Prevalence and incidence of palmoplantar pustulosis in Sweden: a population-based register study.

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic relapsing skin condition characterized by sterile pustules on the palm and soles. Population-based estimates of PPP incidence and prevalence are limited. OBJECTIVES: To estimate the prevalence and incidence of PPP in the Swedish general population and to estimate the prevalence of psoriasis vulgaris among the population with PPP. METHODS: The Swedish National Patient Register was used, covering all inpatient and outpatient nonprimary care for the Swedish population. We identified cases (2004-2015) with one International Classification of Diseases 10th Revision diagnostic code (base case) for PPP. The point prevalence estimates at the end of this period (31 December 2015) were obtained by linkage to the Swedish Total Population Register. In sensitivity analyses, we used alternative case definitions: (i) requiring two visits and (ii) requiring two visits, one of which was within dermatology or internal medicine. RESULTS: The base case prevalence of PPP was estimated to be 147 per 100 000 (women 227, men 68) and the annual prevalence was estimated to 26 per 100 000 in 2015. Among the population of people with PPP, 17% were registered with a diagnostic code for psoriasis vulgaris. The incidence of PPP in 2015 was estimated to be 12·7 per 100 000 (women 18·7, men 6·6). The criteria used had an impact on the prevalence and incidence estimates: strict case 1 gave an overall prevalence of 72 per 100 000 and an incidence of 5·4 per 100 000. CONCLUSIONS: The results indicate that the population-based prevalence of PPP may be larger than previously estimated. However, the estimates were sensitive to the employed PPP case criteria. The findings enhance demands for studies using validated diagnostic algorithms potentially also including data from primary care.

Complete skin clearance and Psoriasis Area and Severity Index response rates in clinical practice: predictors, health-related quality of life improvements and implications for treatment goals.

BACKGROUND: Psoriasis Area and Severity Index (PASI) 90 is suggested to be the new standard endpoint for randomized controlled trials of biologics for psoriasis, whereas treatment guidelines often still refer to PASI 75. OBJECTIVES: To analyse in a real-world setting: firstly, what factors are associated with higher levels of treatment response to biologics; secondly, the health-related quality of life gains associated with different response levels in clinical practice. METHODS: Biologically naïve patients with PASI, Dermatology Life Quality Index (DLQI) and EuroQol (EQ)-5D outcomes before (maximum 6 months) and after (3-12 months) switch to biologics during registration in the Swedish National Registry for Systemic Treatment of Psoriasis (PsoReg) were included (n = 515). Patient characteristics associated with higher treatment response were analysed by regression analyses. Improvements in absolute PASI, DLQI and EQ-5D were assessed in different PASI percentage response levels. RESULTS: High PASI percentage response was associated with higher PASI before switch and lower body mass index. DLQI and EQ-5D improved within all responder groups (P < 0·001). The magnitude of improvements in DLQI (P = 0·02) differed between responder groups. The mean (SD) DLQI improvements for PASI 75<90 responders, PASI 90<100 responders and patients achieving complete skin clearance (PASI 100) were 9·9 (7·4), 11·5 (7·0) and 8·0 (6·1), respectively. CONCLUSIONS: PASI percentage change is largely dependent on absolute PASI before switch. Patients in clinical practice lack 'baseline' PASI values as they may switch directly from one treatment to another or stay successfully treated for a longer time period. Treatment goals such as PASI 90 are thus not suitable for treatment guidelines or for follow-up in clinical practice. What's already known about this topic? Randomized clinical trials of biologics as well as treatment guidelines include treatment goals based on a percentage improvement compared with baseline Psoriasis Area and Severity Index (PASI), such as PASI 75 or PASI 90. Few studies have assessed which factors are associated with high skin clearance rates, or health-related quality of life (HRQoL) improvements associated with different levels of skin clearance in clinical practice. What does this study add? A high absolute PASI before switch to biologics and low body mass index are associated with higher PASI percentage response. Few patients with baseline PASI >30 achieved complete skin clearance (CSC). All responder groups achieved significant HRQoL improvements. Patients achieving CSC (PASI 100) had lower absolute PASI before switch and lower improvements in absolute PASI and HRQoL than patients with almost cleared skin. What are the clinical implications of this work? Relative measures based on PASI percentage, such as PASI 75 or PASI 90, are not suitable for treatment guidelines or for follow-up in clinical practice.

Multi-indication and Combination Pricing and Reimbursement of Pharmaceuticals: Opportunities for Improved Health Care through Faster Uptake of New Innovations.

