Outpatient Antibiotic Use is Not Associated with an Increased Risk of First-Time Symptomatic Kidney Stones.

SIGNIFICANCE STATEMENT: Antibiotics modify human microbiomes and may contribute to kidney stone risk. In a population-based case-control study using 1247 chart-validated first-time symptomatic kidney stone formers and 4024 age- and sex-matched controls, the risk of kidney stones was transiently higher during the first year after antibiotic use. However, this risk was no longer evident after adjustment for comorbidities and excluding participants with prior urinary symptoms. Findings were consistent across antibiotic classes and the number of antibiotic courses received. This suggests that antibiotics are not important risk factors of kidney stones. Rather, kidney stones when they initially cause urinary symptoms are under-recognized, resulting in antibiotic use before a formal diagnosis of kidney stones ( i.e. , reverse causality). BACKGROUND: Antibiotics modify gastrointestinal and urinary microbiomes, which may contribute to kidney stone formation. This study examined whether an increased risk of a first-time symptomatic kidney stone episode follows antibiotic use. METHODS: A population-based case-control study surveyed 1247 chart-validated first-time symptomatic kidney stone formers with a documented obstructing or passed stone (cases) in Olmsted County, Minnesota, from 2008 to 2013 and 4024 age- and sex-matched controls. All prescriptions for outpatient oral antibiotic use within 5 years before the onset of symptomatic stone for the cases and their matched controls were identified. Conditional logistic regression estimated the odds ratio (OR) of a first-time symptomatic kidney stone across time after antibiotic use. Analyses were also performed after excluding cases and controls with prior urinary tract infection or hematuria because urinary symptoms resulting in antibiotic prescription could have been warranted because of undiagnosed kidney stones. RESULTS: The risk of a symptomatic kidney stone was only increased during the 1-year period after antibiotic use (unadjusted OR, 1.31; P = 0.001), and this risk was attenuated after adjustment for comorbidities (OR, 1.16; P = 0.08). After excluding cases and controls with prior urinary symptoms, there was no increased risk of a symptomatic kidney stone during the 1-year period after antibiotic use (unadjusted OR, 1.04; P = 0.70). Findings were consistent across antibiotic classes and the number of antibiotic courses received. CONCLUSIONS: The increased risk of a first-time symptomatic kidney stone with antibiotic use seems largely due to both comorbidities and prescription of antibiotics for urinary symptoms. Under-recognition of kidney stones that initially cause urinary symptoms resulting in antibiotic use may explain much of the perceived stone risk with antibiotics ( i.e. , reverse causality).

Characterization of Stone Events in Patients With Type 3 Primary Hyperoxaluria.

PURPOSE: Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We characterized stone events and examined associations with urine parameters and kidney function in a primary hyperoxaluria type 3 population. MATERIALS AND METHODS: We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. RESULTS: Kidney stones occurred in 65/70 primary hyperoxaluria type 3 patients (93%). Among the 49 patients with imaging available, the median (IQR) number of stones was 4 (2, 5), with largest stone 7 mm (4, 10) at first imaging. Clinical stone events occurred in 62/70 (89%) with median number of events per patient 3 (2, 6; range 1-49). Age at first stone event was 3 years (0.99, 8.7). Lifetime stone event rate was 0.19 events/year (0.12, 0.38) during follow-up of 10.7 (4.2, 26.3) years. Among 326 total clinical stone events, 139 (42.6%) required surgical intervention. High stone event rates persisted for most patients through the sixth decade of life. Analysis was available for 55 stones: pure calcium oxalate accounted for 69%, with mixed calcium oxalate and phosphate in 22%. Higher calcium oxalate supersaturation was associated with increased lifetime stone event rate after adjusting for age at first event (IRR [95%CI] 1.23 [1.16, 1.32]; P < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population. CONCLUSIONS: Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.

Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls.

