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PubMed2004

The genetic relationship of personality to major depression and schizophrenia.

Since ancient times, dimensions of personality have been linked with the liability to psychiatric illness. In modern times, several research approaches suggest that personality and the liability to psychiatric illness such as schizophrenia and major depression (MD) are influenced by many of the same genes. If this is true, it could shed light on the genetic architecture of psychiatric illness. It could also validate the use of personality measures in unaffected relatives in linkage and association studies of psychiatric illness. This approach could potentially increase statistical power to detect genetic effects. The personality trait neuroticism (N) may be genetically related to MD, while schizotypal traits may be genetically related to schizophrenia. Twin studies have reported that most of the covariation between N and MD is due to shared additive genetic factors. Adoption studies have demonstrated that the biological offspring of schizophrenic mothers are more likely to have schizotypal personality disorder than are children of control mothers. At the current time, only one genome wide scan of N has been published, which does show some overlap in linkage results with genome scans of MD. However, this should be replicated and more rigorously studied. At the present time, there are no established susceptibility genes for MD. When these are established, it will be necessary to assess their relationship with N. Currently, no genome scans of schizotypy have been published. Furthermore, although several putative susceptibility genes for schizophrenia have been reported and replicated, only one--catechol-O-methyltransferase (COMT)--has been tested in schizotypy.

Major Depressive Disorder↗
PubMed1997

[Combined breast-preserving surgery, chemotherapy and radiotherapy in the treatment of breast carcinoma. Effect of the interval between surgery and the beginning of radiotherapy].

BACKGROUND: The timing of breast conserving surgery, chemotherapy, and radiotherapy in breast cancer treatment has become the subject of increasing interest over the last years. PATIENTS AND METHOD: Seventy-four patients who underwent postoperative radiotherapy at our institution between 1985 and 1992 form the basis of this study. Median follow-up time was 5 years. Seventy-three percent of patients were pre- or perimenopausal. Almost all patients (91%) were UICC-stage II. Axillary lymph nodes were positive in 95% of cases. Complete gross resection was achieved in all patients, and in 65% final pathological margins were free of invasive or intraductal carcinoma. Postoperatively, 70% of patients received 6 cycles of polychemotherapy (predominantly CMF) before onset of irradiation. The radiation dose was in almost all cases 60 Gy including 10 Gy boost. RESULTS: Five years after start of treatment overall survival, disease-free survival, and local recurrence rates were 86% (95%-confidence limits, 76 to 93%), 73% (61 to 83%), and 8% (3 to 16%), respectively. For disease-free survival, the only significant prognostic factor was the number of involved lymph nodes: 0 to 3 = 86%, > or = 4 = 40% (p < 0.0001). The interval between surgery and radiation (< or = versus > 20 weeks) had no significant influence on disease-free survival or local tumor control. In contrast, there was a trend of increased regional and distant failure with shortening of the interval due to the delivery of less than 6 cycles chemotherapy before the onset of radiotherapy. CONCLUSIONS: In our experience, there was no negative impact of a delay of radiotherapy in order to deliver full course chemotherapy before initiation of radiotherapy. However, the low statistical power of this analysis due to the small number of patients must be considered. it appears possible that a less intense chemotherapy before starting radiation treatment correlates with enhanced distant failure and subsequently decreased disease-free survival rates. Therefore, for patients at increased risk for distant metastasis, we prefer to give 6 cycles polychemotherapy before irradiation.

Adult↗
PubMed2003

Binge eating disorder versus overeating: a failure to replicate and common factors in severely obese treatment seeking women.

The disordered eating symptoms, general psychopathology and dieting history among obese women diagnosed with Binge Eating Disorder (BED) and obese women who overeat (OE) are examined. One hundred and thirty women (n=83 with BED and n=47 who overeat) seeking treatment for an eating disorder were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria and the Eating Disorders Examination (EDE). They also completed a battery of psychometric tests. Despite adequate statistical power to detect differences, MANOVAs revealed very few significant differences between the groups. Loss of control of eating does not adequately differentiate these two groups within an eating disorders treatment-seeking context. It is likely that only the most acutely distressed from each group is seeking treatment, so that differences found in a community sample would not be found. Using a principal components analysis, factors within each group that may underlie the common psychopathology of both groups (i.e. disordered eating symptoms, general psychopathology and dieting history) were found.

