Comparison of the performances of the ADXBLADDER test and urinary cytology in the follow-up of non-muscle-invasive bladder cancer: a blinded prospective multicentric study.

OBJECTIVE: To compare directly the performance of the ADXBLADDER test with that of cytology in the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences. BACKGROUND: ADXBLADDER is a urine test based on the detection of MCM5, a DNA licensing factor expressed in all cells capable of dividing. Expression is usually restricted to the basal stem cell compartment; however, in malignancy, MCM5-expressing cells can be found throughout the epithelium. Detection of MCM5 in urine sediment can be indicative of the presence of a bladder tumour. PATIENTS AND METHODS: A multicentre prospective, blinded study was carried out from August 2017 and July 2019 at 21 European Union centres, 14 of which collected matching cytology data. Urine was collected from patients prior to cystoscopy. Urine cytology and ADXBLADDER were performed and compared to the diagnosis obtained by cystoscopy. The performance of cytology and ADXBLADDER were then compared. RESULTS: The overall performance of ADXBLADDER demonstrated a sensitivity of 51.9%, a specificity of 66.4%, and a negative predictive value (NPV) of 92%. The sensitivity of ADXBLADDER for low- and high-grade recurrences was 44.1% and 58.8%, respectively. By contrast, cytology sensitivity was 16.7%, specificity was 98% and NPV was 90.7%. Cytology sensitivity for both low- and high-grade disease was 17.6%. CONCLUSIONS: ADXBLADDER detection of both low- and high-grade NMIBC recurrence is superior to that of cytology, with ADXBLADDER able to exclude the presence of high-grade recurrence in 97.8% of cases compared to 97.1% with cytology. These results show that ADXBLADDER has promise as a more reliable alternative to urine cytology in the follow-up of NMIBC.

Diagnostic Accuracy of MCM5 for the Detection of Recurrence in Nonmuscle Invasive Bladder Cancer Followup: A Blinded, Prospective Cohort, Multicenter European Study.

PURPOSE: Detection of MCM5 containing cells in urine has been shown to be indicative of the presence of a bladder tumor on primary diagnosis. In this study we evaluate diagnostic performance of ADXBLADDER in patients undergoing cystoscopic surveillance in nonmuscle invasive bladder cancer followup. MATERIALS AND METHODS: A multicenter prospective blinded study was performed at 21 European centers with patients undergoing cystoscopy for nonmuscle invasive bladder cancer surveillance, diagnosed in the preceding 2 years. Urine was collected from all eligible patients and ADXBLADDER-MCM5 testing was performed. Performance characteristics were calculated by comparing MCM5 results to the outcome of cystoscopy plus pathological assessment. RESULTS: Of 1,431 eligible patients enrolled 127 were diagnosed with a bladder cancer recurrence. The overall sensitivity for the ADXBLADDER-MCM5 test in detecting bladder cancer recurrence was 44.9% (95% CI 36.1-54) with a 75.6% sensitivity for nonpTaLG tumors (95% CI 59.7-87.6). Specificity was 71.1% (95% CI 68.5-73.5). The overall negative predictive value was 93% (95% CI 91.2-94.5). However, ADXBLADDER was able to rule out the presence of a nonpTaLG recurrent tumor with a negative predictive value of 99.0% (95% CI 98.2-99.5). No statistically significant differences in the performance of ADXBLADDER were observed as a result of age or sex. CONCLUSIONS: This large blinded prospective study demonstrates that in the followup of patients with nonmuscle invasive bladder cancer ADXBLADDER is able to exclude the presence of the most aggressive tumors with a negative predictive value of 99%. These results indicate that ADXBLADDER could be incorporated in the followup strategy of nonmuscle invasive bladder cancer.

Impact of forearm fatigue on the postural response to an externally initiated, predictable perturbation.