BACKGROUND: The urine metabolites and chemistries that contribute to kidney stone formation are not fully understood. This study examined differences between the urine metabolic and chemistries profiles of first-time stone formers and controls. METHODS: High-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was performed in 24-hour urine samples from a prospective cohort of 418 first-time symptomatic kidney stone formers and 440 controls. In total, 48 NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed. Analysis of covariance was used to determine the association of stone former status with urine metabolites or chemistries after adjusting for age and sex and correcting for the false discovery rate. Gradient-boosted machine methods with nested cross-validation were applied to predict stone former status. RESULTS: Among the standard urine chemistries, stone formers had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine. Among NMR urine metabolites, stone formers had lower hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate and higher creatine and alanine. A cross-validated model using urine chemistries, age, and sex yielded a mean AUC of 0.76 (95% CI, 0.73 to 0.79). A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC, 0.78; 95% CI, 0.75 to 0.81). In this combined model, among the top ten discriminating features, four were urine chemistries and six NMR-quantified metabolites. CONCLUSIONS: Although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.

Estimated GFR Slope Across CKD Stages in Primary Hyperoxaluria Type 1.

RATIONALE & OBJECTIVE: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism that results in early-onset kidney stone disease, nephrocalcinosis, and kidney failure. There is an unmet need for reliable markers of disease progression to test effectiveness of new treatments for patients with PH. In this study, we assessed the rate of estimated glomerular filtration rate (eGFR) decline across chronic kidney disease (CKD) glomerular filtration rate (GFR) categories (CKD G2-G5) in a cohort of patients with PH1. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Patients with PH1 enrolled in the Rare Kidney Stone Consortium (RKSC) registry who did not have kidney failure at diagnosis and who had at least 2 eGFR values recorded from within 1 month of diagnosis until their last contact date or incident kidney failure event. PREDICTORS: CKD GFR category, baseline patient and laboratory characteristics. OUTCOME: Annualized rate of eGFR decline. ANALYTICAL APPROACH: Generalized estimating equations and linear regression were used to evaluate the associations between CKD GFR category, baseline patient and laboratory characteristics, and annual change in eGFR during follow-up. RESULTS: Compared with the slope in CKD G2 (-2.3 mL/min/1.73 m2 per year), the mean annual eGFR decline was nominally steeper in CKD G3a (-5.3 mL/min/1.73 m2 per year) and statistically significantly more rapid in CKD G3b and G4 (-14.7 and -16.6 mL/min/1.73 m2 per year, respectively). In CKD G2, older age was associated with a more rapid rate of eGFR decline (P = 0.01). A common PH1-causing variant of alanine glyoxylate aminotransferase, a glycine to arginine substitution at amino acid 170 (G170R), appeared to be associated with less severe annual decline in eGFR. LIMITATIONS: Data at regular time points were not available for all patients due to reliance on voluntary reporting in a retrospective rare disease registry. CONCLUSIONS: The eGFR decline was not uniform across CKD GFR categories in this PH1 population, with a higher rate of eGFR decline in CKD G3b and G4. Thus, CKD GFR category needs to be accounted for when analyzing eGFR change in the setting of PH1.

Risk of Symptomatic Kidney Stones During and After Pregnancy.

