Impact of diabetes on healthcare costs in a population-based cohort: a cost analysis.

AIMS: To estimate the healthcare costs attributable to diabetes in Ontario, Canada using a propensity-matched control design and health administrative data from the perspective of a single-payer healthcare system. METHODS: Incident diabetes cases among adults in Ontario were identified from the Ontario Diabetes Database between 2004 and 2012 and matched 1:3 to control subjects without diabetes identified in health administrative databases on the basis of sociodemographics and propensity score. Using a comprehensive source of administrative databases, direct per-person costs (Canadian dollars 2012) were calculated. A cost analysis was performed to calculate the attributable costs of diabetes; i.e. the difference of costs between patients with diabetes and control subjects without diabetes. RESULTS: The study sample included 699 042 incident diabetes cases. The costs attributable to diabetes were greatest in the year after diagnosis [C$3,785 (95% CI 3708, 3862) per person for women and C$3,826 (95% CI 3751, 3901) for men], increasing substantially for older age groups and patients who died during follow-up. After accounting for baseline comorbidities, attributable costs were primarily incurred through inpatient acute hospitalizations, physician visits and prescription medications and assistive devices. CONCLUSIONS: The excess healthcare costs attributable to diabetes are substantial and pose a significant clinical and public health challenge. This burden is an important consideration for decision-makers, particularly given increasing concern over the sustainability of the healthcare system, aging population structure and increasing prevalence of diabetic risk factors, such as obesity.

The development and validation of a meta-tool for quality appraisal of public health evidence: Meta Quality Appraisal Tool (MetaQAT).

OBJECTIVES: Most quality appraisal tools were developed for clinical medicine and tend to be study-specific with a strong emphasis on risk of bias. In order to be more relevant to public health, an appropriate quality appraisal tool needs to be less reliant on the evidence hierarchy and consider practice applicability. Given the broad range of study designs used in public health, the objective of this study was to develop and validate a meta-tool that combines public health-focused principles of appraisal coupled with a set of design-specific companion tools. STUDY DESIGN: Several design methods were used to develop and validate the tool including literature review, synthesis, and validation with a reference standard. METHODS: A search of critical appraisal tools relevant to public health was conducted; core concepts were collated. The resulting framework was piloted during three feedback sessions with public health practitioners. Following subsequent revisions, the final meta-tool, the Meta Quality Appraisal Tool (MetaQAT), was then validated through a content analysis of appraisals conducted by two groups of experienced public health researchers (MetaQAT vs generic appraisal form). RESULTS: The MetaQAT framework consists of four domains: relevancy, reliability, validity, and applicability. In addition, a companion tool was assembled from existing critical appraisal tools to provide study design-specific guidance on validity appraisal. Content analysis showed similar methodological and generalizability concerns were raised by both groups; however, the MetaQAT appraisers commented more extensively on applicability to public health practice. CONCLUSIONS: Critical appraisal tools designed for clinical medicine have limitations for use in the context of public health. The meta-tool structure of the MetaQAT allows for rigorous appraisal, while allowing users to simultaneously appraise the multitude of study designs relevant to public health research and assess non-standard domains, such as applicability.

Measurement of muon antineutrino quasielastic scattering on a hydrocarbon target at Eν ~ 3.5 GeV.

We have isolated ν(µ) charged-current quasielastic (QE) interactions occurring in the segmented scintillator tracking region of the MINERvA detector running in the NuMI neutrino beam at Fermilab. We measure the flux-averaged differential cross section, dσ/dQ², and compare to several theoretical models of QE scattering. Good agreement is obtained with a model where the nucleon axial mass, M(A), is set to 0.99 GeV/c² but the nucleon vector form factors are modified to account for the observed enhancement, relative to the free nucleon case, of the cross section for the exchange of transversely polarized photons in electron-nucleus scattering. Our data at higher Q² favor this interpretation over an alternative in which the axial mass is increased.

Measurement of muon neutrino quasielastic scattering on a hydrocarbon target at Eν ~ 3.5 GeV.

