The impact of first year adherence to antiretroviral therapy on long-term clinical and immunological outcomes in the DART trial in Uganda and Zimbabwe.

OBJECTIVES: To describe associations between different summaries of adherence in the first year on antiretroviral therapy (ART) and the subsequent risk of mortality, to identify patients at high risk because of early adherence behaviour. METHODS: We previously described an approach where adherence behaviour at successive clinic visits during the first year on ART was seen as a Markov chain (MC), and the individually estimated transition probabilities between 'good', 'poor' and 'non-response' adherence states were used to classify HIV-infected adults in the DART trial into subgroups with similar behaviour. The impact of this classification and classifications based on traditional 'averaged' measures [mean drug possession ratio (DPR) and self-reported adherence] were compared in terms of their impact on longer-term mortality over the 2-5 years on ART using Cox proportional hazards models. RESULTS: Of 2960 participants in follow-up after 1 year on ART, 29% had never missed pills in the last month and 11% had 100% DPR throughout the first year. The poorest adherers by self-reported measures were more likely to have only none/primary education (P < 0.01). Being in the poorest adherence subgroup by MC and DPR was independently associated with increased mortality [HR = 1.57 (95% CI 1.02, 2.42); 1.82 (1.32, 2.51) respectively]. CONCLUSIONS: Classification based on dynamic adherence behaviour is associated with mortality independently of DPR. The classifications could be useful in understanding adherence, targeting focused interventions and improving longer-term adherence to therapy.

Responsiveness of the frontal EMG for monitoring the sedation state of critically ill patients.

BACKGROUND: Excessive sedation is associated with adverse patient outcomes during critical illness, and a validated monitoring technology could improve care. We developed a novel method, the responsiveness index (RI) of the frontal EMG. We compared RI data with Ramsay clinical sedation assessments in general and cardiac intensive care unit (ICU) patients. METHODS: We developed the algorithm by iterative analysis of detailed observational data in 30 medical-surgical ICU patients and described its performance in this cohort and 15 patients recovering from scheduled cardiac surgery. Continuous EMG data were collected via frontal electrodes and RI data compared with modified Ramsay sedation state assessments recorded regularly by a blinded trained observer. RI performance was compared with Entropy™ across Ramsay categories to assess validity. RESULTS: RI correlated well with the Ramsay category, especially for the cardiac surgery cohort (general ICU patients ρ=0.55; cardiac surgery patients ρ=0.85, both P<0.0001). Discrimination across all Ramsay categories was reasonable in the general ICU patient cohort [P(K)=0.74 (sem 0.02)] and excellent in the cardiac surgery cohort [P(K)=0.92 (0.02)]. Discrimination between 'lighter' vs 'deeper' (Ramsay 1-3 vs 4-6) was good for general ICU patients [P(K)=0.80 (0.02)] and excellent for cardiac surgery patients [P(K)=0.96 (0.02)]. Performance was significantly better than Entropy™. Examination of individual cases suggested good face validity. CONCLUSIONS: RI of the frontal EMG has promise as a continuous sedation state monitor in critically ill patients. Further investigation to determine its utility in ICU decision-making is warranted.

Estimation of population attributable fraction (PAF) for disease occurrence in a cohort study design.

The population attributable fraction (PAF) is a useful measure for describing the expected change in an outcome if its risk factors are modified. Cohort studies allow researchers to assess the predictive value of the risk factor modification on the incidence of the outcome during a certain follow-up. Estimation of PAF for both mortality and morbidity in cohort studies with censored survival data has been developed in the recent years. So far, however, censoring due to death in the estimation of PAF for morbidity has been ignored, resulting in estimation of a quantity which is not relevant in practice as some people are likely to die during the follow-up. The risk factors related to the disease incidence may also be related to mortality, and modification of these risk factors is likely to delay the occurrence of both events. Thus, censoring due to death and the impact of risk factor modification must be considered when estimating PAF for disease incidence. We consider both and introduce two measures of disease burden: PAF for the incidence of disease during lifetime and PAF for the prevalence of disease in the population at a certain time. We demonstrate how consideration of censoring due to death changes the estimated PAF for disease incidence and its confidence interval. This underlines the importance of choosing a correct PAF measure depending on the outcome of interest and the risk factors of interest to obtain accurate and interpretable results.

