Insulin degludec/liraglutide (IDegLira) maintains glycaemic control and improves clinical outcomes, regardless of pre-trial insulin dose, in people with type 2 diabetes that is uncontrolled on basal insulin.

AIMS: To assess whether people with type 2 diabetes transferring from higher basal insulin doses (> 20 units) to a starting dose of 16 units of insulin degludec/liraglutide (IDegLira) benefit from IDegLira with/without transient loss of glycaemic control. METHODS: Post hoc analysis of DUAL V and VII assessed fasting self-measured blood glucose (SMBG) over weeks 1-8, changes in HbA1c, body weight and mean insulin dose over 26 weeks, and percentage of participants achieving HbA1c < 53 mmol/mol (7.0%) by end of trial in participants with type 2 diabetes uncontrolled with basal insulin. IDegLira was compared with continued up-titration of insulin glargine (IGlar U100) in DUAL V, or switching to basal-bolus therapy in DUAL VII (IGlar U100 and insulin aspart), across pre-trial insulin dose groups (20-29, 30-39 and 40-50 units/day). RESULTS: In all subgroups, participants treated with IDegLira experienced significant improvements in HbA1c by end of trial, which were greater than with IGlar U100 up-titration (estimated treatment difference -5.86, -6.59 and -6.91 mmol/mol for pre-trial insulin doses of 20-29, 30-39 and 40-50 units/day, respectively) and similar to basal-bolus therapy (estimated treatment difference -0.16, -1.0 and -0.01 mmol/mol for pre-trial insulin doses of 20-29, 30-39 and 40-50 units/day, respectively). Compared with IGlar U100 and basal-bolus therapy, IDegLira participants experienced weight loss vs. weight gain, lower rates of hypoglycaemia and a lower mean end of trial total daily insulin dose. In both trials, mean fasting SMBG decreased from weeks 1 to 8 across all subgroups, despite a temporary increase in mean fasting SMBG in the 40-50 units pre-trial insulin dose group during week 1 [mean increase (sd) +1.1 (2.0) mmol/l for DUAL V and +1.1 (2.1) mmol/l for DUAL VII], which reverted to baseline by week 4. CONCLUSIONS: Regardless of pre-trial insulin dose, IDegLira resulted in improved clinical outcomes, even in participants transferring from 40-50 units of basal insulin, despite a transient (< 4 weeks), clinically non-relevant, elevation in pre-breakfast SMBG. (Clinical Trial Registry Number NCT01952145 and NCT02420262).

Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.

BACKGROUND: Although volume of intracerebral hemorrhage (ICH) is a predictor of mortality, it is unknown whether subsequent hematoma growth further increases the risk of death or poor functional outcome. METHODS: To determine if hematoma growth independently predicts poor outcome, the authors performed an individual meta-analysis of patients with spontaneous ICH who had CT within 3 hours of onset and 24-hour follow-up. Placebo patients were pooled from three trials investigating dosing, safety, and efficacy of rFVIIa (n = 115), and 103 patients from the Cincinnati study (total 218). Other baseline factors included age, gender, blood glucose, blood pressure, Glasgow Coma Score (GCS), intraventricular hemorrhage (IVH), and location. RESULTS: Overall, 72.9% of patients exhibited some degree of hematoma growth. Percentage hematoma growth (hazard ratio [HR] 1.05 per 10% increase [95% CI: 1.03, 1.08; p < 0.0001]), initial ICH volume (HR 1.01 per mL [95% CI: 1.00, 1.02; p = 0.003]), GCS (HR 0.88 [95% CI: 0.81, 0.96; p = 0.003]), and IVH (HR 2.23 [95% CI: 1.25, 3.98; p = 0.007]) were all associated with increased mortality. Percentage growth (cumulative OR 0.84 [95% CI: 0.75, 0.92; p < 0.0001]), initial ICH volume (cumulative OR 0.94 [95% CI: 0.91, 0.97; p < 0.0001]), GCS (cumulative OR 1.46 [95% CI: 1.21, 1.82; p < 0.0001]), and age (cumulative OR 0.95 [95% CI: 0.92, 0.98; p = 0.0009]) predicted outcome modified Rankin Scale. Gender, location, blood glucose, and blood pressure did not predict outcomes. CONCLUSIONS: Hematoma growth is an independent determinant of both mortality and functional outcome after intracerebral hemorrhage. Attenuation of growth is an important therapeutic strategy.