PURPOSE: The objective was to examine the impact of non-postural muscle fatigue on anticipatory postural control, during postural perturbations induced by platform translations. The experimental setup investigated the central changes caused by fatigue without the potential confounding influence of peripheral fatigue within the postural muscles. METHODS: Fatigue induced in forearm muscles by a maximal handgrip contraction has been previously shown to influence forearm force production for 10 min, reduce ankle plantarflexion force for 1 min and create measureable central fatigue for 30 s. The peak-to-peak anterior/posterior displacement of the center of mass and center of pressure (COP) and muscle activity were measured during the postural perturbation tasks performed before the fatigue protocol and for 10 min post-fatigue. RESULTS: The fatigue protocol decreased the peak-to-peak COP displacement from 128.0 ± 12.3 mm pre-fatigue to 81.9 ± 7.8 mm post-fatigue during the forwards platform translation (p < 0.05) and from 133.8 ± 12.0 to 89.2 ± 7.9 mm during the backwards translation (p < 0.05). The fatigue protocol also caused the tibialis anterior (TA pre-fatigue = -0.25 ± 0.04 s, TA post-fatigue = -0.41 ± 0.02 s, p = 0.001) and medial gastrocnemius muscles (MG pre-fatigue = -0.39 ± 0.03 s, MG post-fatigue = -0.48 ± 0.02 s, p = 0.028) to be recruited significantly earlier relative to the pre-fatigue condition. CONCLUSION: This experimental setup ensured that peripheral fatigue did not develop in the postural muscles; therefore, a general fatigued-induced modification of the postural strategy is proposed as the origin of the postural changes and delayed recovery.

Fatiguing handgrip exercise alters maximal force-generating capacity of plantar-flexors.

Exercise-induced fatigue causes changes within the central nervous system that decrease force production capacity in fatigued muscles. The impact on unrelated, non-exercised muscle performance is still unclear. The primary aim of this study was to examine the impact of a bilateral forearm muscle contraction on the motor function of the distal and unrelated ankle plantar-flexor muscles. The secondary aim was to compare the impact of maximal and submaximal forearm contractions on the non-fatigued ankle plantar-flexor muscles. Maximal voluntary contractions (MVC) of the forearm and ankle plantar-flexor muscles as well as voluntary activation (VA) and twitch torque of the ankle plantar-flexor muscles were assessed pre-fatigue and throughout a 10-min recovery period. Maximal (100 % MVC) and submaximal (30 % MVC) sustained isometric handgrip contractions caused a decreased handgrip MVC (to 49.3 ± 15.4 and 45.4 ± 11.4 % of the initial MVC for maximal and submaximal contraction, respectively) that remained throughout the 10-min recovery period. The fatigue protocols also caused a decreased ankle plantar-flexor MVC (to 77 ± 8.3 and 92.4 ± 6.2 % of pre-fatigue MVC for maximal and submaximal contraction, respectively) and VA (to 84.3 ± 15.7 and 97.7 ± 16.1 % of pre-fatigue VA for maximal and submaximal contraction, respectively). These results suggest central fatigue created by the fatiguing handgrip contraction translated to the performance of the non-exercised ankle muscles. Our results also show that the maximal fatigue protocol affected ankle plantar-flexor MVC and VA more severely than the submaximal protocol, highlighting the task-specificity of neuromuscular fatigue.

Impact of ankle muscle fatigue and recovery on the anticipatory postural adjustments to externally initiated perturbations in dynamic postural control.

The aim of this study was to determine whether and how young participants modulate their postural response to compensate for postural muscle fatigue during predictable but externally initiated continuous and oscillatory perturbations. Twelve participants performed ten postural trials before and after an ankle muscle fatigue protocol. Each postural trial was 1 min long and consisted of continuous backward and forward oscillations of the platform. Fatigue was induced by intermittent, bilateral isometric contractions of the ankle plantar- and dorsiflexors until the force production was reduced to 50 % of the pre-fatigue maximal voluntary contraction. Changes in the center of mass (COM) displacement, center of pressure (COP) displacement, and anterior-posterior location of the COP within the base of support were quantified as well as the activity of the tibialis anterior (TA), medial gastrocnemius (MG), quadriceps, and hamstring. All participants demonstrated postural stability post-fatigue by maintaining the displacement of their COM. Everyone also demonstrated a general forward shift in the anterior-posterior location of the COP within the base of support; however, two distinct postural modifications, corresponding to either an immediate fatigue-induced increase or decrease in the COP displacement during the backward platform translation, were recorded immediately post-fatigue. The changes in muscle onset latencies lasted beyond the recovery of the force production of the fatigued postural muscles. By 10 min post-fatigue, the participants showed a decrease in the COP displacement as well as an earlier activation of the postural muscles and an increased TA/MG co-activation relative to pre-fatigue. Although different strategies were used, the participants were able to adjust to and overcome postural muscle fatigue and remain balanced during the postural perturbations regardless of the direction of the platform movement. These adjustments lasted beyond the recovery of the ankle muscle force production indicating that they may be part of a centrally mediated protective response as opposed to a peripherally induced limitation to performance.