Noninvasive Neuromonitoring of Hypothermic Circulatory Arrest in Aortic Surgery.

BACKGROUND AND AIMS: Circulatory arrest carries a high risk of neurological damage, but modern monitoring methods lack reliability, and is susceptible to the generalized effects of both anesthesia and hypothermia. The objective of this prospective, explorative study was to research promising, reliable, and noninvasive methods of neuromonitoring, capable of predicting neurological outcome after hypothermic circulatory arrest. MATERIALS AND METHODS: Thirty patients undergoing hypothermic circulatory arrest during surgery of the thoracic aorta were recruited in a single center and over the course of 4 years. Neuromonitoring was performed with a four-channel electroencephalogram montage and a near-infrared spectroscopy monitor. All data were tested off-line against primary neurological outcome, which was poor if the patient suffered a significant neurological complication (stroke, operative death). RESULTS: A poor primary neurological outcome seen in 10 (33%) patients. A majority (63%) of the cases were emergency surgery, and thus, no neurological baseline evaluation was possible. The frontal hemispheric asymmetry of electroencephalogram, as measured by the brain symmetry index, predicted primary neurological outcome with a sensitivity of 79 (interquartile range; 62%-88%) and specificity of 71 (interquartile range; 61%-84%) during the first 6 h after end of circulatory arrest. CONCLUSION: The hemispheric asymmetry of frontal electroencephalogram is inherently resistant to generalized dampening effects and is predictive of primary neurological outcome. The brain symmetry index provides an easy-to-use, noninvasive neuromonitoring method for surgery of the thoracic aorta and postoperative intensive care.

Gene-environment interaction in vulnerability to schizophrenia: findings from the Finnish Adoptive Family Study of Schizophrenia.

OBJECTIVE: This study assessed the interaction of genetic risk and rearing-family risk as a subsyndromal test measure of schizophrenic thought disorder in adoptees. METHOD: A group of 58 adoptees with schizophrenic biological mothers was compared with 96 comparison adoptees at ordinary genetic risk; putative adoptee vulnerability was assessed blindly and reliably by using the Rorschach Index of Primitive Thought. Environmental risk was measured by using frequency of communication deviance as a continuous variable, scored independently from Rorschach assessments of the adoptive parents. RESULTS: High genetic risk in itself was not associated with greater vulnerability to schizophrenic thought disorder in the adoptees, as indicated by the Index of Primitive Thought. Also, greater communication deviance in the adoptive parents was not associated with greater thought disorder in the comparison adoptees. However, there was a highly significant gene-environment interaction. Among the offspring of the adoptive parents with high levels of communication deviance, a higher proportion of high-risk than comparison adoptees showed evidence of thought disorder. In contrast, among the offspring of adoptive parents with low communication deviance, a lower proportion of high-risk than comparison adoptees showed evidence of thought disorder. The distribution of communication deviance scores did not differ significantly between the adoptive parents of high-risk offspring and the adoptive parents of comparison offspring. CONCLUSIONS: The findings are consistent with genetic control of sensitivity to the environment. There is no evidence that high genetic risk of schizophrenia among offspring is associated with high levels of communication problems in rearing parents.

How should relative risk estimates for acute otitis media in children aged less than 2 years be perceived?

To determine how the effects of certain risk factors for acute otitis media (AOM) vary according to the values of other risk determinants, and thus to obtain risk estimates more applicable to individual children, the medical records of a random sample of 2,512 children in northern Finland were monitored for the disease for up to an average age of 22 months. Information on determinants of AOM was obtained from parental questionnaires. The risk of the first AOM episode and that of later episodes were modelled separately by logistic regression using time-dependent values for some determinants. The odds ratio (OR) estimates for the alterable risk factors varied markedly over categories of other determinants as follows: nursery day care versus home care (OR from 1.1 to 3.0), parental smoking (OR from 0.9 to 1.5), and breast-feeding (OR from 0.5 to 1.0). Hence, to assess the significance of each risk factor for an individual child, the values for other relevant factors must be considered concurrently.

