, NovoNordisk, Pfizer, PRMA, Roche and Takeda, and has received research funding from the Association of the British Pharmaceutical Industry, European Federation of Pharmaceutical Industries & Associations, Pfizer and Sanofi. He is a partner and director of Visible Analytics Limited, a healthcare consultancy company., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

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 relatively 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. We systematically developed an ELISA, optimizing different antigens and amplification steps, in serum and saliva from non-hospitalized SARS-CoV-2-infected subjects. 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 IgG, IgA and IgM antibody responses were readily detectable in saliva from a minority of RT-PCR confirmed, non-hospitalized symptomatic individuals, and these were mostly subjects who had the highest levels of anti-spike serum antibodies. Therefore, detecting antibody responses in both saliva and serum can contribute to determining virus exposure and understanding immune responses after SARS-CoV-2 infection., (© 2021 The Authors. Immunology published by John Wiley & Sons Ltd.)

Background: The UK's transition from the European Union creates both an urgent need and key opportunity for the UK and its global collaborators to consider new approaches to the regulation of emerging technologies, underpinned by regulatory science. This survey aimed to identify the most accurate definition of regulatory science, to define strategic areas of the regulation of healthcare innovation which can be informed through regulatory science and to explore the training and infrastructure needed to advance UK and international regulatory science., Methods: A survey was distributed to UK healthcare professionals, academics, patients, health technology assessment agencies, ethicists and trade associations, as well as international regulators, pharmaceutical companies and small or medium enterprises which have expertise in regulatory science and in developing or applying regulation in healthcare. Subsequently, a descriptive quantitative analyses of survey results and directed thematic analysis of free-text comments were applied., Results: Priority areas for UK regulatory science identified by 145 participants included the following: flexibility: the capability of regulations to adapt to novel products and target patient outcomes; co-development: collaboration across sectors, e.g. patients, manufacturers, regulators, and educators working together to develop appropriate training for novel product deployment; responsiveness: the preparation of frameworks which enable timely innovation required by emerging events; speed: the rate at which new products can reach the market; reimbursement: developing effective tools to track and evaluate outcomes for "pay for performance" products; and education and professional development., Conclusions: The UK has a time-critical opportunity to establish its national and international strategy for regulatory science leadership by harnessing broader academic input, developing strategic cross-sector collaborations, incorporating patients' experiences and perspectives, and investing in a skilled workforce.