Reducing the Frequency of Follow-up Cystoscopy in Low-grade pTa Non-muscle-invasive Bladder Cancer Using the ADXBLADDER Biomarker.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is one of the most expensive cancers owing to frequent follow-up cystoscopies for detection of recurrence. OBJECTIVE: To assess if the noninvasive ADXBLADDER urine test could permit a less intensive surveillance schedule for patients with low-grade (LG) pTa tumor without carcinoma in situ (CIS) at the previous diagnosis. DESIGN, SETTING, AND PARTICIPANTS: In a prospective, double-blind, multicenter study, 629 patients underwent follow-up cystoscopy, transurethral resection of bladder tumor/biopsy of suspect lesions, and ADXBLADDER testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Diagnostic test accuracy and decision curve analysis were used to evaluate the impact of ADXBLADDER on decision-making on whether to perform follow-up cystoscopy. The primary endpoint was the negative predictive value (NPV) of ADXBLADDER for detection of high-grade and/or CIS (HG/CIS) recurrence and its impact on reducing unnecessary cystoscopies. RESULTS AND LIMITATIONS: ADXBLADDER had sensitivity of 66.7% (95% confidence interval [CI] 34.9-90.1%) and an NPV of 99.15% (95% CI 97.8-99.8%) for detection of HG/CIS recurrence. The probability of HG/CIS recurrence was 5.0% for ADXBLADDER-positive patients and 0.85% for ADXBLADDER-negative patients. For HG/CIS recurrence threshold probabilities between 0.85% and 5.0%, ADXBLADDER yields a net benefit with omission of cystoscopy for ADXBLADDER-negative patients. The corresponding net reduction in unnecessary cystoscopies ranges from 11 to 62 per 100 patients. CONCLUSIONS: Patients with LG pTa tumor at the previous diagnosis, for which the risk of HG/CIS recurrence is low and the ADXBLADDER NPV for ruling out HG/CIS recurrence is 99.15%, are ideally suited for a less intensive, personalized follow-up surveillance strategy using ADXBLADDER, with omission of cystoscopy for ADXBLADDER-negative patients. PATIENT SUMMARY: ADXBLADDER is a urine test that can predict the probability of recurrence of bladder cancer. Patients diagnosed with low-grade cancer confined to the bladder mucosa are ideally suited for less intensive follow-up using this test, which could reduce unnecessary cystoscopy procedures for those with a negative result, potentially improve quality of life, and reduce overall health care costs.

Neuromuscular fatigue induced by alternating isometric contractions of the ankle plantar and dorsiflexors.

Ankle muscle activity is important in regulating postural control as well as more complex movement tasks. Fatigue of these muscles clearly influences postural stability; however, the mechanisms responsible for this change have not been well characterized. In this study the fatigue produced in the plantar (PF) and dorsiflexors (DF) during intermittent, isometric contractions was examined and the recovery process was monitored for ten minutes post-fatigue. Fifteen healthy participants alternated between isometric PF and DF contractions until the torque was reduced to >50% of the pre-fatigue maximal voluntary contraction level in both directions. Peripheral fatigue was identified by measuring the change in the twitch torque and M-wave amplitude pre and post-fatigue. Central fatigue was determined by comparing the level of voluntary activation in the PF and DF between pre and post-fatigue. The fatigue protocol decreased the torque production in PF and DF to similar levels; however, the characteristics and recovery of the fatigue were different for the two muscle groups. This study demonstrates that although the torque produced by two antagonist muscles can be reduced to the same level, the mechanisms responsible for this change may not be similar and therefore may not impact motor tasks in the same way.

Prospective correlation between serum relaxin concentration and anterior cruciate ligament tears among elite collegiate female athletes.

