Decreased Arterial Vascular Tone in Small Arteries in Severe Hidradenitis Suppurativa - A Study Using Finger Photopulseplethysmography.

A previous study has found an association between chronic inflammatory disorders e.g. psoriasis, rheumatoid arthritis, and inflammatory bowel disease and increased vascular stiffness(1). Psoriasis and hidradenitis suppurativa (HS) are believed to have shared comorbidities and pathophysiology despite their morphologically different manifestations in the skin. In order to evaluate a putative association between the chronic inflammatory skin disease HS and arterial stiffness, an observational cross-sectional retrospective study was carried out as part of the Danish General Suburban Population Study (GESUS) (1), in which 430 patients with HS from the general population (representing mild HS; Table 1), 32 patients with HS from a hospital-based out-patient clinic (representing severe HS, Table 1), and 20,780 controls underwent measurements of arterial vascular tone and stiffness using photoplethysmography (Pulse Trace PCA2®; Micro Medical Ltd, Kent, UK). The method of Pulse Trace has been validated by correlation with intra-arterial sensing techniques, and is a simple cost-effective screening method[2]. All analyses were performed using SAS 9.3. This study was accepted by the ethics committee of Region Zealand (project number SJ-191, SJ-113, SJ-114) in Denmark (2,3). RESULTS Reflection index (RI) is an expression of arterial vascular tone and stiffness of small arteries. The raw data showed a significantly lower RI for both HS groups groups, compared to controls. The results remained significant when adjusting for confounders (age, sex, smoking and metabolic syndrome) in the out-patient clinic HS group (-11.26 (-17.75- -4.76), P=0.0002*), but not in the population HS group (Table 2). Stiffness index (SI) expresses arterial stiffness in large arteries. Both HS groups showed no significant difference in either SI or vascular age in multivariate analysis, when compared with controls (Table 2). DISCUSSION This study suggests that decreased vascular tone and stiffness of small arteries may be associated with severe HS, and at the same time found no difference in arterial stiffness in large arteries. The significance for the out-patient clinic HS group, but not the population HS group may reflect a dose-response relationship. Vascular tone in vascular smooth muscle cells of small arteries depends on competing vasodilators and vasoconstrictors. We speculate that the inflammation of HS may induce a dysfunctional balance e.g. through increased TNF-alpha with subsequent increase of the vasodilator nitric oxide resulting in the lower arterial vascular tone observed. Additionally, mast cells are increased in HS [4], possibly increasing levels of the vasodilator histamine. HS patients often suffer from stress which could increase sympathetic activity, thereby adrenalin/cortisol and subsequent vasodilation in e.g. muscles. The more peripheral an artery is, the more collagen it contains and the stiffer it is. The finding of lower vascular tone may also be suggestive of a different elastin:collagen ratio in small arteries in HS. The healing process of HS lesions is known to involve scarring formation of sinus tracts [5], which may suggest a hypothesis of altered connective tissue. This study found no difference in SI expressing arterial stiffness of large arteries between HS and controls. Our previous study found an association between HS and myocardial infarction, but no association with stroke, nor peripheral arterial stiffness of lower extremities in medium/large arteries [6], suggesting regional differences in vascular beds in HS. The major limitation of the study is the missing values of pulse trace measurement (Table 1) creating possible selection bias. Although unable to draw any clinical conclusions, we believe these results may contribute to the future research of the complexity of HS and cardiovascular risk profiling. This study suggests that decreased vascular tone and stiffness of small arteries may be associated with severe HS, and at the same time found no difference in arterial stiffness in large arteries. The significance for the out-patient clinic HS group, but not the population HS group may reflect a dose-response relationship. Vascular tone in vascular smooth muscle cells of small arteries depends on competing vasodilators and vasoconstrictors. We speculate that the inflammation of HS may induce a dysfunctional balance e.g. through increased TNF-alpha with subsequent increase of the vasodilator nitric oxide resulting in the lower arterial vascular tone observed. Additionally, mast cells are increased in HS [4], possibly increasing levels of the vasodilator histamine. HS patients often suffer from stress which could increase sympathetic activity, thereby adrenalin/cortisol and subsequent vasodilation in e.g. muscles. The more peripheral an artery is, the more collagen it contains and the stiffer it is. The finding of lower vascular tone may also be suggestive of a different elastin:collagen ratio in small arteries in HS. The healing process of HS lesions is known to involve scarring formation of sinus tracts [5], which may suggest a hypothesis of altered connective tissue. This study found no difference in SI expressing arterial stiffness of large arteries between HS and controls. Our previous study found an association between HS and myocardial infarction, but no association with stroke, nor peripheral arterial stiffness of lower extremities in medium/large arteries [6], suggesting regional differences in vascular beds in HS. The major limitation of the study is the missing values of pulse trace measurement (Table 1) creating possible selection bias. Although unable to draw any clinical conclusions, we believe these results may contribute to the future research of the complexity of HS and cardiovascular risk profiling.

