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AbstractBackground: Little is known about the extent of impairments in work and activities of daily life (ADL) in patients with psoriasis, and the influence of contextual factors such as disease-related characteristics and treatment. Therefore, this study aimed to assess these impairments in patients with psoriasis who started using biologicals/small molecule inhibitors.Methods: Using data from the prospective BioCAPTURE registry, we collected patient, disease, and treatment parameters, as well as work/ADL impairments at baseline, 6 and 12 months. Changes in impairment parameters and correlations between impairment and patient/disease characteristics were assessed using generalized estimating equations.Results: We included 194 patients in our analysis. After biological initiation, disease activity decreased significantly (PASI 11.2 at baseline versus 3.9 at 12 months, p

Abstract Hypertriglyceridemia‐induced acute pancreatitis (HTG‐AP) is the third most common cause of AP after gallstones and alcohol. Supportive measures, intravenous insulin, and plasmapheresis are possible treatment modalities for HTG‐AP; however, definitive guidelines evaluating the best therapeutic approach are not clearly established. We present a rare case of a 42‐year‐old male without known comorbidities who was found to have HTG‐AP. Despite early initiation of intravenous insulin and plasmapheresis and the initial decline in his triglycerides level, his condition was complicated by necrotizing pancreatitis and subsequent multi‐organ failure. Future studies are warranted to evaluate the role of plasmapheresis in HTG‐AP and its efficacy.

Abstract Background Limited real‐world studies are available comparing infection risk between biologics for psoriasis. Objectives The primary aim was to determine the differential effect of currently available biologics on the risk of respiratory tract infections (RTI) among psoriasis patients in a real‐world setting. Secondary aims were to explore the differential risk of all types of serious infections (SI) between biologics and to provide an early overview of SARS‐CoV‐2 infections during the pre‐vaccine era. Methods Crude incidence rates of RTI and SI were calculated per 100 patient‐years (PY) per biologic using prospective BioCAPTURE data. Negative Binomial Regression modeling was used to explore the risk of RTI. Frailty Cox proportional hazards modeling was used to estimate hazard ratios for the risk of the first SI. Confounders adjusted for both models were selected by a directed acyclic graph. A post hoc exploratory analysis of SARS‐CoV‐2 infection incidence rates during 2020 was performed. Results We included 714 patients with 1325 treatment episodes (3607.7PY between 2005 and 2020), in which 2224 RTI and 63 SI occurred. Among RTI, 1.3% were serious. The crude incidence rates were 61.7 (95% confidence interval [CI]: 59.1–64.3) per 100PY for RTI, and 1.8 (95% CI: 1.4–2.2) per 100PY for SI. Confounder adjusted analyses showed no differential risk of RTI between adalimumab, etanercept, infliximab, ustekinumab, secukinumab, ixekizumab and guselkumab. For SI, no differential risk was found between biologics either. Extended single‐center data showed 3.8 (95% CI: 2.2–6.1) SARS‐CoV‐2 infections per 100PY in 2020. Conclusions Confounder adjusted analyses showed no differential risks of RTI or SI between included biologics (adalimumab, etanercept, infliximab, ustekinumab, secukinumab, ixekizumab and guselkumab) in a prospective psoriasis patients cohort. In general, absolute numbers of all types of SI were low.