RATIONALE & OBJECTIVE: There are several well-known anatomical and physiological changes during pregnancy that could contribute to kidney stone formation, but evidence that they increase the risk of kidney stones during pregnancy is lacking. We determined whether there was an increased risk of a first-time symptomatic kidney stone during and after pregnancy. STUDY DESIGN: A population-based matched case-control study. SETTING & PARTICIPANTS: 945 female first-time symptomatic kidney stone formers aged 15-45 years and 1,890 age-matched female controls in Olmsted County, MN, from 1984-2012. The index date was the date of onset of a symptomatic kidney stone for both the case and her matched controls. EXPOSURE: The primary exposure was pregnancy with assessment for variation in risk across different time intervals before, during, and after pregnancy. Medical records were manually reviewed to determine the conception and delivery dates for pregnancies. OUTCOME: Medical record-validated first-time symptomatic kidney stone. ANALYTICAL APPROACH: Conditional and unconditional multivariable logistic regression analysis. RESULTS: Compared with nonpregnant women, the odds of a symptomatic kidney stone forming in women was similar in the first trimester (OR, 0.92; P=0.8), began to increase during the second trimester (OR, 2.00; P=0.007), further increased during the third trimester (OR, 2.69; P=0.001), peaked at 0 to 3 months after delivery (OR, 3.53; P<0.001), and returned to baseline by 1year after delivery. These associations persisted after adjustment for age and race or for diabetes mellitus, hypertension, and obesity. These results did not significantly differ by age, race, time period, or number of prior pregnancies. Having a prior pregnancy (delivery date>1year ago) was also associated with a first-time symptomatic kidney stone (OR, 1.27; P=0.01). LIMITATIONS: Observational study design in a predominantly White population. The exact timing of stone formation cannot be determined. CONCLUSIONS: Pregnancy increases the risk of a first-time symptomatic kidney stone. This risk peaks close to delivery and then improves by 1 year after delivery, though a modest risk of a kidney stone still exists beyond 1 year after delivery.

The association of microhematuria with mesangial hypercellularity, endocapillary hypercellularity, crescent score and renal outcomes in immunoglobulin A nephropathy.

BACKGROUND: Microhematuria is common in immunoglobulin A nephropathy (IgAN). However, current prognostication is based on proteinuria and mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis and crescent (MEST-C) scores. METHODS: In this retrospective study, we evaluated whether MEST-C score components are associated with the presence of microhematuria at biopsy and whether the degree of microhematuria during follow-up is associated with change in estimated glomerular filtration rate (eGFR), after adjusting for clinical and histological parameters. We identified 125 patients with biopsy-proven IgAN and MEST-C scoring who were not on immunosuppressive therapy at biopsy. Microhematuria was defined as ≥3 red blood cells (RBCs)/high-power field (hpf). RESULTS: Of the 125 patients, 97 had microhematuria at baseline and were more likely to have M1, E1 and C ≥ 1 lesions (P < 0.05 for all) compared with patients without microhematuria. Of the 125 patients, 72 had follow-up data available. An increase in the degree of microhematuria was significantly associated with an eGFR decline of -0.81 mL/min/1.73 m2 [95% confidence interval (CI) -1.44 to -0.19, P = 0.01], after adjusting for follow-up time, proteinuria and T score. Severe microhematuria (≥21 RBCs/hpf) was associated with an even larger decline in eGFR (-3.99 mL/min/1.73 m2; 95% CI -6.9411 to -1.0552, P = 0.008), after similar adjustments. CONCLUSION: Degree of microhematuria during follow-up is an independent predictor of eGFR decline after adjusting for clinical and histological parameters. Therefore, monitoring the degree of microhematuria as well as proteinuria is important when evaluating patients with IgAN. Additional studies using improvement in microhematuria as a primary surrogate outcome are needed.

Comparison of the current renal staging, progression and response criteria to predict renal survival in AL amyloidosis using a Mayo cohort.

Three sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5-5.3, p = .001] and 2.5 [CI: 1.4-4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17-0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post-treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post-treatment. These differences are important when choosing endpoints for clinical trials.

Risk of substance use disorders among adolescents and emerging adults with type 1 diabetes: A population-based cohort study.