Many pharmaceuticals are effective in multiple indications and the degree of effectiveness may differ. A product-based pricing and reimbursement system with a single price per product is insufficient to reflect the variable values between different indications. The objective of this article is to present examples of actual pricing and reimbursement decisions using current value-based pricing in Sweden and to discuss their implications and possible solutions. The value of several cancer drugs was estimated for various indications based on a willingness-to-pay threshold of 1 million SEK (EUR 104,000) per QALY gained. For some drugs, the estimated value was higher than the drug acquisition cost in several indications, whilst in others, the estimated value was lower than the drug acquisition cost. Drugs used in combination present a special case. If a drug prolongs survival and consequently also a continued use of the anchor drug, the combination use may not be cost effective even at a zero price. In a product-based pricing and reimbursement system, patients may not get access to drugs or access may be delayed and manufacturers may be discouraged to invest in future indications. To overcome these issues, there are several approaches to link price and value. One approach is a "weighted-average" price based on an average of the value across all indications. Another is "multi-indication pricing," which enables price differentiation between indications. However, there are several barriers for applying multi-indication pricing and reimbursement schemes. One barrier is the lack of existing administrative infrastructure to track patients' indications.

Real-world outcomes in 2646 psoriasis patients: one in five has PASI ≥10 and/or DLQI ≥10 under ongoing systemic therapy.

BACKGROUND: Although biologics introduced a new era in psoriasis care when available a decade ago, it is unclear to what extent the available systemic treatments treat patients adequately. OBJECTIVE: To analyse the clinical severity and quality of life of the psoriasis population in Sweden treated with systemics. METHODS: Data included 2646 patients from the Swedish Registry for Systemic Treatment of Psoriasis. Average Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and EQ-5D were reported. A subgroup of persisting moderate-to-severe psoriasis as defined by PASI ≥10 and/or DLQI ≥10 after >12 weeks treatment was analysed. RESULTS: Mean (SD) PASI, DLQI and EQ-5D were 4.12 (4.57), 4.11 (5.24) and 0.79 (0.22). Eighteen percent had persisting moderate-to-severe psoriasis (n = 472). These patients were younger, had higher BMI, had psoriasis arthritis and were smoking to a larger extent (p < 0.01) compared with lower-severity patients (n = 2174). Mean (SD) EQ-5D was also considerably lower 0.63 (0.29) vs. 0.82 (0.19) (p < 0.01). CONCLUSION: Almost one in every five patients had persisting moderate-to-severe psoriasis, despite ongoing systemic treatment. Both comorbidities and life style factors were associated with persisting moderate-to-severe psoriasis. The considerably lower generic quality of life in these patients demonstrates an unmet need. Subsequently, improved access to biologics and continuous drug development is needed in psoriasis.

Health related quality of life in patients with actinic keratosis--an observational study of patients treated in dermatology specialist care in Denmark.

BACKGROUND: Actinic keratosis (AK) is a common skin condition that may progress to non-melanoma skin cancer (NMSC). The disease may influence Health Related Quality of Life (HRQoL), but studies of HRQoL in patients with AK are limited. The purpose of the study was to analyze HRQoL in patients with different severity levels of AK treated in dermatology specialist care using generic and disease-specific HRQoL instruments and to analyze their relationship. METHODS: AK patients who visited dermatological clinics in Denmark were included in an observational, cross-sectional, study in a multi-center setting. Dermatologists assessed AK severity and patients completed: Actinic Keratosis Quality of Life Questionnaire (AKQoL), Dermatology Life Quality Index (DLQI), and EQ-5D-5 L including EQ-VAS. Differences between categorical subgroups were tested with Wilcoxon rank-sum test. The relationship between instruments was analyzed with the Spearman correlation test. RESULTS: A total of 312 patients were included in the analyses. Patients reported impairment in the disease specific HRQoL instrument AKQoL (mean AKQoL 6.7, DLQI 2, EQ-5D-5 L 0.88, and EQ-VAS 79). HRQoL was least affected in patients with mild actinic disease, whereas patients with severe actinic damage suffered from further impaired HRQoL (mean AKQoL 10.1 and DLQI 4.6). Correlations between DLQI and AKQoL were moderate, whereas the correlations between DLQI and EQ-5D-5 L and between AKQoL and EQ-5D-5 L were weak. CONCLUSIONS: Patients with severe actinic damage showed more impairment in HRQoL than those with mild disease. Correlations between instruments suggest that they are complementary as they measure different aspects of HRQoL and are used for different purposes.

