Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A : A nationwide real-world study with 700 person-years

AimFor previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). MethodsFrom the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. ResultsAll 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1years. The mean (SD) annual treatment costs (Europerkg) were 4391Euro (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383448Euro (259085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. ConclusionsEarly high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2years.Peer reviewe

Multiple psychological factors predict pain and disability among community-dwelling knee osteoarthritis patients : a five-year prospective study

Objective: To identify predictors of long-term pain and disability in knee osteoarthritis. Design: A longitudinal cohort study of five years. Setting: Primary care providers. Subjects: In all, 108 patients (mean age = 63.6 years, standard deviation (SD) = 7.2 years) with knee pain (> 40 mm on a 100 mm visual analogue scale in the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain scale) and radiographic grading (Kellgren-Lawrence: 2-4) of knee osteoarthritis who participated in a randomized controlled trial. Main measures: Disease-specific pain and functioning were assessed using the corresponding WOMAC subscales. Generic functioning was assessed by the RAND-36 subscales for function and physical and mental component summary scores. Possible baseline predictors for these outcomes were (1) demographic and disease-related variables and (2) psychological variables of mood (anxiety, depression), pain-related cognitions (pain self-efficacy, pain catastrophizing, kinesiophobia), and positive resource factors (life satisfaction, sense of coherence). Results: Multivariate linear mixed model analyses revealed that minimal anxiety at baseline predicted significantly better results for pain (WOMAC, P = 0.019) and function (WOMAC, P = 0.001, RAND-36 function P = 0.001). High pain self-efficacy predicted significantly better scores in RAND-36 function (P = 0.006), physical (P = 0.004) and mental (P = 0.001) component summaries. Pain catastrophizing predicted higher pain (P = 0.015), whereas fear of movement predicted poorer functioning in RAND-36 physical (P = 0.016) and mental (P = 0.009) component summaries. Those satisfied with life reported higher scores in RAND-36 function (P = 0.002) and mental component summary (P = 0.041). A low number of comorbidities predicted significantly better results in pain (WOMAC P = 0.019) and function (WOMAC P = 0.033, RAND-36 P = 0.009). Conclusion: Anxiety, pain-related cognitions, and psychological resources predict symptoms in knee osteoarthritis in the long term.Peer reviewe

Genetic Polymorphism in Evolving Population

We present a model for evolving population which maintains genetic polymorphism. By introducing random mutation in the model population at a constant rate, we observe that the population does not become extinct but survives, keeping diversity in the gene pool under abrupt environmental changes. The model provides reasonable estimates for the proportions of polymorphic and heterozygous loci and for the mutation rate, as observed in nature

Rhodium(II)-catalyzed stereocontrolled synthesis of dihydrofuran-3-imines from 1-Tosyl-1,2,3-triazoles

Rhodium(II) acetate catalyzes the denitrogenative transformation of 5-substituted and 4,5-disubstituted 1-sulfonyl-1,2,3-triazoles with pendent allyl and propargyl ether motifs to oxonium ylides that undergo [2,3]-sigmatropic rearrangement to give substituted dihydrofuran-3-imines in high yield and diastereoselectivity

Maternal Transmission of Resistance to Development of Allergic Airway Disease

Parental phenotype is known to influence the inheritance of atopic diseases, such as allergic asthma, with a maternal history being a more significant risk factor for progeny than paternal history. We hypothesized that recall Th1- or Th2-type immune responses during pregnancy would result in transfer of maternal factors that would differentially impact development of immune responsiveness in offspring. Following weaning, susceptibility and severity of allergic airway disease (a murine model of human asthma) was evaluated in progeny, disease being elicited by immunization with OVA-Al(OH)3 and challenge with aerosolized OVA. We found that progeny of mothers with Th1-biased immunity to OVA subjected to recall aerosol challenge during pregnancy had reduced levels of Ag-specific IgE and airway eosinophilia compared with progeny of mothers with Th2-biased immunity to OVA or naive mothers. Interestingly, progeny of mothers with Th1-type immunity to a heterologous albumin, BSA, were not protected from developing OVA-induced allergic airway disease. These findings demonstrated that maternal transfer of protection from development of allergic airway disease to offspring in this model of maternal Th1-type immunity was Ag specific

Hypertension and exposure to noise near airports: the HYENA study

BACKGROUND: An increasing number of people are exposed to aircraft and road traffic noise. Hypertension is an important risk factor for cardiovascular disease, and even a small contribution in risk from environmental factors may have a major impact on public health. OBJECTIVES: The HYENA (Hypertension and Exposure to Noise near Airports) study aimed to assess the relations between noise from aircraft or road traffic near airports and the risk of hypertension. METHODS: We measured blood pressure and collected data on health, socioeconomic, and lifestyle factors, including diet and physical activity, via questionnaire at home visits for 4,861 persons 45-70 years of age, who had lived at least 5 years near any of six major European airports. We assessed noise exposure using detailed models with a resolution of 1 dB (5 dB for United Kingdom road traffic noise), and a spatial resolution of 250 x 250 m for aircraft and 10 x 10 m for road traffic noise. RESULTS: We found significant exposure-response relationships between night-time aircraft as well as average daily road traffic noise exposure and risk of hypertension after adjustment for major confounders. For night-time aircraft noise, a 10-dB increase in exposure was associated with an odds ratio (OR) of 1.14 [95% confidence interval (CI), 1.01-1.29]. The exposure-response relationships were similar for road traffic noise and stronger for men with an OR of 1.54 (95% CI, 0.99-2.40) in the highest exposure category (> 65 dB; p(trend) = 0.008). CONCLUSIONS: Our results indicate excess risks of hypertension related to long-term noise exposure, primarily for night-time aircraft noise and daily average road traffic noise

Parthenogenesis In The Tropical Gekkonid Lizard, Nactus Arnouxii (Sauria: Gekkonidae)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137400/1/evo02464.pd

Studies on the genetic and non-genetic (physiological) variation of human erythrocyte glutamic oxaloacetic transaminase

The thermostability profile of seven different electrophoretic variants of human erythrocyte GOT found in 13 different, unrelated families from a racially heterogeneous population was examined. The five different slow-variant and the two different fast-variant classes could be grouped into four different thermostability classes which were termed unstable, less stable, normal and more stable than normal. The thermostability differences among and within the electrophoretic variant classes permitted differentiation of the 13 individusals possessing an electrophoretic variant phenotype into a total of ten different variants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66025/1/j.1469-1809.1982.tb00711.x.pd

Retinoic Acid Promotes the Generation of Pancreatic Endocrine Progenitor Cells and Their Further Differentiation into β-Cells

The identification of secreted factors that can selectively stimulate the generation of insulin producing β-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based β-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of β-cells during normal pancreatic development such putative factors may be identified. In the mouse, β-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of β-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when β-cells are generated. We also provide evidence that RA induces the generation of Ngn3+ endocrine progenitor cells and stimulates their further differentiation into β-cells by activating a program of cell differentiation that recapitulates the normal temporal program of β-cell differentiation