Level of evidence for promising subgroup findings: The case of trends and multiple subgroups

Subgroup analyses are an essential part of fully understanding the complete results from confirmatory clinical trials. However, they come with substantial methodological challenges. In case no statistically significant overall treatment effect is found in a clinical trial, this does not necessarily indicate that no patients will benefit from treatment. Subgroup analyses could be conducted to investigate whether a treatment might still be beneficial for particular subgroups of patients. Assessment of the level of evidence associated with such subgroup findings is primordial as it may form the basis for performing a new clinical trial or even drawing the conclusion that a specific patient group could benefit from a new therapy. Previous research addressed the overall type I error and the power associated with a single subgroup finding for continuous outcomes and suitable replication strategies. The current study aims at investigating two scenarios as part of a nonconfirmatory strategy in a trial with dichotomous outcomes: (a) when a covariate of interest is represented by ordered subgroups, eg, in case of biomarkers, and thus, a trend can be studied that may reflect an underlying mechanism, and (b) when multiple covariates, and thus multiple subgroups, are investigated at the same time. Based on simulation studies, this paper assesses the credibility of subgroup findings in overall nonsignificant trials and provides practical recommendations for evaluating the strength of evidence of subgroup findings in these settings.     

Damage to the intestinal epithelial barrier by antibiotic pretreatment of salmonella-infected rats is lessened by dietary calcium or tannic acid

Perturbation of the intestinal microbiota by antibiotics predisposes the host to food-borne pathogens like Salmonella. The effects of antibiotic treatment on intestinal permeability during infection and the efficacy of dietary components to improve resistance to infection have not been studied. Therefore, we investigated the effect of clindamycin on intestinal barrier function in Salmonella-infected rats. We also studied the ability of dietary calcium and tannic acid to protect against infection and concomitant diarrhea and we assessed intestinal barrier function. Rats were fed a purified control diet including the permeability marker chromium EDTA (CrEDTA) (2 g/kg) or the same diet supplemented with calcium (4.8 g/kg) or tannic acid (3.75 g/kg). After adaptation, rats were orally treated with clindamycin for 4 d followed by oral infection with Salmonella enteritidis. Two additional control groups were not treated with antibiotics and received either saline or Salmonella. Urine and feces were collected to quantify intestinal permeability, diarrhea, cytotoxicity of fecal water, and Salmonella excretion. In addition, Salmonella translocation was determined. Diarrhea, CrEDTA excretion, and cytotoxicity of fecal water were higher in the clindamycin-treated infected rats than in the non-clindamycin-treated infected control group. Intestinal barrier function was less in the Salmonella-infected rats pretreated with antibiotics compared with the non-clindamycin- treated rats. Both calcium and tannic acid reduced infection-associated diarrhea and inhibited the adverse intestinal permeability changes but did not decrease Salmonella colonization and translocation. Our results indicate that calcium protects against intestinal changes due to Salmonella infection by reducing luminal cytotoxicity, whereas tannic acid offers protection by improving the mucosal resistance.     

In vitro and ex vivo evidence for modulation of P-glycoprotein activity by progestins

The well known gender-related differences in drug action may partly be explained by changes in activity and expression of drug metabolising enzymes, but also by modulation of active drug transport systems (e.g. P-glycoprotein, Pgp) by sexual steroids, which is yet not well investigated. Because many women are using hormones (e.g. as oral contraceptives) we investigated the influence of different synthetic progestins on Pgp activity. Pgp inhibition of progesterone, medroxyprogesterone, chlormadinone, cyproterone, levonorgestrel, norethisterone, desogestrel, and norgestimate was measured in vitro in two Pgp over-expressing cell lines (L-MDR1, P388/dx cells) and the corresponding parental cell lines by means of calcein assay, and ex vivo in human peripheral blood mononuclear cells (PBMCs) by rhodamine123 efflux. For most progestins tested, concentrations needed to double baseline fluorescence (f2) in L-MDR1 cells were similar to that of the potent Pgp inhibitor quinidine, whereas levonorgestrel and norethisterone did not reach f2. The results in P388/dx cells essentially confirmed our findings in L-MDR1 cells. Additionally, Pgp inhibitory activity of all progestins tested was also shown ex vivo in PBMCs. The potent Pgp inhibition by several synthetic progestins in vitro and ex vivo suggests that such an interaction might be clinically relevant despite generally low plasma concentrations of progestins. The results may be of particular importance for Pgp substrates, such as protease inhibitors and chemotherapeutic agents, for which intracellular concentrations are critical.     

Correlation between ocular pulse amplitude measured by dynamic contour tonometer and visual field defects

Purpose To investigate the correlation between ocular pulse amplitude and visual field defects in patients with glaucoma, ocular hypertension, and glaucoma suspicion when measured with the Pascal Dynamic Contour Tonometer, and to verify if the ocular pulse amplitude is an independent predictor for visual field parameters. Methods Seventy-seven eyes (42 patients) with glaucoma, ocular hypertension or glaucoma suspicion were examined. Ocular pulse amplitude was measured with the dynamic contour tonometer by one investigator masked to the visual field data. Visual fields were performed within three months of ocular pulse amplitude measurement by the Octopus or Humphrey Field Analyser, and were analysed with Peridata Software. Mean defect, pattern standard deviation (√ Loss Variance) and regression analysis of those parameters (Trend Indices) were correlated with the ocular pulse amplitude for each eye. Results Forty-nine eyes had glaucoma, 14 had ocular hypertension, and 14 were glaucoma suspects. The mean follow-up was 46.5 (range 6–96) months. There was a significant correlation between OPA and MD and OPA and PSD, even after correction for IOP (and diagnostic group and eye): the estimated slope equals 2.68 (S.E. = 0.82, p = 0.003) and −0.86 (S.E. = 0.33, p = 0.014), respectively. There was even a weak correlation between OPA and the evolution of MD (dB/year). The slope estimate for OPA equals 0.070 (S.E. = 0.033), p = 0.037. However, after correction for IOP (and diagnostic group and eye), the strength of the relationship is reduced and the evidence disappears: the slope estimate for OPA now equals 0.039 (S.E. = 0.041), p = 0.34. There is no evidence for an association between OPA and the evolution of Trend-PSD. Conclusion A small ocular pulse amplitude, as measured with a dynamic contour tonometer, is correlated with moderate to severe glaucomatous visual field loss and might be a risk factor for the development of glaucomatous visual field defects.     