Preoperative pulmonary function in all comers for cardiac surgery predicts mortality†.

OBJECTIVES: Although reduced lung function and chronic obstructive pulmonary disease (COPD) is associated with higher risk of death following cardiac surgery, preoperative spirometry is not performed routinely. The aim of this study was to investigate the relationship between preoperative lung function and postoperative complications in all comers for cardiac surgery irrespective of smoking or COPD history. METHODS: Preoperative spirometry was performed in elective adult cardiac surgery patients. Airflow obstruction was defined as the ratio of forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio below the lower limit of normal (LLN) and reduced forced ventilatory capacity defined as FEV1

Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years.

Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19-29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding.

Serum Vaccine Antibody Concentrations in Adolescents Exposed to Perfluorinated Compounds.

BACKGROUND: Postnatal exposure to perfluorinated alkylate substances (PFASs) is associated with lower serum concentrations of specific antibodies against certain childhood vaccines at 7 y. OBJECTIVES: We prospectively followed a Faroese birth cohort to determine these associations at 13 y. METHODS: In 516 subjects (79% of eligible cohort members) who were 13 years old, serum concentrations of PFASs and of antibodies against diphtheria and tetanus were measured and were compared with data from the previous examination at 7 y. Multiple regression analyses and structural equation models were applied to determine the association between postnatal PFAS exposures and antibody concentrations. RESULTS: Serum concentrations of PFASs and antibodies generally declined from 7 y to 13 y. However, 68 subjects had visited the emergency room and had likely received a vaccination booster, and a total of 202 children showed higher vaccine antibody concentrations at 13 y than at 7 y. Therefore, separate analyses were conducted after exclusion of these two subgroups. Diphtheria antibody concentrations decreased at elevated PFAS concentrations at 13 y and 7 y; the associations were statistically significant for perfluorodecanoate (PFDA) at 7 y and for perfluorooctanoate (PFOA) at 13 y, both suggesting a decrease by ∼25% for each doubling of exposure. Structural equation models showed that a doubling in PFAS exposure at 7 y was associated with losses in diphtheria antibody concentrations at 13 y of 10­30% for the five PFASs. Few associations were observed for anti-tetanus concentrations. CONCLUSIONS: These results are in accord with previous findings of PFAS immunotoxicity at current exposure levels. https://doi.org/10.1289/EHP275.