Background: Thyroid hormones are controlled by the hypothalamic–pituitary–thyroid (HPT) axis through a complex network of regulatory loops, involving the hormones TRH, TSH, FT4, and FT3. The relationship between TSH and FT4 is widely used for diagnosing thyroid diseases. However, mechanisms of FT3 homeostasis are not well understood. Objective: We used mathematical modelling to further examine mechanisms that exist in the HPT axis regulation for protecting circulating FT3 levels. Methods: A mathematical model consisting of a system of four coupled first-order parameterized non-linear ordinary differential equations (ODEs) was developed, accounting for the interdependencies between the hormones in the HPT axis regulation. While TRH and TSH feed forward to the pituitary and thyroid, respectively, FT4 and FT3 feed backward to both the pituitary and hypothalamus. Stable equilibrium solutions of the ODE system express homeostasis for a particular variable, such as FT3, if this variable stays in a narrow range while certain other parameter(s) and system variable(s) may vary substantially. Results: The model predicts that (1) TSH-feedforward protects FT3 levels if the FT4 production rate declines and (2) combined negative feedback by FT4 and FT3 on both TSH and TRH production rates keeps FT3 levels insensitive to moderate changes in FT4 production rates and FT4 levels. The optimum FT4 and FT3 feedback and TRH and TSH-feedforward ranges that preserve FT3 homeostasis were found by numerical continuation analysis. Model predictions were in close agreement with clinical studies and individual patient examples of hypothyroidism and hyperthyroidism. Conclusions: These findings further extend the concept of HPT axis regulation beyond TSH and FT4 to integrate the more active sister hormone FT3 and mechanisms of FT3 homeostasis. Disruption of homeostatic mechanisms leads to disease. This provides a perspective for novel testable concepts in clinical studies to therapeutically target the disruptive mechanisms.

Background: Little is known about the extent of impairments in work and activities of daily life (ADL) in patients with psoriasis, and the influence of contextual factors such as disease-related characteristics and treatment. Therefore, this study aimed to assess these impairments in patients with psoriasis who started using biologicals/small molecule inhibitors. Methods: Using data from the prospective BioCAPTURE registry, we collected patient, disease, and treatment parameters, as well as work/ADL impairments at baseline, 6 and 12 months. Changes in impairment parameters and correlations between impairment and patient/disease characteristics were assessed using generalized estimating equations. Results: We included 194 patients in our analysis. After biological initiation, disease activity decreased significantly (PASI 11.2 at baseline versus 3.9 at 12 months, p<0.001). Work-for-pay in this cohort was lower than in the Dutch general population (53% versus 67%, p=0.01). In patients who had work-for-pay, presenteeism improved over time (5% at baseline versus 0% at 12months, p=0.04). Up to half of the patients reported impairments in ADL, which did not change over time. Associations between impairments and contextual factors varied, but all impairments were associated with worse mental/physical general functioning. Conclusion: Patients with psoriasis using biologicals are less likely to have work-for-pay. Treatment improves the work productivity of employed patients, but we were unable to detect changes in ADL performance. [ABSTRACT FROM AUTHOR]

Endocrine regulation in the hypothalamic-pituitary-thyroid (HPT) axis is orchestrated by physiological circuits which integrate multiple internal and external influences. Essentially, it provides either of the two responses to overt biological challenges: to defend the homeostatic range of a target hormone or adapt it to changing environmental conditions. Under certain conditions, such flexibility may exceed the capability of a simple feedback control loop, rather requiring more intricate networks of communication between the system’s components. A new minimal mathematical model, in the form of a parametrized nonlinear dynamical system, is here formulated as a proof-of-concept to elucidate the principles of the HPT axis regulation. In particular, it allows uncovering mechanisms for the homeostasis of the key biologically active hormone free triiodothyronine (FT3). One mechanism supports the preservation of FT3 homeostasis, whilst the other is responsible for the adaptation of the homeostatic state to a new level. Together these allow optimum resilience in stressful situations. Preservation of FT3 homeostasis, despite changes in FT4 and TSH levels, is found to be an achievable system goal by joining elements of top-down and bottom-up regulation in a cascade of targeted feedforward and feedback loops. Simultaneously, the model accounts for the combination of properties regarded as essential to endocrine regulation, namely sensitivity, the anticipation of an adverse event, robustness, and adaptation. The model therefore offers fundamental theoretical insights into the effective system control of the HPT axis.