BACKGROUND: Adolescents and emerging adults with chronic health conditions such as type 1 diabetes mellitus (T1D) are more likely to engage in high-risk behaviors. Previous studies regarding substance use in adolescents and emerging adults with T1D are mostly derived from cross-sectional studies utilizing self-administered questionnaires and are limited by lack of population-based comparison groups. In addition, despite the rising popularity of vaping, little is known about the incidence of vaping in adolescents and emerging adults with T1D. METHODS: We explored the incidence and prospective risk of substance use disorders (SUD) and vaping in adolescents and emerging adults with T1D compared to age and gender matched nondiabetic referents residing in Olmsted County, Rochester, MN. RESULTS: Risk of incident SUD was higher in those with T1D compared to matched referents with alcohol, marijuana, and smoked tobacco being most common substances. When stratified by gender, these differences remained significant in males, but not females. CONCLUSIONS: While further work is needed to delineate the causative relationships between T1D, mental health, and substance abuse, our findings confirm the critical need for substance use screening and mental health support for adolescents and emerging adults with T1D.

Clinical outcomes of solid organ transplant recipients with metastatic cancers who are treated with immune checkpoint inhibitors: A single-center analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation. METHODS: Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival. RESULTS: The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7 months (interquartile range, 0.4-7.6 months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune-related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI-induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6 months and 12 months. Eleven patients (65%) died over the median follow-up period of 4.6 months (interquartile range, 1.5-13.2 months) from the time of ICI initiation, with cancer progression being the most common cause of death. CONCLUSIONS: ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further.

Urinary monocyte chemoattractant protein 1 associated with calcium oxalate crystallization in patients with primary hyperoxaluria.

BACKGROUND: Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidney disease. Noninvasive urine markers reflective of active kidney injury could be useful to gauge the effectiveness of ongoing treatments. METHODS: A panel of biomarkers that reflect different nephron sites and potential mechanisms of injury (clusterin, neutrophil gelatinase-associated lipocalin (NGAL), 8-isoprostane (8IP), monocyte-chemoattractant protein 1(MCP-1), liver-type fatty acid binding protein (L-FABP), heart-type fatty acid binding protein (H-FABP), and osteopontin (OPN)) were measured in 114 urine specimens from 30 PH patients over multiple visits. Generalized estimating equations were used to assess associations between biomarkers and 24 h urine excretions, calculated proximal tubular oxalate concentration (PTOx), and eGFR. RESULTS: Mean (±SD) age at first visit was 19.5 ± 16.6 years with an estimated glomerular filtration rate (eGFR) of 68.4 ± 21.0 ml/min/1.73m2. After adjustment for age, sex, and eGFR, a higher urine MCP-1 concentration and MCP-1/creatinine ratio was positively associated with CaOx supersaturation (SS). Higher urine NGAL and NGAL/creatinine as well as OPN and OPN/creatinine were associated with higher eGFR. 8IP was negatively associated with PTOx and urinary Ox, but positively associated with CaOx SS. CONCLUSION: In PH patients greater urine MCP-1 and 8IP excretion might reflect ongoing collecting tubule crystallization, while greater NGAL and OPN excretion may reflect preservation of kidney mass and function. CaOx crystals, rather than oxalate ion may mediate oxidative stress in hyperoxaluric conditions. Further studies are warranted to determine whether urine MCP-1 excretion predicts long term outcome or is altered in response to treatment.

Plasma Oxalate as a Predictor of Kidney Function Decline in a Primary Hyperoxaluria Cohort.

This retrospective analysis investigated plasma oxalate (POx) as a potential predictor of end-stage kidney disease (ESKD) among primary hyperoxaluria (PH) patients. PH patients with type 1, 2, and 3, age 2 or older, were identified in the Rare Kidney Stone Consortium (RKSC) PH Registry. Since POx increased with falling estimated glomerular filtration rate (eGFR), patients were stratified by chronic kidney disease (CKD) subgroups (stages 1, 2, 3a, and 3b). POx values were categorized into quartiles for analysis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of ESKD were estimated using the Cox proportional hazards model with a time-dependent covariate. There were 118 patients in the CKD1 group (nine ESKD events during follow-up), 135 in the CKD 2 (29 events), 72 in CKD3a (34 events), and 45 patients in CKD 3b (31 events). During follow-up, POx Q4 was a significant predictor of ESKD compared to Q1 across CKD2 (HR 14.2, 95% CI 1.8-115), 3a (HR 13.7, 95% CI 3.0-62), and 3b stages (HR 5.2, 95% CI 1.1-25), p < 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1-Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.

