Role of Hysteropexy in the Management of Pelvic Organ Prolapse.

PURPOSE OF REVIEW: To discuss considerations for hysteropexy for apical pelvic organ prolapse (POP) and summarize available literature comparing various hysteropexy techniques to analogous procedures involving hysterectomy. RECENT FINDINGS: Hysteropexy for apical POP has increased in popularity in recent years, although anatomic factors and gynecologic cancer risk must be taken into account. Native tissue hysteropexy options include the LeFort colpocleisis, sacrospinous hysteropexy, and uterosacral hysteropexy. Although vaginal mesh was banned by the Food and Drug Administration in 2019, abdominal mesh sacrohysteropexy done either open or laparoscopically remains an option in the USA. Overall, short-term prolapse outcomes appear to be comparable between uterus-sparing approaches and hysterectomy, with less blood loss and shorter operating room time observed with the uterine-sparing approaches, although long-term outcome data remains variable and limited. Uterine-sparing apical POP repair may be offered to appropriate patients without certain risk factors, although longer-term data will be required to evaluate durability.

Results of the patient report of intermittent catheterization experience (PRICE) study.

AIMS: Patient satisfaction is paramount to health-related quality of life (HR-QoL) outcomes. High quality, quantitative data from the US describing patients' actual experiences, difficulties, and HR-QoL while on an intermittent self-catheterization (ISC) regimen is very scarce. Our objective was to better understand patient practices with and attitudes towards ISC. METHODS: This is a cross-sectional, multi-centered, clinical study of adult men and women performing ISC in the United States. Data collected included demographics, medical history, catheter characteristics, specific self-catheterization habits and two validated HR-QoL questionnaires: The Intermittent Self-Catheterization Questionnaire (ISC-Q) and the Intermittent Catheterization Difficulty Questionnaire (ICDQ). RESULTS: Two hundred participants were recruited from six sites; 70.0% were male, 73.5% were Caucasian with a median age was 51.0 years (range 19-90 years). The ISC-Q showed that the vast majority of participants reported ease with ISC (82.0% satisfaction score) had confidence in their ability to perform ISC (91.9% satisfaction score); yet, many felt self-conscious about doing so (58.3% satisfaction score) and had concerns about long-term adverse effects (58.1% satisfaction score). The ICDQ indicated little to no difficulty for most participants with all routine ISC practices. A small minority of participants reported some difficulty with a "blocking sensation" during initiation of catheterization, leg spasticity, and painful catheterization. Multivariate linear regression results are also reported. DISCUSSION/CONCLUSION: Participants are confident with ISC and have little overall difficulty, which may be a product of successful education and/or catheter design. urinary tract infections (UTIs) were common (yet variable) and may contribute to the noted long-term ISC concerns. Limitations exist including various selection biases leading to concerns of external validity. Future educational interventions in this population may further improve HR-QoL, optimize UTIs prevention, and diminish concerns with long-term ISC.

Economic Considerations in the Management of Nephrolithiasis.

PURPOSE OF REVIEW: From health systems to individuals, nephrolithiasis is economically burdensome. The aim of the current paper is to characterize the financial burden of disease associated with nephrolithiasis with an emphasis on investigating treatment modality economic efficiency. RECENT FINDINGS: For small volume practices and cases where there is high risk of scope damage, disposable flexible ureteroscope utilization seems to provide economic efficiency. The rise in global prevalence of stone disease is a large contributing factor to increasing costs associated with nephrolithiasis. A large proportion of costs from kidney stones stem from ED visits and inpatient care. There are opportunities to save money by transitioning care to outpatient settings in scenarios that allow such transition. Metaphylaxis and prevention strategies are effective at lowering costs in properly selected patient populations. Flexible ureteroscopy and percutaneous nephrolithotomy (PCNL) are the most economically efficient methods of surgically treating stone disease, with PCNL being reserved for large and lower pole stones. Time off work and other indirect costs, while challenging to quantify, are important considerations in the economics of nephrolithiasis.

S-opsin knockout mice with the endogenous M-opsin gene replaced by an L-opsin variant.