We report a study of ν(µ) charged-current quasielastic events in the segmented scintillator inner tracker of the MINERvA experiment running in the NuMI neutrino beam at Fermilab. The events were selected by requiring a µ- and low calorimetric recoil energy separated from the interaction vertex. We measure the flux-averaged differential cross section, dσ/dQ², and study the low energy particle content of the final state. Deviations are found between the measured dσ/dQ² and the expectations of a model of independent nucleons in a relativistic Fermi gas. We also observe an excess of energy near the vertex consistent with multiple protons in the final state.

Timing of paediatric orchidopexy in universal healthcare systems: international administrative data cohort study.

BACKGROUND: International guidelines in 2008 recommended orchidopexy for undescended testis at 6-12 months of age to reduce the risk of testicular cancer and infertility. Using administrative data from England, Finland, Ontario (Canada), Scotland and Sweden (with data from Victoria (Australia) and Iceland in supplementary analyses), the aim of this study was to investigate compliance with these guidelines and identify potential socioeconomic inequities in the timing of surgery before 1 and 3 years. METHODS: All boys born in 2003-2011 with a diagnosis code of undescended testis and procedure codes indicating orchidopexy before their fifth birthday were identified from administrative health records. Trends in the proportion of orchidopexies performed before 1 and 3 years of age were investigated, as were socioeconomic inequities in adherence to the guidelines. RESULTS: Across all jurisdictions, the proportion of orchidopexies occurring before the first birthday increased over the study period. By 2011, from 7·6 per cent (Sweden) to 27·9 per cent (Scotland) of boys had undergone orchidopexy by their first birthday and 71·5 per cent (Sweden) to 90·4 per cent (Scotland) by 3 years of age. There was limited evidence of socioeconomic inequities for orchidopexy before the introduction of guidelines (2008). Across all jurisdictions for boys born after 2008, there was consistent evidence of inequities in orchidopexy by the first birthday, favouring higher socioeconomic position. Absolute differences in these proportions between the highest and lowest socioeconomic groups ranged from 2·5 to 5·9 per cent across jurisdictions. CONCLUSION: Consistent lack of adherence to the guidelines across jurisdictions questions whether the guidelines are appropriate.

ANTECEDENTES: En el 2008, las guías internacionales recomendaban efectuar una orquidopexia para los testículos no descendidos entre los seis y los 12 meses de edad para reducir los riesgos de cáncer testicular e infertilidad. Utilizando datos administrativos de Inglaterra, Finlandia, Ontario (Canadá), Escocia y Suecia (con datos de Victoria, Australia e Islandia para análisis complementarios), el objetivo de este estudio fue investigar el cumplimiento de estas guías y la identificación de posibles desigualdades socioeconómicas con relación al momento de la cirugía antes de 1 y 3 años de edad. MÉTODOS: A partir de los registros administrativos de salud, se identificaron todos los niños nacidos entre 2003 y 2011 con código diagnóstico de testículos no descendidos y con código de procedimiento correspondiente a orquidopexia antes de cumplir 5 años. Se investigaron las tendencias en la proporción de orquidopexias realizadas antes de 1 y 3 años de edad, respectivamente, al igual que las desigualdades socioeconómicas en el cumplimiento de las directrices de las guías. RESULTADOS: En todas las jurisdicciones, la proporción de orquidopexias realizadas antes del primer año de vida aumentó durante el periodo de estudio. En 2011, del 7,6% (Suecia) al 27,9% (Escocia) de los niños habían sido sometidos a orquidopexia en su primer año de vida y del 71,5% (Suecia) al 90,4% (Escocia) a los 3 años de edad. Hubo evidencia limitada de las inequidades socioeconómicas para la orquidopexia antes de la introducción de las guías (2008). En todas las jurisdicciones para los niños nacidos después de 2008, hubo evidencia consistente de inequidades para la práctica de una orquidopexia en el primer año de vida en favor de una posición socioeconómica más alta (socioeconomic position, SEP). Las diferencias absolutas en estas proporciones entre los grupos SEP más altos y más bajos oscilaron entre el 2,5% y el 5,9% en todas las jurisdicciones. CONCLUSIÓN: La falta de adherencia a las guías observada consistentemente en todas las jurisdicciones cuestiona si las guías son apropiadas.

Changes in distribution pattern of cytoplasmic filaments in human melanocytes during ultraviolet-mediated melanin pigmentation. The role of the 100-Angstrom filaments in the elongation of melanocytic dendrites and in the movement and transfer of melanosomes.

Human melanocytes characteristically contain 100-A filaments. These 100-A filaments shift from the perinuclear area to the center of the dendritic processes and are in close association with melanosomes during the different stages of UV-mediated melanin pigmentation. We suggest that these 100-A filaments in human melanocytes participate in the elongation of the dendrites and in the transfer of melanosomes.

Mitotic activity in non-neoplastic melanocytes in vivo as determined by histochemical, autoradiographic, and electron microscope studies.

Mitotic figures were demonstrated in the differentiated melanocytes of normal epidermal and nonepidermal tissues without the presence of external stimuli. These dividine melanocytes were present in human and mouse skin, mouse hair, chick feathers, and embryonic chick retinal pigment epithelium. In normal adult human epidermis, dividing melanocytes, though rare, were found in the nonstimulated areas. L-3,4-dihydroxyphenylalanine reaction on the melanocytes during mitosis demonstrated activity of the melanin-forming enzyme, tyrosinase, and ultrastructural studies demonstrated the characteristic melanosomes in variour stages of maturation. Other ultrastructural characteristics of the melanocytes during mitosis, except for the Golgi apparatus, which was smaller and less complex, were similar to those seen in well-differentiated nondividing melanocytes. Autoradiographic studies of thymidine incorporation into mouse skin indicated that 0.7% of epidermal melanocytes, when slightly stimulated, are in the S phase. Thus, in vivo differentiation of non-neoplastic melanocytes (to produce pyrosinase and melanosomes) does not preclude their replication by mitotic division.

Tyrosinase-mediated inhibition of in vitro leucine incorporation into mouse melanoma by 4-isopropylcatechol.

The effect of 4-isopropylcatechol (4-IPC), a potent, irreversible cutaneous depigmenting agent, on protein biosynthesis of malignant melanoma cells in mice was studied by examining the in vitro amino acid (leucine) incorporation into a microsome fraction in cell sap. The present study revealed that 4-IPC does not inhibit the protein biosynthesis of the cell-free system in mouse liver, but remarkably inhibits it in mouse melanoma cells, which contain a high level of tyrosinase. The enhanced inhibition was found also in the mouse liver cell-free system when tyrosinase was added. Air oxidation products of 4-IPC were not responsible for such inhibition. These results may indicate that 4-IPC directly inhibits protein biosynthesis, probably by some intermediates that occur in an early stage of enzymatic oxidation of 4-IPC.

The effect of histidine-228 on the catalytic efficiency and stereospecificity of the serine hydroxymethyltransferase catalysed exchange of the alpha-protons of amino acids.

13C-NMR has been used to determine how replacing the histidine-228 residue of serine hydroxymethyltransferase (EC 2.1.2.1) by an asparagine residue effects the catalysis of the hydrogen-deuterium exchange of the alpha-protons of [2-13C]glycine at pH 7.8. The H228N mutation did not lead to a large change in the stereospecificity of the first order exchange rates of the alpha-protons of glycine both in the presence and in the absence of tetrahydrofolate. However, the mutation did lead to large decreases in the stereospecificity of the second order exchange rate in both the presence and the absence of tetrahydrofolate. In the absence of tetrahydrofolate this decrease in stereospecificity was largely due to the decrease in the second order exchange rate of the pro-2S proton, while in the presence of tetrahydrofolate the large increase in the second order exchange rate of the pro-2R proton of glycine made a major contribution. We conclude that the H228N mutation has significant effects on the catalytic efficiency and stereospecificity of the second order exchange reactions, but only a small effect on the corresponding first order exchange reactions.

Lentigo maligna melanoma has no better prognosis than other types of melanoma.

We studied 48 patients with lentigo maligna melanoma (LMM) and compared the clinical stage I patients with non-LMM melanoma patients (matched by site and thickness) to see if prognosis differed. There was no significant difference in mortality from melanoma between the two groups (P = .68) after a mean follow-up time of five years (67.5 months for LMM, 60.5 months for non-LMM). In addition, a Cox multivariate analysis of the entire matched group showed that only thickness was significantly associated with death from melanoma (P = .0007) while histology (LMM v non-LMM) did not make a significant contribution (P = .61). Our data suggest that after accounting for primary tumor thickness and site, LMM and non-LMM have the same prognosis and biologic behavior, in contrast to the widely held belief that LMM has a better prognosis than other forms of melanoma.

Platelets and the vascular responses to arachidonic acid in dogs.

UNLABELLED: Platelets are rich in components of the prostaglandin synthetase system which converts arachidonic acid into vasoactive and platelet-active prostanoate and nonprostanoate compounds. Repeated injections of arachidonic acid in dogs cause hypotension of reproducible magnitude and lower circulating platelet counts with each injection. However, the circulatory response to injected arachidonic acid was unchanged when platelet-poor blood was exchanged in dogs. Moreover, in the hind limb preparation and the isolated lung lobe, the vasoactive responses to arachidonic acid were indistinguishable whether perfused with whole blood or an artificial perfusate. CONCLUSION: the vascular responses to arachidonic acid do not appear dependent on the presence of platelets.

Acid phosphatase in melanosome formation: a cytochemical study in normal human melanocytes.

A cytochemical study of acid phosphatase (AcPase) activity was conducted in normal epidermal melanocytes from both sun-exposed and sun-protected human skin to define the relationship between enzyme activity and melanosome formation. In the perikarya of melanocytes of both sun-exposed and sun-protected skin, it was determined that only a small proportion of stage 1 and 2 melanosomes had AcPase activity (20-33% and 9-26%, respectively). The proportion of AcPase-positive melanosomes in perikarya increased in stage 3 (39-56%), reaching a maximum in stage 4 (67-84%). In the dendrite of melanocytes, where melanosomes were mostly in stages 3 and 4, the vast majority of melanosomes demonstrated AcPase activity (79-87% and 88-93%, respectively). The preferential incorporation of AcPase in the later stages of melanogenesis is more consistent with a possible role for this enzyme in the degradation or transfer of melanosomes, rather than as an essential component in the early process of melanization.

Morphologic alterations of epidermal melanocytes and melanosomes in PUVA lentigines: a comparative ultrastructural investigation of lentigines induced by PUVA and sunlight.

Ultrastructural studies were conducted in order to determine morphologic and functional differences in melanocytes and melanosomes in PUVA lentigines and solar lentigines, and light-protected buttock skin. Compared to melanocytes in solar lentigines from 7 subjects and light-protected buttock skin from 5 subjects (none of these subjects had received UV radiation therapy), melanocytes in PUVA lentigines from 6 subjects generally had longer and more numerous dendrites, and showed more active melanogenesis. Basal keratinocytes in PUVA lentigines had a significantly increased frequency of large, single melanosomes, and revealed significantly larger individual melanosomes within compound melanosomes. Other findings in some PUVA lentigines included the close apposition of Langerhans cells to melanocytes, and atypical nuclear, cytoplasmic and melanosomal alterations, including melanosomal pleomorphism and melanin macroglobules. The presence of relatively large and predominantly single melanosomes in basal keratinocytes of PUVA lentigines suggests more active melanogenesis and/or an irreversible somatic alteration. It will be important to determine the clinical course and ultrastructural findings of PUVA lentigines that persist long after PUVA is discontinued.

Ocular findings in patients treated with PUVA.