Leukocyte Profile in Peripheral Blood and Neutrophil-Lymphocyte Ratio in Hidradenitis Suppurativa: A Comparative Cross-Sectional Study of 462 Cases.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease. Increasing evidence suggests that HS involves dysfunctional immune responses in both the adaptive and the innate immune system. The recently proposed association of HS with metabolic syndrome may further add to the inflammatory state in HS. OBJECTIVE: To investigate the status of inflammation and leukocyte profile in the peripheral blood of HS patients. MATERIALS AND METHODS: Using a comparative cross-sectional study design, we investigated blood samples of high-sensitivity C-reactive protein (hs-CRP) and leukocyte profile in hospital-treated HS patients (HS-HOSP), self-reported population-based HS patients (HS-POP) and population controls. RESULTS: Our study comprised 32 individuals in the HS-HOSP group, 430 in the HS-POP group, and 20,780 controls. The median hs-CRP for the HS-HOSP group was 5.1 mg/l (quartile range 2.6-8.2), 2.2 mg/l (1.0-4.3) for the HS-POP group and 1.3 mg/l (0.7-2.9) for the controls. An age-sex-adjusted analysis revealed a significantly higher hs-CRP for both HS groups compared to controls (p < 0.0001). When performing age-sex-adjusted analysis, both HS groups had significantly higher odds of leukocytosis when compared to controls with an odds ratio for the HS-HOSP group of 4.38 (95% CI = 2.18-8.80; p < 0.0001) and 1.95 (95% CI = 1.58-2.42; p < 0.0001) for the HS-POP group. The age-sex-adjusted leukocyte differential count yielded significantly higher neutrophil (p < 0.0001) and monocyte (p = 0.0014, p = 0.0004) levels in the HS groups compared with controls. CONCLUSION: The hs-CRP levels associated with HS appear to be intermediate (2.2-5.1 mg/l), implying systemic inflammation rather than infection. The peripheral blood leukocytosis in HS was dominated by neutrophils and monocytes.

A Population- and Hospital-based Cross-sectional Study of Renal Function in Hidradenitis Suppurativa.

The chronic inflammatory skin diseases hidradenitis suppurativa (HS) and psoriasis have been linked to cardiovascular risk factors and the latter has also been linked to possible renal dysfunction. Since basement membrane thinning in the skin of HS patients has been described, we speculated whether similar basement membrane defects might occur in renal tissue. Our objective was to investigate a possible association between HS and renal dysfunction. We performed a hospital and population-based cross-sectional study using estimated Glomerular-Filtration-Rate (eGFR) to assess renal function. Thirty-two hospital individuals with HS, 430 population individuals with HS, and 20,780 population individuals without HS were (controls) identified. The age-, sex-, smoking-, BMI-, hypertension- and diabetes-adjusted analysis revealed a statistically significant higher eGFR for the hospital group with HS and a mean difference in eGFR of 6.81 (1.27-12.35) ml/min/1.73 m2 between the hospital group with HS and the population group without HS. The observed higher eGFR in the hospital group with HS indicates a possible association of HS and renal dysfunction.

Gallstones are associated with hidradenitis suppurativa: a population-based and hospital-based cross-sectional study from Denmark.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory dermatological disease that was recently linked to the metabolic syndrome (MetS). MetS has been associated with gallstones, and nonalcoholic fatty liver has been suggested to be the hepatic expression of MetS. OBJECTIVE: The objective of the study was to investigate whether there was an association of HS with gallstones as well as with hepatic dysfunction. PATIENTS AND METHODS: This was a cross-sectional study comparing a hospital-based HS group, a population-based HS group, and controls for self-reported gallstone and blood sample verified hepatic dysfunction. Blood samples were analyzed for alanine transaminase, bilirubin, alkaline phosphatase, albumin, thrombocytes, and the international normalized ratio. RESULTS: A total of 32 hospital HS patients, 430 population-based HS patients, and 20 780 non-HS controls were identified. The age-sex-smoking-adjusted analysis of gallstones revealed a significant OR of 1.72 (95% CI 1.23-2.42, P=0.0191) and a borderline significant OR of 3.28 (95% CI 1.24-8.74, P=0.0516) for the population HS group and hospital HS group versus controls, respectively. Furthermore, no clinically significant evidence was found with regard to hepatic dysfunction. CONCLUSION: This study demonstrates an association of HS with gallstones, but not with hepatic dysfunction. The association with gallstones may be partly explained by the comorbidity of hypertriglyceridemia and obesity as a part of MetS.

Breastfeeding as an Exposure Pathway for Perfluorinated Alkylates.