Is a child's risk of early onset schizophrenia increased in the highest social class?

In a sample from the unselected, general population Northern Finland 1966 Birth Cohort, 11017 individuals alive at the age of 16 years were studied until the age of 27. The cumulative incidence of early onset schizophrenia until 23 years was higher (1.14%; 9/792) among young persons from the highest social class or class I (determined according to father's occupation) than among children from lower social classes (0.47%; 48/10225), the difference being statistically significant (p < 0.05). The incidence of schizophrenia in the highest social class was higher than expected among girls, firstborns, children of young mothers under 30 and urban residents (p < 0.05) compared with lower social classes. When cases from the highest and other social classes were compared, there was no clear difference in background factors or clinical course. Four alcoholics, one of them also schizophrenic, were found among nine social class I fathers. The results suggest that in some families in Northern Finland, a father's professional advancement, often linked to mental disorder, may be one determinant of an increased risk of schizophrenia in the child.

Early developmental milestones in adult schizophrenia and other psychoses. A 31-year follow-up of the Northern Finland 1966 Birth Cohort.

Delayed childhood development may precede adult psychoses. We tested this hypothesis in a large, general population birth cohort (n=12058) followed to age 31 years. The ages at which individuals learned to stand, walk, speak, and became potty-trained (bowel control) and dry (bladder control), were recorded at a 1-year examination. Psychiatric outcome was ascertained through linkage to a national hospital discharge register. Cumulative incidence of DSM-III-R schizophrenia, other psychoses and non-psychotic disorders were stratified according to the timing of milestones and compared within the cohort using internal standardization. 100 cases of DSM-III-R schizophrenia, 55 other psychoses, and 315 non-psychotic disorders were identified. The ages at learning to stand, walk and become potty-trained were each related to subsequent incidence of schizophrenia and other psychoses. Compared with the whole cohort, earlier milestones reduced, and later milestones increased, the risk in a linear manner. These developmental effects were not seen for non-psychotic outcomes. The findings support hypotheses regarding psychosis as having a developmental dimension with precursors apparent in early life.

Teenage alcohol drinking and non-standard family background.

The teenage alcohol drinking in 1980 is described in a cohort of 12,058 subjects born in Northern Finland in 1966, with special reference to non-standard families (with one or both parents absent). The percentage of boys (girls) who had been drinking alcohol at the age of 14 years, was 59.1 (58.3)%, being 57.5 (55.6%) in standard, full families and 66.0 (69.0)% in non-standard families. The percentage of having been drunk was 25.2 (25.1)%, or 22.8 (22.1)% in full families and 36.1 (37.1)% in the non-standard families. When adjusted for the maternal age at birth, place of residence, social class and child's status in the family (firstborn or not, only child or not) by means of regression modelling, the risk of alcohol drinking/having been drunk was still increased in non-standard families, especially in cases of divorce or same-sex parental death, the risk differences as compared to the standard family usually being between 10-20%. The results suggest that a non-standard family structure is associated with early juvenile alcohol drinking. Parental loss or absence may constitute one important factor leading to excessive haste in adopting the adolescent culture, including its potentially destructive habits.

Chronic otitis media with effusion in infancy. How frequent is it? How does it develop?

OBJECTIVE: To study the occurrence and development of chronic otitis media with effusion in infancy. DESIGN: A retrospective birth cohort with a 2-year follow-up. Infection data were gathered from medical records; background information came from questionnaires. SETTING: Primary health care centers, hospitals, and private practices in 10 randomly selected local government districts in the two northernmost provinces of Finland. SUBJECTS: A random sample of 2512 children from the cohort. MAIN OUTCOME MEASURES: Chronic otitis media with effusion determined as a minimum of 2 months of asymptomatic middle ear effusion revealed by tympanocentesis and specific operative findings. RESULTS: The periodic prevalence rate of chronic otitis media with effusion up to the age of 24 months was 4.4% (95% confidence interval, 3.5 to 5.3). The maximum risk was at age 16 months. The number of acute otitis media episodes among children who developed chronic otitis media with effusion was more than double that of normal healthy children before the onset of chronic inflammation and about five times as high during prolonged mucous middle ear effusion. Inadequate treatment of prior acute otitis media was not the reason for the chronic inflammation, which was a direct continuation of an acute episode in only half of the cases and was otherwise preceded by a latent period of varying duration. CONCLUSIONS: Chronic otitis media with effusion, which may cause adverse developmental effects such as delayed language development, is a fairly common disease in infancy and is closely related to acute otitis media episodes.

