Interval cancers are primary breast cancers diagnosed in women after a negative screening test and before the next screening invitation. Our aim was to evaluate risk factors for interval cancer and their subtypes and to compare the risk factors identified with those associated with incident screen-detected cancers.We analyzed data from 645,764 women participating in the Spanish breast cancer screening program from 2000–2006 and followed-up until 2009. A total of 5,309 screen-detected and 1,653 interval cancers were diagnosed. Among the latter, 1,012 could be classified on the basis of findings in screening and diagnostic mammograms, consisting of 489 true interval cancers (48.2%), 235 false-negatives (23.2%), 172 minimal-signs (17.2%) and 114 occult tumors (11.3%). Information on the screening protocol and women's characteristics were obtained from the screening program registry. Cause-specific Cox regression models were used to estimate the hazard ratios (HR) of risks factors for interval cancer and incident screen-detected cancer. A multinomial regression model, using screen-detected tumors as a reference group, was used to assess the effect of breast density and other factors on the occurrence of interval cancer subtypes.A previous false-positive was the main risk factor for interval cancer ; this risk was higher for false-negatives  than for true interval cancer . A family history of breast cancer was associated with true intervals , previous benign biopsy with a false-negatives . High breast density was mainly associated with occult tumors , followed by true intervals  and false-negatives .The role of women's characteristics differs among interval cancer subtypes. This information could be useful to improve effectiveness of breast cancer screening programmes and to better classify subgroups of women with different risks of developing cancer. Evaluation of the impact of population-based breast cancer screening programmes is complex and can only be achieved in the long term. Regular screening contributes to reducing mortality from breast cancer, but also has adverse effects, such as false-positives, overdiagnosis and interval cancers Interval cancers are primary breast cancers diagnosed in women after a negative screening test and before the next screening invitation Numerous studies have examined interval cancer rates in distinct screening programmes Study of interval cancers has focused on detecting differences with screen-detected cancers according to personal and tumor-related characteristics The aim of our study was to evaluate the factors associated with a higher probability of interval cancer  and to compare them with those associated with incident screen-detected cancers. We also studied the influence of breast density on detection mode and the occurrence of subtypes.The study was approved by the Mar Teaching Hospital Research Ethics Committee. The data was analyzed anonymously and therefore no additional informed consent was required. Further information about our data and the methods used can be requested from the authors.Population-based breast cancer screening in Spain is offered individually to 100% of the target population by the National Health Service. This programme adheres to the European Guidelines All women aged 50 years (or 45 years depending on the region) to 69 years are actively invited to participate by letter every 2 years We built a retrospective cohort of 645,764 screened women from 32 radiology units in five regions of Spain who underwent mammography between January 1, 2000 and December 31, 2006 and who were followed up until June 30, 2009 for interval cancer identification. These women underwent a total of 1,508,584 screening mammograms . During Screening mammography has three possible outcomes: a negative result, a positive result  or early recall . Cancers detected at intermediate mammogram were considered screen-detected cancers A positive result is considered to be screen-detected tumour if, after further assessments, there is histopathological confirmation of cancer. Otherwise, the result is considered a false-positive and woman is invited at 2 years. Further assessments can include non-invasive procedures  and/or invasive .Interval cancer was defined as “a primary breast cancer arising after a negative screening episode and before the next invitation to screening or within 24 months for women who reached the upper age limit” Interval cancers were classified by three panels, formed by three experienced radiologists. The panels performed a semi-informed independent review of both screening and diagnostic mammograms with independent double reading and arbitration. Of 1,653 interval cancers, 1,012 had available screening and diagnostic mammograms, and therefore could be classified into the four interval cancer categories. Briefly, screening mammograms were first reviewed alone and provisionally classified into positive, negative, and minimal-signs. Afterwards, the screening and diagnostic mammograms were reviewed together and interval cancers were definitively classified into: true interval cancers , false-negatives , minimal-signs (detectable but non-specific signs were identified on the screening mammogram) and occult tumours  The breast density of the cancer-free breast was determined by one radiologist from each panel, using Boyd's scale, a semi-quantitative score of six categories using percentages of density: A: 0%; B: 1–10%; C:10–25%; D:25–50%; E:50–75%; F:75–100% All information was collected from each woman at each attendance. The variables related to the screening protocol included the reading method (single or double reading) and mammography type . The variables related to women's personal characteristics were use of hormonal replacement therapy (HRT) at screening or in the previous 6 months (Yes/No), menopausal status , previous benign biopsy outside screening (Yes/No), the presence or absence of a first-degree familial history of breast cancer (Yes/No), mammography date, number of participations, the existence of a previous false-positive (Yes/No), and the existence of an early recall (Yes/No).Breast cancer rates per 1,000 women and per 10,000 mammograms were estimated, for interval cancers and for screen-detected cancers.The cumulative probability of suffering an interval cancer was calculated using the Kaplan-Meier estimator with time-dependent variables according the distinct study variables. We estimated the hazard ratios (HR) of interval cancer and incident screen-detected cancer using a multivariate cause-specific Cox model with time-dependent variables. Radiology units were included as a random effect Given that incidence of breast cancer depends on age, we used age as time scale in the Kaplan-Meier and Cox regression analyses We conducted a case-control analysis to determine whether the study variables differed between interval cancers (cases) and screen-detected cancers (controls), using a multivariate logistic regression model. For the analysis of variables associated to the subtypes of interval cancer, we fitted a multinomial regression model, using the screen-detected cancers as a reference group. The multinomial model estimates k-1 models, comparing each group to the referent group. The exponentiated multinomial logit coefficient provides an estimate of the relative risk and, commonly, is expressed as relative risk ratio (RRR).All P-values were based on two-sided tests and were considered statistically significant if less than 0.05. Statistical analyses were performed using the R statistical software (version 3.0.1) The interval cancer rate was 2.57 per 1,000 screened women and 10.99 per 10,000 screening mammograms . The larAmong classified interval cancers, 42.1% of occult tumours, 32.3% of false-negatives and 31.0% of minimal-signs were diagnosed in the first 12 months after the participation and only 19.6% of true interval cancers emerged in the same period.The hazard risks from cause-specific survival analyses for incident screen-detected cancers and interval cancers  are shown in The effect of the risk factors on developing interval cancer differed according to subtypes. DM was associated with true interval cancer , but not with false-negatives . The effect of a previous false-positive result was higher for false-negatives  than for true interval cancer . HRT use was a statistically significant risk factor for minimal-signs  and a family history of breast cancer was a risk factor for true interval cancer  and minimal-signs as well . Previous benign biopsy outside screening was a risk factor for a false-negative cancers .The proportion of women with extremely dense breasts  was highThis study provides information on the determinants of interval cancer and its subtypes and a comparison with screen-detected cancer in a retrospective cohort of screened women. Women's characteristics  were risk factors for both interval and screen-detected cancer, showing a similar strength of association. A family history of breast cancer had the strongest association with true interval cancer while previous benign biopsy was a significant risk factor only for false-negatives. The presence of a previous false-positive result was a risk factor for both screen-detected and interval cancer but the association with interval cancer was stronger, especially for false-negative cancers. Double reading, digital mammography and early recall were associated with screen-detected cancer but not with interval cancer.Few studies have analysed the determinants of interval cancer and even fewer have taken subtypes into account. Previous studies have described interval cancer rates ranging from 1.8 to 2.9 per 1,000 women and from 10.6 to 29.5 per 10,000 mammograms DM was not associated with increased risk of interval cancer, in line with the study by Hoff et al. Premenopausal status, a family history of breast cancer and previous benign breast biopsy result are well-known risk factors for breast cancer Because information on breast density was not available for the whole cohort, we analyzed the effect of breast density as a risk factor for interval cancer subtypes compared with those of screen-detected cancers in a case-control. In previous study in the same cohort we explored the role of breast density within interval cancer subtypes, adjusting by tumour characteristics This study has some limitations. First, we could not get all diagnostic mammograms from interval cancers mainly because logistic reasons, avoiding a complete interval cancer classification. Moreover, misclassification among interval cancers cannot be excluded because is inherent to radiologist subjectivity. However, this misclassification would attenuate differences among study groups. Breast density was not available for the entire population because it was not systematically collected and registered. Therefore, we could not include this factor in the analysis of determinants. In addition, breast density was visually assessed, implying also some subjectivity and misclassification. Equally, information was unavailable on other important cancer-related variables such as age at menarche, age at maternity, the number of children and body mass index, type of mammographic abnormality and clinico-histopathological features of the breast cancers. The small numbers of occult tumours did not provide sufficient statistical power for this subgroup in some analyses.A strength of study was the cohort size and the consolidation of the screening programmes in Spain. The participating radiology units had completed at least five rounds ensuring the quality indicators were stable. There are other studies with radiologically classified interval cancers, but the present is, to our knowledge, the largest one with information on breast density for the different subtypes.In conclusion, the current work provides comprehensive data on the relationship between personal and organizational characteristics and the risk of interval cancer. This information could be useful to better classify subgroups of women at different risks of developing cancer in a moment when personalization of breast cancer screening is being proposed Table S1Incidence of variables related to the screening protocol and women's characteristics by screen-detected and interval cancer .(DOC)Click here for additional data file.Table S2Crude hazard ratios from cause-specific survival analyses for incident screen-detected cancers and for interval cancer .(DOC)Click here for additional data file.