Reproductive history and allergic rhinitis among 31145 Danish women.

BACKGROUND AND OBJECTIVE: A successful pregnancy is associated with a strong skewing of the immune system towards a Th2-type immune response. Because such a deviation is also the hallmark of allergic disease, it was investigated whether allergic rhinitis in women was associated with an increased likelihood of becoming pregnant and having a successful outcome of pregnancies. MATERIAL AND METHODS: Information on allergic rhinitis and reproductive history was obtained for 31145 pregnant women who participated in a national birth cohort study in Denmark during September 1997 to March 2000, and for whom complete information on siblings and place of residence and birth was available via the Civil Registration System. Data were analysed using logistic regression. RESULTS: Women who had previously been pregnant (OR = 0.91, 95% CI 0.85-0.98) or who had given birth previously (OR = 0.91, 95% CI 0.85-0.98) were less likely to report allergic rhinitis than others. The number of previous spontaneous abortions, gestational week of the first spontaneous abortion and fertility treatment were not associated with allergic rhinitis. Women who had waited less than a year to become pregnant more often had allergic rhinitis (OR = 1.18, 95% CI 1.06-1.32, P = 0.002) than women who had waited for more than a year. Early age at menarche was associated with an increased likelihood of allergic rhinitis (Ptrend = 0.003). CONCLUSIONS: Our findings did not support the hypothesis that an atopic genotype overall should be associated with an increased likelihood of successful outcome of pregnancies, but it might be associated with a decreased waiting time to pregnancy.

Community-based controlled trial of dietary management of children with persistent diarrhea: sustained beneficial effect on ponderal and linear growth.

BACKGROUND: Uncontrolled hospital-based studies in developing countries have reported promising results of dietary rehabilitation of children with persistent diarrhea. OBJECTIVE: The objective was to determine the immediate and long-term effects of a dietary supplement and micronutrients given to children with persistent diarrhea during the episode and for 1 wk during convalescence. DESIGN: The study was open, controlled, and community-based and was conducted in a periurban area in Guinea-BISSAU: Children <3 y of age with persistent diarrhea were identified during weekly household visits. The children randomly assigned to the treatment and control groups were examined by a physician and all medical conditions were treated. The children in the treatment group were offered home-based dietary treatment consisting of locally available foods and micronutrient supplements. RESULTS: There were 141 episodes of persistent diarrhea during the study: 70 in the treatment group (in 58 children) and 71 in the control group (in 62 children). During the intervention period (median: 17 d), weight gain in the treatment group exceeded that of the control group by 61.5 g/wk (95% CI: 49.2, 73.8), whereas there was no significant difference in linear growth on the basis of knee-heel length. At a median follow-up period of 6.6 mo after the intervention was stopped, weight gain in the treatment group exceeded that of the control group by 12.5 g/wk (95% CI: 7.7, 17.3); knee-heel length was 7.5 mm/y (4.8, 10.2) greater and total length was 0.65 cm/y (0.11, 1.19) greater in the treatment group. CONCLUSION: Therapeutic feeding and micronutrient supplementation had an immediate and sustained beneficial effect on growth in children with persistent diarrhea.

Antibody responses to Campylobacter infections determined by an enzyme-linked immunosorbent assay: 2-year follow-up study of 210 patients.

