OBJECTIVES: To consider methods and related evidence for evaluating bias in non-randomised intervention studies. DATA SOURCES: Systematic reviews and methodological papers were identified from a search of electronic databases; handsearches of key medical journals and contact with experts working in the field. New empirical studies were conducted using data from two large randomised clinical trials. METHODS: Three systematic reviews and new empirical investigations were conducted. The reviews considered, in regard to non-randomised studies, (1) the existing evidence of bias, (2) the content of quality assessment tools, (3) the ways that study quality has been assessed and addressed. (4) The empirical investigations were conducted generating non-randomised studies from two large, multicentre randomised controlled trials (RCTs) and selectively resampling trial participants according to allocated treatment, centre and period. RESULTS: In the systematic reviews, eight studies compared results of randomised and non-randomised studies across multiple interventions using meta-epidemiological techniques. A total of 194 tools were identified that could be or had been used to assess non-randomised studies. Sixty tools covered at least five of six pre-specified internal validity domains. Fourteen tools covered three of four core items of particular importance for non-randomised studies. Six tools were thought suitable for use in systematic reviews. Of 511 systematic reviews that included non-randomised studies, only 169 (33%) assessed study quality. Sixty-nine reviews investigated the impact of quality on study results in a quantitative manner. The new empirical studies estimated the bias associated with non-random allocation and found that the bias could lead to consistent over- or underestimations of treatment effects, also the bias increased variation in results for both historical and concurrent controls, owing to haphazard differences in case-mix between groups. The biases were large enough to lead studies falsely to conclude significant findings of benefit or harm. Four strategies for case-mix adjustment were evaluated: none adequately adjusted for bias in historically and concurrently controlled studies. Logistic regression on average increased bias. Propensity score methods performed better, but were not satisfactory in most situations. Detailed investigation revealed that adequate adjustment can only be achieved in the unrealistic situation when selection depends on a single factor. CONCLUSIONS: Results of non-randomised studies sometimes, but not always, differ from results of randomised studies of the same intervention. Non-randomised studies may still give seriously misleading results when treated and control groups appear similar in key prognostic factors. Standard methods of case-mix adjustment do not guarantee removal of bias. Residual confounding may be high even when good prognostic data are available, and in some situations adjusted results may appear more biased than unadjusted results. Although many quality assessment tools exist and have been used for appraising non-randomised studies, most omit key quality domains. Healthcare policies based upon non-randomised studies or systematic reviews of non-randomised studies may need re-evaluation if the uncertainty in the true evidence base was not fully appreciated when policies were made. The inability of case-mix adjustment methods to compensate for selection bias and our inability to identify non-randomised studies that are free of selection bias indicate that non-randomised studies should only be undertaken when RCTs are infeasible or unethical. Recommendations for further research include: applying the resampling methodology in other clinical areas to ascertain whether the biases described are typical; developing or refining existing quality assessment tools for non-randomised studies; investigating how quality assessments of non-randomised studies can be incorporated into reviews and the implications of individual quality features for interpretation of a review's results; examination of the reasons for the apparent failure of case-mix adjustment methods; and further evaluation of the role of the propensity score.

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Evaluating non-randomised intervention studies.

Toxocariasis is caused by a series of related nematode species (ascarids) that routinely infect dogs and cats throughout the world. The eggs from these ascarids are common environmental contaminants of human habitation, due largely to the fact that many kinds of dogs and cats serve as pets, while countless others run wild throughout the streets of most urban centers. The eggs, present in dog and cat feces, become infectious within weeks after they are deposited in the local environment (e.g., sandboxes, city parks, and public beaches, etc.). Humans, particularly children, frequently ingest these eggs by accident and become infected. Infection in humans, in contrast to their definitive hosts, remains occult, often resulting in disease caused by the migrating larval stages. Visceral larva migrans (VLM) and ocular larva migrans (OLM) are two clinical manifestations that result in definable syndromes and present as serious health problems wherever they occur. Diagnosis and treatment of VLM and OLM are difficult. These issues are summarized in this review, with emphasis on the ecology of transmission and control of spread to both humans and animals through public health initiatives employing treatment of pets and environmental intervention strategies that limit the areas that dogs and cats are allowed within the confines of urban centers.

Toxocariasis: Clinical Aspects, Epidemiology, Medical Ecology, and Molecular Aspects

Bacterial sepsis in the neonate is a clinical syndrome characterized by systemic signs of infection and accompanied by bacteremia in the first month of life. Meningitis in the neonate usually is a sequela of bacteremia and is discussed in this chapter because meningitis and sepsis typically share a common cause and pathogenesis. Infections of the bones, joints, and soft tissues and of the respiratory, genitourinary, and gastrointestinal tracts can be accompanied by bacteremia, but the cause, clinical features, diagnosis, and management of these infections are sufficiently different to warrant separate discussions. Sepsis and meningitis caused by group B Streptococcus, Staphylococcus aureus, Neisseria gonorrhoeae, Listeria monocytogenes, Salmonella species, and Mycobacterium tuberculosis are described in other chapters.