The use of high-fidelity simulation is emerging as a desirable method for competency-based assessment in postgraduate medical education. We aimed to demonstrate the feasibility and validity of a multi-centre simulation-based Objective Structured Clinical Examination (OSCE) of resuscitation competence with Canadian Emergency Medicine (EM) trainees.n=98) from five Canadian academic centres participated in a high fidelity, 3-station simulation-based OSCE. Expert panels of three emergency physicians evaluated trainee performances at each centre using the Queen’s Simulation Assessment Tool (QSAT). Intraclass correlation coefficients were used to measure the inter-rater reliability, and analysis of variance was used to measure the discriminatory validity of each scenario. A fully crossed generalizability study was also conducted for each examination centre.EM postgraduate trainees . Generalizability studies found significant variations at two of the study centres.Inter-rater reliability in four of the five centres was strong with a median absolute intraclass correlation coefficient (ICC) across centres and scenarios of 0.89 [0.65–0.97]. Discriminatory validity was also strong (This study demonstrates the successful pilot administration of a multi-centre, 3-station simulation-based OSCE for the assessment of resuscitation competence in post-graduate Emergency Medicine trainees. The assessment of resuscitation skills in postgraduate medical trainees is moving towards competency-based methods, and away from knowledge-based examination.6High fidelity simulations using computer-controlled mannequins with mechanized movements, cues, and simulated vital signs are being used throughout medical education to emulate real patient encounters.13An examination of the literature for simulation-based assessment within EM and across the other specialties reveals a deficit of easily modifiable and useful assessment tools for dynamic resuscitation skill performance. Many studies have been published within Anesthesia, Pediatrics, and EM that demonstrate excellent discriminatory ability and inter-rater reliability in the assessment of specific ACLS,Valid and reliable simulation-based competency assessment of resuscitation skills would be beneficial to postgraduate licensing bodies and training programs both in EM and in other specialties.The Queen’s Simulation Assessment Tool (QSAT) was developed to allow for competency-based assessment of any EM resident trainee in a simulated resuscitation under a number of different clinical and team-based circumstances.A prospective observational design was employed to study a multi-centre, simulation-based OSCE for assessment of resuscitation skills in EM postgraduate trainees. A previously developed and validated simulation-based resuscitation assessment tool was used to assess the performances of all trainees.The QSAT was designed to be simple and modifiable in assessing specific and generalized resuscitation parameters.® and Susie® , and Laerdal SimJunior® . All simulations were run by a simulation technician and a member of the research team . Physiologic parameters  were adjusted using a predetermined set of palettes. The progression of palettes followed the therapeutic actions of the trainees during the OSCE scenario in a standardized fashion. The simulation lab at each centre was set-up on each occasion to re-create the physical environment of an emergency department resuscitation bay, and all necessary equipment or tools were available to the trainees.The study took place over an 18-month period at five academic University simulation centres across Canada: 1) Queen’s University (Kingston Resuscitation Institute Lab), 2) University of Toronto (Sunnybrook campus), 3) University of Ottawa (Ottawa Civic Campus), 4) University of Calgary , and 5) Dalhousie University . Multiple models of high-fidelity simulation mannequins were employed: Gaumard HalA total of 98 postgraduate trainees, EM physician trainees from the Fellow of the Royal College of Physicians & Surgeons of Canada – Emergency Medicine (FRCPC-EM) program and the Certificate of the College of Family Physicians of Canada – Special Competence in Emergency Medicine (CCFP-EM) program participated in this study. Participation was voluntary and written consent was obtained. Approval was obtained from the Ethics Review Boards at all five participating centres.Three previously developed and validated standardized emergency department resuscitation scenarios, each with a corresponding QSAT, were used.The 3-station, simulation-based OSCE was administered at each of the five academic centres. Each trainee completed the 3 standardized scenarios over a total of 30 minutes. Each trainee was provided with verbal instructions for the OSCE prior to their participation and given one minute to read a written scenario stem immediately prior to performing each scenario. The trainees’ performances were recorded from 3 fixed camera angles to allow adequate views of the trainee, the mannequin, and the cardiac monitors . MembersData analyses were performed using IBM SPSS version 22.0. The initial analyses focused on the inter-rater reliability in order to establish that the raters could provide consistent scores for the residents across centres. Intraclass correlation coefficients (ICCs) are a preferred method to determine the average rate of absolute agreement when there are two or more raters scoring the same trainees.F-test was conducted to determine if any group differences exited. Given that there were three scenarios, a Bonferroni correction was used to reduce the likelihood of a Type I error. Thus the null hypothesis was rejected if α <0.017 (0.05/3). If a significant group difference was found, post hoc analyses of the main effects were conducted using the Tukey’s HSD method (α <0.017).Our next set of analyses focused on the ability of the QSAT to discriminate across trainees based on their level of training. Trainees were separated based on their level of training (junior FRCP , CCFP-EM [PGY 3], and senior FRCP ). These groups were compared using three one-way (level of training) ANOVAs, using the three scenarios as dependent variables. For each scenario, the null hypothesis was that trainees’ scores would not differ based on their level of training. Discriminatory evidence was provided if trainees with higher levels of training obtained significantly higher scores on the 3 scenarios. An omnibus G-study) was conducted for trainees’ scores at each centre (Trainee X Rater X Scenario) to determine the variance components and G-coefficients. G-Studies are useful for initial test design research as they can be used to identify the sources of score variation and then to help determine the optimal number of stations needed for reliable estimates of trainee performance. G-studies identify variance components for main and interaction effects. For these analyses, trainees were the object of measurement and raters and scenarios served as the potential sources of error. The calculated variance components were subsequently used to conduct a series of Decision studies (D-studies) to determine the generalizability that could be obtained using different combinations of raters and scenarios, maximizing efficiency and accuracy of assessments.Finally, a Generalizability study  from Queen’s University, Ottawa University, the University of Toronto, the University of Calgary, and Dalhousie University participated in the study. Each centre had unequal distributions of trainee level participation, both within centre and across centres. Three blinded expert EM examiners (raters) from each centre rated all trainee from one of the other four centres. This was done in all 5 centres. On the rare occasion when there were technical errors with the recorded performances  or if expert data sheets revealed aberrancies (multiple scores circled or incomplete entries), a participant’s data were excluded. As a result, the final sample consisted of 98 trainees with complete data for all 3 scenarios .The intraclass correlation coefficients (ICC), which provide a measure of the inter-rater reliability of the ratings, of the QSAT ratings for each scenario are shown in F2,96 = 12.12, p < .001; Scenario 2, F2,96 = 9.82, p < .001; Scenario 3, F2,96 = 11.49, p < .001). Post hoc analyses indicated that Jr-FRCP  trainees scored significantly lower than Sr-FRCP trainees   . No signG-study) was conducted using a fully crossed trainee by rater by scenario (T × R × S) design. Since each group of raters only marked the trainees from a single centre, separate analyses were conducted for each of the 5 centres. The estimated variance components, the relative contributions to score variance, and the G-coefficients are provided in G-theory is essentially highlighting content specificity, which has been previously documented in the medical education literature.36Finally, a Generalizability study  when increasing the number of scenarios regardless of the number of raters.inations . CoefficSimulation-based education has become an integral part of postgraduate training of resuscitation skills for EM, Anesthesiology, Internal Medicine, Surgery, and Critical Care.The inter-rater reliability (ICCs) of the QSAT was high to very high (0.84–0.97) in all but one centre (Toronto). The lower values at the Toronto centre were likely due to the raters of the Toronto trainees noticing various aspects of poor performance, resulting from a restricted, homogenous sample.Importantly, the QSAT was found to be able to differentiate between levels of trainees, highlighting its effectiveness to discriminate between likely levels of competence. Residents with higher levels of training (SR-FRCP) consistently demonstrated higher scores compared to those with lower levels of training (JR-FRCP). This means the 3-stations were able to differentiate between varying levels of trainee competence and could be used in future high stakes summative exams to assess thresholds of performance. It is important to note that a third group of trainees was also examined: the CCFP-EM senior resident group. This group was specifically separated out from the Jr-FRCP and Sr-FRCP groups for analysis because of their different certification model. The CCFP-EM group, with two years of Family Medicine training followed by a single year of EM, is a very heterogeneous group with high variability in their expected performances for resuscitation scenarios. There were no significant differences between CCFP-EM trainees when compared to either the Jr-FRCP or Sr-FRCP groups. Admittedly, the smaller CCFP-EM sample likely impacted the analyses. Our future studies will revisit this CCFP-EM trainee group while also continue to examine the different levels within the FRCP.D-study results which found that an ideal number of scenarios to achieve a G-coefficient greater than 0.8 with only 1 rater would be greater than 6, which is consistent with existing literature.Lastly, the generalizability of the QSAT was examined, with the intention of providing guidance for the subsequent use of QSAT in actual testing conditions. In our study, the largest sources of variance were the trainees, followed by the trainee × scenario component at four of the five centres.G) values as strong as the previous single centre QSAT study,Our methodology and results were not without limitations. Although this study did not reproduce ICC and generalizability , the FMEC (Canada), and the Ottawa conference proceedings .6Looking forward, the next step will be to develop a competency-based summative assessment resuscitation OSCE with a centralized single centre model with multi-centre recruitment, with six or more scenarios, and one expert examiner per station. Such a study could focus on senior level residents alone and work towards an appropriate benchmarking strategy for competency thresholds for high stakes pass/fail summative examination. As well, a single centre model would help standardize trainee recruitment, OSCE station execution, and training of expert raters.In this study, we conducted a 3-station simulation-based OSCE at 5 academic EM training programs across Canada. We assessed the performance of EM postgraduate trainee resuscitation skills using the QSAT, a simple and modifiable competency-based assessment tool that has been validated previously at Queen’s University. Our study demonstrates a framework by which competency-based assessment can be performed in a simulation setting with a tool that shows promise in its discriminatory capabilities, inter-rater reliabilities, and generalizability. Future research should be directed at developing a multi-centre, single centre, multi-station OSCE format that further tests the use of this assessment system.