Larger nephron size, low nephron number, and nephrosclerosis on biopsy as predictors of kidney function after donating a kidney.

It is unclear whether structural findings in the kidneys of living kidney donors predict postdonation kidney function. We studied living kidney donors who had a kidney biopsy during donation. Nephron size was measured by glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area. Age-specific thresholds were defined for low nephron number (calculated from CT and biopsy measures) and nephrosclerosis (global glomerulosclerosis, interstitial fibrosis/tubular atrophy, and arteriosclerosis). These structural measures were assessed as predictors of postdonation measured GFR, 24-hour urine albumin, and hypertension. Analyses were adjusted for baseline age, gender, body mass index, systolic and diastolic blood pressure, hypertension, measured GFR, urine albumin, living related donor status, and time since donation. Of 2673 donors, 1334 returned for a follow-up visit at a median 4.4 months after donation, with measured GFR <60 mL/min/1.73 m2 in 34%, urine albumin >5 mg/24 h in 13%, and hypertension in 5.3%. Larger glomerular volume and interstitial fibrosis/tubular atrophy predicted follow-up measured GFR <60 mL/min/1.73 m2 . Larger cortex volume per glomerulus and low nephron number predicted follow-up urine albumin >5 mg/24 h. Arteriosclerosis predicted hypertension. Microstructural findings predict GFR <60 mL/min/1.73 m2 , modest increases in urine albumin, and hypertension shortly after kidney donation.

FIRSTT study: randomized controlled trial of uterine artery embolization vs focused ultrasound surgery.

BACKGROUND: Uterine leiomyomas (fibroid tumors) cause considerable symptoms in 30-50% of women and are the leading cause of hysterectomy in the United States. Women with uterine fibroid tumors often seek uterine-preserving treatments, but comparative effectiveness trials are lacking. OBJECTIVE: The purpose of this study was to report treatment effectiveness and ovarian function after uterine artery embolization vs magnetic resonance imaging-guided focused ultrasound surgery from the Fibroid Interventions: Reducing Symptoms Today and Tomorrow study. STUDY DESIGN: The Fibroid Interventions: Reducing Symptoms Today and Tomorrow study, which is a randomized controlled trial of uterine artery embolization vs magnetic resonance imaging-guided focused ultrasound surgery, enrolled premenopausal women with symptomatic uterine fibroid tumors; women who declined randomization were enrolled in a parallel observational cohort. A comprehensive cohort design was used for outcomes analysis. Our target enrollment was 220 women, of which we achieved 41% (n=91) in the randomized and parallel arms of the trial. Primary outcome was reintervention for uterine fibroid tumors within 36 months. Secondary outcomes were change in serum anti-Müllerian hormone levels and standardized measures of fibroid symptoms, quality of life, pain, and sexual function. RESULTS: From 2010-2014, 83 women (mean age, 44.4 years) were treated in the comprehensive cohort design (43 for magnetic resonance imaging-guided focused ultrasound surgery [27 randomized]; 40 for uterine artery embolization [22 randomized]); baseline clinical and uterine characteristics were similar between treatment arms, except for higher fibroid load in the uterine artery embolization arm. The risk of reintervention was higher with magnetic resonance imaging-guided focused ultrasound surgery than uterine artery embolization (hazard ratio, 2.81; 95% confidence interval, 1.01-7.79). Uterine artery embolization showed a significantly greater absolute decrease in anti-Müllerian hormone levels at 24 months compared with magnetic resonance imaging-guided focused ultrasound surgery. Quality of life and pain scores improved in both arms but to a greater extent in the uterine artery embolization arm. Higher pretreatment anti-Müllerian hormone level and younger age at treatment increased the overall risk of reintervention. CONCLUSION: Our study demonstrates a lower reintervention rate and greater improvement in symptoms after uterine artery embolization, although some of the effectiveness may come through impairment of ovarian reserve. Both pretreatment anti-Müllerian hormone level and age are associated with risk of reintervention. CLINICAL TRIAL REGISTRATION NUMBER: NCT00995878, clinicaltrials.gov.

Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile.

BACKGROUND: Vaginal diazepam is frequently used to treat pelvic floor tension myalgia and pelvic pain despite limited knowledge of systemic absorption. AIM: To determine the pharmacokinetic and adverse event profile of diazepam vaginal suppositories. METHODS: We used a prospective pharmacokinetic design with repeated assessments of diazepam levels. Eight healthy volunteers were administered a 10-mg compounded vaginal diazepam suppository in the outpatient gynecologic clinic. Serum samples were collected at 0, 45, 90, 120, and 180 minutes; 8, 24, and 72 hours; and 1 week following administration of a 10-mg vaginal suppository. The occurrence of adverse events was assessed using the alternate step and tandem walk tests, the Brief Confusion Assessment Method, and numerical ratings. Plasma concentrations of diazepam and active long-acting metabolites were measured. Pharmacokinetic parameters were calculated by standard noncompartmental methods. RESULTS: The mean peak diazepam concentration (Cmax) of 31.0 ng/mL was detected at a mean time (Tmax) of 3.1 hours after suppository placement. The bioavailability was found to be 70.5%, and the mean terminal elimination half-life was 82 hours. The plasma levels of temazepam and nordiazepam peaked at 0.8 ng/mL at 29 hours and 6.4 ng/mL at 132 hours, respectively. Fatigue was reported by 3 of 8 participants. CLINICAL IMPLICATIONS: Serum plasma concentrations of vaginally administered diazepam are low; however the half-life is prolonged. STRENGTHS & LIMITATIONS: Strengths include use of inclusion and exclusion criteria aimed at mitigating clinical factors that could adversely impact diazepam absorption and metabolism, and the use of an ultrasensitive LC-MS/MS assay. Limitations included the lack of addressing the efficacy of vaginal diazepam in lieu of performing a pure pharmacokinetic study with healthy participants. CONCLUSION: Vaginal administration of diazepam results in lower peak serum plasma concentration, longer time to peak concentration, and lower bioavailability than standard oral use. Providers should be aware that with diazepam's long half-life, accumulating levels would occur with chronic daily doses, and steady-state levels would not be reached for up to 1 week. This profile would favor intermittent use to allow participation in physical therapy and intimacy. Larish AM, Dickson RR, Kudgus RA, et al. Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile. J Sex Med 2019;16;763-766.

Vaginal bromocriptine improves pain, menstrual bleeding and quality of life in women with adenomyosis: A pilot study.

INTRODUCTION: Adenomyosis is a benign uterine disease where endometrial glands and stroma are found within the myometrium surrounded by an area of hypertrophic myometrium. Symptomatology includes heavy menstrual bleeding and pelvic pain. The pathogenesis of adenomyosis is not known; however, animal models have shown increased uterine concentration of prolactin as a risk factor. Prolactin acts as a smooth muscle cell mitogen. If prolactin is central to adenomyosis pathogenesis, reducing uterine prolactin could be a possible medical treatment option. In this pilot study, we aim to evaluate the effect of bromocriptine, a prolactin inhibitor, on menstrual bleeding and pain in women with adenomyosis. MATERIAL AND METHODS: 23 women with diffuse adenomyosis were enrolled from a university hospital in Sweden and a tertiary care center in the USA. Nineteen patients completed 6 months of treatment with vaginal bromocriptine at a dose of 5 mg daily. Participants completed validated measures at baseline, 3 and 6 months of treatment, and at 9 months (3 months after cessation of bromocriptine). Validated measures utilized included Pictorial Blood Loss Assessment Chart (PBLAC), