How distressing is referral to colposcopy in cervical cancer screening?

Objective Referral for colposcopy because of abnormal Pap test results is likely to be distressing, but the extent and duration of these effects are unknown. We aimed to fill this gap. Methods We conducted a prospective observational study at two departments of Obstetrics and Gynecology (an academic and a non-academic setting). Women referred for colposcopy completed questionnaires before colposcopy, and at 1, 3, and 6 months afterwards. A reference group of 706 screen participants, aged 29-60 years old, was included and completed questionnaires once. Main outcome measures were generic health-related quality of life (HRQoL), assessed through the EQ-5D and the SF-12 physical and mental scores (PCS-12 and MCS-12); anxiety as assessed by STAI-6, and screen-specific anxiety as assessed by the psychological consequences questionnaire (PCQ). Results 154 women responded to the questionnaire, of whom 132 were included in the analyses. Histological results were CIN 1 in 17/115 women (15%) and CIN 2 + in 62 (54%). In 36 women (31%) there was no histologically confirmed neoplasia. Before colposcopy physical HRQoL scores were similar or slightly better than in the reference group, while mental HRQoL (MSC-12) and (screen-specific) anxiety were worse (p < 0.001). Irrespective of CIN-grades, anxiety washed out during follow-up (p < 0.001), with changes being clinically relevant. Conclusions Referral for gynecological evaluation because of abnormal PAP-test results was distressing. Anxiety - and not the physical burden of management - seemed to be the most bothersome to women. For all CIN-grades, distress disappeared over six months following colposcopy, suggesting a reassuring effect of gynecological mana

Season of Sampling and Season of Birth Influence Serotonin Metabolite Levels in Human Cerebrospinal Fluid

BACKGROUND: Animal studies have revealed seasonal patterns in cerebrospinal fluid (CSF) monoamine (MA) turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large set of healthy adults. METHODOLOGY/PRINCIPAL FINDINGS: Standardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG) were measured using high performance liquid chromatography (HPLC). Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75). The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050), with predicted maximum (PC(max)) and minimum (PC(min)) concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PC(max) = 172 and PC(min) = 126). The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations. CONCLUSION: In subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall

Assessment of Chlamydia trachomatis infection of semen specimens by ligase chain reaction

Diagnostic potential of the Chlamydia trachomatis ligase chain reaction system (LCx) to assess the presence of C. trachomatis in urine and semen specimens was evaluated. Paired urine and semen specimens from 153 asymptomatic male partners of subfertile couples attending our Center for Reproductive Medicine were examined by LCx. As controls, 19 semen samples from four donors who were participating in the programme for artificial insemination were used. Of these, 12 samples had previously been shown to be C. trachomatis-positive by an in-house PCR. C. trachomatis was detected by LCx in seven of 153 (5 %) urine samples. None of the 153 semen samples tested positive by LCx. Also, none of the 12 C. trachomatis-containing control semen samples were positive by LCx. By in-house PCR, seven urine specimens and two of 153 (1 %) semen samples tested positive. The corresponding urine samples of these male partners were also C. trachomatis-positive, as well as the 12 C. trachomatis-containing samples from donors. In conclusion, LCx is not sensitive enough to assess the presence of C. trachomatis in semen specimens; therefore, this method is not recommended to routinely screen semen specimens from donors who participate in programmes for artificial insemination or male partners of subfertile couples for C. trachomati

PCR Assessment of Chlamydia trachomatis Infection of Semen Specimens Processed for Artificial Insemination

In order to ascertain the microbiological quality of stored semen specimens processed for artificial insemination by a donor (AID), we developed a PCR assay targeting the chlamydial plasmid to detect Chlamydia trachomatis in semen. The lower limit of detection of this assay corresponded to 2.5 to 5 elementary bodies per μl of semen. A total of 669 cryopreserved ejaculates from 97 asymptomatic donors were tested for C. trachomatis infection. Twelve ejaculates, originating from four donors, were found to be positive, indicating a 4% prevalence of C. trachomatis infection among the donor population studied. Cross-contamination between the cryopreserved specimens in the storage container was studied by typing using sequence analysis of PCR-amplified omp1 genes of the strains. Two donors were infected with serovar E, one was infected with serovar F, and one was infected with serovar K. For two donors, the duration of C. trachomatis positivity could be assessed. One donor donated C. trachomatis-positive semen for at least 4 successive months, and the other did so for at least 16 months. The occurrence of C. trachomatis infection in cryopreserved donor semen indicates that ejaculates from donors not tested for a C. trachomatis infection just prior to donation should be tested for infection by a direct test such as the PCR described here. Direct testing of semen specimens will detect not only donors with an active infection but also C. trachomatis-infected ejaculates already stored and will thus improve the microbiological quality of AID, since discrepancies in the presence of C. trachomatis in urine and semen specimens have been reported