Amikacin and kanamycin are mainly used for treating multidrug-resistant tuberculosis (MDR-TB), especially in developing countries where the burden of MDR-TB is highest. Their protracted use in MDR-TB treatment is known to cause dose-dependent irreversible hearing loss, requiring hearing aids, cochlear implants or rehabilitation. Therapeutic drug monitoring and regular audiological assessments may help to prevent or detect the onset of hearing loss, but these services are not always available or affordable in many developing countries. We aimed to compare the cumulative incidence of hearing loss among patients treated for MDR-TB with amikacin or kanamycin-based regimens, and to identify the most-at-risk patients, based on the real-life clinical practice experiences in Namibia.P-value < 0.05 was statistically significant.We conducted a retrospective cohort study of patients treated with amikacin or kanamycin-based regimens in four public sector MDR-TB treatment sites in Namibia between June 2004 and March 2014. Patients were audiologically assessed as part of clinical care. The study outcome was the occurrence of any hearing loss. Data were manually extracted from patients’ treatment records. We compared proportions using the Chi-square test; applied stratified analysis and logistic regression to study the risk of hearing loss and to identify the most-at-risk patients through effect-modification analysis. A All 353 patients had normal baseline hearing, 46 % were HIV co-infected. Cumulative incidence of any hearing loss was 58 %, which was mostly bilateral (83 %), and mild (32 %), moderate (23 %), moderate-severe (16 %), severe (10 %), or profound (15 %). Patients using amikacin had a greater risk of developing the more severe forms of hearing loss than those using kanamycin (adjusted odds ratio (OR) = 4.0, 95 % CI: 1.5–10.8). Patients co-infected with HIV , males  and those with lower baseline body weight , were most-at-risk of developing hearing loss.Amikacin use in the long-term MDR-TB treatment led to a higher risk of occurrence of the more severe forms of hearing loss compared to kanamycin use. Males, patients with low baseline body weight and those co-infected with HIV were most-at-risk. MDR-TB treatment programmes should consider replacing amikacin with kanamycin and strengthen the routine renal, serum therapeutic drug levels and audiometric monitoring in the most-at-risk patients treated with aminoglycosides.The online version of this article (doi:10.1186/s40360-015-0036-7) contains supplementary material, which is available to authorized users. Amikacin and kanamycin belong to a group of antibiotics called aminoglycosides, which are used in the treatment of Gram-negative bacterial and mycobacterial infections. These aminoglycosides, in combination with fluoroquinolones, form the backbone for the treatment of multidrug-resistant tuberculosis (MDR-TB), as recommended by the World Health Organization (WHO) –3. A majAminoglycosides have a narrow therapeutic index; hence require careful monitoring of serum levels, particularly during their prolonged use in MDR-TB treatment, to prevent the occurrence of dose-dependent ototoxicity , 10. In Namibia is a developing country situated in the south-western part of Africa. It is classified by the World Bank as an upper middle income country . At the Even though amikacin and kanamycin have been in clinical use for over 50 years, surprisingly to-date, the evidence on their comparative risk of inducing hearing loss is scarce. Moreover, studies often have not been well done, especially in terms of measuring the hearing loss and patients with human immunodeficiency virus (HIV) co-infection have been underrepresented . In sub-The aim of this study was to compare the cumulative incidence of hearing loss among patients treated for MDR-TB using amikacin or kanamycin-based regimens, and to identify those that were most-at-risk. The high prevalence of HIV co-infection among patients diagnosed with MDR-TB in Namibia during the period of the study also enabled us to examine the influence of HIV infection on the risk of aminoglycoside-induced hearing loss.We conducted a retrospective cohort study of MDR-TB patients treated with amikacin or kanamycin-based regimens between June 2004 and March 2014 at four public sector MDR-TB treatment sites in Namibia. Our study included the four high burden sites that collectively treated over 70 % of the MDR-TB cases in Namibia, during the study period. These were the Katutura, Oshakati, Rundu, and Walvis Bay MDR-TB treatment facilities.Mycobacterium tuberculosis. Thereafter, treatment was changed to the continuous phase for 12–18 months that was administered on an outpatient basis. The average daily patient dose of amikacin or kanamycin was 15 mg per kilogram body weight, although dosing could be adjusted depending on the patient age group, weight band and renal function [The study population comprised of patients receiving treatment for MDR-TB at public sector facilities in Namibia. Our study sample included all patients who were clinically assessed and audiologically tested for hearing function at baseline and at least once, after commencing their MDR-TB treatment. Patients presenting with symptoms of hearing loss prior to the start of MDR-TB treatment were excluded from our cohort. Upon suspicion or after being diagnosed with MDR-TB infection, patients were initiated on six-to-eight months of intensive phase treatment with a regimen that contained either amikacin or kanamycin, until two sputum smears and two successive cultures turned negative for function .The occurrence of hearing loss after initiation of MDR-TB treatment was the main outcome of this study and was determined by an audiologist using pure tone audiometry as part of the usual care of patients treated for MDR-TB infection at the sites. Audiometry was performed at baseline, during the intensive phase of MDR-TB treatment and also in the continuation phase. No audiometry was done after completion of the MDR-TB treatment for patients who did not develop hearing loss. Hearing ability was tested by establishing the lowest intensity of sound in decibels (dB) that the person could hear at successive frequencies from 250 Hertz to 8,000 Hertz. Based on the audiogram chart provided by the Namibian Ministry of Health and Social Services  and the accuracy of entry verified against the original paper forms. All patient names and other identifiers were omitted from the final dataset to protect their privacy and to ensure their confidentiality. The anonymized and de-identified patient records were analyzed and reported in an aggregate manner, except for one patient whose serial audiograms have been anonymously published.t-test and categorical variables using the Chi-square test or the Fisher exact test. We performed univariable unconditional logistic regression analysis to assess the relationship between aminoglycoside use (amikacin or kanamycin) and the occurrence of any hearing loss. We repeated the same analysis for the less severe forms of hearing loss (mild or moderate); and the more severe forms of hearing loss . We performed stratified analyses to assess effect modification by patients’ age group, sex, baseline body weight band and HIV status. The Breslow-Day test of homogeneity was used to determine if the strata-specific odds ratios were similar. Multivariable logistic regression was conducted to adjust for potential confounders for variables whose P-value for the association with hearing loss was < 0.2. We used Epi Info™ Version 7.1.4 software , for the analysis.Data were summarized using descriptive statistics. We compared continuous variables using the Student’s The study was approved by the institutional review board (IRB) of the Utrecht University (Reference: UP1307) and the research and ethics committee of the Namibian Ministry of Health and Social Services, (MoHSS), (Reference: 17/3/3). A waiver of the requirement for informed consent from the patients was requested from the IRB and the MoHSS, because the study involved the review and analysis of clinical data that are routinely collected as part of the usual medical care of patients being treated for MDR-TB in Namibia. All patient names and other identifiers were omitted from the final dataset to protect their privacy and to ensure their confidentiality.There were 353 patients whose records were retrieved, all of whom had documented normal hearing at the start of their tuberculosis treatment. Fifty one 14 %) of the patients were treated with amikacin-based regimens and 302 (86 %) with kanamycin-based regimens. There were 164 patients (46 %) who were HIV co-infected, of whom 132 (80 %) were on highly active antiretroviral treatment. These patient characteristics were comparable between the amikacin and kanamycin-exposed groups  developed hearing loss of any severity grading , always beginning with high frequency loss (4–8 kHz), and then progressing to involve the lower frequencies 0.25–3 kHz) that are used for speech and conversation as shown in one of the patient’s audiogram in Fig. 5–3 kHz tp = 0.01), (Table p = 0.01). Patients treated with amikacin had more than twice the odds of kanamycin of developing any hearing loss (crude odds ratio (OR) = 2.3; 95 % CI 1.2–4.6), although the confidence interval for the odds ratio for the association became wider after adjusting for confounders  as shown in Table The cumulative incidence of any hearing loss was greater among patients treated with amikacin-based regimens than in those treated with kanamycin-based regimens , Table , and theIn stratified analyses by patients’ age group, baseline body weight band and by HIV infection status respectively, we noticed differences in the odds ratios of the amikacin/kanamycin and hearing loss relationship in the different strata of these variables. Although effect modification could not be statistically confirmed due to low numbers, patients co-infected with HIV , males  and those weighing 40–59 kg , appeared to be at higher risk of developing hearing loss (Table Adverse drug reactions are an important consideration for patients treated for MDR-TB infection where the prolonged treatment with amikacin or kanamycin is likely to result in the development of permanent hearing loss . We repoP = 0.02) and decreased renal function (P = 0.01) were significantly associated with the development of hearing loss [To the best of our knowledge, the current study is the first one to quantify the comparative risk of hearing loss of amikacin versus kanamycin in their real-life use for MDR-TB treatment in a low-resource setting. It builds on previous research from other settings, which suggested that amikacin was associated with a greater risk of hearing loss, but did not quantify the magnitude of that risk . Our fining loss . AlthougThe hearing loss seen in our study was sensorineural, mostly bilateral and began by affecting higher frequencies, then progressing to lower conversational-level frequencies as the severity of deafness increased. This finding is consistent with the pathophysiology of aminoglycoside-induced hearing loss , 9. AfteWe, therefore, advocate for MDR-TB treatment programs to implement routine serial audiometry in patients treated with aminoglycosides even in resource constrained settings, so that patients showing early signs of hearing loss can be identified long before the damage is too late to be reversed. When the drugs for preventing aminoglycoside-induced hearing loss become licensed for clinical use, they should be readily made available to patients, as an additional means of protecting patients from developing aminoglycoside-induced hearing loss.The risk of aminoglycoside-induced hearing loss was greatest in patients with lower baseline body weight (40–59 kg). This could be due to a drug dosing problem whereby clinicians may fail to titrate accurately the aminoglycoside doses according to individual patient body weight. Alternatively, these could be patients who were much sicker of tuberculosis disease than the heavier weighing patients. Since we are unable to ascertain the reason for this observation due to lack of data on serum drug concentrations, we recommend further studies on the long-term pharmacokinetics and pharmacodynamics of aminoglycosides in the context of MDR-TB treatment, taking into consideration patients’ renal function, anthropometric and genetic characteristics.Patients co-infected with HIV were more at risk of amikacin-induced hearing loss than the HIV uninfected ones. There is emerging epidemiologic and clinical evidence about the association between HIV infection and hearing loss , 38, 39.Amikacin, kanamycin and other aminoglycosides are practically not metabolized by the human body and are excreted unchanged almost exclusively by glomerular filtration, hence they require the careful monitoring of their plasma levels during therapy , 42. UnfRenal clearance may strongly affect the toxicity of aminoglycosides , 42, 44.Our study was an epidemiologic one, reflecting the real-life usage of amikacin and kanamycin in routine clinical practice. Using this study design, we identified patients that were most-at-risk of developing aminoglycoside-induced hearing loss. Importantly, hearing function was assessed using audiograms, which were part of the routine clinical follow-up of patients treated for MDR-TB. However, the data on the time-to-onset of hearing loss was unreliable because of the “batching” of patients for audiometry, due to the shortage of audiologists and audiology assistants.Due to practical limitations about the documentation of audiometry in patients treated for MDR-TB at the sites prior to 2007, we could only retrieve information on 51 patients that were treated with amikacin for the period covered by this research. On the other hand, for kanamycin, we retrieved 302 patients, causing an imbalance in the numbers of patients exposed to amikacin and kanamycin, respectively. To assess for possible bias, the 51 patients on amikacin were checked for the risk of hearing loss against 51 randomly selected patients on kanamycin and the results were similar to those of the 353 patient sample.There were several other limitations of this study. For example, there were too few patients in some sub-groups which limited the power of the study for multiple sub-group analyses. Besides, we were unable to collect data on other potential risk factors like the usage of antiretroviral medicines in HIV infected patients, genetic markers of ototoxicity and other unmeasured confounders including the use of other medicines known to be ototoxic.The long-term use of amikacin in MDR-TB treatment led to a higher risk of the more severe forms of hearing loss compared to the use of kanamycin for the same indication. Males, patients with low baseline body weight and those co-infected with HIV were most-at-risk. We recommend that managers of MDR-TB treatment programmes should consider using kanamycin instead of amikacin for the treatment of MDR-TB; and invest more resources in building the capacity and skills of health care personnel for routine renal, serum therapeutic drug levels and audiometric monitoring of the most-at-risk patients treated with aminoglycosides. More research needs to be done to better understand the combined risk of hearing loss in patients concomitantly treated for MDR-TB and HIV infections. A better designed and more powered study is needed to confirm the comparative ototoxicity risk of amikacin and kanamycin; and associated risk factors.