Bacterial Sepsis and Meningitis

In 1999, a Task Force on Mild Traumatic Brain Injury (MTBI) was set up under the auspices of the European Federation of Neurological Societies. Its aim was to propose an acceptable uniform nomenclature for MTBI and definition of MTBI, and to develop a set of rules to guide initial management with respect to ancillary investigations, hospital admission, observation and follow-up.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1468-1331.2002.00407.x

EFNS guideline on mild traumatic brain injury: report of an EFNS task force

How common is human toxocariasis? Towards standardizing our knowledge.

Antibiotic prophylaxis after basilar skull fractures remains controversial. Previous studies have not clearly delineated the utility of prophylactic antibiotics in this setting. We undertook this study to determine if antibiotic prophylaxis after basilar skull fractures prevented meningitis. We performed a formal systematic review of previously published studies after a computerized search with use of the MEDLINE data base (1970-1996). Fourteen studies were identified, and 12 studies met the criteria for inclusion. Study design and quality were assessed by two independent investigators with use of a predetermined protocol. A total of 1,241 patients with basilar skull fractures were included; 719 patients received antibiotics, and 522 patients did not receive antibiotics. Overall results suggest that antibiotic prophylaxis did not prevent meningitis among patients with basilar skull fractures (odds ratio [OR] = 1.15; 95% confidence interval [CI] = 0.68-1.94; P = .678). Patients with basilar skull fractures and cerebrospinal fluid leakage were analyzed separately (OR = 1.34; 95% CI = 0.75-2.41; P = .358), as were children (OR = 1.04; 95% CI = 0.07-14.90; P = 1.000). Antibiotic prophylaxis after basilar skull fractures does not appear to decrease the risk of meningitis.

Antibiotic Prophylaxis After Basilar Skull Fractures: A Meta-Analysis

:This is a case of visceral larva migrans and hypereosinophilia syndrome with persistently elevated white blood cell count despite adequate medical therapy in a 4-year-old boy with leukocytosis and splenomegaly. Medical history included reactive airway disease and geophagia (pica). Serology

Visceral larva migrans and the hypereosinophilia syndrome.

Neonatal meningococcal meningitis: case reports and review of literature.

Background Children infected with the human immunodeficiency virus (HIV) often have hypergammaglobulinemia, causing elevation of the erythrocyte sedimentation rate (ESR). This study was done to determine whether C-reactive protein (CRP) is a better indicator of acute infection than ESR in HIV-infected children. Methods Erythrocyte sedimentation rate, CRP, and immunoglobulin G (IgG) levels were measured in sick and otherwise healthy HIV-infected children. McNemar's test was used to compare ESR and CRP. Results In 22 of the 26 cases (85%), the IgG level was elevated, and in all cases ESR was elevated. In 20 of these 22 (91%), both ESR and CRP were elevated. Of the 18 controls, 17 (94%) had elevated IgG, 14 of 17 (82%) had elevated ESR, and 1 (7%) had elevated CRP. The sensitivity for ESR and CRP was 96% and 92%, respectively, and the specificity for ESR and CRP was 17% and 94%, respectively. Conclusions Since CRP is more specific than ESR in predicting acute infection in HIV-infected children, it should be used in the evaluation of acute infection in this population.

Usefulness of acute phase reactants in the diagnosis of acute infections in HIV-infected children.

A pneumothorax is a pathological collection of air in the pleural space within the thoracic cavity. Pneumothoraxes are classified by the underlying etiology as spontaneous or traumatic, with spontaneous pneumothoraxes being further categorized into primary and secondary causes. Management historically involved admission with possible administration of oxygen or chest tube placements based on severity. We herein describe a pediatric case of a likely blunt-force traumatic pneumothorax after a fall, successfully managed conservatively in the outpatient setting. The case highlights an acceleration-deceleration blunt trauma caused during a tackle at a football game and the importance of the clinical presentation, physical exam, and confirmation with a chest X-ray.

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Carlos Arango

Papers

Antibiotic Prophylaxis After Basilar Skull Fractures: A Meta-Analysis

Visceral larva migrans and the hypereosinophilia syndrome.

Neonatal meningococcal meningitis: case reports and review of literature.

Usefulness of acute phase reactants in the diagnosis of acute infections in HIV-infected children.

Pneumothorax After a Fall in a Healthy Adolescent Athlete