An enzyme-linked immunosorbent assay (ELISA) was adapted to measure immunoglobulin G (IgG), IgM, and IgA classes of human serum antibody to Campylobacter jejuni and Campylobacter coli. Heat-stable antigen, a combination of C. jejuni serotype O:1,44 and O:53 in the ratio 1:1, was used as a coating antigen in the ELISA test. A total of 631 sera from 210 patients with verified Campylobacter enteritis were examined at various intervals after infection, and a control group of 164 sera were tested to determine the cut-off for negative results. With a 90th percentile of specificity, IgG, IgM, and IgA showed a sensitivity of 71, 60, and 80%, respectively. By combining all three antibody classes, the sensitivity was 92% within 35 days after infection, whereas within 90 days after infection, a combined sensitivity of 90% was found (IgG 68%, IgM 52%, and IgA 76%). At follow-up of the patients, IgG antibodies were elevated 4.5 months after infection but exhibited a large degree of variation in antibody decay profiles. IgA and IgM antibodies were elevated during the acute phase of infection (up to 2 months from onset of infection). The antibody response did not depend on Campylobacter species or C. jejuni serotype, with the important exception of response to C. jejuni O:19, the serotype most frequently associated with Guillain-Barré syndrome. All of the patients infected with this serotype had higher levels of both IgM (P = 0.006) and IgA (P = 0.06) compared with other C. jejuni and C. coli serotypes.

Anopheles arabiensis and An. funestus are equally important vectors of malaria in Matola coastal suburb of Maputo, southern Mozambique.

Transmission characteristics of malaria were studied in Matola, a coastal suburb of Maputo, the capital City, in southern Mozambique, from November 1994 to April 1996. The local climate alternates between cool dry season (May-October) and hot rainy season (November-April) with mean annual rainfall 650-850 mm. Saltmarsh and freshwater pools provide mosquito breeding sites in Matola. Malaria prevalence reached approximately 60% among people living nearest to the main breeding sites of the vectors. Plasmodium falciparum caused 97% of malaria cases, others being P. malariae and P. ovale. Potential malaria vector mosquitoes (Diptera: Culicidae) collected at Matola during daytime indoor-resting (n = 1021) and on human bait at night (n = 5893) comprised 12% Anopheles coustani Laveran (93% biting outdoors), 46% An. funestus Giles (68% biting indoors) and 42% An. gambiae Giles sensu lato (60% biting outdoors). All 215 specimens of An. gambiae s.l. identified genetically were An. arabiensis Patton. Anopheles funestus populations remained stable throughout the year, whereas densities of the An. gambiae complex fluctuated considerably, with An. arabiensis peaking during the rainy season. No concomitant rise in malaria incidence was observed. Human landing indices of An. funestus and An. arabiensis averaged 1.8 and 3.8 per man-night, respectively. Overall Plasmodium sporozoite rates were 2.42+/-1.24% in 2181 An. funestus and 1.11+/-1.25% in 1689 An. arabiensis dissected and examined microscopically. Mean daily survival rates were 0.79 for both vector species. Estimated infective bites/person/year were 15 An. funestus and 12 An. arabiensis. Biting rates were greatest at 2100-24.00 hours for An. funestus (68% endophagic) and 21.00-03.00 hours for An. arabiensis (40% endophagic). The entomological inoculation rate (EIR) declined sharply over very short distances (50% per 90m) away from breeding-sites of the vectors. Consequently, P. falciparum prevalence among Matola residents was halved 350 m within the town. Implications for the protective effectiveness of a 'cordon sanitaire' by residual house-spraying and/or the use of insecticide-treated bednets are discussed.

Differences in susceptibility to AIDS development: a cohort study of Danish and American homosexual-bisexual men, 1981 to 1995.

We estimated the annual hazard rate for progression to AIDS as defined by the 1987 case definition in HIV-infected members of a cohort of Danish and American homosexual-bisexual men who were observed from 1981 to 1995. Furthermore, we extrapolated the hazard to 25 years based on imputed future time to AIDS. Of 201 HIV-positive subjects, 112 developed AIDS before the end of follow-up. The hazard increased rapidly during the first years following infection, attained a peak of about 15% per year at year 7, and was moderately lower during years 8 through 10. In subsequent analysis, we imputed future time to AIDS in 89 subjects who had not progressed by the end of follow-up by extrapolation from subject-specific CD4 trend lines. A CD4 count of < or = 100 cells/microl was the best surrogate for clinical AIDS. Under this model, the imputed AIDS hazard stabilized at around 8% per year after 10 years. We projected that 13% (95% confidence interval [CI], 8%-19%) of the infected men may remain free from AIDS 25 years after seroconversion. Our direct data suggest that incubation times reflect a mixture of a population that is susceptible to disease progression and has short incubation periods with a group that is relatively resistant. Based on an extrapolation model, > 10% of HIV-infected persons may survive for up to 25 years without developing AIDS.