Adult↗
PubMed2002

Physical activity does not mitigate G-protein-related genetic risk for obesity in individuals of African descent.

The G-protein beta3 subunit 825 TT genotype has been associated with obesity and hypertension. We examined the interaction between the G-protein TT genotype, physical activity and body mass index (BMI) in a cross-sectional study of African immigrants and African Americans. The genotype frequencies were 6.3% CC, 37.7% CT, and 56% TT. After adjusting for potential confounders, BMI was found to be significantly higher in the sedentary than in the physically active participants (p=0.045). There was no statistically significant effect for genotype (p=0.215) or the interaction between genotype and the level of physical activity (p=0.219). However, the individuals with the CC or CT genotype who were physically active had substantially lower BMIs (M+/-SE) (i.e., 25.74+/-2.02) than any of the other groups: sedentary CC + CT (30.58+/-1.03), sedentary TT (30.65+/-1.00) or active TT (29.43+/-1.65). Because of the low statistical power of this study, further research is needed to confirm these findings and to explore potential gene-environment/lifestyle interactions.

Adult↗
PubMed2001

Prospective cohort studies using hydrolysed formulas for allergy prevention in atopy-prone newborns: a systematic review.

UNLABELLED: The aim of this study is to give a systematic overview on publications having investigated the allergy preventive effect of extensively and/or partially hydrolysed infant formulas. Publications were searched by several strategies. Inclusion criteria were: prospective cohort study, randomisation, family history of atopy of the subjects, follow-up for at least the 1st year of life. Studies were described systematically as to methods, study participants, interventions and co-interventions, and study outcomes. The methodological quality was judged according to an instrument assessing the reduction of bias (score between 0 and 7 points). Data of studies having examined partial hydrolysates are presented as odds ratios. Of 16 studies found, 10 fulfilled the inclusion criteria. Study designs showed considerable differences as to methods, intervention and co-intervention procedures and definition of outcomes. Methodological quality varied between 0 and 6 points. The comparison of exclusively test- and control formula-fed groups showed a uniform tendency towards allergy protection in studies with partial hydrolysates. Study results on the effect of extensive hydrolysates were not comparable because of major differences in study designs. CONCLUSION: More well-designed studies with an adequate statistical power are needed to compare the allergy preventive effect of partially and extensively hydrolysed formulas with a standard infant formula.

Cohort Studies↗
PubMed2002

[High-dose chemotherapy in breast cancer].

BACKGROUND: The role of high-dose chemotherapy (HDCT) in primary and metastatic breast cancer remains controversial. Although results of several randomized trials have become available, the data is still inconclusive. ADJUVANT HDCT: In the adjuvant setting, only one trial has shown an advantage in recurrence-free survival, whereas none of the randomized trials showed a significant improvement in overall survival. HDCT FOR STAGE IV DISEASE: In metastatic breast cancer, four of five randomized trials revealed a significant benefit in progression-free survival for patients treated with HDCT. However, differences in overall survival have not been observed. INTERPRETATION OF TRIALS: Interpretation of the trials is limited due to a lack of statistical power in some of the trials, a relatively short follow-up, a relatively intensive chemotherapy regimen in the control arm, and an inappropriate selection of cytotoxic agents with only moderate activity and/or unacceptable toxicity. CONCLUSION: Several questions, especially the approach of early intensification or tandem HDCT, have to be answered yet. The results of ongoing studies are urgently needed.

Adult↗
PubMed2003

[Genetic risk factors for hepatic fibrosis in chronic liver diseases].

Hepatic fibrosis is the result of chronic viral, toxic, autoimmune, or cholestatic liver injury. During the complex fibrotic response, hepatic stellate cells transdifferentiate into matrix-producing myofibroblasts, and interactions between multiple cytokines, receptors and extracellular matrix components modulate the fibrotic phenotypes. Of note, course and extent of hepatic fibrosis display significant variability among individual patients. These well-known differences in progression of hepatic fibrosis have been attributed to age, sex, and exogenous factors, e. g., coinfections or alcohol consumption. However, host genetic factors are likely to play key roles in the modulation of hepatic fibrosis and to contribute to the overall variability in disease progression. In recent years, different genetic polymorphisms that may influence the progression of hepatic fibrosis have been identified in animal models and human case-control studies. These findings indicate that variants of genes encoding immunoregulatory proteins as well as pro- and anti-inflammatory cytokines determine liver fibrosis in patients with chronic hepatitis C virus infection, alcoholic liver disease, and autoimmune liver diseases. However, the results of these studies are mixed and restricted to selected known genes. Therefore, definition of consensus criteria for association studies and multicenter studies are needed to increase statistical power. Genome-wide scans in experimental animal crosses should be employed to identify unknown gene loci that confer susceptibility to hepatic fibrosis (Hfib loci). In conclusion, genetic association studies have a great potential for identification of fibrogenic genes, but large-scale, well-designed studies are required to clarify their actual relevance and to provide a solid framework for future therapeutic strategies.

Animals↗
PubMed2005

[Donepezil in patients with Alzheimer's disease--a critical appraisal of the AD2000 study].

The AD2000 study was a randomized placebo-controlled trial, the effects of donepezil, a cholinesterase inhibitor, in patients with Alzheimer's disease. It was the first long-term RCT not sponsored by the pharmaceutical industry. The study did not show any significant effect on patient-relevant outcomes. However, donepezil had a significant effect on cognitive scores. More patients taking donepezil stopped treatment due to adverse events, even when taking only 5 mg once daily. There are major concerns regarding the conduction of the AD2000 study as well as the presentation of the results. Much less patients than previously planned have been recruited, resulting in a low statistical power to detect a significant difference between both treatments. In addition, no true intention-to-treat analysis based on the first randomization is presented. The validity of the AD2000 trial has to be questioned. However, there is still insufficient evidence to support the claim that cholinesterase inhibitors have beneficial effects on patient-relevant outcomes in patients with Alzheimer's disease. The change of cognitive performance as measured by different scales does not necessarily correspond to substantial changes in patient-relevant outcomes. In conclusion, the widespread use of cholinesterase inhibitors in patients with Alzheimer's disease is not supported by current evidence. Long-term-randomized controlled trials focusing on patient-relevant outcomes instead of cognitive scores are urgently needed.

Activities of Daily Living↗
PubMed2005

Three-times-daily radiotherapy with induction chemotherapy in locally advanced non-small cell lung cancer. Feasibility and toxicity study.

PURPOSE: To evaluate the feasibility and toxicity of three-times-daily radiotherapy (3tdRT), preceded by induction chemotherapy (iCT), in stage IIIA-IIIB non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: iCT consisted of three cycles of cisplatin and gemcitabine. Surgery was considered for stage IIIA patients responsive to iCT; definitive or postoperative 3tdRT was planned. Doses of 54.4 Gy and 64.6 Gy in postoperative and definitive treatments, respectively, were delivered in three daily fractions. RESULTS: From February 1998 to October 2000, 37 patients received 3tdRT as definitive (n = 18) or postoperative treatment (n = 19). Toxicity was limited to RTOG grade 2 (25 patients, 67.6%) and grade 3 (four patients, 10.8%) acute esophagitis; no grade 3 late esophagitis occurred. Late lung toxicity was represented by one grade 3 pneumonitis. No correlation emerged between acute esophageal toxicity and irradiated esophageal volume or disease- and treatment-related factors. A significant correlation was found for stage (IIIA vs. IIIB; p = 0.03) and a trend for the N-class (N2 vs. N3; p = 0.08). CONCLUSION: In this experience of 3tdRT preceded by iCT, the low toxicity profile confirmed the feasibility of this combination. The limited statistical power does not permit a definition of predictors for radiation-induced esophagitis incidence and severity; additional studies are required to clarify the impact of volumetric and dosimetric parameters. Failure patterns and survival results are warranted to confirm the efficacy of this approach in locally advanced NSCLC.

Antineoplastic Agents↗
PubMed2006

[Perioperative administration of beta-blockers. Critical appraisal of recent meta-analyses].