Teriparatide (TPTD) is an anabolic agent indicated for the treatment of severely osteoporotic patients who are at high risk of fragility fractures. The originally approved duration of TPTD treatment in several regions, including Europe, was 18 months. However, studies of areal bone mineral density (aBMD) showed additional benefit when treatment is continued beyond 18 months, and the drug is currently licenced for 24 months. Improvements in cortical structure at the proximal femur have already been shown in patients given TPTD for 24 months using quantitative computed tomography (QCT). Here, we investigate whether cortical and endocortical trabecular changes differ between an 18- and 24-month treatment.Since an 18- versus 24-month TPTD study using QCT has not been conducted, we studied combined QCT data from four previous clinical trials. Combined femoral QCT data from three 18-month TPTD studies (‘18-month group’) were compared with data from a fourth 24-month trial (‘24-month group’). Cortical parameters were measured over the entire proximal femur which allowed for a comparison of the mean changes as well as a visual comparison of the colour maps of changes after 18 and 24 months TPTD.For both the combined 18-month group and the 24-month group, overall cortical thickness and endocortical trabecular density increased, while overall cortical bone mineral density decreased. While the changes in the 24-month group were of greater magnitude compared to the 18-month group, the differences were only significant for the endocortical trabecular density (ECTD), corrected for age, weight, femoral neck T-score, total hip T-score and the baseline mean ECTD.Although the combination of data from different clinical trials is not optimal, these data support the concept that the duration of TPTD in the 18–24 month phase is of clinical relevance when considering improvement in hip structure. Osteoporosis is an age-related disease characterized by a deterioration of the bone micro-structure through porosity and thinning, which results from an imbalance between bone formation and resorption. This causes the bone to become more fragile and increases the risk of fracture.In 2002 the FDA approved Teriparatide (TPTD) for the treatment of postmenopausal women with osteoporosis at high risk of fracture for a duration of 24 months. In a large prospective study TPTD was shown to increase hip and spine areal bone mineral density (aBMD) and reduce vertebral and nonvertebral fracture incidence within a mean treatment duration of 18 months  indicateIn an ancillary study of the same clinical trial, quantitative computed tomography (QCT) scans were acquired at 6, 12 and 24 months [To investigate cortical and trabecular responses, in this retrospective analysis, we combined the QCT data from three clinical trials of an 18-month TPTD treatment. We then compared this dataset with QCT data from a fourth clinical trial which examined changes in the proximal femur after 24 months of TPTD therapy. In addition, we performed a statistical parametric mapping analysis on the data, which allowed us to visualise where statistically significant changes occurred on the proximal femur for the 18- and 24-month treatments.This study combines the data from four clinical trials where patients received 20 μg TPTD by daily subcutaneous injection and hip QCT scans were available. For examining the effects of an 18-month treatment by TPTD, three datasets were used, denoted GHDJ, GHBM and GHCM:The GHDJ dataset, resulting from the Micro-MRI US trial , includes 24 osteoporotic women with a mean age of 60.9 ± 7.4 years who received 18 months of TPTD therapy [The GHBM dataset results from the FACT study  which compared a TPTD treatment with an alendronate (ALN) treatment [The GHCM (Add vs. Switch) dataset results from a study  examining the effects of switching to or adding an 18-month TPTD treatment to a previous treatment by ALN or raloxifene (RLX). From this dataset we include only the subjects whereby a previous ALN or RLX treatment was switched to a TPTD treatment. In this dataset, the QCT scans that were acquired after switching to TPTD were used as baseline with follow-up QCT scans after the 18-month TPTD treatment. This dataset contains 65 postmenopausal women with a mean age of 68.9 ± 8.4 years. The details of this clinical trial are reported in [These three datasets were combined into a single ‘18-month group’ which consists of 108 subjects with a mean age of 66.8 ± 8.6 years who all received TPTD for 18 months.The full set of baseline characteristics are presented in For the ‘24-month group’ we used the QCT scans resulting from the EUROFORS trial . This clinical trial examined the effects of various sequential treatments after TPTD in postmenopausal woman with established osteoporosis. Results of this trial on aBMD measurements were previously reported in , and a sAll scans were acquired with the Mindways calibration phantom in the field of view, allowing for the Hounsfield units to be converted to bone mineral density values. Institutional Review Board approval was obtained from each of the clinical study sites, and written informed consent was obtained from each participant.http://mi.eng.cam.ac.uk/~rwp/stradwin/). Using this software, the contours of the bone surface are semi-automatically drawn in the QCT slices. These are then processed into a triangular surface mesh on which the cortical measurements are performed. Samples are taken in the QCT volume perpendicular to the bone surface, resulting in a profile of the QCT values with an inherent smoothness. By fitting a blurred model of the cortex to the data samples, Stradwin is able to accurately estimate the CTh (mm) and the CBMD (mg/cm3) as well as the endocortical trabecular density , which is the trabecular density directly adjacent to the cortex. From the cortical thickness and CBMD, we also compute the cortical mass surface density (CMSD) as CMSD = 0.1 × CTh × CBMD, which represents the mass per unit surface area (mg/cm2). In this study, cortical bone mapping version 2 (CBMv2) is used, as referenced in [The cortical parameter measurement and mapping technique has been previously described , 11, 12 http://mi.eng.cam.ac.uk/~ahg/wxRegSurf/) to give us a one-to-one correspondence between the cortical parameters of each femur across all four studies. This first requires a canonical shape to be registered to the individual shape by a deformable registration. After this registration, the parameters are mapped to the canonical surface by, for each vertex in the canonical mesh, finding the closest point in the individual mesh and taking the associated cortical parameter.Stradwin measures the cortical parameters at each vertex of the bone surface mesh which results in a colour coded map of the cortical parameter values. Cortical parameter maps are subsequently produced for each QCT scan which are all mapped to a canonical surface using wxRegSurf  are indicated in grey. This cortical parameter mapping technique is explained in detail in .All cortical parameter changes are presented in Both the 18-month combination group and the 24-month treatment group showed a statistically significant increase in overall CTh and ECTD with a significant decrease in CBMD. These changes are greater for the 24-month cohort compared to the 18-month groups, although the differences are not significant for the CTh and CBMD. ECTD increases, however, are significantly greater for the 24-month compare to the 18-month group corrected for age, weight, height, femoral neck T-score, total hip T-score and baseline ECTD (p = 0.004). There were no significant changes for CMSD measurements, nor are there for any of the individual 18-month treatment groups.When examining the colour coded maps , large rThis study combines the data from various different clinical trials to form an 18-month TPTD treatment group. Combining data from patients with different demographics is precarious and should be handled with great care. The population characteristics have been assessed for differences between the three 18-month treatment groups. This indicated that there were indeed significant differences between these populations.The significances of the differences in cortical changes between the three groups were also assessed. Here we used a linear model to correct for age, weight, height, femoral neck T-score, total hip T-score and the corresponding baseline mean parameter value. This showed no significant difference between the 18-month groups. This indicates that, although the cortical parameter changes vary considerably between groups , these dThe cortical changes in the combined 18-month cohort were compared to the cortical changes from a fourth independent clinical trial with a 24 month TPTD treatment period. The cortical changes were compared for the significance in difference with the combined 18-month cohort by ANOVA tests corrected for age, weight, height, femoral neck T-score, total hip T-score and the corresponding baseline mean parameter value. Only the changes in ECTD remain significantly greater for the 24-month group compared to the 18-month group. This might indicate persistent bone forming activity even after the 18-month time point. This is clinically relevant since a recent study showed ECTD to be a strong predictor of hip fractures . ImproviAs in our previous studies , 15, 16,Previous studies indicate that a prior antiresorptive treatment might blunt areal BMD increases by TPTD, depending on the type of antiresorptive . Both thThe main limitation of this study is the fact that the trial group and the time point are confounded. We do not know whether the 24-month group had the same cortical changes at the 18 month time point as the pooled 18-month study group, and there is no common therapy time point that can be adjusted against. Furthermore, there are substantial limitations in combining study subjects from different clinical trials, performed at different locations and using different populations, even when the study drug is the same. The combination of different trials prevents us from making firm conclusive statements about the outcome. However, we do see a greater endocortical trabecular response in the 24-month group compared to the combined 18-month group, where the increases of the 24-month group were statistically significantly greater than the 18-month groups even when corrected for the demographics and the mean ECTD at baseline. The magnitude of the changes for the other parameters appear greater with 24 months treatment, but do not achieve statistical significance after correcting for demographics and baseline mean differences. As the ECTD has recently been shown to be a strong predictor for hip fractures, an additional 6-month TPTD treatment might reduce the risk of hip fracture by increasing the trabecular bone, which potentially outweighs possible adverse effects and added costs. The increased ECTD is also reflected by the cortical maps which show greater changes for the 24-month treatment compare to the combined 18-month treatment group. In addition, the geometrical spread of changes is very similar between the two groups, which is some indication of the validity of comparing this data. Although no firm conclusions can be made from this multi-trial retrospective analysis, this study does suggest that a 6-month treatment with TPTD after a previous 18-month treatment could enhance trabecular bone structure of the hip.