This 5-year prospective study of ophthalmologic findings in 1299 patients treated with oral 8-methoxypsoralen photochemotherapy (PUVA) for psoriasis failed to demonstrate a significant dose-dependent increase in the risk of developing symptomatic cataracts. These patients were instructed to wear UVA-blocking eyeglasses when exposed to sunlight and during treatment for a 12-h period beginning from the time of 8-methoxypsoralen ingestion. However, we did observe a small increase in the risk for development of nuclear sclerosis and posterior subcapsular opacities among patients who received at least 100 PUVA treatments, compared to patients with fewer than 100 treatments (relative risk = 2.3 and 3.0, respectively; p less than .05 both comparisons). We compared our results to those of a large, population-based study and found, after adjusting for differences in methods, that the prevalence of cataracts in our study patients, aged 52-75 years, was not significantly different. Since the latency period for development of symptomatic ocular abnormalities may be longer than 5 years, continued surveillance of our cohort and continued use of appropriate ocular protection by all patients treated with PUVA is indicated.

Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism.

Subcellular defects of hypomelanosis in tuberous sclerosis (TS) (28 subjects) were compared by light and electron microscopy with oThere forms of congenital circumscribed hypomelanosis that occur in nevus depigmentosus (ND) (8 subjects) and in piebaldism (PB) (4 subjects), respectively. On the light microscopic level in both TS and ND, the population density of functioning melanocytes was normal but each perikaryon was small, and dopa activity was decreased. On the ultrastructural level, the hypomelanotic skin and hair of TS were associated with a decrease in the synthesis, melanization, and size of melanosomes; the decrease in the size of melanosomes resulted in the aggregation of melanosomes (i.e., a melanosome complex) in the keratinocytes in all the specimens examined. In ND, ther were no obvious changes in the size and melanocytes. the hypomelanosis of ND is related to the decreased synthesis and also, perhaps, abnormal transfer of melanosomes. In PB the hypomelanosis of the skin and hair results from the absence of functional melanocytes. The hypermelanotic areas of PB, however, characteristically contain melanocytes that synthesize abnormal (sperical and granular) as well as normal (ellipsoidal and lamellar) melanosomes.

Some aspects of melanin biology: 1950-1975.

Recent advances in the biology of mammalian pigmentation are reviewed. The multicellular epidermal melanin unit (melanocyte and associated pool of keratinocytes) rather than the melanocyte alone forms the focal point for melanin metabolism within mammalian epidermis. Within an epidermal melanin unit, melanosomes are synthesized by melanocytes and transferred to keratinocytes where they are degraded as they ascend to the epidermal surface. During the past 25 years, technical advances in biology and biochemistry have frosted a multidisciplinary approach to research on mammalian pigmentation. Emphasizing this perspective, we have examined the current state of knowledge of the form and function of epidermal melanin units from the levels of biologic organization ranging from the molecules relevant to melanin synthesis through the skin as a totally intergrated system. To an unusual degree, advances in melanin pigmentation have resulted from the integration of clinical medicine and basic science.

A new liquid formulation of 8-methoxypsoralen: bioactivity and effect of diet.