Which children are being operated on for recurrent acute otitis media?

OBJECTIVE: To examine at the population level which children were operated on for recurrent acute otitis media episodes, how ill they were, and what factors affected the operation rate. DESIGN: A retrospective birth cohort with an approximate 2-year follow-up. Infection data were gathered from medical records, and background information was gathered from questionnaires. SETTING: Primary health care centers, hospitals, and private practices in 10 randomly selected local government districts in the two northernmost provinces of Finland. SUBJECTS: A random sample of 2512 children from the cohort. OUTCOME MEASURES: Adenoidectomy and/or tympanostomy tube insertion. RESULTS: Only one of 10 of those with actual recurrent disease (> or = 4 episodes) had been operated on, and three of every five children operated on, in fact, had rather few episodes. The operation rate among those children with only a few episodes was increased by factors such as consulting an ear, nose, and throat specialist (risk ratio [RR], 13.0; 95% confidence interval [CI], 7.6 to 22.2); parental exaggeration of the episodes (RR, 6.7; 95% CI, 3.8 to 11.9); having the first episode under 6 months of age (RR, 4.5; 95% CI, 2.5 to 7.9); recurrent respiratory tract infections (RR, 3.3; 95% CI, 1.9 to 5.7); male sex (RR, 2.6; 95% CI, 1.4 to 4.6); urban domicile (RR, 2.4; 95% CI, 1.1 to 4.9); and day care (RR, 2.1; 95% CI, 1.1 to 3.8). The decision to operate was more or less a random phenomenon among those children with numerous episodes. CONCLUSIONS: Physicians at the primary care level should be familiar with these pitfalls concerning patient selection so that the operations are targeted at those children who are most seriously ill.

Control of the temporal aspect when considering risk factors for acute otitis media.

A random sample of 2512 children was monitored to age 2 years to study the biologic effects of various risk variables on acute otitis media using a new dynamic modeling that controls both the confounding effects and time dependency. Dynamic modeling proved to be superior to conventional approaches, both the random and systematic error being much smaller and the effect estimates being biologically interpretable. The major risk factors were the existence of a previous episode of acute otitis media in general (odds ratio, 2.03; 95% confidence interval [Cl], 1.81 to 2.25) or particularly during the preceding 3 months (odds ratio, 3.74; 95% Cl, 3.40 to 4.10) and attending a day nursery (odds radio, 2.06; 95% Cl, 1.81 to 2.34). As the form of day care is the only modifiable risk variable of significant importance and previous episodes entail a risk of future ones, infants should be cared for at home, particularly after they have already experienced an episode of acute otitis media.

Risk factors for chronic otitis media with effusion in infancy. Each acute otitis media episode induces a high but transient risk.

OBJECTIVE: To examine the effects of a history of acute otitis media and different extrinsic factors on the risk of chronic otitis media with effusion in infancy. DESIGN: A retrospective birth cohort with a 2-year follow-up. Infection data were gathered from medical records and background information came from questionnaires. The monthly risk of chronic otitis media with effusion was dynamically modeled to control the confounding effects and time-dependency of the risk factors. SETTING: Primary health care centers, hospitals, and private practices in 10 randomly selected local government districts in the two northern most provinces of Finland. SUBJECTS: A random sample of 2512 children from the cohort. MAIN OUTCOME MEASURES: Chronic otitis media with effusion, defined as a minimum of 2 months of middle-ear effusion, usually is disclosed by tympanocentesis and specific operative findings. RESULTS: Previous acute otitis media episodes were the greatest risk factor. Each acute episode induced a highly increased risk (odds ratio, 11.9; 95% confidence interval, 5.7 to 24.9) that disappeared in 3 months. Successive episodes were risky, but this risk also decreased rapidly. Other significant risk variables were attendance at a day nursery (odds ratio, 2.56; confidence interval, 1.17 to 5.57), male sex (odds ratio, 2.17; confidence interval, 1.37 to 3.44), and autumn season (odds ratio, 1.99; confidence interval, 1.11 to 3.55). CONCLUSIONS: Acute otitis media episodes constitute the greatest risk of chronic otitis media with effusion. Each episode has a high transient risk for 3 months but no further direct effect on the risk.