Factors affecting inter-individual variability in endoxifen concentrations in patients with breast cancer: results from the prospective TOTAM trial

Introduction: Endoxifen—the principal metabolite of tamoxifen—is subject to a high inter-individual variability in serum concentration. Numerous attempts have been made to explain this, but thus far only with limited success. By applying predictive modeling, we aimed to identify factors that determine the inter-individual variability. Our purpose was to develop a prediction model for endoxifen concentrations, as a strategy to individualize tamoxifen treatment by model-informed dosing in order to prevent subtherapeutic exposure (endoxifen < 16 nmol/L) and thus potential failure of therapy. Methods: Tamoxifen pharmacokinetics with demographic and pharmacogenetic data of 303 participants of the prospective TOTAM study were used. The inter-individual variability in endoxifen was analyzed according to multiple regression techniques in combination with multiple imputations to adjust for missing data and bootstrapping to adjust for the over-optimism of parameter estimates used for internal model validation. Results: Key predictors of endoxifen concentration were CYP2D6 genotype, age and weight, explaining altogether an average-based optimism corrected 57% (95% CI 0.49–0.64) of the inter-individual variability. CYP2D6 genotype explained 54% of the variability. The remaining 3% could be explained by age and weight. Predictors of risk for subtherapeutic endoxifen (< 16 nmol/L) were CYP2D6 genotype and age. The model showed an optimism-corrected discrimination of 90% (95% CI 0.86–0.95) and sensitivity and specificity of 66% and 98%, respectively. Consecutively, there is a high probability of misclassifying patients with subtherapeutic endoxifen concentrations based on the prediction rule. Conclusion: The inter-individual variability of endoxifen concentration could largely be explained by CYP2D6 genotype and for a small proportion by age and weight. The model showed a sensitivity and specificity of 66 and 98%, respectively, indicating a high probability of (misclassification) error for the patients with subtherapeutic endoxifen concentrations (< 16 nmol/L). The remaining unexplained inter-individual variability is still high and therefore model-informed tamoxifen dosing should be accompanied by therapeutic drug monitoring

Quantification of mitral valve regurgitation from 4d flow mri using semiautomated flow tracking

Purpose: To compare the accuracy of semiautomated flow tracking with that of semiautomated valve tracking in the quantification of mitral valve (MV) regurgitation from clinical four-dimensional (4D) flow MRI data obtained in patients with mild, moderate, or severe MV regurgitation. Materials and Methods: The 4D flow MRI data were retrospectively collected from 30 patients (21 men; mean age, 61 years ± 10 [stan-dard deviation]) who underwent 4D flow MRI from 2006 to 2016. Ten patients had mild MV regurgitation, nine had moderate MV regurgitation, and 11 had severe MV regurgitation, as diagnosed by using semiquantitative echocardiography. The regurgitant volume (Rvol) across the MV was obtained using three methods: indirect quantification of Rvol (RvolINDIRECT ), semiautomated quantification of Rvol using valve tracking (RvolVALVE ), and semiautomated quantification of Rvol using flow tracking (RvolFLOW ). A second observer repeated the measurements. Aortic valve flow was quantified as well to test for intervalve consistency. The Wilcoxon signed rank test, orthogonal regression, Bland-Altman analysis, and coefficients of variation were used to assess agreement among measurements and between observers. Results: RvolFLOW was higher (median, 24.8 mL; interquartile range [IQR], 14.3–45.7 mL) than RvolVALVE (median, 9.9 mL; IQR, 6.0–16.9 mL; P < .001). Both RvolFLOW and RvolVALVE differed significantly from RvolINDIRECT (median, 19.1 mL; IQR, 4.1–47.5 mL; P = .03). RvolFLOW agreed more with RvolINDIRECT (ŷ = 0.78x + 12, r = 0.88) than with RvolVALVE (ŷ = 0.16x + 8.1, r = 0.53). Bland-Altman analysis revealed underestimation of RvolVALVE in severe MV regurgitation. Interobserver agreement was excellent for RvolFLOW (r = 0.95, coefficient of variation = 27%) and moderate for RvolVALVE (r = 0.72, coefficient of variation = 57%). Orthogonal regression demonstrated better intervalve consistency for flow tracking (ŷ = 1.2x-13.4, r = 0.82) than for valve tracking (ŷ = 2.7x-92.4, r = 0.67). Conclusion: Flow tracking enables more accurate 4D flow MRI–derived MV regurgitation quantification than valve tracking in terms of agreement with indirect quantification and intervalve consistency, particularly in severe MV regurgitation