Octanoate and nonaoate oxidation increases 50-80% over the first two days of life in piglet triceps brachii and gracilis muscle strips.

An in vitro muscle strip incubation system was developed to measure the rate of catabolism of 1 mmol/L [1-(14)C]octanoate, 1 mmol/L [1-(14)C]nonanoate, 1 mmol/L [9-(14)C]nonanoate, and 10 mmol/L [U-(14)C]glucose by measuring the recovery of (14)CO(2). Muscle strips (13 mm × 1.5 mm, ~50 mg) were isolated from triceps brachii and gracilis muscles of newborn and 2-d-old, small (<950 g) and large (>1450 g) piglets. The position of the (14)C label in the substrate affected the rate and amount of recovery in (14)CO(2). Therefore, comparisons were made between age groups (0 vs. 2 d old) within substrates but limited across substrates to comparisons of [1-(14)C]-labeled fatty acids. The medium-chain fatty acid (MCFA) oxidation rates [pmol/(h · mg)] in muscle strips isolated from piglets from the 2 weight groups (<950 and >1450 g) did not differ (P > 0.99), there was a trend towards a difference between triceps brachii and gracilis muscle (P = 0.09; data not shown), and there were no significant interactions involving pig weight or muscle type; therefore, results were pooled across these factors. During the first 2 d of life, MCFA oxidation [pmol/(h • · mg muscle strip)] increased (P < 0.05) 50-80%, but the glucose oxidation rate did not change (P > 0.82). By d 2, the oxidation rate of nonanoate as represented by the one carbon was 25% greater than for octanoate (P < 0.05). The conversion of [9-(14)C]nonanoate to (14)CO(2) indicated that muscle had the capacity to oxidize the propionyl-CoA produced by ß-oxidation of nonanoate and that odd-chain C-9 MCFA provided anabolic carbon to the citric acid cycle.

Analysis of three outcome measures in moderate to severe psoriasis: a registry-based study of 2450 patients.

BACKGROUND: As moderate to severe psoriasis is a systemic disease with large effects on health-related quality of life, generic measures that include overall health, not only skin involvement, are necessary. Knowledge about the relationship between the generic preference-based EuroQol 5D (EQ-5D) and dermatology-specific measures in psoriasis is limited. OBJECTIVES: To analyse EQ-5D, the Dermatology Life Quality Index (DLQI) and the Psoriasis Area and Severity Index (PASI) in patients with moderate to severe psoriasis in Swedish clinical practice by demographic characteristics, to compare EQ-5D among patients vs. Swedish population values, and to analyse the relationships between EQ-5D, DLQI and PASI. METHODS: This observational cohort study was based on PsoReg, the Swedish National Registry for Systemic Treatment of Psoriasis. EQ-5D was compared among patients with psoriasis vs. a defined general population in Sweden, retrieved from a previous study. Relationships between measures were examined with correlation tests and regression analysis. RESULTS: In total, 2450 patients (1479 men and 971 women) were included. Median EQ-5D, DLQI and PASI scores were 0·769, 4 and 4·7, respectively. Patients with psoriasis had a significantly lower EQ-5D compared with the defined general population. EQ-5D correlated moderately with DLQI (-0·55) and weakly with PASI (-0·25) (P < 0·001). CONCLUSIONS: When assessing psoriasis treatments and making decisions about treatment guidelines and resource allocation, EQ-5D, DLQI and PASI provide a useful set of complementary tools, answering to different needs. If EQ-5D is not included in the original trial the second-best option in cost-effectiveness studies is to use mapping between DLQI and EQ-5D.

Blood D-(-)-3-hydroxybutyrate concentrations after oral administration of trioctanoin, trinonanoin, or tridecanoin to newborn rhesus monkeys (Macaca mulatta).

