Direct Comparison of Real-world Effectiveness of Biologics for Psoriasis using Absolute and Relative Psoriasis Area and Severity Index Scores in a Prospective Multicentre Cohort.

Real-world evidence, directly comparing the effectiveness of interleukin (IL)17-inhibitors, IL23-inhibitors, tumour necrosis factor alpha (TNF-α)-inhibitors and an IL12/23-inhibitor in psoriasis, is scarce. The aim of this study was to directly compare the first-year effectiveness of biologic therapies for psoriasis, corrected for confounders. This prospective, multicentre cohort study assessed BioCAPTURE data on etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab, and guselkumab in 1,080 treatment episodes of 700 patients with psoriasis. The course of the mean absolute Psoriasis Area and Severity Index (PASI) and the proportion of patients who achieved PASI90/PASI75 were compared using linear mixed models and mixed logistic regression models respectively, corrected for baseline PASI, biologic naivety, and weight. Patients treated with adalimumab, ustekinumab, secukinumab, ixekizumab, or guselkumab all had a significantly lower mean PASI after 12 months compared with etanercept, and significantly higher overall odds of reaching PASI90 than those treated with etanercept. Patients treated with ixekizumab or guselkumab also had higher probabilities of reaching PASI90 than adalimumab, ustekinumab, and secukinumab. Relative to randomized controlled trials, the proportions of patients who reached PASI90/75 were lower in this real-world study.

Triiodothyronine secretion in early thyroid failure: The adaptive response of central feedforward control.

BACKGROUND: Defined by thyroid-pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production. MATERIALS & METHODS: A system of five coupled first-order nonlinear parameterised ordinary differential equations (ODEs) is used to model the feedback control of TSH and TRH by thyroid hormones together with the feedforward control of thyroidal T3 secretion and enzymatic T4-T3 conversion. Dependencies of the stable equilibrium solutions of this ODE system, that is the homeostasis of the underlying physiological process, on the system parameters were investigated whether they accounted for clinical observations. RESULTS: During the modelled transition to hypothyroidism, central control imposed an increasing influence in maintaining serum FT3 levels, compared to peripheral conversion efficiency. Numerical continuation analysis revealed dependencies of T3 production on different elements of TSH feedforward control. While T4-T3 conversion provided the main T3 source in euthyroidism, this was overtaken by increasing glandular T3 secretion when thyroid reserve declined. The computational results were in good agreement with data from untreated patients with autoimmune thyroiditis. CONCLUSIONS: Dependencies revealed in the expression of control differ in thyroid health and disease, using a physiologically based mathematical model of combined feedback-feedforward control of the hypothalamic-pituitary-thyroid regulation. Strong T3-protective mechanisms of the control system emerge with declining thyroid function, when glandular T3 secretion becomes increasingly influential over conversion efficiency. This has wide-ranging implications for the utility of TSH in clinical decision-making.

Time for a reassessment of the treatment of hypothyroidism.

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.

Real-life treatment of cutaneous warts with cantharidin podophyllin salicylic acid solution.

Patients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects, and patient satisfaction after topical application of cantharidin 1% podophyllin 2% salicylic acid 30% (CPS1) solution in a large series of children and adults with cutaneous warts. Fifty-two children and 83 adults with warts, treated with CPS1 solution between October 2012 and October 2014, were included. Complete clearance of warts occurred in 86.5% of children and 62.7% of adults treated with CPS1 solution (p < .01). Resolution of warts was partial in 3.9 and 24.1% and absent in 9.6 and 13.2% of children and adults respectively. Side effects were present in 41.2% of children and 46.3% of adults (p = .7). Most common side effects were blistering, pain, and burning sensation. No serious adverse events occurred. On a 10-point scale, median patient satisfaction score was 9.0 (interquartile range 7.8-10.0) and 8.0 (interquartile range 5.1-9.7) for children and adults respectively (p < .01). CPS1 solution is a safe and promising treatment modality with a high clearance and high patient satisfaction rate for the management of cutaneous warts, particularly in children.

The role of functional thyroid capacity in pituitary thyroid feedback regulation.