Specific variants of human long-wavelength (L) and middle-wavelength (M) cone opsin genes have recently been associated with a variety of vision disorders caused by cone malfunction, including red-green color vision deficiency, blue cone monochromacy, myopia, and cone dystrophy. Strikingly, unlike disease-causing mutations in rhodopsin, most of the cone opsin alleles that are associated with vision disorders do not have deleterious point mutations. Instead, specific combinations of normal polymorphisms that arose by genetic recombination between the genes encoding L and M opsins appear to cause disease. Knockout/knock-in mice promise to make it possible to study how these deleterious cone opsin variants affect the structure, function, and viability of the cone photoreceptors. Ideally, we would like to evaluate different variants that cause vision disorders in humans against a control pigment that is not associated with vision disorders, and each variant should be expressed as the sole photopigment in each mouse cone, as is the case in humans. To evaluate the feasibility of this approach, we created a line of mice to serve as the control in the analysis of disease-causing mutations by replacing exon 2 through 6 of the mouse M-opsin gene with the corresponding cDNA for a human L-opsin variant that is associated with normal vision. Experiments reported here establish that the resulting pigment, which differs from the endogenous mouse M opsin at 35 amino acid positions, functions normally in mouse cones. This pigment was evaluated in mice with and without coexpression of the mouse short wavelength (S) opsin. Here, the creation and validation of two lines of genetically engineered mice that can be used to study disease-causing variants of human L/M-opsins, in vivo, are described.

Pathologic and survival outcomes following radical cystectomy for "progressive" and "de novo" muscle-invasive bladder cancer: A meta-analysis stratified by neoadjuvant chemotherapy status.

OBJECTIVE: To compare survival and pathologic outcomes in patients with progressive muscle-invasive bladder cancer (pgMIBC) and de novo muscle-invasive bladder cancer (dnMIBC) after radical cystectomy (RC), with a focus on the role of neoadjuvant chemotherapy (NAC). METHODS: A comprehensive literature search was conducted on PubMed and EMBASE databases to identify studies comparing pgMIBC to dnMIBC. Survival outcomes, including cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS), and pathologic outcomes (rates of ≤pT1, pT0, pT3/T4, and pN+ disease) were compared between pgMIBC and dnMIBC. RESULTS: The analysis included 19 cohorts from 16 studies, categorized into 3 groups based on NAC use: 1. patients who underwent RC and were all treated with NAC (RC + NAC only group); 2. patients who underwent RC, with or without NAC (RC +/- NAC group); 3. patients who only underwent RC without NAC (RC only group). Compared to dnMIBC, pgMIBC demonstrated worse outcomes for CSS, OS, and RFS. In the RC + NAC only group (3 cohorts), the hazard ratio (HR) for CSS was 1.52 (95% confidence interval [CI] = 1.05-2.2), while the HR for OS was 1.46 (95%CI = 1.05-2.02). Similarly, in the RC +/- NAC group (6 cohorts for CSS and 3 cohorts for OS), the HR for CSS was 1.27 (95%CI = 1.05-1.55), and the HR for OS was 1.27 (95%CI = 1.08-1.51). There were no significant differences observed in pathologic outcomes, including rates of ≤pT1, pT0, and pT3/T4 disease, across all subgroups. However, pgMIBC was associated with a higher risk of nodal metastatic (pN+) disease in the RC + NAC only group (4 cohorts, relative risk [RR] = 1.43, 95%CI = 1.12-1.84). CONCLUSIONS: The findings highlight the potentially worse prognosis in patients with pgMIBC compared to dnMIBC, even with the modern use of NAC. The study emphasizes the importance of careful patient counseling, further classification of patients for treatment selection, and the consideration of additional or innovative systemic therapies for pgMIBC.

Oncologic control and predictors of urologic reconstruction after Mohs micrographic surgery for low-risk penile malignancy.