A new encapsulated liquid preparation of methoxsalen (8-MOP) and a commonly used crystalline preparation (Oxsoralen) were compared in 12 subjects. Each subject ingested 0.6 mg/kg body weight of each formulation on different days. Six subjects ingested a low-fat meal before ingestion of drug, and 6 subjects ingested a high-fat meal. Photosensitivity was tested from 1/2 to 6 h after ingestion of 8-MOP by exposure to 320-400 nm radiation (UVA) from a filtered xenon are lamp. A series of graduated doses of UVA were administered at each time point to determine the minimum phototoxic dose (MPD). Ingestion of 8-MOP and grading of erythema were conducted in a double-blind manner, and bilaterally symmetrical exposure sites were used to test each preparation. The phototoxic reaction was observed at 24, 48, and 72 h by two experienced observers who were unaware which formulation had been ingested. The two test days were separated by 48 h. The encapsulated liquid preparation induced greater photosensitivity than Oxsoralen (mean MPDs +/- SD: 7.1 +/- 4.7 vs 12.9 +/- 6.7 J/cm2, respectively; n = 12; p less than 0.05). The encapsulated liquid preparation also induced photosensitivity earlier than Oxsoralen (mean hours after ingestion to achieve peak photosensitivity +/- SD: 2.1 +/- 1.2 vs 3.9 +/- 1.6, respectively; n = 9; borderline significance). On a low-fat diet the encapsulated liquid peaked 2.5 h earlier than Oxsoralen, as well as showing the shortest and the most predictable period of photosensitivity. However, overall, the degree and time of peak photosensitivity induced by either preparation were unaffected by diet. Ingestion of the encapsulated liquid induced photosensitivity in all 12 subjects; Oxsoralen failed to sensitize 3 subjects. Side effects were similar after both preparations. A new encapsulated liquid preparation of 8-MOP may thus allow lower doses of UVA to achieve therapeutic results in photochemotherapy, and a shortened waiting period following ingestion of drug.

The nature and origin of the melanin macroglobule.

The melanin macroglobule (MMG), formerly called "macromelanosome," is a cytoplasmic spherical granule formed in the melanocyte, varying in size from one to several microns, much larger than normal ellipsoidal melanosomes. Although ultrastructural features of MMG have been adequately described in the past, there has been a disagreement about the formation process of MMG. In order to further elucidate the nature and origin of MMG, electron microscopic studies were conducted in several pigmentary disorders. Our findings included: (1) The most remarkable characteristics of MMG are (a) the pleomorphism of their internal structure and (b) the variation of their size. (2) MMG do not represent true melanosomes but unique forms of autolysosomes resulting from the fusion of autophagosomes (containing various numbers of melanosomes) with primary and/or secondary lysosomes. (3) MMG are retained within melanocytes or transferred to keratinocytes and to Langerhans cells in the epidermis, and to macrophages in the dermis in any of their developmental stages. After transfer, MMG can fuse with other heterolysosomes and probably increase in size in these cells. We regard melanosome complexes as but one step in an autophagic process within melanocytes which can, on occasion, produce MMG as residual bodies.

Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical trial. 1977.

Extensive psoriasis in 1,308 patients has been treated two or three times a week with oral 8-methoxypsoralen followed by high intensity, long-wave ultraviolet light (PUVA). Excluding 169 patients still under early treatment, psoriasis cleared in 88% and failed to clear in 3%. One percent dropped out due to complications of treatment, and 8% for other reasons. The twice-a-week schedule was superior for patients with lighter skin types. Once a remission was induced, there was no difference in its maintenance when patients were treated once a week, once every other week, or once every third week. Each of these schedules was superior to no maintenance treatment. Immediate side effects of the 45,000 treatments administered in the first 18 months of this study were uncommon, temporary, and generally mild. No clinically significant changes in laboratory screening or eye examinations attributable to PUVA have been uncovered.

Actinic degeneration in association with long-term use of PUVA.

To determine the extent of clinical actinic damage that occurred in association with exposure to oral methoxsalen photochemotherapy (PUVA), dermatologists at 16 university centers assessed the wrinkling, telangiectasia, and altered skin markings on the buttocks and the dorsa of the hands among 1380 patients treated with PUVA. These changes are similar to those seen in skin that is chronically exposed to sunlight. After more than 5 years of prospective study, patients with psoriasis exposed to PUVA showed a significant dose-dependent increase in the prevalence of clinical actinic degeneration of the skin of the buttocks (p less than .05, F-test). The prevalence of moderate or severe change among those patients exposed to high doses of PUVA (more than 160 treatments) was low (11%). The degree of increased clinical actinic degeneration noted on the dorsa of the hands was also significantly related to total exposure to PUVA (p less than .05, F-test). Our findings indicate that long-term PUVA exposure is associated with an increase in clinical actinic degeneration of the skin. However, the magnitude of this increase is small and, after more than 5 years, is of limited clinical consequence to most patients.