Statistical analysis and interpretation of prenatal diagnostic imaging studies, part 3: approach to study design

A critical step in planning a successful study is choosing the appropriate design to feasibly answer the clinical question at hand. We provide an overview of common study designs, discuss their advantages and disadvantages, and provide practical examples from the prenatal diagnosis and ultrasound literature. In addition, we highlight specific design considerations that need to be built into the analysis of study results.     

Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients

The immunosuppressive environment of advanced tumors is a primary obstacle to the efficacy of immunostimulatory and vaccine approaches. Here, we report an approach to arm an oncolytic virus with CD40 ligand (CD40L) to stimulate beneficial immunologic responses in patients. A double-targeted chimeric adenovirus controlled by the hTERT promoter and expressing CD40L (CGTG-401) was constructed and nine patients with progressing advanced solid tumors refractory to standard therapies were treated intratumorally. No serious adverse events resulting in patient hospitalization occurred. Moderate or no increases in neutralizing antibodies were seen, suggesting effective Th1 immunologic effects. An assessment of the blood levels of virus indicated 17.5% of the samples (n = 40) were positive at a low level early after treatment, but not thereafter. In contrast, high levels of virus, CD40L, and RANTES were documented locally at the tumor. Peripheral blood mononuclear cells were analyzed by IFN-γ ELISPOT analysis and induction of both survivin-specific and adenovirus-specific T cells was seen. Antitumor T-cell responses were even more pronounced when assessed by intracellular cytokine staining after stimulation with tumor type-specific peptide pools. Of the evaluable patients, 83% displayed disease control at 3 months and in both cases in which treatment was continued the effect was sustained for at least 8 months. Injected and noninjected lesions responded identically. Together, these findings support further clinical evaluation of CGTG-401.     

Daylight saving time transitions and hospital treatments due to accidents or manic episodes

Background

Daylight saving time affects millions of people annually but its impacts are still widely unknown. Sleep deprivation and the change of circadian rhythm can trigger mental illness and cause higher accident rates. Transitions into and out of daylight saving time changes the circadian rhythm and may cause sleep deprivation. Thus it seems plausible that the prevalence of accidents and/or manic episodes may be higher after transition into and out of daylight saving time. The aim of this study was to explore the effects of transitions into and out of daylight saving time on the incidence of accidents and manic episodes in the Finnish population during the years of 1987 to 2003.

Methods

The nationwide data were derived from the Finnish Hospital Discharge Register. From the register we obtained the information about the hospital-treated accidents and manic episodes during two weeks before and two weeks after the transitions in 1987–2003.

Results

The results were negative, as the transitions into or out of daylight saving time had no significant effect on the incidence of accidents or manic episodes.

Conclusion

One-hour transitions do not increase the incidence of manic episodes or accidents which require hospital treatment.     

Postictal diffusion weighted imaging

PURPOSE: Our aim was to determine whether diffusion weighted imaging can detect abnormalities of diffusivity after single seizures, and investigate the localisation and time course of any changes. METHODS: Twenty-one patients with intractable focal epilepsy were imaged interictally and after 23 seizures. Voxel-based statistical parametric mapping was used to detect postictal changes in mean diffusivity (MD), compared to the changes noted in 20 controls scanned twice. The time course and magnitude of the changes were evaluated by measuring MD in the areas of change identified by the voxel-based analysis. RESULTS: Thirty-four focal changes in MD (24 decreases, 10 increases) were detected after 12 of 23 seizures in 11 patients, after a median interval of 53 min from the time of seizure onset. Five patients had areas of both increased and decreased diffusion after seizures. In four patients, postictal changes in diffusion corresponded with the presumed seizure focus. Repeated postictal scanning, after a further interval of a median of 46 min in eight patients, showed that postictal changes in MD, both increases and decreases, were returning towards interictal values. CONCLUSIONS: Diffusion weighted imaging identified focal changes in MD after 52% of single complex partial and secondarily generalised seizures. Changes in MD corresponded to the putative seizure focus in a minority of cases suggesting that the technique is not promising as a method for localising seizure foci, but may indicate the networks involved in seizures.     

Ampicillin versus penicillin in the empiric therapy of extremely low‐birthweight neonates at risk of early onset sepsis

Background: There are no comparative data on the impact of different empiric antibiotic regimens on early bowel colonization as well as on clinical efficacy in extremely low‐birthweight (ELBW) neonates at risk of early onset sepsis (EOS). Methods: A subgroup analysis was carried out of ELBW neonates recruited into a two‐center, prospective, cluster randomized study comparing ampicillin and penicillin both combined with gentamicin, within the first 72 h of life. A composite primary end‐point (need for change of antibiotics within 72 h and/or 7 day all‐cause mortality) and the rate and duration of colonization by opportunistic aerobic microorganisms were assessed using hierarchical models corrected for study center and period. Results: In the ampicillin (n= 36) and penicillin (n= 39) groups change of antibiotics, 7 day mortality and the composite end‐point occurred at similar rates. Neonatal intensive care unit mortality for infants with gestational age <26 weeks was lower in the ampicillin group. Ampicillin treatment was associated with a higher colonization rate by Klebsiella pneumoniae, including ampicillin‐resistant strains. Conclusion: Preliminary data indicate an urgent need for adequately powered studies of early antibiotic therapy in the subpopulation of ELBW neonates at risk of EOS.     

The role of serum markers and uterine artery Doppler in identifying at-risk pregnancies

Measures of placental dysfunction, including maternal serum analytes and Doppler studies, have been linked to adverse pregnancy outcomes, although the predictive ability of any single one is poor. Improved knowledge of the multifactorial nature of many of the adverse outcomes of pregnancy has sparked interest in the use of multi-parameter models that combine maternal serum analytes with measures of placental structure and blood flow. The combination of various first-trimester and second-trimester analytes and uterine artery Doppler screening show promise as potential screening tools, but large prospective studies are needed to further define their role in clinical practice.