Perfluorinated alkylate substances (PFASs) are widely used and have resulted in human exposures worldwide. PFASs occur in breast milk, and the duration of breastfeeding is associated with serum-PFAS concentrations in children. To determine the time-dependent impact of this exposure pathway, we examined the serum concentrations of five major PFASs in a Faroese birth cohort at birth, and at ages 11, 18, and 60 months. Information about the children's breastfeeding history was obtained from the mothers. The trajectory of serum-PFAS concentrations during months with and without breastfeeding was examined by linear mixed models that accounted for the correlations of the PFAS measurements for each child. The models were adjusted for confounders such as body size. The duration of exclusive breastfeeding was associated with increases of most PFAS concentrations by up to 30% per month, with lower increases during partial breast-feeding. In contrast to this main pattern, perfluorohexanesulfonate was not affected by breast-feeding. After cessation of breastfeeding, all serum concentrations decreased. This finding supports the evidence of breastfeeding being an important exposure pathway to some PFASs in infants.

Coagulation Status in Hidradenitis Suppurativa: A Danish Population- and Hospital-Based Cross-Sectional Study.

BACKGROUND: Chronic inflammatory diseases other than hidradenitis suppurativa (HS) have been associated with prothrombotic/hypercoagulable status. OBJECTIVE: To investigate a possible association between the chronic inflammatory skin disease HS and prothrombotic/hypercoagulable state. METHODS: We performed a hospital- and population-based cross-sectional study investigating the coagulation status (thrombocytes, mean platelet volume [MPV], international normalized ratio [INR] and activated partial thromboplastin time [APTT]). RESULTS: 32 hospital HS subjects, 430 population HS subjects and 20,780 population non-HS control subjects were identified. The adjusted analyses showed no differences in the levels of thrombocytes, MPV, INR or APTT between the HS groups (hospital HS group, population HS group) when compared to controls (p = 0.089, p = 0.3078; p = 0.5499, p = 0.0659; p = 0.0932; p = 0.3432). CONCLUSION: We did not find an association between HS and prothrombotic/hypercoagulable status. Thus, thrombocytes may not be activated in HS. Furthermore, INR may not be affected in HS, suggesting that intrinsic and vitamin K-dependent coagulation factors appear unaffected.

Structural equation modeling of immunotoxicity associated with exposure to perfluorinated alkylates.

BACKGROUND: Exposure to perfluorinated alkylate substances (PFASs) is associated with immune suppression in animal models, and serum concentrations of specific antibodies against certain childhood vaccines tend to decrease at higher exposures. As such, we investigated the immunotoxic impacts of the three major PFASs in a Faroese birth cohort. METHODS: A total of 464 children contributed blood samples collected at age 7 years. PFAS concentrations and concentrations of antibodies against diphtheria and tetanus were assessed in serum at age 7 years, and results were available from samples collected at age 5. In addition to standard regressions, structural equation models were generated to determine the association between three major PFASs measured at the two points in time and the two antibody concentrations. RESULTS: Concentrations of all three 7-year PFAS concentrations were individually associated with a decrease in concentrations of antibodies, however, it was not possible to attribute causality to any single PFAS concentration. Hence, the three 7-year concentrations were combined and showed that a 2-fold increase in PFAS was associated with a decrease by 54.4% (95% CI: 22.0%, 73.3%) in the antibody concentration. If considering both the age-5 and age-7 concentrations of the three major PFASs, the exposure showed a slightly greater loss. CONCLUSIONS: These analyses strengthen the evidence of human PFAS immunotoxicity at current exposure levels and reflect the usefulness of structural equation models to adjust for imprecision in the exposure variables.

Negative confounding by essential fatty acids in methylmercury neurotoxicity associations.