Risk factors for Kaposi's-sarcoma-associated herpesvirus (KSHV/HHV-8) seropositivity in a cohort of homosexual men, 1981-1996.

A newly identified herpesvirus has been associated with Kaposi's sarcoma. We determined risk factors for Kaposi's-sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) seropositivity and incidence of infection over time in a cohort of Danish homosexual men followed from 1981 to 1996. Antibodies to a latent nuclear (LANA) and a structural (orf65) antigen of KSHV/HHV-8 were measured by immunofluorescence and ELISA/WB respectively. Through linkage with the national AIDS registry, all cohort members diagnosed with AIDS as of September 1996 were identified and their hospital records were scrutinized to record all diagnoses of KS. Overall, 21.1% (52/246) of the men were KSHV/HHV-8-seropositive in 1981. Among the initially seronegative, the rate of KSHV/HHV-8 seroconversion was highest between 1981 and 1982 and declined steadily thereafter. In a multivariate analysis of the status at enrollment in 1981, KSHV/HHV-8 seropositivity was not associated with age but was independently associated both with number of receptive anal intercourses (OR = 2.83; p = 0.03) and with sex with US men (OR = 2.27; p < 0.05). In a multivariate analysis of follow-up data, risk of KSHV/HHV-8 seroconversion was independently associated with having visited homosexual communities in the United States, and current HIV-positive status. More than 5 years' homosexual experience was associated with an insignificantly increased risk (RR = 2.68). KS occurred only in HIV-positive men who were KSHV/HHV-8-positive at or prior to their KS diagnosis. In conclusion, KSHV/HHV-8 appears to be sexually transmitted, probably by receptive anal intercourse, and may have been introduced to Danish homosexual men via sex with US men. The epidemic of KSHV/HHV-8 is now declining. These findings are concordant with the view that KSHV/HHV-8 may have been actively spread simultaneously with and by the same activities that lead to the spread of HIV.

The differing impact of chloroquine and pyrimethamine/sulfadoxine upon the infectivity of malaria species to the mosquito vector.

Using serum or infected blood from Danish volunteers and Plasmodium falciparum-infected Mozambican patients, respectively, the impact of curative doses of chloroquine and pyrimethamine/sulfadoxine upon infectivity of P. falciparum to Anopheles arabiensis and An. gambiae or of P. berghei to An. stephensi was studied. Both treatments cleared circulating P. falciparum gametocytes within 28 days. Before this clearance, chloroquine enhanced infectivity to An. arabiensis, whereas pyrimethamine/sulfadoxine decreased infectivity. Patients harboring chloroquine-resistant parasites as opposed to -sensitive ones were 4.4 times more likely to have gametocytes following treatment. In contrast, pyrimethamine/sulfadoxine-resistant parasites were 1.9 times less likely to produce gametocytes. In laboratory infections using replicated P. berghei or P. falciparum preparations, serum from chloroquine-treated, uninfected, nonimmune volunteers enhanced gametocyte infectivity with increasing efficiency for 21 days following treatment, whereas pyrimethamine/sulfadoxine significantly suppressed infectivity. The observed enhancement in infectivity induced by the use of chloroquine combined with increased gametocytemias in chloroquine-resistant strains may in part explain the rapid spread of chloroquine resistance in endemic populations.

The Matola malaria project: a temporal and spatial study of malaria transmission and disease in a suburban area of Maputo, Mozambique.

A temporal and spatial study of malaria transmission in a suburban area of Maputo, Mozambique with a mean population density of 2,737/km2 was made from December 1992 to June 1995. A steep but continuous gradient was observed in the Plasmodium falciparum prevalence from 59.0% adjacent to the breeding sites to 5.4% only a few hundred meters distant. The entomologic inoculation rate ranged from a number too low to be determined in some districts to 20 infectious bites per person per year in the others. The risk of malaria was 6.2 times higher for individuals living less than 200 meters from the breeding sites than for individuals living 500 meters or more away from the breeding sites. In areas of high human density, mosquito and parasite dispersion is very limited, and therefore malaria control strategies could be more specifically targeted.