Sixty-five patients, with a total of 74 missing maxillary teeth, were selected in the period from February 2007 to July 2010. Two different ways of custom made zirconia abutment and final prosthetic restoration were evaluated: a standard zirconia abutment associated with a pressed layer of lithium disilicate with an all-ceramic cemented restoration versus one-piece restoration with the facing porcelain fired and pressed straight to the custom made zirconia abutment. In 29 cases, the restoration consisted of an all-ceramic restoration for cementation (two pieces); in 45 cases the restoration was a screw-retained restoration (one piece). Three all-ceramic restorations broke during the observation time. Two one-piece restorations fractured after 26 months. At follow-up examination there were no significant differences between one-piece and two-piece groups regarding the PI, BI, and MBL. Awaiting studies with longer follow-up times, a careful conclusion is that zirconia anchorages for single-implant restorations seem to demonstrate good short-term technical and biological results.The purpose of this randomized controlled study is to investigate the clinical results obtained over four years and incidence of complications associated with Among ca alloys  in the ua alloys , 5. The a alloys . In the a alloys . one- versus two-piece custom made zirconia abutments, in single tooth implant-supported restorations of the maxillary anterior region.The aim of this randomized controlled study is to investigate the clinical results obtained over four years and incidence of complications associated withSixty-five patients, including 44 females and 21 males, with a total of 74 missing maxillary teeth, mean age 53 ± 4 years, were selected in the period from February 2007 to July 2010, at the Department of Neurosciences, Reproduction and Odontostomatological Sciences of the University of Naples “Federico II.” The study was designed as a controlled randomized trial on patients who needed single-implant restoration in the maxillary anterior area with healthy nonrestored neighboring teeth. Two different ways of custom made zirconia abutment and final prosthetic restoration were evaluated: a standard zirconia anchorage  associated with a pressed layer of lithium disilicate with an all-ceramic cemented restoration (two pieces) versus one-piece restoration with the facing porcelain fired and pressed straight to the custom made zirconia anchorage . The prosthetic treatment of the patients was chosen with coin toss randomization ; Full-MoAn alveolar nerve block infiltration was administrated with local anesthesia using 2% mepivacaine; 51 implants  68.9%) were placed with a one-stage procedure  in the mEach implant placement was performed with the aim of finding an ideal three-dimensional implant position for better aesthetic results: the respect of the vestibular bone crest, the distance of the implant body not exceeding 1.5 mm from the adjacent root surface, and the position of the implant shoulder approximately 2 mm apical to the midfacial gingival edge of the planned restoration. 26 patients were submitted to GBR in the immediate postextraction time to allow an implant placement following the previous criteria.In all cases the prosthetic procedures were performed six months after implant placement. Two different ways of custom made zirconia anchorage and final prosthetic restoration were evaluated: a standard zirconia anchorage  associated with a pressed layer of lithium disilicate with an all-ceramic cemented restoration (two pieces) versus a one-piece restoration with the facing porcelain fired and pressed straight to the custom made zirconia anchorage . In two-piece group the ceramic restorations (lithium disilicate Ivoclar-Vivadent) were cemented with resin cement .All zirconia abutments, once a clinical check is made, were tightened with 25 N/cm according to manufacturer's instruction  and then we proceeded to the cementation.Radiographs taken at the time of prosthesis delivery  and at the follow-up examination were used to calculate the radiographic bone level at the mesial and at the distal sites of the implants. The radiographic linear distance from the implant shoulder to the first bone-to-implant contact was used to calculate the marginal bone levels. All the radiographs were taken by applying the longcone technique and by using a film holder . The filThe single tooth implant-supported restorations require a minimum 4-year follow-up period (57–83 months).The examination comprised registration of technical and biological data at 12, 24, 36, and 48 months after the prosthesis insertion time.The technical recordings comprised fractures of the abutment, restoration and facing porcelain, loss of retention of the abutment (anchorage screw loosening), or restoration.The biological parameters included mobility of the implant (yes or no), Plaque Index (PI) , BleedinThe causes of missing teeth were endodontic failure , residual roots , nonrestorable caries , and agenesis .65 patients received one implant, but 9 needed two single nonadjacent prosthetic restorations. 51 fixtures 68.9%) were placed with a one-stage procedure  and a he.9% were All patients showed good compliance and the healing period was uneventful. At 4 years of follow-up no patients suffered from pain or peri-implant infection; the implant survival rate was 100% and none of the implants showed mobility. In 29 cases, the restoration consisted of an all-ceramic restoration for cementation (two pieces) ; in 45 cThree (10.3%) all-ceramic restorations broke during the observation time. All two-piece restorations, except one (3.4%), had excellent edge fit between restoration and abutment.Only 2 (4.4%) one-piece restorations fractured after 26 months. No anchorage screw loosening was reported. The mean PI and rehabilitation BI values at 12, 24, 36, and 48 months after the prostheses insertion time are reported in Kaplan-Meier's survival analysis was performed to compare the two groups. The implant placement technique (one stage or two stages) did not significantly influence the clinical outcomes. At follow-up examination there were no significant differences between one-piece and two-piece groups regarding the PI, BI, and MBL Tables  and 4.Only 2 implants (6.8%) had lost more than tone thread Figures  and 12. The zirconia (zirconium dioxide) characteristics have led to its increased use for many dental applications . Many adA 3-year randomized controlled clinical trial comparing customized zirconia and titanium anchorages showed no difference in the outcome from technical, biological, but also aesthetical points of view . AnotherThe loosening of the anchorage screw did not occur in the present study confirming some recent articles performed either in vivo –16 or inOur study reports the clinical, radiographic outcomes of two different prosthetic ways to use the custom made zirconia anchorages and evidence that the custom zirconia anchorages used for one- and two-piece restoration restorations performed well over a follow-up period of up to 4 years with satisfaction by the patients.However, there were few complications during our observation time. Two one-piece restorations with the facing porcelain fired straight to the abutment fractured after 26 months. One of this fractures could be related to functional overload due to the loss of a mobile prosthesis restoring posterior teeth. This abutment was replaced and no further problems occurred. Although in the two-piece restoration 3 fractures are reported, data from the present study show no statistically significant differences between one-piece and two-piece prostheses in terms of fractures and other complications. At 48 months' follow-up there were no statistical differences either in the peri-implant edgeal bone loss or in soft-tissue conditions between the screw-retained one-piece restorations and single-tooth implant restorations cemented to the anchorage (Tables About the MBL the limitations of the radiographic technique and the method of measurement should be considered.The survival rate and the rate of technical and biological complications in the present study were similar to the rates reported in a systematic review of ceramic anchorages by Sailer et al. . The preAwaiting studies with longer follow-up times, a careful conclusion is that zirconia anchorages for single-implant restorations seem to demonstrate good short-term technical and biological results.