PURPOSE: Mohs micrographic surgery (MMS) is a low-risk penile cancer management option. However, contemporary patients' short-term oncologic control and preoperative characteristics predicting reconstruction needs are undefined. This study assesses MMS's oncologic efficacy for low-risk penile cancer and identifies baseline predictors of post-resection reconstruction referral. METHODS: We retrospectively reviewed 73 adult males with 78 penile cutaneous malignancies treated with MMS from 2005 to 2019. Patients underwent MMS with or without surgical reconstruction. Demographic information, MMS operative details, lesion pathology, and short-term outcomes were recorded. Descriptive statistics for all variables were calculated, and logistic regression identified predictive factors for urologic referral for complex reconstruction. RESULTS: Seventy-three men with 78 lesions, all staged ≤ cT1a prior to MMS, were identified. Twenty-one men were found to have invasive SCC. Median follow-up was 2.0 years (IQR 0.8-5.2 years). MMS was able to clear the disease in 90.4% of cases. One patient had disease related death following progression. Dermatology closed primarily in 68% of patients. Twenty percent of patients had a complication, most commonly poor wound healing. On univariate and multivariate linear regression analysis, lesion size > 3 cm and involvement of the glans independently predicted the need for referral to a reconstructive surgeon. CONCLUSIONS: MMS for penile cancer appears to provide sound oncologic control in the properly selected patient. Involvement of a reconstructive surgeon may be needed for glandular and large lesions, necessitating early referral to a comprehensive multidisciplinary care team.

Urologist-level variation in the management of T1a renal cell carcinoma: A population-based cohort study.

OBJECTIVES: Lack of strict indications in current guidelines have led to significant variation in management patterns of small renal masses. The impact of the urologist on the management approach for patients with small renal masses has not been explored previously. MATERIALS AND METHODS: Using the linked Surveillance, Epidemiology, and End Results-Medicare database, patients aged ≥66 years diagnosed with small renal masses from January 1, 2004 to December 31, 2013 were identified and assigned to primary urologists. Mixed-effects logistic models were used to evaluate factors associated with different management approaches, estimate urologist-level probabilities of each approach, assess management variation, and determine urologist impact on choice of approach. RESULTS: A total of 12,402 patients with 2,794 corresponding primary urologists were included in the study. At the individual urologist level, the estimated case-adjusted probability of different approaches varied markedly: nonsurgical management (mean, 12.8%; range, 4.9%-36.1%); thermal ablation (mean, 10.8%; range, 2.4%-66.3%); partial nephrectomy (mean, 30.1%; range, 10.1%-66.6%); and radical nephrectomy (mean, 40.4%; range, 17.7%-71.6%). Compared to patient and tumor characteristics, the primary urologist was a more influential measured factor, accounting for 13.6% (vs. 12.9%), 33.8% (vs. 2.1%), 15.1% (vs. 8.4%), and 13.5% (vs. 4.0%) of the variation in management choice for nonsurgical management, thermal ablation, partial nephrectomy, and radical nephrectomy, respectively. CONCLUSIONS: Significant variation exists in the management of small renal masses and appears to be driven primarily by urologist preference and practice patterns. Our findings emphasize the need for unified guidance regarding management of these masses to reduce unwarranted variation in care.

Prostate-Specific Antigen Screening in Smokers: A Comprehensive Analysis Using a National Behavioral Survey.

INTRODUCTION: Cigarette smoking is associated with higher-risk prostate cancer at the time of diagnosis and increased overall and prostate cancer‒specific mortality. Previous studies indicate smokers are less likely to undergo PSA screening. Herein we investigate the association between smoking and PSA screening using a nationally representative US survey. We hypothesize that smokers are less likely to undergo guideline-concordant PSA screening. METHODS: We performed a cross-sectional analysis of men aged 55 to 69 who responded to the cigarette smoking and PSA screening questions of the 2018 Behavioral Risk Factor Surveillance System survey. Adjusted prevalence and adjusted risk differences were calculated using complex weighted multivariable Poisson regression modeling. RESULTS: We identified 58,996 individuals who qualified for analysis. PSA screening prevalence was 39% (95% CI: 39%-40%) nationally, 42% (95% CI: 41%-44%) for never smokers, 42% (95% CI: 39%-40%) for former smokers, and 27% (95% CI: 25%-29%) for current smokers, including 27% (95% CI: 24%-29%) for daily smokers and 29% (95% CI: 24%-33%) for nondaily smokers. Compared to never smokers, the adjusted relative risk for undergoing PSA screening was 0.81 for current smokers (95% CI: 0.75-0.88, P < .01) and 0.99 for former smokers (95% CI: 0.94-1.03, P = .53). CONCLUSIONS: Current smokers are less likely to undergo recommended PSA screening, but former smokers are screened at similar rates as never smokers. As delays in diagnosis may substantially contribute to worse prostate cancer outcomes, targeted interventions to increase screening in this population may yield significant effects.