[Marked increase in incidence of non-Hodgkin's lymphoma among young people in Denmark during 1943-1989]. / Markant stigning i forekomsten af non-Hodgkins lymfom blandt unge i Danmark i perioden 1943-1989.

Time related trends in incidence of non-Hodgkin's lymphoma in Denmark in the period 1943-1989 were analysed. A total of 13,822 patients were included in the study. World standardized incidence rates per 100,000 population increased from 2.5 in men and 1.9 in women in 1943-1947 to 9.3 in men and 6.5 in women in 1988-1989. Trends in age-specific incidence were analysed for two periods, i.e. 1943-1977 and 1978-1989. In both periods, the incidence of NHL increased in all age-groups. In general, the rate of increase was higher in the recent period, with the exception of the oldest age-group among whom the incidence increased by 7% annually between 1943 and 1962. In recent years an increase in incidence averaging 8% annually was observed in men and women aged 40 to 49 years. The remarkable and parallel time trends observed in young men and women in recent years indicate that factors other than AIDS must be contemplated.

Progression to acquired immunodeficiency syndrome is influenced by CD4 T-lymphocyte count and time since seroconversion.

Progression to acquired immunodeficiency syndrome (AIDS) among persons infected with human immunodeficiency virus (HIV) varies considerably and may be influenced by factors such as age, smoking, number of male partners per year, and CD4 T-lymphocyte count. The loss of CD4 lymphocytes is known to be the dominant factor in the progression to AIDS. However, it is unclear whether the effect of the CD4 lymphocyte count is of such importance that persons with similar CD4 cell counts who have been infected for widely different lengths of time have the same risk of AIDS. While a CD4 count is easily obtainable, the precise amount of time since HIV infection is in most circumstances difficult to assess. In the present analysis, 259 Danish and 245 American homosexual men were followed for up to 14 years from 1981 to 1995. Two hundred and one persons seroconverted during the study period, and 112 had developed AIDS before the end of follow-up. CD4 lymphocyte count was highly correlated with the risk of developing AIDS (p < 0.001), but AIDS risk was not affected significantly by either age at infection, smoking, or number of male partners per year (p > 0.20 in all cases). Controlled for CD4 lymphocyte count, time since seroconversion was significant in explaining the risk of AIDS (p = 0.018), with a lower risk being seen during the first 3 years after seroconversion but no effect thereafter. These data confirm the central importance of CD4 lymphocyte level in the progression of HIV disease to AIDS, and suggest that rapid progression within 3 years of infection may be related to factors other than CD4 cell count.

Recent increase in the incidence of non-Hodgkin's lymphoma among young men and women in Denmark.

Time-related trends in the incidence of non-Hodgkin's lymphoma (NHL) in Denmark were analysed for the period 1943-89. A total of 13 822 patients (7565 men and 6257 women) were included in the study. In men, world-standardised incidence rates per 100 000 population increased from 2.5 in 1943-47 to 9.3 in 1988-89. In women, a similar increase was seen, i.e. from 1.9 in 1943-47 to 6.5 per 100 000 population in 1988-89. For all birth cohorts, the male-to-female incidence ratio was highest among young subjects and fell significantly after the age of 29 years. Trends in age-specific incidence were analysed separately for two periods, i.e. 1943-77 and 1978-89, reflecting an early, pre-AIDS period and a later period possibly influenced by AIDS. In both periods, the incidence of NHL increased in all age groups. However, in recent years a noticeable increase in incidence averaging 8% annually was observed in men and women aged 40-49 years. A number of factors including changes in the perception of NHL and in the diagnostic methods available are considered insufficient to explain the observed increase. The remarkable and parallel time trends observed in young men and women in recent years indicate that factors other than AIDS must be considered.

Estimation from current-status data in continuous time.

The nonparametric maximum likelihood estimator for current-status data has been known for at least 40 years, but only recently have the mathematical-statistical properties been clarified. This note provides a case study in the important and often studied context of estimating age-specific immunization intensities from a seroprevalence survey. Fully parametric and spline-based alternatives (also based on continuous-time models) are given. The basic reproduction number R0 exemplifies estimation of a functional. The limitations implied by the necessarily rather restrictive epidemiological assumptions are briefly discussed.