Total anomalous pulmonary venous connection (TAPVC) is an anomaly in which the pulmonary veins are directly connected to one of the systemic veins or drain into the right atrium. Management of pulmonary hypertension after the total correction of this congenital cardiac anomaly is very important. Unligation of the vertical vein in the supracardiac type of this anomaly can be a draining pathway for the prevention of postoperative pulmonary hypertension crisis. Late onset transcatheter closure of the unligated vertical vein after a decrease in pulmonary pressure with the Amplatzer vascular plug type 1can prevent residual left-to-right shunting. Here we describe two patients who previously underwent surgical correction of supracardiac TAPVC and their vertical veinwas partially ligated due to severe pulmonary hypertension. Consequently, because of increased left-to-right shunting in the follow-up period, transcatheter occlusion of the vertical vein was done for them and this procedure seemed safe and less invasive compared to the surgical approach.At 2 years'follow-up, there was marked pulmonary artery pressure and clinical improvement. Rather, the pulmonary veins are directly connected to one of the systemic veins or drain into the right atrium.2 The signs and symptoms of TAPVC are variable depending on the site of the drainage of the pulmonary veins and the presence of an obstructive lesion in the pulmonaryvenous channel.3 Patients with unobstructed TAPVC are usually asymptomatic at birth; however, by the first few weeks of life, they will present with evidence of a large left-to-right shunt, cardiomegaly, failure to thrive, mild cyanosis, and cardiorespiratory failure. Children with obstructed TAPVC will present with respiratory problems, hypoxia, pulmonary hypertension, rapid progression to cardiorespiratory failure, and respiratory-distress-syndrome-like pattern.1, 2 These children require urgent repair, while those with unobstructed TAPVC can have a more elective correction.2The frequency of TAPVC is between 1-1.5% of all congenital heart diseases and it can be associated with other cardiac anomalies, especially the heterotaxysyndrome.3 The unligated vertical vein has been reported to atrophy spontaneously, but there have been reports where the unligated vertical vein remains patent and results in significant symptoms due to a left-to-right shunt.4 Such patients can be candidates for percutaneous angiographic closure by device. The transcatheter closure of the unligated vertical vein with a ductus occluder in supracardiac TAPVC has been reported in a few instances.5, 6The surgical repair of supracardiac TAPVC has undergone several modifications, and most surgeons prefer to ligate the vertical vein to prevent residual left-to-right shunting. However, with smaller left-sided chambers and non-compliant left atrium, an unligated vertical vein may improve survival by providing a transitory decompression of the right side of the heart for postoperative pulmonary hypertension crises.In this study, we report the transcatheter closure of a partially ligated vertical vein using the vascular plug device in our patients with previous repair of supracardiac TAPVC.Patient 1A 2-year-old (10 kg) infant with unobstructed supracardiac TAPVC underwent surgical correction at Faghihi Hospital, Shiraz, Iran. Preoperative echocardiography showed that the pulmonary venous channel drained through a vertical vein into the innominate vein and thereafterinto the superior vena cava. During surgery, the vertical vein was partially banded due tohigh pulmonary artery pressure. After discharge, the patient presented with a gradual decrease in pulmonary pressure and desirable weight gain. In echocardiography, return of the pulmonary veins to the left atrium, an open vertical vein with an ascending flow into the innominate vein, and mildly dilated right atrium and right ventricle were detected. Thus, the patient wascandidated for the percutaneous closure of the vertical vein by device.Cardiac catheterization was performed 23months after the surgical correction. Through a 5-Fr sheath via the femoral vein, a 5-Fr NIH catheter was advanced to the branch pulmonary arteries. Injection of contrast showed that the pulmonary veins drainedinto the left atrium and flowedinto the innominate vein through a patent and dilated vertical vein. In addition, a 5-Fr right Judkins catheter was advanced over a 0.035-in guide wire through the superior vena cava and theinnominate vein into the vertical vein. The mean pressure in the vertical vein was 10mmHg, mean right atrial pressure was 6 mmHg, right ventricular pressure was 40 mmHg, and mean pulmonary artery pressure was 17 mmHg. Angiography of the vertical vein demonstrated that it drained into the innominate vein . In the Patient 2A 5-year-old (15 kg) infant with unobstructed supracardiac TAPVC underwent surgical repair and the vertical vein was partially ligated as was described in the previous case.Postoperative findings via echocardiography showed a gradual decrease in pulmonary pressure and good growth. In cardiac catheterization, which was performed 14 months after the primary repair, the mean right atrial pressure was 8 mmHg, right ventricular pressure was 30 mmHg, and mean pulmonary artery pressure was 21 mmHg. The stenotic part was 6 mm, and the vertical vein was successfully closed with an 8-mm vascular plug type 1 . The pat7 Nowadays, the mortality rate has decreased due to the recent modifications in the surgical repair; i.e., leaving the vertical vein open at the time of TAPVC correction inpatients with a significantly small and non-compliant left atrium.4, 7, 8TAPVC is categorized into four types defined by the site ofthe entry of the anomalous connection. The most common type is the supracardiac type, followed by the infracardiac type, while the cardiac and mixed types are relatively uncommon.5 suggested that leaving the vertical vein patent at the time of TAPVC repair may afford better postoperative conditions by providing a temporary pop-off for pulmonary hypertensive crisis.5 Since the patient's venous pathway can continue to function as a conduit for a significant left-to-right shunt, this overload increases the work of the right heart chambers and leads to symptoms. Consequently, the transcatheter closure of an open vertical vein has been recommended. Few instances havealso been reported for the device closure of the vertical vein. N. Wilson6 and HG. Schneider et al.9 reported the successful closure of unligated vertical veins usingductusoccluders in 2 patients with supracardiac TAPVC. Also, D. Kobayashi et al.4 reported the successful transcatheter closure of a persistent patent vertical vein usingthe Amplatzer vascular plug device and a Gianturco coil.Maully J. Shah et al.In the present study, we described 2 patients with partially ligated vertical veins who showed a gradual decrease in pulmonary pressure and improvement of cardiacas well as pulmonary function. The transcatheter closure of the open vertical veins with vascular plugs type I was done successfully and no adverse event was observed during a 2-year follow-up period. Therefore, this procedure could be a useful method for the closure of a persistent patent vertical vein in surgically corrected TAPVC.The transcatheter closure of a partially ligated vertical vein using the vascular plug device in patients with previous repair of supracardiac TAPVC could be a useful and safe management modality for the prevention of subsequent complications due to residual left-to-right shunting.


To compare theProblem-based learning (PBL) with the traditional lecture-based curricula.The single bestanswer Multiple Choice Questions (MCQ) and the Objective Structured ClinicalExamination (OSCE) were used to compare performance of the lecture-basedcurriculum with the PBL medical student groups. The reliability for the MCQsand OSCE was calculated with Kuder-Richardson formula and Cronbach’s alpha,respectively. The content validity of the MCQs and OSCE were tested by theIndependent Subject Experts (ISE). The Student’s t-test for independent sampleswas used to compare the item difficulty of the MCQs and OSCE’s, and theChi-square test was used to compare the grades between the two student groups.The PBL studentsoutperformed the old curriculum students in overall grades, theoreticalknowledge base (tested with K2 type MCQs) and OSCE. The number of the PBLstudents with scores between 80-90% (grade B) was significantly (p=0.035)higher while their number with scores between 60 to 69% (grade C) wassignificantly p=0.001) lower than the old curriculum students. Similarly, themean MCQ and the OSCE scores of the new curriculum students were significantlyhigher  than the old curriculumstudents. Lastly, the old curriculum students found the K2-MCQs to be more (p =0.001) difficult than the single correct answer (K1 type) MCQs while no suchdifference was found by the new curriculum students.Suitablydesigned MCQs can be used to tap the higher cognitive knowledge base acquiredin the PBL setting.  Some students drop out as years progress while some failed students take re-sit exam with the previous year’s class. The faculty curricula, for both preclinical and clinical programs, were reformed in 2005-6. The traditional teacher-centered, didactic lecture-based classroom teaching was replaced with the student-centered, small group, problem-based learning (PBL). The weekly learning objectives (WLOs) for the 8-week psychiatric rotation were identified, and the didactic lectures (N= 24) were replaced with 14 (2 for each case) PBL group meetings. Based on the WLOs, seven PBL cases, comprising psychoses, affective disorders, anxiety disorders, somatoform disorders, organic mental syndrome (delirium), substance abuse, and child psychiatry (attention deficit disorder), were identified. During the daily Case Conference meetings (N=28), the students, under supervision of their respective tutors, made case presentations and demonstrated the clinical findings with live patient interviews.A cross-sectional descriptive study design was used. The data was accessed from the on-site evaluations of both the old and the new curricula students.The participants included 91 students  of the 2009/2010- year and 69 students  of the 2011/2012- academic year. The old curriculum students included 16 re-sits while 25 students had dropped out from the new curriculum class. All the old curriculum students were examined only once at the end of the academic year while the new students were examined twice; once at the end of the 8-week psychiatry rotation, and then during the annual examination.The institutional scientific and research committee was approached for ethical approval which allowed the study to proceed without any further review as it did not involve human subjects or animals and the study data consisted of students’ performance in examinations.In accordance with the weekly learning objectives, a total number of seven PBL cases were identified. Each PBL case was discussed in two sessions. A typical PBL group, comprising 5 to 6 students, began the session (one) with analysis of the unfamiliar terms and defining the stimulus (case trigger) in a concise statement (describing the nature of the disorder) followed by the brainstorming session. Drawing upon their pre-existing knowledge and engaging in the process of elaboration, the students brought forth different hypotheses to explain the possible underlying  mechanisms for the given clinical case manifestations. This exercise helped students identify gaps in their knowledge in ascertaining clinical manifestations, differential diagnoses, and management of the given case. The students then dispersed to engage in self-directed learning. Using a variety of resources, they sought out and learned additional information which helped to bridge the gaps in their pre-existing knowledge. Additional information containing details of history, clinical manifestations, and investigations was sent to them during this time. In addition, the students clerked and presented patients with similar manifestations during the once daily Tutor-supervised Clerkship sessions and the Case Conferences. This helped them to narrow down the hypotheses (generated during the previous group meeting) to the main diagnosis and formulate the individual management plans for the case. The second PBL group meeting, called the Reporting back session, was conducted six days later. It began with 5-7 minute learning topic presentations by the students. Then, the case review was carried out in which the underlying mechanisms (psychopathology) for the given clinical manifestations were discussed and the management plan formulated. The session ended with the process