Acute epiglottitis and infant conjugate Haemophilus influenzae type b vaccination in northern Finland.

OBJECTIVE: To determine the incidence and characteristics of acute epiglottitis among children (< or = 19 years of age) and adults (> or = 20 years of age) before and after widespread conjugate Haemophilus influenzae type b vaccination for infants. DESIGN: A retrospective population-based survey over a 27-year period from 1967 through 1993 in 35 communities in a northern province of Finland with a population of approximately 300,000. SETTING: An academic tertiary referral center. MAIN OUTCOME MEASURES: All acute epiglottitis cases in the area identified from the hospital discharge register and the regional autopsy register. RESULTS: The average incidence rate for children was 1.8 cases per 100,000 individuals per year (95% confidence interval [CI], 1.3 to 2.5). As no vaccine failures emerged, the incidence rate for children aged 0 to 4 years declined sharply once the vaccination started in 1986 from 7.6 (95% CI, 5.3 to 10.4) to 0 (95% CI, 0 to 3.3) cases per 100,000 individuals per year. By contrast, a fourfold increase in adult acute epiglottitis (incidence rate ratio, 4.6; 95% CI, 2.7 to 7.9) was detected after vaccination of the children, the average incidence rate for the whole period being 1.0 cases per 100,000 individuals per year (95% CI, 0.8 to 1.3). No marked change in the adult patient profile was found during this increase, however. CONCLUSION: Acute epiglottitis practically vanished among young children in this population after conjugate H influenzae vaccination, but adult cases increased, the patient profile remaining the same.

Perinatal risk for infants of unmarried mothers over a period of 20 years.

The perinatal events of the infants of 444 unmarried mothers, 3.7% of the total Northern Finland birth cohort from 1966, were compared with those of infants of 11,525 married mothers (95.5%), and a similar comparison was made between 395 (4.2%) unmarried mothers and 7516 (80.3%) married mothers in a second Northern Finland birth cohort in 1985-86. 1336 mothers, 14.3% of the mothers in this later cohort, were cohabiting. Divorced and widowed mothers were excluded from both cohorts. The infants of the unmarried mothers had a significantly lower mean birth weight, were more likely to be small for their gestational age (SGA), of low birth weight (LBW) (below 2500 g) and had a higher incidence of pre-term births than those of the married mothers in both cohorts. Perinatal mortality was significantly higher among the unmarried mothers only in the former cohort. These differences in perinatal events diminished markedly after adjustment for maternal age, parity, height, years of schooling and smoking habits, but did not totally disappear. The difference in the incidence of pre-term births diminished, but remained significant in both cohorts. The difference in mean birth weight, in the incidence of LBW infants and in perinatal mortality remained significantly less favourable to the unmarried mothers only in the 1966 cohort. It seems that the gap between the married and unmarried mothers had diminished. The incidence of SGA infants did not differ significantly between the married and unmarried mothers in either cohort after adjustment for the background variables. The cohabiting mothers formed an intermediate group between the married and single unmarried mothers in respect of perinatal events, but were close to the married mothers. In raw figures, the mean birth weight in this group was significantly lower and the incidence of SGA infants higher than among the married mothers, but these differences also disappeared after adjustment of the background variables.

Dynamic multivariate modelling: day care and consultation rate for acute otitis media.