Premature newborn infants are born with limited stores of glycogen and fat. Energy, such as medium-chain triglycerides (MCT), which can spare the use of body protein as metabolic energy, may be beneficial. This study compares MCT containing C8, C9, or C10 fatty acids as oral sources of energy for newborn rhesus monkeys (Macaca mulatta). On day 1 of life, 4 groups of 5 monkeys were given a single dose of water or MCT by nasogastric tube. The dose provided approximately 80% of the expected energy requirement. Plasma C8:0, C9:0, and C10:0 fatty acids and whole-blood D-(-)-3-hydroxybutyrate (3HB) concentrations were measured at 0, 1, and 3 h after dosing. Concentrations of free fatty acids (C8, C9, or C10) and ketone (3HB) increased with time after the dose. At 1 and 3 h, concentrations of C8 and C9 did not differ, but C9 was greater than C10. At 1 h, blood 3HB concentrations due to C8 triglyceride were higher than C9 or C10 (503 versus 174 and 225 µmol/L respectively). As MCT chain length increased from C8 to C10, blood concentration of 3HB decreased. Odd-chain MCT (C9 versus C8) resulted in lower whole-blood ketone (3HB), perhaps due to C9 metabolism or the rate of release or uptake of fatty acids. These results have implications for the use of MCT in nutritional supplements for preterm infants.

Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium.

This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-alpha and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione concentrations and the SAM-SAH ratio; increasing cytochrome P4502E1 activation and lipid peroxidation; up-regulating endoplasmic reticulum stress markers, including sterol regulatory element-binding protein-1, and proapoptotic gene caspase-12; and decreasing global DNA methylation. Betaine may attenuate ALD by increasing the synthesis of SAM and, eventually, glutathione, decreasing the hepatic concentrations of homocysteine and SAH, and increasing the SAM-SAH ratio, which can trigger a cascade of events that lead to the activation of phosphatidylethanolamine methyltransferase, increased phosphatidylcholine synthesis, and formation of VLDL for the export of triacylglycerol from the liver to the circulation. Additionally, decreased concentrations of homocysteine can down-regulate endoplasmic reticulum stress, which leads to the attenuation of apoptosis and fatty acid synthesis.

Unique aspects of lysine nutrition and metabolism.

Lysine nutrition is unique among indispensable amino acids in that it can be conserved and can be fed 12 h out of phase (delayed supplement) with the other dietary amino acids. In piglets, high levels (2-6%) of L-lysine added to a 10% protein diet can be tolerated without obvious detrimental effects. In both rat and piglet liver preparations, the first enzyme in the saccharopine-dependent pathway of lysine catabolism, lysine alpha-ketoglutarate reductase (LKR), is found only in the mitochondrial matrix. For Lys catabolism to occur, Lys must first enter the matrix of the mitochondrion. LKR, saccharopine dehydrogenase, mitochondrial lysine uptake, and lysine oxidation (LOX) all increased>3-fold in rats fed high levels of dietary protein (up to 60%). The activities of mitochondrial Lys uptake and LOX were similar when expressed as mmol/(d.100 g body weight). Thus, LOX can be a proxy for mitochondrial Lys uptake. Piglet liver LKR and LOX increase 5- to 10-fold when piglets are fed high-protein (50 or 75%) diets. In both the rat and piglet, after adapting to the high protein diet, the activity of LKR is 400-500 times that of LOX, suggesting that Lys uptake by a transporter(s) is rate limiting. Quantitative 24-h dietary infusion studies in piglets revealed that>80% of the Lys infused (4% of the diet) could not be recovered in the urine or body or accounted for by calculated Lys oxidation based on liver activity of LOX. Other pathways and tissues may account for the Lys oxidation in piglets.

Consideration of betaine and one-carbon sources of N5-methyltetrahydrofolate for use in homocystinuria and neural tube defects.

A major focus in attempts to ameliorate homocystinuria and neural tube defects is supplementation of the diet with B vitamins. The metabolic defect in these cases may be due in part to a deficiency of methyl groups. B vitamin supplementation supports the need for enzyme cofactors but cannot provide substrate in the form of methyl groups. l-Methionine is an essential amino acid and is required for protein synthesis, but it also plays a unique role in metabolism as S-adenosylmethionine, which is the primary methyl donor in metabolism. The observation that l-homocysteine, which is produced in the metabolism of l-methionine, is remethylated 2-4 times before it is destroyed is key to understanding the possibility of a methyl group deficiency. This suggests that the requirement for methyl groups (ie, S-adenosylmethionine) may be 2-4 times that for methionine in support of protein synthesis. l-Homocysteine can be remethylated to form l-methionine by betaine or N(5)-methyltetrahydrofolate. Betaine and one-carbon sources that lead to the production of N(5)-methyltetrahydrofolate and the remethylation of l-homocysteine to form l-methionine should be considered along with B vitamin supplementation in the treatment of homocystinuria and neural tube defects.

Glomerulus-specific mRNA transcripts and proteins identified through kidney expressed sequence tag database analysis.

The kidney glomerulus plays a crucial role in blood filtration but the molecular composition and physiology of the glomerulus is not well understood. We previously constructed and large-scale sequenced four mouse glomerular expressed sequence tag (EST) libraries from newborn and adult mouse glomeruli. Here, we compared glomerular EST profiles with whole kidney EST profiles, thereby identifying 497 transcripts corresponding to UniGene clusters that were glomerulus-enriched, that is expressed more abundantly in glomeruli than in whole kidney. These include several known protein-coding glomerulus-specific transcripts critical for glomerulus development and function, but also a large number of gene transcripts, which have not previously been shown to be expressed in the glomerulus, or implicated in glomerular functions. We used in situ hybridization to demonstrate glomerulus-specific RNA expression for six novel glomerular genes and the public Human Protein Atlas to verify glomerular protein expression for another two. The higher mRNA abundance for the eight genes in glomeruli compared with whole kidney was also verified by Taqman quantitative polymerase chain reaction. We surmise that the further characterization of these genes and proteins will increase our understanding of glomerular development and physiology.

The contribution of body protein to the supply of energy in starved newborn piglets is not preferentially suppressed by intravenous provision of glucose and fat.

Newborn piglets were used to study body protein preservation because it is critical to the survival of premature infants. Quantitative estimates of endogenous fuel use were obtained from 12 to 72 h of age in male piglets. Of the 40 piglets used (1300 +/- 205 g, mean +/- SD), 16 served as a 12-h-old body composition reference (R), 16 were starved (S) and received water only, and 8 received supplemental energy (E), obtaining 70% [210 kJ/(kg x d)] of their resting energy requirement as an i.v. mixture of glucose and Intralipid (65:35 energy ratio). Urine was collected continuously from the bladder via an umbilical urachal catheter. Total body water, glycogen, lipid, ash, and Kjeldahl-N were determined on whole-pig homogenates. Comparative slaughter was used to estimate the disappearance of body constituents of S and E pigs from 12 to 72 h of age. Midpoint body weight was used in these calculations. Supplemental energy decreased use of all body energy sources as indicated by the decrease in body dry matter disappearance, 41.6 +/- 8.8 vs. 25.5 +/- 5.9 g/kg (P = 0.0021) and protein (urinary N excretion), 995 +/- 508 vs. 329 +/- 135 mg/kg (P = 0.0119) over 60 h. Supplemental energy did not preferentially spare the percentage of the resting energy expenditure supplied by endogenous body protein (protein 37.6% +/- 9.6 vs. 41.7% +/- 10.4; lipid 25.7% +/- 5.2 vs. 20% +/- 4.1; glycogen 36.8% +/- 7.5 vs. 38.3% +/- 9.9; S vs. E) because it made up approximately 40% of the total in food-deprived and supplemented piglets.

Recovery of (15)n in the body, urine, and gas phase of piglets infused intravenously with (15)n L-alanine from 12-72 hours of age.

Previous studies of nitrogen metabolism provided evidence suggesting that nitrogen excretory product(s) not measured by standard methods of analysis escape detection. To determine whether (15)N could be recovered quantitatively in the body, urine, or expired gas, newborn piglets (n = 16; 1.47 +/- 0.27 kg) were infused intravenously with (15)N L-alanine from 12 to 72 h of age at a rate providing 25% of the piglets' resting energy expenditure and a (15)N abundance of 2.3 (n = 4), 2.8 (n = 10), or 3.3 (n = 2) atom percent. To investigate the possibility of gaseous nitrogen excretion, 4 piglets infused with (15)N L-alanine were housed in a closed circuit respiration system initially flushed with an 80% argon:20% O(2) mixture. The gas composition of the system was monitored at 12-h intervals throughout the experiment. Mean total recovery of (15)N was 93.3 +/- 2.8% and was significantly different from 100% (P < 0.001). To determine whether (15)N recovery was altered by metabolism, 2 piglets (1.34 +/- 0.13 kg) were killed 6 min after a bolus i.v. infusion of (15)N L-alanine (97.96 +/- 1.13 atom percent). Mean recovery of (15)N in the bodies of these piglets was 101.5 +/- 1.6% and was not different from 100%. No change in chamber gas (28)N(2) (P = 0.0969) or (29)N(2) (P = 0.08565) over 72 h was evident. The inability to recover 6.7 +/- 2.8% of infused (15)N suggests that a nitrogen-containing excretory product or metabolite may be escaping detection, but the discrepancy cannot be explained by gaseous nitrogen ((28)N(2), (29)N(2), or (30)N(2)) excretion.