review when the group members reflected on the productivity of the PBL sessions. The role of the PBL facilitator, a subject specialist, was limited to maintenance of cooperative, productive, and positive group environment. Using his content knowledge sparingly, he helped foster receptive and non-judgmental group culture, encouraged free and frank expression by all group students and ensured that the group remained focused.The 2009-10 assessment included 220 MCQs and eight OSCE stations. The 2011-12 examination consisted of 225 MCQs and ten OSCE stations.,,,,It has been argued that MCQs most often test basic cognitive level of the knowledge-base, namely the factual information recall and comprehension with little consideration for the degree or depth of cognitive level of the learning involved.The clinical skills and professional competency were assessed with the 7-minute couplet-OSCE stations. The clinical competency level of the OSCE stations conformed to the course objectives and covered a variety of clinical problems including insomnia, suicidal risk, cognitive impairment, delirium, depressed mood, hallucinating patient, panic disorder, somatization disorder, psychoeducation and counselling for patients and their families. Each station was followed by a couplet, pen-and-pencil station in which students were required to answer questions concerning diagnosis/management of the clinical problem, assessed in the previous station.Independent subject experts  cross-checked the MCQs and categorized them into K1 or K2 type. Most  of the new curriculum questions were classified as K2 type while most  of the old curriculum questions were categorized as K1 type. The performance of the students on both K1 and K2 type MCQs was compared to see if performance differed in the two groups.The MCQs internal reliability coefficient, indicator of the homogeneity of test items,The data were analyzed on SPSS, version 20.  The Student’s t-test for independent samples was used to compare the post-hoc mean item difficulties between the old and new curricula MCQ scores The Chi-square tests were used to compare the grades for the two groups of students.The reliability coefficients of the new and the old curricula MCQs were 0.8 and 0.72 respectively, which lie well within the acceptable range. The Cronbach’s alpha values for the OSCE were 0.75 and 0.82, for the new and the old curriculum, respectively, which again were well within acceptable limits. The number of the PBL students with scores between 80-90% (grade B) was significantly (p = 0.035) higher while their number with scores between 60 to 69% (grade C) was significantly (p = 0.001) lower than the old curriculum students . SimilarThe post-test item analysis showed that the old curriculum students found K2-questions to be significantly (p = 0.001) more difficult than K1-questions while no such difference was found by the new curriculum students . In otheOur findings suggest that the PBL-based curriculum students performed significantly better than the didactic lecture-based curriculum students both in theoretical knowledge base (K2 type MCQs) and clinical examination (OSCE). The proportion of the new curriculum students with top grades was significantly higher while their number with lower grades was significantly less than the lecture-based curriculum students. Moreover, the old curriculum students found K2 questions to be more difficult while the new curriculum students found no such difference between the K2 and K1 type questions. Similarly, the mean OSCE scores of the new curriculum students were significantly higher than the old curriculum students.,The PBL-based curriculum has been shown to be more effective in promoting clinical competency with little or no impact on the theoretical knowledge base.,,,Since the K2 type MCQs measure comprehension, analysis, integration, and application of knowledge,,,,,,,,,,,Our findings are consistent with the previous studies reporting significant improvement in the PBL-driven  curriculum students’ deeper understanding of the knowledge base; greater student satisfaction, and more positive student attitudes and perceptions of education.,,,,,,It is important to mention some shortcomings of the study here. First, although mainly driven by PBL, the delivery of our curriculum involved complementary teaching activities including the tutor-supervised, small group clerkship sessions; teaching OSCE sessions; and the Case Conferences, which served as additional learning forums for the students. The PBL has generally been construed as a general construct with little consideration for the complexity of its implementation and the multiple factors likely to affect the outcome of this approach.In summary our experience of replacing the traditional didactic lecture-based with the PBL-driven, curriculum has shown promising results. The synchronization of the different teaching methods, namely aligning the tutor-supervised clerkship sessions and the Case Conferences with the PBL case for the given week, in addition to promoting the PBL processes, resulted in deeper understanding, and superior performance, of our students in the broad knowledge base and clinical competency. This study contributes to the understanding of different educational approaches and describes the usefulness of K2 type MCQs as a reliable and valid tool to evaluate efficacy of the PBL. In particular, it suggests a novel approach to compare the outcome of the PBL with the traditional lecture-based teaching in undergraduate medical students. Further methodologically sound studies are needed to establish the usefulness of the K2 type MCQs to measure the higher cognitive level and deeper understanding of the broad knowledge base, attributed to the PBL curricula.The authors declare that they have no conflict of interest.


It has been applied with aplomb to many different cellular processes and has significantly enlightened our understanding of the heterogeneity and complexity of biological systems. Recently, high-resolution fluorescence microscopy has been brought to bear on telomeres, leading to new insights into telomere spatial organization and accessibility, and into the mechanistic nuances of telomere elongation. We provide a snapshot of some of these recent advances with a focus on mammalian systems, and show how three-dimensional, time-lapse microscopy and single-molecule fluorescence shine a new light on the end of the chromosome.Fluorescence microscopy can be used to assess the dynamic localization and intensity of single entities More than a century later, fluorescence microscopy has proven transformative in our ability to illuminate almost all aspects of cellular biology. One of the more recent frontiers in fluorescence microscopy is the resolution of biological phenomena at the single molecule level, called single molecule fluorescence2. Biological processes have evolved to be inherently heterogeneous, transient and dynamic3, and therefore difficult to track. Single molecule microscopy often permits a birds-eye view of ephemeral and complex mechanisms. This review will focus on selected recent advances in high-resolution microscopy including, but not limited to, single-molecule fluorescence microscopy, that have enlightened our understanding of chromosome ends and the enzyme that replenishes them.Oskar Heimstädt, who built the first fluorescence microscope, ended his 1911 paper with the following perspective: “If and to what degree fluorescence microscopy will widen the possibilities of microscopic imaging only the future will show”4. We now appreciate that telomeres are a highly specialized nucleoprotein structure whose maintenance is critical to genome stability  localization of mammalian telomeres in normal cellsversus cancer cells12. Time-lapse microscopy has also revealed increased mobility of telomeres upon induction of a DNA break13 as well as unexpected long-range telomere associations in telomerase-negative cells after DNA breakage14. In the budding yeastSaccharomyces cerevisiae, fluorescent tagging of several components of telomerase have also provided considerable insight into the temporal and spatial dynamics of telomerase recruitment in living cells18.Fluorescence microscopy has revolutionized our ability to probe the length, location, and recombination of telomeres19, Chen and colleagues targeted an enhanced green fluorescent protein (EGFP)-tagged catalytically inert Cas9 specifically to telomeres20. Telomere-recruited Cas9 demonstrated a punctate pattern that spatially overlapped with that of the telomeric DNA binding protein, telomeric-repeat binding factor 2 (TRF2). Furthermore, EGFP intensity correlated linearly with telomere intensities obtained using fluorescencein situ hybridization (FISH)  20. This21. Super-resolution microscopy, specifically stochastic optical reconstruction microscopy (STORM), has recently enabled an unprecedented visualization of T-loops that are crosslinked and purified from murine cells22  has been applied to the molecular dynamics of G-quadruplex formationin vitro28 31. Furthermore, this technique also revealed the binding and unfolding of G-quadruplexes by proteins such as RAD51, WRN, BLM, RecQ and RPA36. Recently, the use of smFRET combined with magnetic tweezers spectroscopy37 has been used to measure the thermodynamic properties of G-quadruplex folding38. These findings provide important insights into the dynamics of telomeric DNA structure in a more native nucleoprotein context.Telomeric DNA sequences can also formitro28 . The smF40. Although much information has been gleaned using standard biochemical techniques regarding the complex DNA-protein, RNA-protein and protein-protein interactions that contribute to telomerase RAP  precludes single base resolution, this technique promises to provide an unprecedented, single-molecule view of the intricacies of the telomerase elongation cycle.The telomerase reverse transcriptase, TERT, is able to synthesize new telomeric DNA, one nucleotide at a time, by virtue of an integral telomerase RNA that contains a short telomere-complementary sequence . Althougal time . Their r48. Using different combinations of regular and chain-terminating nucleotides, information about the position of the DNA oligonucleotide substrate was registered at single-base pair resolution during elongation. While the substrate appears in a compact conformation after initial binding by telomerase, after a round of DNA synthesis the substrate realigns with the templatevia Watson-Crick base pair interactions. The aforementioned study by Parks and colleagues suggests that DNA dissociation and realignment is not the limiting step, and that an additional conformational adjustment is necessary after DNA:RNA repositioning to re-acquire a catalytically competent state48. This study illustrates the power of non-linear Gaussian curve fitting and hidden Markov modeling to extract the dwell time of the different FRET states from individual traces, which in turn permits a very precise dissection of the catalytic mechanism, albeit only over the short distances in which FRET can be observed.In another smFRET approach, the distance between the region 5’ of the RNA template of telomerase and a DNA substrate was followed during telomeric repeat synthesis 48. Usin51. It has also been applied to examine the assembly and activity of theTetrahymena thermophila telomerase RNP53 and, more recently, the role of the N-terminal domain ofT. thermophila TERT in the stabilization of short RNA:DNA hybrids during telomerase catalysis54. In addition to valuable insights into telomerase catalysis, these techniques might also permit a precise elucidation of the mechanism-of-action of chemical modulators of telomerase activity, as well as anin vivo determination of human telomerase component stoichiometry, as was recently demonstrated for budding yeast telomerase18.smFRET has also been used to evince the real-time dynamics of folding of the pseudoknot domain with the telomerase RNA55. We have reached a technological watershed in biology that will enable an unprecedented single-molecule and high-resolution view of the inner workings of many cellular machines. As we have illustrated here with but a few selected examples, fluorescence microscopy can be applied in many different ways to different problems, but key advances are the ability to dissect individual events instead of ensemble, population-based outputs, and to permit dynamic measurements in living cells, in real time. How far we have come from seeing telomeres as a cytogenetic “knob”, and how far we have yet to come.In the year in which fluorescence microscopy was first described, Arthur Brisbane offered the sage advice: “Use a picture. It’s worth a thousand words.”