Practical applications of implementing integrated mental health practices with primary care providers.

Community Health Advanced by Medical Practice Superstars is a 1-year, Health Resources and Services Administration (HRSA)-funded fellowship for early career physicians and physician assistants/associates to become primary care transformational leaders. Fellows implement practice-based health care transformation projects in one of the three HRSA priority areas: childhood obesity, mental health, and opioid use disorder. The purpose of these projects is to expand on integrated health in primary care settings where there is a shortage of mental health professionals. The fellows identified areas in which they were able to incorporate mental health care provision to improve diagnostic capacity and whole health delivery, facilitate appropriate behavioral health outcomes, and improve patient physical health outcomes. Project modalities included initiating or increasing behavioral health screenings, aligning screenings with patient outcomes, and coordinating behavioral health care with physical health care. This article describes six mental health-related health care practice transformation projects implemented across rural health care settings, including Federally Qualified Health Centers and academic medical centers. The topics included (a) depression in pregnant and postpartum mothers; (b) adverse childhood experiences screening; (c) depression and chronic disease outcomes, especially diabetes; (d) the use of automated enhancements in patients' electronic medical records for management of clinical depression; (e) improving health outcomes and medication adherence of patients with opioid use disorder; and (f) the (in)adequacy of the Patient Health Questionairre-2 (PHQ-2) for the assessment of depression among patients with diabetes. Clinical specialties included family medicine, pediatrics, and women's health. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Diminished Short-Term Efficacy of Reduced-Dose Induction BCG in the Treatment of Non-Muscle Invasive Bladder Cancer.

The ongoing Bacillus Calmette-Guérin (BCG) shortage has created challenges for the treatment of non-muscle invasive bladder cancer (NMIBCa). Our objective was to evaluate the efficacy of reduced-dose induction BCG (RD-iBCG) compared to full-dose induction BCG (FD-iBCG) regarding recurrence rates. We hypothesized that patients receiving RD-iBCG may recur at a higher rate compared to those who received FD-iBCG therapy. A retrospective review of all patients with NMIBCa treated with intravesical therapy at our institution between 2015-2020 was conducted. Inclusion criteria consisted of having a diagnosis of AUA intermediate or high-risk NMIBCa with an indication for a six-week induction course of FD or RD-BCG with at least 1 year of documented follow up. The data were censored at one year. Propensity score matching for age, sex, tumor pathology, and initial vs. recurrent disease was performed. The primary endpoint was bladder cancer recurrence, reported as recurrence-free survival. A total of 254 patients were reviewed for this study. Our final cohort was 139 patients after exclusion. Thirty-nine percent of patients had HGT1 disease. 38.6% of patients receiving RD-BCG developed a recurrence of bladder cancer within a one-year follow-up as compared to 33.7% of patients receiving FD therapy. After propensity matching, this value remained statistically significant (p = 0.03). In conclusion, RD-iBCG for NMIBCa is associated with a significantly greater risk of recurrence than full-dose induction therapy, suggesting that RD-iBCG may not be equivalent or non-inferior to full-dose administration in the short term.

Effect of high-intensity interval training on cardiovascular function, VO2max, and muscular force.

The purpose of this study was to examine the effects of short-term high-intensity interval training (HIIT) on cardiovascular function, cardiorespiratory fitness, and muscular force. Active, young (age and body fat = 25.3 ± 4.5 years and 14.3 ± 6.4%) men and women (N = 20) of a similar age, physical activity, and maximal oxygen uptake (VO2max) completed 6 sessions of HIIT consisting of repeated Wingate tests over a 2- to 3-week period. Subjects completed 4 Wingate tests on days 1 and 2, 5 on days 3 and 4, and 6 on days 5 and 6. A control group of 9 men and women (age and body fat = 22.8 ± 2.8 years and 15.2 ± 6.9%) completed all testing but did not perform HIIT. Changes in resting blood pressure (BP) and heart rate (HR), VO2max, body composition, oxygen (O2) pulse, peak, mean, and minimum power output, fatigue index, and voluntary force production of the knee flexors and extensors were examined pretraining and posttraining. Results showed significant (p < 0.05) improvements in VO2max, O2 pulse, and Wingate-derived power output with HIIT. The magnitude of improvement in VO2max was related to baseline VO2max (r = -0.44, p = 0.05) and fatigue index (r = 0.50, p < 0.05). No change (p > 0.05) in resting BP, HR, or force production was revealed. Data show that HIIT significantly enhanced VO2max and O2 pulse and power output in active men and women.

Primary follicular lymphoma of the prostate presenting with elevated PSA and a PI-RADS 3 lesion on MRI: A case report.

Prostate cancer is the most common malignancy diagnosed in men. PI-RADS 3 lesions on multiparametric MRI, when histologically proven malignant, overwhelmingly represent prostatic adenocarcinoma. Primary lymphoma of the prostate, especially follicular lymphoma, is exceedingly rare. To our knowledge, its presentation with a PI-RADS 3 lesion and elevated PSA has not been previously described. We report the case of a 68-year-old, healthy male presenting with elevated PSA and lower urinary tract symptoms found to have a PI-RADS 3 lesion. Prostate biopsy revealed low-grade follicular lymphoma, and staging showed no other lesions. The patient is currently being managed with close surveillance.

Effective control of recurrent and metastatic GU SCC by employing a multimodal approach in a patient with a history of radiation and transscrotal surgery for stage I seminoma.

This 68-year-old male, with a history of treated testicular seminoma, developed scrotal SCC 30 years later, with a metastatic SCC recurrence following another interval of 10 years. He exhibited good response to multimodal therapy, though subsequently underwent orchiectomy, revealing SCC invading his solitary testicle. This case presents a unique danger of adjuvant radiation in testicular cancer survivors, demonstrates the efficacy of multimodal therapy with GU SCC, and describes a highly unusual histologic finding.

Prognostic significance of sarcomatoid features in metastatic renal cell carcinoma treated with cytoreductive nephrectomy and targeted therapy.

INTRODUCTION: The presence of sarcomatoid features in localized renal cell carcinoma (RCC) is associated with worse outcomes. We sought to use a national database to evaluate the outcomes and prognosis of metastatic RCC (mRCC) with sarcomatoid features treated with cytoreductive nephrectomy (CN) and targeted therapy (TT). METHODS: The National Cancer Database (2010-2013) was used to identify patients with mRCC at diagnosis. Only patients who underwent CN followed by TT were included. Kaplan-Meier curves, log-rank test, and multivariate Cox regression analysis were used to compare overall survival (OS) between mRCC with and without sarcomatoid features. Subgroup analysis in patients with clear cell RCC (ccRCC) was performed. RESULTS: A total of 1,427 patients with mRCC treated with CN followed by TT were included of which 364 (26%) had mRCC with sarcomatoid features. mRCC with sarcomatoid features were more likely to have Fuhrman grade 4 cancer. mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (24.6 vs 12.0 months, P < 0.001). For the clear cell cohort, mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (26.2 vs 14.0 months, P < 0.001). Multivariate Cox regression showed sarcomatoid features was significantly associated with worse OS in the overall cohort (hazard ratio [HR] =1.63, 95% confidence interval [CI] =1.38-1.91, P < 0.001) and the ccRCC subcohort (HR=1.53, 95% CI=1.23-1.90, P < 0.001). DISCUSSION/CONCLUSION: mRCC with sarcomatoid features treated with CN and TT has a very poor and drastically different prognosis compared with mRCC without sarcomatoid features. With the expansion of systemic RCC therapies, investigation is needed to optimize treatment in this high-risk cohort.

Adaptations to high-intensity training are independent of gender.

The purpose of this study was to identify potential gender discrepancies in adaptation to low-volume high-intensity interval training (HIT). Active, young men (n = 11, age = 25.3 ± 5.5 years) and women (n = 9, age = 25.2 ± 3.1 years) matched for age, physical activity, and VO(2max) completed six sessions of HIT separated by 48 h over a 2-3 week period. Subjects completed four Wingate tests on days 1 and 2, five on days 3 and 4, and six on days 5 and 6. A control group of five men and four women (age = 22.8 ± 2.8 years) completed all testing, but did not perform HIT. Changes in VO(2max), oxygen (O(2)) pulse, peak/mean power output, fatiguability, substrate oxidation, and voluntary force production of the knee flexors and extensors were examined pre- and post-training with repeated measures ANOVA, with gender and group as between-subjects variables. Results showed significant (p < 0.05) improvements in VCO(2max) and peak/mean power output in response to HIT, as well as reduced respiratory exchange ratio and heart rate during submaximal exercise. The magnitude of change in VO(2max) (5.9 vs. 6.8%), power output (10.4-14.9% vs. 9.1-10.9%), and substrate oxidation was similar (p > 0.05) between men and women. Data show that adaptations to 6 days of low-volume HIT are similar in men and women matched for VO(2max) and physical activity.

Outcomes of mohs microgrpahic resection for cutaneous malignancy involving the scrotum.

INTRODUCTION: Squamous cell carcinoma (SCC) and extramammary Paget's Disease (EMPD) of the scrotum are exceedingly rare. Given their propensity for local invasion and treatment with wide local excision, they can be highly morbid conditions. Outcomes of Mohs Micrographic Surgery (MMS) for scrotal cutaneous malignancy is not well described in current literature. We hypothesized that MMS for scrotal cutaneous malignancy would provide equivalent or improved oncologic outcomes while limiting the morbidity associated with wide excision. MATERIALS/METHODS: This is a retrospective review and analysis of a prospectively maintained database spanning entries from 2005 to 2019. Collected data included general patient characteristics and surgical characteristics reported on a per lesion basis. MMS was performed by our institution's department of dermatology using their standard technique. RESULTS: Overall, a total of 26 consecutive patients with 28 lesions (SCC or EMPD) were analyzed. Out of our cohort of 15 patients with 16 scrotal SCC lesions, 10 (66%) patients were current or former smokers, 4 (26%) were immunosuppressed, and 2 (13%) had HPV infections. The median preoperative and postoperative size of SCC lesions were 5.7cm [2] and 20.2cm [2] respectively. There was one (6%) oncologic recurrence of SCC of the scrotum and one (6%) local wound complication. Our cohort also included 11 patients with 12 scrotal EMPD lesions. One patient (9%) had an underlying associated malignancy (prostate cancer). The preoperative and postoperative area of lesions were 50.6cm [2] and 96.4cm [2] respectively. One (9%) EMPD lesion had a positive final margin at resection requiring reoperation. After achieving negative surgical margins, no patients in this cohort had an oncologic recurrence. 3 (26%) scrotal EMPD cases had local wound postoperative complications, only one required reoperation. CONCLUSION: To our knowledge, this is the first case series focused on MMS for both SCC and EMPD with scrotal involvement. Our data suggests that MMS for scrotal cutaneous malignancy may improve oncologic outcomes and may decreases local post-operative reconstructive issues when compared to reported outcomes of treatment with wide local excision. When able, scrotal cutaneous malignancy patients should be referred to urologists at centers with MMS capabilities as it likely will improve their outcomes. The urologist should maintain active involvement with these patients to coordinate this complex and advanced pattern of care.

Efficacy of acute caffeine ingestion for short-term high-intensity exercise performance: a systematic review.

Caffeine is the most widely used drug in the world, commonly ingested in coffee, tea, soda, and energy drinks. Its ability to enhance muscular work has been apparent since the early 1900s. Caffeine typically increases endurance performance; however, efficacy of caffeine ingestion for short-term high-intensity exercise is equivocal, which may be explained by discrepancies in exercise protocols, dosing, and subjects' training status and habitual caffeine intake found across studies. The primary aim of this review is to critically examine studies that have tested caffeine's ability to augment performance during exercise dependent on nonoxidative metabolism such as sprinting, team sports, and resistance training. A review of the literature revealed 29 studies that measured alterations in short-term performance after caffeine ingestion. Each study was critically analyzed using the Physiotherapy Evidence Database (PEDro) scale. The mean PEDro score was 7.76 +/- 0.87. Eleven of 17 studies revealed significant improvements in team sports exercise and power-based sports with caffeine ingestion, yet these effects were more common in elite athletes who do not regularly ingest caffeine. Six of 11 studies revealed significant benefits of caffeine for resistance training. Some studies show decreased performance with caffeine ingestion when repeated bouts are completed. The exact mechanism explaining the ergogenic effect of caffeine for short-term exercise is unknown.