BACKGROUND: Methylmercury, a worldwide contaminant of fish and seafood, can cause adverse effects on the developing nervous system. However, long-chain n-3 polyunsaturated fatty acids in seafood provide beneficial effects on brain development. Negative confounding will likely result in underestimation of both mercury toxicity and nutrient benefits unless mutual adjustment is included in the analysis. METHODS: We examined these associations in 176 Faroese children, in whom prenatal methylmercury exposure was assessed from mercury concentrations in cord blood and maternal hair. The relative concentrations of fatty acids were determined in cord serum phospholipids. Neuropsychological performance in verbal, motor, attention, spatial, and memory functions was assessed at 7 years of age. Multiple regression and structural equation models (SEMs) were carried out to determine the confounder-adjusted associations with methylmercury exposure. RESULTS: A short delay recall (in percent change) in the California Verbal Learning Test (CVLT) was associated with a doubling of cord blood methylmercury (-18.9, 95% confidence interval [CI]=-36.3, -1.51). The association became stronger after the inclusion of fatty acid concentrations in the analysis (-22.0, 95% confidence interval [CI]=-39.4, -4.62). In structural equation models, poorer memory function (corresponding to a lower score in the learning trials and short delay recall in CVLT) was associated with a doubling of prenatal exposure to methylmercury after the inclusion of fatty acid concentrations in the analysis (-1.94, 95% CI=-3.39, -0.49). CONCLUSIONS: Associations between prenatal exposure to methylmercury and neurobehavioral deficits in memory function at school age were strengthened after fatty acid adjustment, thus suggesting that n-3 fatty acids need to be included in analysis of similar studies to avoid underestimation of the associations with methylmercury exposure.

A random forest approach for competing risks based on pseudo-values.

Random forest is a supervised learning method that combines many classification or regression trees for prediction. Here we describe an extension of the random forest method for building event risk prediction models in survival analysis with competing risks. In case of right-censored data, the event status at the prediction horizon is unknown for some subjects. We propose to replace the censored event status by a jackknife pseudo-value, and then to apply an implementation of random forests for uncensored data. Because the pseudo-responses take on values on a continuous scale, the node variance is chosen as split criterion for growing regression trees. In a simulation study, the pseudo split criterion is compared with the Gini split criterion when the latter is applied to the uncensored event status. To investigate the resulting pseudo random forest method for building risk prediction models, we analyze it in a simulation study of predictive performance where we compare it to Cox regression and random survival forest. The method is further illustrated in two real data sets.

Evaluating Random Forests for Survival Analysis using Prediction Error Curves.

Prediction error curves are increasingly used to assess and compare predictions in survival analysis. This article surveys the R package pec which provides a set of functions for efficient computation of prediction error curves. The software implements inverse probability of censoring weights to deal with right censored data and several variants of cross-validation to deal with the apparent error problem. In principle, all kinds of prediction models can be assessed, and the package readily supports most traditional regression modeling strategies, like Cox regression or additive hazard regression, as well as state of the art machine learning methods such as random forests, a nonparametric method which provides promising alternatives to traditional strategies in low and high-dimensional settings. We show how the functionality of pec can be extended to yet unsupported prediction models. As an example, we implement support for random forest prediction models based on the R-packages randomSurvivalForest and party. Using data of the Copenhagen Stroke Study we use pec to compare random forests to a Cox regression model derived from stepwise variable selection. Reproducible results on the user level are given for publicly available data from the German breast cancer study group.

Oral methotrexate/6-mercaptopurine may be superior to a multidrug LSA2L2 Maintenance therapy for higher risk childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.

The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy with a multidrug cyclic LSA2L2 regimen. 135 children with B-lineage ALL and a white blood count > or =50 x 10/L and 98 children with T-lineage ALL were included. Of the 234 patients, the 135 patients who received MTX/6MP maintenance therapy had a lower relapse risk than the 98 patients who received LSA2L2 maintenance therapy, which was the case for both B-lineage (27%+/-5% vs. 45%+/-9%; P=0.02) and T-lineage ALL (8%+/-5% vs. 21%+/-5%; P=0.12). In multivariate Cox regression analysis stratified for immune phenotype, a higher white blood count (P=0.01) and administration of LSA2L2 maintenance therapy (P=0.04) were both related to an increased risk of an event (overall P value of the Cox model: 0.003), whereas neither sex, age at diagnosis, administration of central nervous system irradiation, nor presence of a day 15 bone marrow with > or =25% versus <25% lymphoblasts were of statistical significance. These results indicate that oral MTX/6MP maintenance therapy administered after the first year of remission can improve the cure rates of children with T-lineage or with higher risk B-lineage ALL.