Based on a recent, still unpublished study points in time: prior to treatment baseline , after preliminary results at six weeks , that showed an two, four, and six weeks and also after three and six average post-treatment VAS pain score of 1. The two latter 2. With these assumptions, the trial needed to the TB group failed to show up at the therapy accrue at least 76 patients in total.
All data were instruction visit. Also during the remainder of the collected in a specially developed Statistical Package study, some subjects stopped their treatment and of Social Sciences database version Statistical failed to comply with their scheduled clinic visits.
The analysis was performed using R version 2. At the three- and six- weeks, a linear mixed-effects model was applied to fit month observations, the number of subjects in both the equally spaced repeated time measurements groups had decreased substantially, precluding within patients random factor and between the further meaningful statistical analyses. Details on interventions, adjusting for baseline values fixed the study population, which actually started treat- factors.
The most appropriate random-effects covar- ment, are presented in Table 1. There were no iance structure was obtained by minimizing the significant differences with respect to gender, mean general information criterion. Interactions of therapy age, or baseline measurements between both groups, over time as fixed factors were tested but not found neither in the original 96 patients, nor in the 79 to be significant.
Mandibular function impairment questionnaire Results MFIQ Ninety-six subjects 83 females and 13 males; mean The sum score of the MFIQ was used to assess age: 38 years; range: 17—73 years with myogenic mandibular function.
In the TB group, the median MFIQ score 36 years; range: 17—73 years , who were randomized significantly dropped from All patient data at the various time and Treatment of myogenic temporomandibular disorder Table 2 Change in MFIQ values over time by randomization function and tasks such as eating, drinking, speak- group ing, etc.
Baseline Both treatment groups improved significantly for Sample size 38 41 79 pain and for passive and active mouth opening.
No Median These Sample size 31 30 61 Median The MFIQ scores are associated with a reduction of mandibular for TB over time were found to be significantly function impairment and pain, and an increase in different P From the time of diagnosis to the end in the short-term. The pain-scores for the TB group valid instruments are used to evaluate mandibular over time were not found to be significantly different function impairment in patients with TMJ com- compared to the PT exercise group P This questionnaire has the Active and passive MIO values were corrected for advantage of clear operational criteria for example vertical overbite.
In both treatment groups there was eating an apple , and furthermore, it has been a significant improvement in active and passive MIO recommended as a valid and moderate to high over time P,0. No significant differences in reliable instrument to measure changes in mandibular improvement or average gain in active or passive impairment. As an example, between pre- and post-therapeutic outcome variables the active MIO values over time per randomization not only reflects therapeutic effects, but also the group are shown in Fig.
Therefore, the authors took Compliance and familiarity with exercises into account that an improvement of at least 10 units Patient self-reporting through the questionnaire on this 0 to 68 scaled questionnaire, as described by showed good compliance for both the PT exercises Kropmans et al. Almost all patients. In a disorder where spontaneous remissions are not Moreover, the TB was reportedly easy to use.
However, the vast majority of comparing traditional PT exercises with use of the TB patients had considerable complaints both of pain passive jaw mobilization device, demonstrates a and limited mouth opening, and only symptomatic significant faster functional improvement in the treatment of the pain was deemed not an acceptable experimental TB group.
At six weeks, mandibular option. Treatment of myogenic temporomandibular disorder Figure 3 Mandibular function impairment questionnaire MFIQ values with standard error of mean at the various time points per randomization group. In the case of the case in clinical studies, there were quite a few the PT exercises, most dropouts were no-shows and dropouts and missing data, already starting between non-responders to reminders for the later appoint- the time of diagnosis and randomization and the ments.
RCTs can be analyzed by intentionto-treat analysis ITT; subjects analyzed in the groups to which they were randomized , per protocol only participants who completed the treatment originally allocated are analyzed , or other variations, with ITT often regarded least biased. All RCTs should have pre-specified primary outcomes, should be registered with a clinical trials database and should have appropriate ethical approvals.
RCTs can have their drawbacks, including their high cost in terms of time and money, problems with generalisabilty participants that volunteer to participate might not be representative of the population being studied and loss to follow up. While expensive and time consuming, RCTs are the gold-standard for studying causal relationships as randomization eliminates much of the bias inherent with other study designs. To provide true assessment of causality RCTs need to be conducted appropriately i.
Disclosures: The authors have no financial interests to disclose. National Center for Biotechnology Information , U. Author manuscript; available in PMC Dec 1. Prospective vs. Retrospective Studies Prospective A prospective study watches for outcomes, such as the development of a disease, during the study period and relates this to other factors such as suspected risk or protection factor s.
Retrospective A retrospective study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study. Case-Control studies Case-Control studies are usually but not exclusively retrospective, the opposite is true for cohort studies.
Cohort studies Cohort studies are usually but not exclusively prospective, the opposite is true for case-control studies. The following notes relate cohort to case-control studies: outcome is measured after exposure yields true incidence rates and relative risks may uncover unanticipated associations with outcome best for common outcomes expensive requires large numbers takes a long time to complete prone to attrition bias compensate by using person-time methods prone to the bias of change in methods over time related methods are risk prospective , relative risk meta-analysis , risk difference meta-analysis and proportions.
Polymicrobial infections were more common among patients enrolled in PRTs Fourteen patients Patients not enrolled in PRTs had a higher incidence of resistance to antibiotics These patients required more days of intravenous antibiotic therapy Forty-seven patients Patients with an abscess were more likely to be cured than those with generalized peritonitis Sixty-eight episodes of extraabdominal infections occurred in 44 patients.
Patients not enrolled in PRTs were more likely to have extraabdominal infections The development of an extraabdominal infection was associated with a lower rate of cure Patients requiring ICU care were less likely to be cured At our institution, patients with intraabdominal infections who were enrolled in a PRT had better outcomes than those who were excluded or not entered into a clinical trial.
Increasing age 7,8,10,13—21 and higher APACHE II scores 7,10,14,17,19—21 have previously been shown to be independent predictors of treatment failure and death for patients with intraabdominal infections. In the current study, patients older than 50 years and those with APACHE II scores greater than eight had significantly higher rates of treatment failure, a finding observed in both the PRT and not-enrolled groups.
Concomitant illness has been reported to be a significant risk factor for treatment failure in other studies evaluating intraabdominal infection. Trial eligibility criteria restricted the participation of patients with comorbid diseases that have been reported to increase the death rate of patients with intraabdominal infections. Excluding sicker patients from trial participation based on rigid eligibility criteria may have had the unintended effect of creating two heterogeneous groups of patients.
The group not enrolled in PRTs may have been less likely to be cured because of factors imposed by concomitant illnesses that limited their physiologic reserve. In contrast, patients who meet eligibility criteria and therefore can be enrolled in PRTs are healthier overall, have fewer comorbid diseases, and are more likely to be cured of infection.
The source of intraabdominal infection has been shown to be another important determinant of outcomes. Patients with complicated appendicitis have repeatedly been shown to have a lower death rate and fewer complications than patients with other causes for intraabdominal infection.
Postoperative infections have been associated with higher death rates than many other sources of intraabdominal infection. Although there are multiple factors that affect cure and survival in intraabdominal infections, the importance of risk stratification, especially by source of infection, cannot be overemphasized. Intraabdominal abscesses were more common among patients with postoperative infection. Previous reports have shown that patients with a localized infection have better outcomes than those with generalized peritonitis.
The beneficial effect that enrollment in a clinical trial can have on outcomes is not new. One theory suggests that patients enrolled in clinical trials receive better medical care. Patient motivation has been speculated to improve outcomes in cancer chemotherapy trials. In our experience, the overall desire of patients to participate in PRTs is high, which should reduce the potential for this type of bias.
Microbial resistance to the selected antibiotic treatment has been shown to increase the risk of failure for patients with intraabdominal infections. Patients in PRTs had a lower incidence of resistance, which may be due to better antibiotic selection or a less severe disease process. Enrollment in a clinical trial regulates drug selection and may ensure that more effective antibiotics are prescribed initially.
Ineffective empirical antimicrobial therapy has been associated with a greater likelihood of treatment failure in patients with peritonitis 25 and other infections. This factor, combined with the increased monitoring of care by clinical investigators and research nurses, may account for the better outcomes of patients enrolled in PRTs.
Lead-time bias is a well-described phenomenon in screening studies. Protocols generally require immediate screening of patients with the index disease for enrollment into a trial.
Delays in patient presentation and disease recognition may ultimately lead to the exclusion of a patient from trial participation. For example, a patient may enter the hospital with normal renal function, and subsequently peritonitis may develop. A delay in recognition of the infection causes renal function to worsen. If this patient were not immediately screened for enrollment, the subsequent impairment of renal function would lead to exclusion from participation in a trial.
A primary goal of a clinical trial is to select similar groups of patients with a relatively uniform disease process for each treatment arm. The development of homogeneous treatment groups generally is accomplished through the process of randomization, 28 which reduces systematic bias and equally distributes patients with known and unknown risk characteristics into the various treatment arms.
Randomization takes place, however, only after patients have been screened for all potential exclusion criteria; this is an important point that often is not considered. Thus, the treatment arms are balanced with similar groups of patients derived from a homogeneous patient population with a lower severity of disease. The risk characteristics of patients excluded before randomization are not routinely recorded or analyzed, and the treatment results of these patients have not been reported.
Clinical trial investigators attempt to ensure a relatively uniform patient population by carefully controlling enrollment through the establishment of restrictive inclusion and exclusion criteria. One approach is to establish rigid criteria; this leads to a more homogeneous study population and ensures that the observed treatment effect is robust and incontrovertible. Alternatively, the use of less restrictive eligibility criteria selects a more heterogeneous patient population. This approach requires a more sophisticated stratification system based on patient risk factors to analyze the results properly.
The expense and time involved in conducting a carefully designed clinical trial can be enormous, and therefore the need to find a clear treatment effect favors enrollment of a homogeneous patient population.
Under these circumstances, there is a risk of limiting the applicability of the results to other patients who have a similar disease but who were excluded from the study.
Better record keeping and the more extensive collection of additional clinical data allows more accurate risk adjustment in a larger, more heterogeneous patient population. This approach excludes fewer patients and favors the applicability of study findings to a broader group of patients. The results of the current study show that the degree of illness as measured by admission APACHE II score, the presence of antimicrobial resistance on initial culture, and enrollment into a PRT were significant determinants of cure and ultimate survival for patients with serious intraabdominal infections.
As surgeons, we can exercise some control over each of these parameters. Although the severity of illness is often determined at the time the patient is initially seen, avoiding delays in treatment as well as prompt resuscitation and support of organ systems may reduce treatment failure by preventing further physiologic derangements.
The proper selection of antimicrobial agents for the treatment of intraabdominal infections should minimize the occurrence of antibiotic resistance. The advantages of being enrolled in a PRT may relate to the mandated selection of empirical antibiotic dose and therapy, or to improved delivery of care. Although the exact cause cannot be determined at present, these observations nevertheless show a benefit to study participation, which is a key element of informed consent.
We hope that these observations will stimulate further investigations of this and other possible benefits of PRT participation. Some patients are excluded from study participation because of associated organ dysfunction, such as severe renal or hepatic failure.
These diseases often require dosage adjustment of antimicrobial agents, which may lead to subtherapeutic drug concentrations and thus reduce their effectiveness. Other exclusion criteria prohibit the enrollment of patients with compromised immune function, because these patients have a greater risk of treatment failure.
It may be more relevant to avoid the routine exclusion of more seriously ill patients, instead using more rigorous methods to stratify risk characteristics. This would provide a more realistic assessment of the expected outcomes for more seriously ill patients and would improve the external validity and applicability of the results of clinical trials.
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