BACKGROUND: The perioperative administration of beta blockers is a controversial issue. Numerous trials failed to show any significant benefit or disadvantage because of low event rates and insufficient statistical power. METHODS: In July 2005 McGory et al. and Devereaux et al. separately published 2 meta-analyses, raising the question of the perioperative administration of beta blockers for patients undergoing non-cardiac surgery. In February 2006, Schouten et al. published an additional meta-analysis concerning the same question. This evidence is supplemented by the publication of Lindenauer et al. in 2005. These trials will be critically appraised in this review. RESULTS: McGory et al. concluded from their data that the perioperative administration of beta blockers significantly reduced cardiovascular mortality. However, this conclusion is clearly not valid because of methodological deficits of the meta-analysis. In addition, the publications by Devereaux et al. and Schouten et al. did not support the results of the analysis by McGory et al. CONCLUSIONS: There is still no clear evidence to prove a significant benefit for the unselected perioperative use of beta blockers in patients undergoing non-cardiac surgery. While high-risk patients and those undergoing major surgical procedures seem to profit, low-risk patients may be more harmed than helped by this intervention. The fact that 3 meta-analyses raising the same question produced substantially different results, underlines the importance of critically appraising each meta-analysis.

Adrenergic beta-Antagonists↗
PubMed1998

[Combination therapy in oncology (multimodal treatment) in pancreatic tumors].

The majority of patients with pancreatic cancer have systemic disease already at diagnosis, and nearly all patients will develop recurrence following radical resection. Thus, surgical treatment alone is insufficient. The paper focuses on adjuvant multimodal treatment and reviews the current status of pre- and postoperative chemoradiation, intraoperative radiotherapy (IORT), adjuvant chemotherapy, and regional infusion therapy. Studies in this area are hampered by often being non-randomized and with too few patients included. Overall there presently is no adjuvant multimodal treatment which can be suggested for routine use. However, two ongoing prospective randomized studies (ESPAC-1 and an EORTC study) will have enough statistical power to give reliable information on the topic. It is hoped that these and other studies will form the basis for further proper clinical trials on multimodal treatment in pancreatic cancer with the aim at long last to improve the extremely poor survival in these patients.

Adenocarcinoma↗
PubMed2003

Lack of association between the G protein beta3 subunit gene and essential hypertension in Chinese: a case-control and a family-based study.

A C825T polymorphism of the gene encoding the G protein beta3 subunit (GNB3) is associated with enhanced G protein activity and increased intracellular signal transduction. The 825T allele has been implicated in the development of hypertension in some ethnic groups, especially in whites. Studies in Asians and blacks are more controversial, and little information is available on this polymorphism in the susceptibility to hypertension in the Chinese population. Furthermore, the inconsistency between studies may be due to genetic heterogeneity of the population selected and/or the lack of statistical power. We investigated the relationship of this polymorphism with hypertension in two independent northern Chinese populations using both a case-control and a family-based study design. The GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction enzyme digestion. In the case-control study which included 585 hypertensive case subjects and 580 normotensive control subjects there was no significant association between the polymorphism and hypertension status or blood pressure levels. The lack of association was confirmed by the results obtained in 181 hypertensive families using both transmission disequilibrium test and sib transmission disequilibrium test. No preferential transmission was observed for the GNB3 825T allele to the affected subjects. Furthermore, there was no significant association between the polymorphism and body mass index in the case-control study. Therefore our work does not provide evidence in favor of GNB3 C825T being a candidate gene for conferring genetic susceptibility to hypertension or obesity in northern Chinese population.

Blood Pressure↗
PubMed2002

[Evidence based trauma surgery].

It is wise for surgeons to critically analyze their decision making, to add evidence in addition to the normal approaches, i.e. expert opinion and pathophysiological rationale. What evidence, is how it works, how often it is used in orthopedic surgery are the main topics of this article, as well as problems and limits to evidence-based medicine (EbM). EbM operates in five steps: 1. formulate an answerable question with respect to the patient's problems; 2. search the relevant literature; 3. critically appraise the assembled information through evidence based standards; 4. implement these evidence supported findings in your daily practice; 5. evaluate your evidence-based practice. When one builds decisions upon evidence the following effects become apparent: rational choice of possible, alternative decisions, reduction of diagnostic and therapeutic risks, improvements in medical education and efficient delivery of health care. A literature search reveals few evidence-based investigations published in orthopedic surgery. Lastly, we discuss limitations of EbM, showing that both misunderstanding about EbM and technical problems contribute to mistrust in EbM. These may include problems with population heterogeneity, standardization of surgical procedures, conducting random studies, the lack of statistical power and often "publication bias". Overcoming present problems with EbM by further ("evidence-based") research should lead to better understanding of the evidence paradigm and eventually modify this approach. The literature already demonstrates that EbM attains its goal. A valid judgment of EbM will result if one evaluates one's own evidence-based practices. The implementation of EbM is also a matter of policy.

Decision Support Systems, Clinical↗
PubMed2006

PARL Leu262Val is not associated with fasting insulin levels in UK populations.

AIMS/HYPOTHESIS: PARL, the gene encoding presenilins-associated rhomboid-like protein, maps to chromosome 3q27 within a quantitative trait locus that influences components of the metabolic syndrome. Recently, an amino acid substitution (Leu262Val, rs3732581) in PARL was associated with fasting plasma insulin levels in a US white population (N=1031). This variant was also found to modify the positive association between age and fasting insulin. The aim of this study was to test whether these findings could be replicated in two UK population-based cohorts. METHODS: Participants from the Medical Research Council Ely and Hertfordshire cohort studies were genotyped for this variant using a SNaPshot primer extension assay and Taqman assay respectively. Full phenotypic and genotypic data were available for 3,666 study participants. RESULTS: Based on a dominant model, we found no association between the Leu262Val polymorphism and fasting insulin levels (p=0.79) or BMI (p=0.98). We did not observe the previously reported interaction between age and genotype on fasting insulin (p=0.14). CONCLUSIONS/INTERPRETATION: Despite having greater statistical power, our data do not support the previously reported association between PARL Leu262Val and fasting plasma insulin levels, a measure of insulin resistance. Our findings indicate that this variant is unlikely to be an important contributor to insulin resistance in UK populations.

Aged↗
PubMed2003

Intermittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroid-induced osteoporosis: results from a long-term comparative study.

Despite its well-known benefits, chronic corticosteroid therapy causes osteoporotic fractures in approximately 30-50% of patients treated. To prevent the occurrence of these fractures, treatment with oral bisphosphonates is recommended. However, current oral bisphosphonates, which are given either daily or weekly, are associated with stringent, inconvenient dosing guidelines. Less frequent dosing may provide greater acceptability. The objective of this study was to investigate the efficacy and safety of ibandronate, a highly potent nitrogen-containing bisphosphonate, when given by intravenous (i.v.) injection every 3 months in men and women with established corticosteroid-induced osteoporosis (CIO; lumbar spine [L2-L4] bone mineral density [BMD] T-score < or =-2.5). A total of 115 participants were assigned to receive daily calcium supplements (500 mg) plus either ibandronate (2 mg) injections every 3 months or daily oral alfacalcidol (1 microg), for 3 years. Intermittent i.v. ibandronate injections produced significantly greater increases in mean BMD at the lumbar spine (13.3% versus 2.6%, respectively; p<0.001), and femoral neck (5.2% versus 1.9%, respectively; p<0.001) versus daily oral alfacalcidol, after 3 years, relative to baseline. This study was not statistically powered to show a difference between the groups with respect to fracture incidence. Nevertheless, after 36 months, the frequency of patients with new vertebral fractures was significantly lower in the patients receiving ibandronate relative to those taking alfacalcidol (8.6% versus 22.8%, respectively; p=0.043). This is the first time that significant vertebral fracture reduction has been demonstrated with an i.v. bisphosphonate in CIO. Patients treated with i.v. ibandronate injections also experienced less back pain (p<0.001) and less height loss (p=0.001) than those receiving oral alfacalcidol. Both regimens were well tolerated. In conclusion, intermittent i.v. ibandronate injections are efficacious, well-tolerated, and convenient, and promise to offer physicians an important therapeutic advance in the management of osteoporosis.

Aged↗
PubMed2000

Polymorphisms of the VDR, ER and COLIA1 genes and osteoporotic hip fracture in elderly postmenopausal women.

In view of the reported associations between osteoporosis and polymorphisms of the vitamin D receptor (VDR), collagen Ialpha1 (COLIA1) and estrogen receptor (ER) genes, an association study was performed between VDR, COLLIA1, and ER genotypes and bone mineral density, biochemical markers of bone turnover and hip fracture occurrence in Belgian older postmenopausal women. The gene polymorphisms were evaluated by restriction fragment length polymorphism analyses, using the restriction enzymes BsmI (VDR), AccB7I (COLIA1), and PvuII and XbaI (ER), respectively. As expected, bone mineral density and biochemical analyses demonstrated significant differences between hip fracture patients and elderly controls. However, no significant differences in genotype distributions or allele frequencies were observed between the cases (n = 135, age 78 +/- 9 years) and controls (n = 239, age 76 +/- 4 years) for any of the gene polymorphisms. Stratification of both study populations according to VDR, COLIA1 or ER genotype did not reveal any statistically significant difference in bone density or bone turnover between subgroups with different genotypes. In conclusion, despite its limited statistical power the outcome of this study does not support the hypothesis of a major contribution of the VDR, COLIA1 or ER polymorphisms to explain variations in bone mineral density or bone turnover, or to identify elderly women at risk of osteoporotic hip fracture.

Aged↗
PubMed2004

Predictors of acamprosate efficacy: results from a pooled analysis of seven European trials including 1485 alcohol-dependent patients.

RATIONALE: Acamprosate is a proven effective intervention in the treatment of alcohol dependence. However, acamprosate prevents lapses or relapses only in a minority of patients. An important question, therefore, is whether there is a specific subgroup of patients who respond particularly well to acamprosate. OBJECTIVES: To identify predictors of acamprosate efficacy. Based upon the available evidence and hypotheses about the mechanisms underlying acamprosate's effects on drinking behavior, the following variables were considered to be potential positive predictors: high physiological dependence at baseline, negative family history of alcoholism, late age-of-onset, serious anxiety symptomatology at baseline, severe craving at baseline, and female gender. METHOD: Potential predictors of acamprosate's efficacy were analyzed in a pooled analysis of data from seven randomized placebo-controlled trials involving a total of 1485 patients with alcohol dependence. Outcome is measured in terms of cumulative abstinence duration (CAD), continuous abstinence (ABST), and time to first relapse (TFR). RESULTS: CAD and ABST were predicted by baseline measures of craving and anxiety, as well as by study and treatment condition. Acamprosate efficacy was not differentially associated with any of the predictor variables. Importantly, the hypotheses were rejected despite the large sample size and sufficient statistical power. COMMENT: The most straight-forward clinical implication of this study is that acamprosate can be considered as a potentially effective pharmacotherapy for all patients with alcohol dependence. The effect size of acamprosate alone is, however, moderate. Some evidence indicates that the combination of acamprosate with naltrexone or disulfiram leads to substantially better outcomes.

Acamprosate↗
PubMed2005

Medication screening for smoking cessation: a proposal for new methodologies.

RATIONALE: The purpose of medication screening studies is to quickly and cheaply evaluate the clinical potential of medications, so that promising drugs proceed to large-scale clinical trials and unpromising drugs do not. Screening procedures for smoking cessation medications either are not sufficiently practical or lack clinical validity. Clinical trials have clinical validity but are often impractical as initial tests of efficacy (i.e., screening) or suffer from limited statistical power. The alternative approach of short-term, laboratory-based studies of purported mechanisms of efficacy may overcome some of the practical problems of clinical trials but appear to have limited clinical validity. OBJECTIVES: This commentary identifies some of the limitations of current short-term screening procedures and provides suggestions for improving such studies. RESULTS: Short-term screening studies typically use smokers unmotivated to abstain (i.e., nontreatment seekers) as participants and examine brief medication effects on clinical markers or potential mechanisms of action, including relief of withdrawal and craving during enforced abstinence or on reduction in the reinforcing effects of smoked tobacco. The limitation of these approaches is shown by their insensitivity to effects of nicotine replacement and bupropion, which are effective in clinical trials for smoking cessation. CONCLUSIONS: The clinical validity of short-term screening studies may improve if these studies simulate some clinical trial procedures within practical limitations. Thus, they should recruit smokers motivated to abstain, emphasize smoking abstinence as a primary index of medication response, examine effects over sufficiently long time periods to encompass the drug's mechanism of action, and assess responses in the natural environment. Whether these changes improve the sensitivity of screening studies is testable. Other research aimed specifically at identifying the mechanisms of therapeutic action of a medication may also profit from using this approach of simulating a short-term clinical trial.

Administration, Cutaneous↗