Levothyroxine (LT4) therapy has a long history, a well-defined pharmacological profile and a favourable safety record in the alleviation of hypothyroidism. However, questions remain in defining the threshold for the requirement of treatment in patients with subclinical hypothyroidism, assessing the dose adequacy of the drug, and selecting the best treatment mode (LT4 monotherapy versus liothyronine [LT3]/LT4 combinations) for subpopulations with persisting complaints. Supplied as a prodrug, LT4 is enzymatically converted into the biologically more active thyroid hormone, triiodothyronine (T3). Importantly, tetraiodothyronine (T4) to T3 conversion efficiency may be impaired in patients receiving LT4, resulting in a loss of thyroid-stimulating hormone (TSH)-mediated feedforward control of T3, alteration of the interlocking equilibria between serum concentrations of TSH, free thyroxine (FT4), and free triiodothyonine (FT3), and a decrease in FT3 to FT4 ratios. This downgrades the value of the TSH reference system derived in thyroid health for guiding the replacement dose in the treatment situation. Individualised conditionally defined setpoints may therefore provide appropriate biochemical targets to be clinically tested, together with a stronger focus on clinical presentation and future endpoint markers of tissue thyroid state. This cautionary note encompasses the use of aggregated statistical data from clinical trials which are not safely applicable to the individual level of patient care under these circumstances.

Abstract Background In the treatment for hypothyroidism, a historically symptom-orientated approach has given way to reliance on a single biochemical parameter, thyroid stimulating hormone (TSH). Main body The historical developments and motivation leading to that decision and its potential implications are explored from pathophysiological, clinical and statistical viewpoints. An increasing frequency of hypothyroid-like complaints is noted in patients in the wake of this directional shift, together with relaxation of treatment targets. Recent prospective and retrospective studies suggested a changing pattern in patient complaints associated with recent guideline-led low-dose policies. A resulting dramatic rise has ensued in patients, expressing in various ways dissatisfaction with the standard treatment. Contributing factors may include raised problem awareness, overlap of thyroid-related complaints with numerous non-specific symptoms, and apparent deficiencies in the diagnostic process itself. Assuming that maintaining TSH anywhere within its broad reference limits may achieve a satisfactory outcome is challenged. The interrelationship between TSH, free thyroxine (FT4) and free triiodothyronine (FT3) is patient specific and highly individual. Population-based statistical analysis is therefore subject to amalgamation problems (Simpson’s paradox, collider stratification bias). This invalidates group-averaged and range-bound approaches, rather demanding a subject-related statistical approach. Randomised clinical trial (RCT) outcomes may be equally distorted by intra-class clustering. Analytical distinction between an averaged versus typical outcome becomes clinically relevant, because doctors and patients are more interested in the latter. It follows that population-based diagnostic cut-offs for TSH may not be an appropriate treatment target. Studies relating TSH and thyroid hormone concentrations to adverse effects such as osteoporosis and atrial fibrillation invite similar caveats, as measuring TSH within the euthyroid range cannot substitute for FT4 and FT3 concentrations in the risk assessment. Direct markers of thyroid tissue effects and thyroid-specific quality of life instruments are required, but need methodological improvement. Conclusion It appears that we are witnessing a consequential historic shift in the treatment of thyroid disease, driven by over-reliance on a single laboratory parameter TSH. The focus on biochemistry rather than patient symptom relief should be re-assessed. A joint consideration together with a more personalized approach may be required to address the recent surge in patient complaint rates.

Abstract Background In malaria endemic countries, asymptomatic cases constitute an important reservoir of infections sustaining transmission. Estimating the burden of the asymptomatic population and identifying areas with elevated risk is important for malaria control in Burkina Faso. This study analysed the spatial distribution of asymptomatic malaria infection among children under 5 in 24 health districts in Burkina Faso and identified the determinants of this distribution. Methods The data used in this study were collected in a baseline survey on “evaluation of the impact of pay for performance on the quality of care” conducted in 24 health districts in Burkina Faso, between October 2013 and March 2014. This survey involved 7844 households and 1387 community health workers. A Bayesian hierarchical logistic model that included spatial dependence and covariates was implemented to identify the determinants of asymptomatic malaria infection. The posterior probability distribution of a parameter from the model was summarized using odds ratio (OR) and 95% credible interval (95% CI). Results The overall prevalence of asymptomatic malaria infection in children under 5 years of age was estimated at 38.2%. However, significant variation was observed between districts ranging from 11.1% in the district of Barsalgho to 77.8% in the district of Gaoua. Older children (48–59 vs