BACKGROUND: The female anterior cruciate ligament may be more susceptible to injury than the male anterior cruciate ligament because of the gender-specific expression of receptors for relaxin, a collagenolytic hormone that promotes remodeling of the anterior cruciate ligament. PURPOSE: This study was undertaken to investigate whether collegiate female athletes with elevated serum relaxin concentrations (SRC) sustain anterior cruciate ligament tears at an increased rate compared with those with lower SRC. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: From 2005 to 2010, 143 Division I female athletes from 2 universities participating in sports at high risk for anterior cruciate ligament tears (basketball, lacrosse, field hockey, soccer, gymnastics, and volleyball) were recruited to participate. Questionnaires and urine luteinizing hormone (LH) tests were used to determine participants' anterior cruciate ligament injury and menstrual history and to identify their mid-luteal phase or projected cycle days 21 to 24. Serum samples were obtained for progesterone and relaxin ELISA (enzyme-linked immunosorbent assay) analysis. Participants were monitored for anterior cruciate ligament injury over their 4-year National Collegiate Athletic Association athletic career. RESULTS: A total of 128 participants completed the study and were eligible for data analysis. The cumulative incidence of complete anterior cruciate ligament tear over the 4-year study period was 21.9%, and varied significantly by sport (P < .001). The mean SRC for athletes with anterior cruciate ligament tears (6.0 ± 8.1 pg/mL) was significantly higher than that for those without anterior cruciate ligament tears (1.8 ± 3.4 pg/mL; P = .013). In subgroup analysis of the 46 athletes who had detectable SRC, the cumulative incidence of anterior cruciate ligament tear was 14 of 46 (30.4%); the mean SRC among athletes with anterior cruciate ligament tears (14 of 46) was 12.1 ± 7.7 pg/mL and without anterior cruciate ligament tears (32 of 46), 5.7 ± 3.6 pg/mL (P = .002). When 6.0 pg/mL was set as the SRC cutoff for screening athletes for risk of anterior cruciate ligament tear in the subgroup with detectable relaxin levels, the test had 71% sensitivity, 69% specificity, 52% positive predictive value, 88% negative predictive value, and a relative risk of 4.4. These values were significant by χ(2) test (P = .003) and receiver operating characteristic analysis (P = .002). CONCLUSION: Elite female athletes with anterior cruciate ligament tears have higher SRC than those without tears. Those with an SRC greater than 6.0 pg/mL had over 4 times increased risk for a tear. CLINICAL RELEVANCE: Females with higher serum relaxin levels may be at increased risk for anterior cruciate ligament tears. Further investigation of the clinical utility of SRC testing is warranted.

Trends in serum relaxin concentration among elite collegiate female athletes.

PURPOSE: This study was designed to investigate the relationship between serum relaxin concentration (SRC) and menstrual history and hormonal contraceptive use among elite collegiate female athletes. Evaluation of SRC in athletes is necessary, because relaxin has been associated with increased knee joint laxity and decreased anterior cruciate ligament (ACL) strength in animal models. METHODS: National Collegiate Athletic Association Division I female athletes participating in sports at high risk for ACL tears - basketball, field hockey, gymnastics, lacrosse, soccer, and volleyball - were invited to participate. All participants completed a questionnaire about their menstrual history and hormonal contraceptive use. Venipuncture was performed to obtain samples of serum progesterone and relaxin. Samples were obtained during the mid-luteal phase from ovulating participants, and between the actual or projected cycle days 21 to 24, from anovulatory participants. Serum concentration of relaxin and progesterone was determined by ELISA and the data were analyzed using SPSS statistical software with significance set at P = 0.05. RESULTS: 169 female athletes participated. The mean SRC among all participants was 3.08 ± 6.66 pg/mL). The mean SRC differed significantly between those participants using hormonal contraceptives (1.41 pg/mL) and those not using hormonal contraceptives (3.08 pg/mL, P = 0.002). Mean SRC was lowest among amenorrheic participants (1.02 pg/mL) and highest among oligomenorrheic participants (3.71 pg/mL) and eumenorrheic participants (3.06 pg/mL); these differences were not significant (P = 0.53). Mean serum progesterone concentration (SPC) differed significantly between those participants using hormonal contraceptives (2.80 ng/mL), and those not using hormonal contraceptives (6.99 ng/mL, P < 0.0001). CONCLUSIONS: There is a positive correlation between serum progesterone and SRC and an attenuation of SRC with hormonal contraceptive use. Our results underscore the significant role that hormonal contraceptives can play in decreasing relaxin levels, if future investigations establish a link between relaxin levels and ligamentous injury among female athletes.