The effects of a hearing education program on recreational noise exposure,attitudes and beliefs toward noise,hearing loss,and hearing protector devices in young adults

Excessive recreational noise exposure in young adults might result in noise-induced hearing loss (NIHL) and tinnitus. Inducing behavioral change in young adults is one of the aims of a hearing conservation program (HCP). The goal of the current study was to evaluate the effect of a hearing education program after 6 months in young adults in relation to knowledge regarding their individual hearing status. The results of a questionnaire regarding the weekly equivalent recreational noise exposure, attitudes and beliefs toward noise, and hearing loss and hearing protector devices (HPDs) were compared between both sessions. Seventy-eight young adults completed the questionnaire concerning recreational noise exposure, youth attitude to noise scale (YANS), and beliefs about hearing protection and hearing loss (BAHPHL). Their hearing status was evaluated based on admittance measures, audiometry, transient-evoked otoacoustic emissions (TEOAEs), and distortion-product otoacoustic emissions (DPOAEs). The main analysis consisted of a mixed model analysis of variance with dependent variables of either the noise exposure or the scores on (subscales of) YANS and BAHPHL. The independent variables were hearing status and session one versus session two. There was a significant decrease in recreational noise exposure and several (sub) scales of YANS and BAHPHL between both the sessions. This behavioral change resulted in a more frequent use of HPDs in 12% of the participants. However, the behavioral change was not completely related to the knowledge of young adults’ individual hearing status. To prevent hearing damage in young people, investing in HCPs is necessary, apart from regulating sound levels and its compliance at various leisure-time activities. Also, the long-term effect of HCPs and their most cost-efficient repetition rates should be further investigated.     

Estimating marginal causal effects in a secondary analysis of case‐control data

When an initial case‐control study is performed, data can be used in a secondary analysis to evaluate the effect of the case‐defining event on later outcomes. In this paper, we study the example in which the role of the event is changed from a response variable to a treatment of interest. If the aim is to estimate marginal effects, such as average effects in the population, the sampling scheme needs to be adjusted for. We study estimators of the average effect of the treatment in a secondary analysis of matched and unmatched case‐control data where the probability of being a case is known. For a general class of estimators, we show the components of the bias resulting from ignoring the sampling scheme and demonstrate a design‐weighted matching estimator of the average causal effect. In simulations, the finite sample properties of the design‐weighted matching estimator are studied. Using a Swedish diabetes incidence register with a matched case‐control design, we study the effect of childhood onset diabetes on the use of antidepressant medication as an adult. Copyright © 2017 John Wiley & Sons, Ltd.     

Expression pattern of gastrointestinal selenoproteins— targets for selenium supplementation

There is experimental and epidemiological evidence for an association between low selenium levels and gastrointestinal cancer incidence, prevalence, and mortality. To identify targets for selenium supplementation in the human digestive tract, we examined mRNA expression of various selenocysteine‐containing proteins in normal mucosa biopsy specimens. Tissue samples from the esophagus and from different sites of the stomach, small bowel, and colon were obtained during endoscopies of the upper and lower gastrointestinal tract. Northern blot analyses revealed a lack of cytosolic glutathione peroxidase mRNA but a differential mRNA expression pattern of gastrointestinal and plasma glutathione peroxidase, selenoprotein P, and thioredoxin reductase. Glutathione peroxidase and thioredoxin reducíase activities were detected in the mucosa of all biopsies, but the differential pattern did not reflect the differential mRNA steady‐state levels. In addition to gastrointestinal glutathione peroxidase, which was found to play a role in colon cancer resistance, we identified further gastrointestinal selenoproteins, which may be involved in gastrointestinal cell defense and cell differentiation.     

Geriatric Rehabilitation: Elderly Clients' Experiences of a Pre-discharge Occupational Therapy Group Programme

This study describes how elderly people, temporarily living in a pre-discharge community rehabilitation centre, may experience participation in an in-patient occupational therapy programme built around group activities. The group activity programme was comprised of five sessions, each focusing on a theme chosen to encourage reflection and mutual sharing of experiences and support. Data were collected through interviews with each of the three participants immediately after each of the five group sessions. The resultant 15 interviews were analysed by adopting a Grounded Theory approach. The results show that the ways in which the participants experienced participating in the group activity programme can be described from two distinct core categories: experiences of activation and experiences of transformation . The category of activation emerged from their experiences of a creative force whilst engaged in performing the activities and from their discovery that the group was a good place for learning . Engagement in the group activities also seemed to bring about a transformation in the participants in that their experiences triggered reflection and adaptation , which contributed to a change in attitude and a personal synthesis where their new discoveries were internalized. The study shows the potential a group activity programme in occupational therapy has in triggering an adaptational and reflective process within elderly people facing discharge from hospital. Hence, group activity interventions in occupational therapy are suggested as one possible way to support the elderly person in the discharge process from hospital to the home.