Suan Zao Ren Tang (SZRT) and  Zhi Zi Chi Tang  for improving sleep quality and anxiety states with four indices of Polysomnography (PSG), the Insomnia Severity Index (ISI), the Pittsburgh Sleep Quality Index (PSQI), and the Self Rating Anxiety Scale (SAS).  Methods. A randomized, parallel-controlled trial compared SZR-ZZC to lorazepam tablet in insomniacs with anxiety. Patients were randomized to the SZR-ZZC treatment group (n = 60) and the lorazepam tablet treatment group (n = 59). Results. SZR-ZZC significantly improved scores on all four treatment indices. Compared with lorazepam, treatment with SZR-ZZC resulted in a significant reduction in the ISI (P = 0.029), the PSQI (P = 0.017), and wake after sleep onset  scores and improved sleep architecture (P = 0.000–0.003) after a 4-week treatment period. Only one subject in the SZR-ZZC group experienced adverse side effects. Conclusion. Treatment with SZR-ZZC for 4 weeks appears to be a relatively safe and effective complementary therapeutic option when aiming to improve sleep quality and anxiety in insomniacs with anxiety.Insomnia is a serious worldwide health problem that is often comorbid with anxiety. The purpose of the present study was to evaluate the efficacy of a Chinese formula containing  Insomnia not only is one of the most prevalent sleep disorders among the general population, but also presents a significant challenge to the maintenance of one's health. In 2002, approximately 10% of the world's population suffered from chronic or persistent insomnia . In factThe conventional treatments for insomnia include GABA-A receptor modulators and histamine receptor antagonists, but if an insomnia patient presents with anxiety, an anxiolytic or antidepressant drug may also be administered . In gene Suan Zao Ren Tang (SZRT) and Zhi Zi Chi Tang (ZZCT). SZRT and ZZCT have been used to treat insomnia separately for centuries. They were first documented by Zhong-jing Zhang in approximately 210 A.D. in the classic Chinese text Jin Gui Yao Lve (Synopsis of Prescriptions of the Golden Chamber). SZRT is a blend of five medicinal Chinese herbs including Semen Zizyphi Spinosae (Suanzaoren), Sclerotium Poriae Cocos (Fuling), Radix Ligustici Chuanxiong (Chuanxiong), Rhizoma Anemarrhena (Zhimu), and Radix Glycyrrhizae (Gancao), while ZZCT is a combination of the two following dried raw materials from Gardenia Jasminoides fruit (Zhi zi) and fermented soybeans  and performed by the researchers of this study (deputy director of the physician and above). Additionally, each subject was interviewed regarding their medical history and completed a clinical examination that included the Self-Rating Anxiety Scale (SAS), Pittsburgh Sleep Quality Index (PSQI), and Insomnia Severity Index (ISI).The inclusion criteria for the present study were patients between 18 and 60 years of age, who struggled with insomnia for more than 6 months, who met the ICD-10 criteria for nonorganic insomnia, and who had an SAS score > 50, a PSQI score > 6, and an ISI score > 7. The exclusion criteria consisted of working nightshift; a past or current history of schizophrenia, bipolar, or other psychotic disorders; the presence of confounding diseases such as obstructive sleep apnea-hypopnea, restless leg syndrome, cardiac arrhythmia, acute myocardial infarction, or cancer; the use of pharmaceuticals within the previous 1 month that could affect melatonin, acetylcholine, glutamate, serotonin, norepinephrine, GABA, histamine, adenosine, or prostaglandins, and gestating or lactating females.All subjects who were in compliance with the inclusion and exclusion criteria were enrolled in the present study  and undeSubjects in the SZR-ZZC group received packages of the SZR-ZZC decoction and were instructed to drink one bag twice per day . Subjects in the control group were instructed to take two lorazepam tablets orally twice a day .The primary outcome parameters of the present study were the ISI and SAS scores, which were evaluated at baseline and after 2 and 4 weeks of treatment intervention. The secondary outcome parameters were the PSQI scores and PSG measures, which were completed at baseline and after treatment.The ISI is a self-report measure that has been used by a number of research teams over the past 20 years . It is aThe SAS is a self-completed 20-item questionnaire comprised of four parts: (1) anxiety and panic (items 1–4 and 20); (2) vestibular sensations ; (3) somatic control ; and (4) gastrointestinal/muscular sensations . Scores for each item range from 1 to 4 and the total of these scores is multiplied by 1.25 to obtain a standardized score (SS). The SAS has been widely used for the assessment of different populations [The PSQI is a self-rated questionnaire that assesses sleep quality and disturbances over a 1-month time interval and probes clinically important and patient-relevant symptoms in the areas of sleep quality and quantity. The PSQI consists of 19 self-rated items and five other-rated items. Of these 24 items, the scores of the 19th self-rated items and five other-rated items are not included in the total scores. The remaining 18 items are divided into seven subscales: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction . Each suPSG is the gold standard when assessing sleep quality, but it is used infrequently for research purposes due to its complexity and expense. In the present study, the PSG analyses were performed using the Sandman system and Embla N7000 60 recording system . The sleep stages were scored according to the criteria of Rechtschaffen and Kales  based onThroughout the trial, the subjects were monitored closely for adverse events (AEs) and a worsening of symptoms based on data from a blood cell analysis, urinalysis, and liver and kidney function tests, as well as patient complaints. If observed, the duration and severity of the symptoms, any action taken to alleviate these symptoms, and the outcomes were recorded.t-test with a significance level of < 0.05 considered to indicate statistical significance.The quantitative data are summarized using means ± standard deviations (SD) or 95% confidence intervals (CI). The qualitative data are described as proportions (as percentages), and the baseline characteristics of the two groups were compared using a two-sided Chi-squared test or a t-tests were used for intergroup comparisons, paired t-tests were used for intragroup comparisons, and a P value < 0.05 or less was considered to indicate statistical significance.The present analyses evaluated treatment effects according to the primary and secondary outcomes. The primary outcomes were changes in the mean differences of the ISI and SAS scores between the two groups at weeks 2 and 4. The secondary outcomes were subanalyses of the changes in scores from baseline to endpoint for each scored item on the PSQI, as well as changes in the PSG sleep parameters  and sleep architecture (slow wave sleep (SWS), REM) from baseline to endpoint. The statistical analyses for each outcome were performed by intention-to-treats (ITT) analysis using the SPSS 16.0 software package. Any missing values were imputed using the last-observation-carried-forward approach. Two-sample n = 172), not meeting the inclusion criteria (n = 124), and not having interest in participation (n = 68). The 119 enrolled subjects were assigned randomly to either the SZR-ZZC treatment group (n = 60) or the lorazepam tablet control group (n = 59). A total of 56 of SZR-ZZC subjects (93%) and 54 lorazepam subjects (92%) completed the entire 4-week study; the reasons for withdrawal are listed in The present study included 483 patients who were diagnosed with nonorganic insomnia coupled with anxiety. Of these initial 483 patients 364 were excluded from and 119 were enrolled in the present trial. The principal reasons for dismissal from the study were meeting the exclusion criteria (The randomization procedure was effective and that there were no significant differences between the two groups. The mean age of the subjects was 45 years (range: 18–60 years), and females comprised 67% of the SZR-ZZC group and 68% of the lorazepam group.Three patients withdrew from the study due to AEs: one case of diarrhoea in the SZR-ZZC group and two cases of dizziness in the lorazepam group. Further discussion regarding the possibility of diarrhoea caused by the SZR-ZZC formula is provided in P = 0.029). The SAS scores of subjects treated with SZR-ZZC were also decreased at weeks 2 and 4 (Subjects in SZR-ZZC group exhibited a significant reduction in ISI scores at weeks 2 and 4 of the treatment period . Additio 2 and 4 .P = 0.051), there were significant improvements on each of the PSG parameters and PSQI subscales after 4 weeks of treatment (P = 0.008), SWS (P < 0.001), REM (P = 0.003), and habitual sleep efficiency (P = 0.049).Except for the daytime dysfunction subscale  to treat insomnia patients with anxiety. Insomnia is frequently comorbid with anxiety , and theIn the present study, lorazepam tablets were used as the control drug, because the subjects were insomniacs with anxiety. The present findings suggest that SZR-ZZC improves sleep quality and that lorazepam may improve the anxiety status and global sleep quality of insomnia patients Figures . AlthougThe subjects had to withdraw from the SZR-ZZC treatment group due to AEs, primarily diarrhoea. After careful consideration of each case, the possibility that SZR-ZZC caused diarrhoea could not be disproven, and thus, one patient withdrew from the study, and one patient was treated subsequently with a modified SZR-ZZC formula. Therefore, TCM practitioners must be alert to the possibility that SZR-ZZC can cause adverse gastrointestinal effects if misused. The choice of treatment based on the differentiation of syndromes is an important feature of TCM theory, and thus, when a patient is prone to gastrointestinal issues or is spleen or stomach deficiency, TCM can prevent or cure these issues easily , 24. Suan Zao Ren is the most frequently used single herb for insomnia [The mechanisms underlying the efficacy of SZR-ZZC have yet to be fully characterized, but those of SZRT have been investigated by a number of studies. SZRT is very familiar to TCM practitioners, and there is a large amount of evidence supporting its beneficial effects on insomnia , 26. Dueinsomnia , but jujinsomnia . Althouginsomnia . Based oThis study possesses several limitations. First, the present study was conducted for only 4 weeks largely because the long-term use of lorazepam tablets may result in a tolerance to or dependency on the drug. Thus, it was determined that a 4-week treatment course was sufficient to observe its efficacy. Second, no long-term follow-up assessments were performed. In fact, after the 4-week treatment period, a majority of the participants shifted to consolidation therapy and no longer adhered strictly to the study protocol. Third, the present study was an exploratory trial which did not follow strict clinical practices and thus a more pragmatic trial is necessary to conform to TCM principles fully. In this case, the effects of a treatment intervention will more closely mirror those of a real clinical situation than findings from an exploratory trial .The present findings provide preliminary support for use of the SZR-ZZC formula to treat insomniacs with anxiety. SZR-ZZC appears to be a well-accepted and valuable alternative therapeutic option for improving sleep quality and anxiety. Further studies evaluating the safety and underlying mechanisms of action of SZR-ZZC are warranted.