Elevated concentrations of free thyroid hormones are established cardiovascular risk factors, but the association of thyrotropin (TSH) levels to hard endpoints is less clear. This may, at least in part, ensue from the fact that TSH secretion depends not only on the supply with thyroid hormones but on multiple confounders including genetic traits, medication and allostatic load. Especially psychosocial stress is a still underappreciated factor that is able to adjust the set point of thyroid function. In order to improve our understanding of thyroid allostasis, we undertook a systematic meta-analysis of published studies on thyroid function in post-traumatic stress disorder (PTSD). Studies were identified via MEDLINE/PubMed search and available references, and eligible were reports that included TSH or free thyroid hormone measurements in subjects with and without PTSD. Additionally, we re-analyzed data from the NHANES 2007/2008 cohort for a potential correlation of allostatic load and thyroid homeostasis. The available evidence from 13 included studies and 3386 euthyroid subjects supports a strong association of both PTSD and allostatic load to markers of thyroid function. Therefore, psychosocial stress may contribute to cardiovascular risk via an increased set point of thyroid homeostasis, so that TSH concentrations may be increased for reasons other than subclinical hypothyroidism. This provides a strong perspective for a previously understudied psychoendocrine axis, and future studies should address this connection by incorporating indices of allostatic load, peripheral thyroid hormones and calculated parameters of thyroid homeostasis.

Background: For significant numbers of patients dissatisfied on standard levothyroxine (LT4) treatment for hypothyroidism, patient-specific responses to T4 could play a significant role.Aim: To assess response heterogeneity to LT4 treatment, identifying confounders and hidden clusters within a patient panel, we performed a secondary analysis using data from a prospective cross-sectional and retrospective longitudinal study.Methods: Multivariate and multivariable linear models adjusted for covariates (gender, age, and BMI) were stratified by disease-specific treatment indication. During follow-up, pooled observations were compared from the same patient presenting either with or without self-reported symptoms. Statistical analysis was extended to multilevel models to derive intra-class correlation coefficients and reliability measures during follow-up.Results: Equilibria between TSH, FT4, and FT3 serum concentrations in 342 patients were examined by treatment indication (benign goiter, autoimmune thyroiditis, thyroid carcinoma), consequently displaying complex interactive response patterns. Seventy-seven patients treated with LT4 and monitored for thyroid carcinoma presented, in association with changes in LT4 dose, either with hypothyroid symptoms or symptom-free. Significant biochemical differences appeared between the different presentations. Leveled trajectories by subject to relief from hypothyroid symptoms differed significantly, indicating distinct responses, and denying a single shared outcome. These were formally defined by a high coefficient of the intraclass correlation (ICC1, exceeding 0.60 in all thyroid parameters) during follow-up on multiple visits at the same LT4 dose, when lacking symptoms. The intra-personal clusters were clearly differentiated from random variability by random group resampling. Symptomatic change in these patients was strongly associated with serum FT3, but not with FT4 or TSH concentrations. In 25 patients transitioning from asymptomatic to symptomatically hyperthyroid, FT3 concentrations remained within the reference limits, whilst at the same time marked biochemical differences were apparent between the presentations.Conclusions: Considerable intra-individual clustering occurred in the biochemical and symptomatic responses to LT4 treatment, implying statistically multileveled response groups. Unmasking individual differences in the averaged treatment response hereby highlights clinically distinguishable subgroups within an indiscriminate patient panel. This, through well-designed larger clinical trials will better target the different therapeutic needs of individual patients.