A random sample of 2,512 children was monitored to the age of 2 years to study the effects of various risk variables on the consultation rate of acute otitis media. A total of 3,283 episodes of acute otitis media of 2,411 children with a follow-up time of at least 1 month were included in the analysis. During a 3 week-period after onset of the episode, the number of unplanned visits varied between 0 (2,544 episodes; 77.5%) and 6 (2 episodes; 0.1%). The children with day care outside their home showed a diminished risk for unplanned visits during the first week. The odds ratio (OR) and 95% confidence interval (CI) for children in family day care were 0.58 and 0.39-0.8, and 0.72 and 0.47-1.11 for children in nursery day care, respectively. During the second and third weeks the results were reversed: the above odds ratios should be multiplied by interaction terms 2.19 (CI 1.41-3.42; new OR 1.27) for children in family day care and 1.57 (CI 0.97-2.54; new OR 1.13) for children in nursery day care.

Prevalence figures for mild hearing impairments cannot be based on clinical data.

The target population of the present study consisted of a 1-year (July 1985-June 1986) birth cohort from northern Finland. The prevalence of even slight hearing impairments (any threshold from 0.5 to 4 kHz > or = 25 db) at the age of 7 years was investigated among those 8,713 children still living in the area. The subjects for clinical audiometry were obtained in two ways. First, the standard clinical practice brought about 541 children, either with non-confirming results from their child welfare clinic screenings, suspected by their parents or already diagnosed as hearing impaired at a hospital. Secondly, in addition to this group, a random sample of 1,009 children, out of the 8,172 children not suspected, were also invited for audiometry. Of the clinical material, 101 children out of the 438 investigated were found to have impaired hearing according to the above criteria, and another 27 children out of the 789 investigated were obtained from the random sample. The estimated over-all prevalence of hearing impairments, even with the slight ones included, turned out to be 3.9% (95% confidence interval, CI, 2.7-5.7). Only 32% of the hearing impairments could be obtained according to the standard clinical policy! In conclusion, one cannot rely on clinical data when calculating prevalence figures for mild hearing impairments.

Physiological fluctuations in nasal resistance may interfere with nasal monitoring in the nasal provocation test.

The physiological fluctuations in nasal flow and resistance in allergic subjects were studied by monitoring 12 subjects with perennial occupational allergic rhinitis with active anterior rhinomanometry (AAR) for 3 h at 15 min intervals. The subjects were then challenged bilaterally with the diluent solution for allergen extracts and the effect was monitored with AAR. In AAR. cellular rubber nose adapters were used. Many physiological fluctuations in nasal patency were observed. Reference intervals were calculated for the changes in flow and resistance at the gradient pressure of 150 pa. For example, a 100% increase in unilateral resistance was found to be significant at the risk level of 5-10% for the observation time of 30-60 min. The corresponding increase for bilateral resistance was close to 70%. Challenge with diluent solution had a negliglible effect on the resistance fluctuation, the reference intervals being close to those for baseline monitoring. In conclusion, rapid changes in nasal flow and resistance in allergic subjects were common, and caution is necessary when interpreting these changes as a positive nasal reaction in the nasal provocation test. In addition, the use of other objective parameters, such as the amount of nasal secretion is recommended.

What is the natural history of recurrent acute otitis media in infancy?

BACKGROUND: Chemoprophylaxis or tympanostomy tubes are often recommended for recurrent acute otitis media because of the associated morbidity, temporary hearing loss, financial costs, and risks of middle-ear sequelae. The aim of this study was to study the natural course of recurrent acute otitis media in infancy without such prophylactic treatment. METHODS: Two hundred twenty-two children who had recurrent acute otitis media and received no prophylaxis were monitored for subsequent acute otitis media and the development of chronic otitis media with effusion. RESULTS: Only 4% of the 222 infants with recurrent acute otitis media developed chronic otitis media with effusion and an additional 12% continued having recurrent episodes. The most significant factor predicting an increased risk of recurrence was young age (< 16 months of age). Attending day care and having siblings had a less pronounced effect. CONCLUSIONS: Spontaneous recovery from recurrent acute otitis media is common with increasing age. Thus, until reliable causal evidence between recurrent otitis media and developmental disability is presented, chemoprophylaxis or tympanostomy tubes seem superfluous for most infants after the age of 16 months.