This study compares the ability of liberal vs restrictive intubation criteria to detect prolonged intubation and inhalation injury in burn patients with suspected inhalation injury. Emerging evidence suggests that using liberal criteria may lead to unnecessary intubation in some patients. A single-center retrospective cohort study was conducted in adult patients with suspected inhalation injury admitted to intensive care at Queen Elizabeth Hospital, Birmingham between April 2016 and July 2019. Liberal intubation criteria, as reflected in local guidelines, were compared to restrictive intubation criteria, as outlined in the American Burn Association guidelines. The number of patients displaying positive characteristics from either guideline was compared to the number of patients who had prolonged intubation (more than 48 hours) and inhalation injury. In detecting a need for prolonged intubation (n = 85), the liberal criteria had greater sensitivity (liberal = 0.98 [0.94-1.00] vs restrictive = 0.84 [0.75-0.93]; P = .013). However, the restrictive criteria had greater specificity (restrictive = 0.96 [0.89-1.00] vs liberal = 0.48 [0.29-0.67]; P < .001). In detecting inhalation injury (n = 72), the restrictive criteria were equally sensitive (restrictive = 0.94 [0.87-1.00] vs liberal = 0.98 [0.84-1.00]; P = .48) and had greater specificity (restrictive = 0.86 [0.72-1.00] vs liberal = 0.04 [0.00-0.13]; P < .001). In patients who met liberal but not restrictive criteria, 65% were extubated within 48 hours and 90% did not have inhalation injury. Liberal intubation criteria were more sensitive at detecting a need for prolonged intubation, while restrictive criteria were more specific. Most patients intubated based on liberal criteria alone were extubated within 48 hours. Restrictive criteria were highly sensitive and specific at detecting inhalation injury., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Background: The most commonly reported symptom of hyperthyroidism is weight loss; successful treatment increases weight. Weight gain faced by patients with hyperthyroidism is widely considered a simple reaccumulation of premorbid weight, whereas many patients feel there is a significant weight "overshoot" attributable to the treatment. We aimed to establish if weight gain seen following treatment for hyperthyroidism represents replenishment of premorbid weight or "overshoot" beyond expected regain and, if there is excessive weight gain, whether this is associated with the applied treatment modality. Methods: We calculated the risk of becoming obese (body mass index [BMI] >30 kg/m 2 ) following treatment for hyperthyroidism by comparing BMI of 1373 patients with overt hyperthyroidism seen in a secondary care setting with the age- and sex-matched background population (Health Survey for England, 2007-2009). Next, we investigated the effect of treatment with an antithyroid drug (ATD) alone in regard to ATD with radioactive iodine ( 131 I) therapy. We modeled the longitudinal weight data in relation to the treatment pathway to thyroid function and the need for long-term thyroxine replacement. Results: During treatment of hyperthyroidism, men gained 8.0 kg (standard deviation ±7.5) and women 5.5 kg (±6.8). At discharge, there was a significantly increased risk of obesity in male (odds ratio = 1.7 [95% confidence interval 1.3-2.2], p  < 0.001) and female (1.3, 1.2-1.5, p  < 0.001) patients with hyperthyroidism compared with the background population. Treatment with 131 I was associated with additional weight gain (0.6 kg, 0.4-0.8, p  < 0.001), compared with ATD treatment alone. More weight gain was seen if serum thyrotropin (TSH) was markedly increased (TSH >10 mIU/L; 0.5 kg, 0.3-0.7, p  < 0.001) or free thyroxine (fT4) was reduced (fT4 ≤ 10 pmol/L (0.8 ng/dL); 0.3 kg, 0.1-0.4, p  < 0.001) during follow-up. Initiation of levothyroxine was associated with further weight gain (0.4 kg, 0.2-0.6, p  < 0.001) and the predicted excess weight gain in 131 I-induced hypothyroidism was 1.8 kg. Conclusions: Treatment for hyperthyroidism is associated with significant risks of becoming obese. 131 I treatment and subsequent development of hypothyroidism were associated with small but significant amounts of excess weight gain compared with ATD alone. We advocate that the discussion over the weight "overshoot" risk forms part of the individualized treatment decision-making process.

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 (<50, 50-149, 150-250, >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., Competing Interests: The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results. S.-Y.C. is part of an academic consortium that has received research funding from Nestec. All other authors report no conflict of interest.

Background: Graves' disease (GD) as an immune reconstitution inflammatory syndrome during highly active antiretroviral therapy (HAART) for HIV has previously been reported. However, clinical challenges associated with HIV in the context of thyroid eye disease (TED) are not as well-characterized., Objective: To determine the frequency of coexisting HIV and TED, describe TED presentation and course in the context of HIV, and evaluate management difficulties as well as potential solutions., Methods: Cross-sectional study of all patients with coexisting GD and HIV at University Hospitals Birmingham (2003-2014). Retrospective case note review to identify TED with particular reference to HAART regimen, CD4+ T-cell count, HIV viral load, and TED activity and severity., Results: Of 783 subjects with GD and 1186 with HIV, 11 were identified with both GD and HIV. Of these, three had clinical features of TED; each was of Afro-Caribbean origin, was in their fourth decade, and initially presented with undetectable CD4 T cells and high HIV viral loads. All went on to develop GD >3 years after commencing HAART, with normal CD4 count and undetectable viral load at the time of GD diagnosis. The full spectrum of TED was represented, with two subjects requiring orbital decompression surgery., Discussion: TED in the context of HIV is uncommon. Many challenges exist in such patients, particularly HAART drug interactions with antithyroid and immunosuppressant medications. To better understand TED in HIV and to counsel patients with this copathology most effectively, future multicenter surveillance is required.

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.