Randomised controlled trials are deemed to be the strongest class of evidence in evidence-based medicine. Failure of trials to prove superiority of T3/T4 combination therapy over standard LT4 monotherapy has greatly influenced guidelines, while not resolving the ongoing debate. Novel studies have recently produced more evidence from the examination of homeostatic equilibria in humans and experimental treatment protocols in animals. This has exacerbated a serious disagreement with evidence from the clinical trials. We contrasted the weight of statistical evidence against strong physiological counterarguments. Revisiting this controversy, we identify areas of improvement for trial design related to validation and sensitivity of QoL instruments, patient selection, statistical power, collider stratification bias, and response heterogeneity to treatment. Given the high individuality expressed by thyroid hormones, their interrelationships, and shifted comfort zones, the response to LT4 treatment produces a statistical amalgamation bias (Simpson’s paradox), which has a key influence on interpretation. In addition to drug efficacy, as tested by RCTs, efficiency in clinical practice and safety profiles requires reevaluation. Accordingly, results from RCTs remain ambiguous and should therefore not prevail over physiologically based counterarguments. In giving more weight to other forms of valid evidence which contradict key assumptions of historic trials, current treatment options should remain open and rely on personalised biochemical treatment targets. Optimal treatment choices should be guided by strict requirements of organizations such as the FDA, demanding treatment effects to be estimated under actual conditions of use. Various improvements in design and analysis are recommended for future randomised controlled T3/T4 combination trials.

In thyroid health, the pituitary hormone thyroid-stimulating hormone (TSH) raises glandular thyroid hormone production to a physiological level and enhances formation and conversion of T4 to the biologically more active T3. Overstimulation is limited by negative feedback control. In equilibrium defining the euthyroid state, the relationship between TSH and FT4 expresses clusters of genetically determined, interlocked TSH–FT4 pairs, which invalidates their statistical correlation within the euthyroid range. Appropriate reactions to internal or external challenges are defined by unique solutions and homeostatic equilibria. Permissible variations in an individual are much more closely constrained than over a population. Current diagnostic definitions of subclinical thyroid dysfunction are laboratory based, and do not concur with treatment recommendations. An appropriate TSH level is a homeostatic concept that cannot be reduced to a fixed range consideration. The control mode may shift from feedback to tracking where TSH becomes positively, rather than inversely related with FT4. This is obvious in pituitary disease and severe non-thyroid illness, but extends to other prevalent conditions including aging, obesity, and levothyroxine (LT4) treatment. Treatment targets must both be individualized and respect altered equilibria on LT4. To avoid amalgamation bias, clinically meaningful stratification is required in epidemiological studies. In conclusion, pituitary TSH cannot be readily interpreted as a sensitive mirror image of thyroid function because the negative TSH–FT4 correlation is frequently broken, even inverted, by common conditions. The interrelationships between TSH and thyroid hormones and the interlocking elements of the control system are individual, dynamic, and adaptive. This demands a paradigm shift of its diagnostic use.

Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion. Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships. Results: Under varying dose requirements (median 1.84 µg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH–FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3–TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (–0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels. Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH–FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control.

Thyroid hormone concentrations only become sufficient to maintain a euthyroid state through appropriate stimulation by pituitary TSH. In such a dynamic system under constant high pressure, guarding against overstimulation becomes vital. Therefore, several defensive mechanisms protect against accidental overstimulation, such as plasma protein binding, conversion of T4 into the more active T3, active transmembrane transport, counter-regulatory activities of reverse T3 and thyronamines and negative hypothalamic-pituitary-thyroid feedback control of TSH. TSH has gained a dominant but misguided role in interpreting thyroid function testing in assuming that its exceptional sensitivity thereby translates into superior diagnostic performance. However, TSH-dependent thyroid disease classification is heavily influenced by statistical analytic techniques such as uni- or multivariate-defined normality. This demands a separation of its conjoint roles as a sensitive screening test and accurate diagnostic tool. Homeostatic equilibria (set points) in healthy subjects are less variable, and do not follow a pattern of random variation, rather indicating signs of early and progressive homeostatic control across the euthyroid range. In the event of imminent thyroid failure with a reduced FT4 output per unit TSH, conversion efficiency increases in order to maintain FT3 stability. In such situations, T3 stability takes priority over set point maintenance. This suggests a concept of relational stability. These findings have important implications for both TSH reference limits and treatment targets for patients on levothyroxine. The use of archival markers is proposed to facilitate the homeostatic interpretation of all parameters.