Quantification of mitral valve regurgitation from 4d flow mri using semiautomated flow tracking

Purpose: To compare the accuracy of semiautomated flow tracking with that of semiautomated valve tracking in the quantification of mitral valve (MV) regurgitation from clinical four-dimensional (4D) flow MRI data obtained in patients with mild, moderate, or severe MV regurgitation. Materials and Methods: The 4D flow MRI data were retrospectively collected from 30 patients (21 men; mean age, 61 years ± 10 [stan-dard deviation]) who underwent 4D flow MRI from 2006 to 2016. Ten patients had mild MV regurgitation, nine had moderate MV regurgitation, and 11 had severe MV regurgitation, as diagnosed by using semiquantitative echocardiography. The regurgitant volume (Rvol) across the MV was obtained using three methods: indirect quantification of Rvol (RvolINDIRECT ), semiautomated quantification of Rvol using valve tracking (RvolVALVE ), and semiautomated quantification of Rvol using flow tracking (RvolFLOW ). A second observer repeated the measurements. Aortic valve flow was quantified as well to test for intervalve consistency. The Wilcoxon signed rank test, orthogonal regression, Bland-Altman analysis, and coefficients of variation were used to assess agreement among measurements and between observers. Results: RvolFLOW was higher (median, 24.8 mL; interquartile range [IQR], 14.3–45.7 mL) than RvolVALVE (median, 9.9 mL; IQR, 6.0–16.9 mL; P < .001). Both RvolFLOW and RvolVALVE differed significantly from RvolINDIRECT (median, 19.1 mL; IQR, 4.1–47.5 mL; P = .03). RvolFLOW agreed more with RvolINDIRECT (ŷ = 0.78x + 12, r = 0.88) than with RvolVALVE (ŷ = 0.16x + 8.1, r = 0.53). Bland-Altman analysis revealed underestimation of RvolVALVE in severe MV regurgitation. Interobserver agreement was excellent for RvolFLOW (r = 0.95, coefficient of variation = 27%) and moderate for RvolVALVE (r = 0.72, coefficient of variation = 57%). Orthogonal regression demonstrated better intervalve consistency for flow tracking (ŷ = 1.2x-13.4, r = 0.82) than for valve tracking (ŷ = 2.7x-92.4, r = 0.67). Conclusion: Flow tracking enables more accurate 4D flow MRI–derived MV regurgitation quantification than valve tracking in terms of agreement with indirect quantification and intervalve consistency, particularly in severe MV regurgitation

Psychological impact of referral to an oncology hospital on patients with an ovarian mass

OBJECTIVES: In patients with an ovarian mass, a risk of malignancy assessment is used to decide whether referral to an oncology hospital is indicated. Risk assessment strategies do not perform optimally, resulting in either referral of patients with a benign mass or patients with a malignant mass not being referred. This process may affect the psychological well-being of patients. We evaluated cancer-specific distress during work-up for an ovarian mass, and patients' perceptions during work-up, referral, and treatment. METHODS: Patients with an ovarian mass scheduled for surgery were enrolled. Using questionnaires we measured (1) cancer-specific distress using the cancer worry scale, (2) patients' preferences regarding referral (evaluated pre-operatively), and (3) patients' experiences with work-up and treatment (evaluated post-operatively). A cancer worry scale score of ≥14 was considered as clinically significant cancer-specific distress. RESULTS: A total of 417 patients were included, of whom 220 (53%) were treated at a general hospital and 197 (47%) at an oncology hospital. Overall, 57% had a cancer worry scale score of ≥14 and this was higher in referred patients (69%) than in patients treated at a general hospital (43%). 53% of the patients stated that the cancer risk should not be higher than 25% to undergo surgery at a general hospital. 96% of all patients were satisfied with the overall work-up and treatment. No difference in satisfaction was observed between patients correctly (not) referred and patients incorrectly (not) referred. CONCLUSIONS: Relatively many patients with an ovarian mass experienced high cancer-specific distress during work-up. Nevertheless, patients were satisfied with the treatment, regardless of the final diagnosis and the location of treatment. Moreover, patients preferred to be referred even if there was only a relatively low probability of having ovarian cancer. Patients' preferences should be taken into account when deciding on optimal cut-offs for risk assessment strategies