BACKGROUND: Thyroid feedback regulation and equilibria between thyroid hormones differ in the presence or absence of a functioning thyroid remnant. MATERIALS AND METHODS: This study examines the relationship between the sensitivity of TSH feedback and thyroid capacity in untreated patients with thyroid autoimmune disease (n = 86) and healthy controls (n = 271). Functional capacity was estimated at maximum TSH stimulation, and pituitary TSH response was FT4-standardised with two established indices, the TSH index and the thyrotroph thyroid hormone resistance index. RESULTS: The two indices correlated inversely with thyroid volume and functional thyroid capacity. Relationships were shifted upwards in patients with thyroid autoimmune disease. This positioned patients with thyroid autoimmune disease predominantly at the lower capacity range and upper part of TSH index. The relationship was modulated by serum FT3 concentrations, shifting 0.19 [95%CI: 0.12, 0.26] mIU/L per pmol FT3 increase. FT3 correlated with TSH index in total group ( τ  = 0.09, P = 0.009) and both subgroups. FT3 levels were maintained despite a substantial capacity loss by progressively increasing conversion rates of T3 from T4, only collapsing at capacities below <1.5 pmol/s. CONCLUSION: Functional thyroid capacity and preferential T3 generation are essential elements in adjusting the sensitivity of hypothalamic-pituitary-thyroid feedback control and balancing system equilibria. This suggests that the indirect regulatory role of glandular T3 co-secretion exceeds its quantitative contribution to the thyroid hormone pool. Implications for clinical practice extend to the diagnostic use of TSH in patients with impaired thyroid reserve.

Spatial distribution and determinants of asymptomatic malaria risk among children under 5 years in 24 districts in Burkina Faso.

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 < 6 months: OR: 6.79 [5.62, 8.22]), children from very poor households (Richest vs poorest: OR: 0.85 [0.74-0.96]), households located more than 5 km from a health facility (< 5 km vs  ≥ 5 km: OR: 1.14 [1.04-1.25]), in localities with inadequate number of nurses (< 3 vs ≥ 3: 0.72 [0.62, 0.82], from rural areas (OR: 1.67 [1.39-2.01]) and those surveyed in high transmission period of asymptomatic malaria (OR: 1.27 [1.10-1.46]) were most at risk for asymptomatic malaria infection. In addition, the spatial analysis identified the following nine districts that reported significantly higher risks: Batié, Boromo, Dano, Diébougou, Gaoua, Ouahigouya, Ouargaye, Sapouy and Toma. The district of Zabré reported the lowest risk. CONCLUSION: The analysis of spatial distribution of infectious reservoir allowed the identification of risk areas as well as the identification of individual and contextual factors. Such national spatial analysis should help to prioritize areas for increased malaria control activities.

Multigene testing of moderate-risk genes: be mindful of the missense.

BACKGROUND: Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established. METHODS: We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold. RESULTS: Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5. CONCLUSIONS: Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women.

Breast cancer risk is higher in US-born than in foreign-born Hispanics/Latinas and also increases with greater length of US residency. It is only partially known what factors contribute to these patterns of risk. To gain new insights, we tested the association between lifestyle and demographic variables and breast cancer status, with measures of estrogenic (E) and glucocorticogenic (G) activity in Mexican American women. We used Chemical-Activated LUciferase gene eXpression assays to measure E and G activity in total plasma from 90 Mexican American women, without a history of breast cancer at the time of recruitment, from the San Francisco Bay Area Breast Cancer Study. We tested associations of nativity, lifestyle and sociodemographic factors with E and G activity using linear regression models. We did not find a statistically significant difference in E or G activity by nativity. However, in multivariable models, E activity was associated with Indigenous American ancestry (19% decrease in E activity per 10% increase in ancestry, P = 0.014) and with length of US residency (28% increase in E activity for every 10 years, P = 0.035). G activity was associated with breast cancer status (women who have developed breast cancer since recruitment into the study had 21% lower G activity than those who have not, P = 0.054) and alcohol intake (drinkers had 25% higher G activity than non-drinkers, P = 0.015). These associations suggest that previously reported breast cancer risk factors such as genetic ancestry and alcohol intake might in part be associated with breast cancer risk through mechanisms linked to the endocrine system.

Rare mutations in XRCC2 increase the risk of breast cancer.

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry.

BACKGROUND: Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention. METHODS: Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status. RESULTS: High parity (≥3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk. CONCLUSIONS: Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.

Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment.

OBJECTIVE: We examined the interrelationships of pituitary thyrotropin (TSH) with circulating thyroid hormones to determine whether they were expressed either invariably or conditionally and distinctively related to influences such as levothyroxine (L-T4) treatment. DESIGN AND METHODS: This prospective study employing 1912 consecutive patients analyses the interacting equilibria of TSH and free triiodothyronine (FT3) and free thyroxine (FT4) in the circulation. RESULTS: The complex interrelations between FT3, FT4 and TSH were modulated by age, body mass, thyroid volume, antibody status and L-T4 treatment. By group comparison and confirmation by more individual TSH-related regression, FT3 levels were significantly lower in L-T4-treated vs untreated nonhypothyroid autoimmune thyroiditis (median 4·6 vs 4·9 pm, P < 0·001), despite lower TSH (1·49 vs 2·93 mU/l, P < 0·001) and higher FT4 levels (16·8 vs 13·8 pm, P < 0·001) in the treated group. Compared with disease-free controls, the FT3-TSH relationship was significantly displaced in treated patients with carcinoma, with median TSH of 0·21 vs 1·63 (P < 0·001) at a comparable FT3 of 5·0 pm in the groups. Disparities were reflected by calculated deiodinase activity and remained significant even after accounting for confounding influences in a multivariable model. CONCLUSIONS: TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in defining the overall patterns of thyroidal expression, regulation and metabolic activity. Equilibria typical of the healthy state are not invariant, but profoundly altered, for example, by L-T4 treatment. Consequently, this suggests the revisitation of strategies for treatment optimization.

Effect of Radioiodine Treatment on Quality of Life in Patients with Subclinical Hyperthyroidism: A Prospective Controlled Study.

Radioiodine treatment (RIT) has a high success rate in both the treatment of hyperthyroidism and improving the quality of life (QoL) of symptomatic patients. In asymptomatic patients with subclinical hyperthyroidism thyroid related QoL outcomes are less well known. METHODS: Study aim was to evaluate thyroid-related QoL in patients with subclinical hyperthyroidism mostly due to toxic nodular goitre undergoing RIT, compared to a control group of euthyroid subjects. Study design was monocentric, prospective, controlled. Fifty control subjects were enrolled and 51 RIT patients. Most subjects were examined at least twice at an interval of 6 months, with visits immediately before and 6 months after treatment in the RIT group. QoL was estimated with the ThyPRO questionnaire, using its composite scale as primary outcome. Treatment effect was the mean adjusted difference (MAD) between groups over time, using repeated? measures mixed? effects models. RESULTS: TSH concentrations were lower in the RIT group prior to treatment and recovered thereafter slightly above the level of the control group. Correspondingly, QoL improved significantly after 6 months from a worse level in the RIT group, compared to controls (MAD -10.3 [95% CI -14.9, -5.7], p<0.001). QoL improvements were strong for general items, but less pronounced for the hyperthyroid domain. Compared to controls, thyroid volume, thyroid functional capacity (SPINA-GT) and deiodinase activity (SPINA-GD) were significantly reduced in the RIT group. CONCLUSION: Patients with subclinical hyperthyroidism improve both biochemically and in their QoL after RIT, compared to controls. QoL assessment should have a wider role in clinical practice to complement biochemical tests and help with treatment decisions.

Hypertriglyceridemia-induced acute necrotizing pancreatitis: Poor clinical outcomes requiring revisiting management modalities.

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.

Impairment in work and activities of daily life in patients with psoriasis: results of the prospective BioCAPTURE registry.

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 12 months, 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.

Tumour morphology predicts PALB2 germline mutation status.

BACKGROUND: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. METHODS: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. RESULTS: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0-64.6; P=5 × 10(-7)). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. CONCLUSION: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.

The role of supporting and disruptive mechanisms of FT3 homeostasis in regulating the hypothalamic-pituitary-thyroid axis.

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.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Principles of Endocrine Regulation: Reconciling Tensions Between Robustness in Performance and Adaptation to Change.

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.

Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations.

BACKGROUND: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. METHODS: We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. RESULTS: For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. CONCLUSION: First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

The Two Faces of Janus: Why Thyrotropin as a Cardiovascular Risk Factor May Be an Ambiguous Target.

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.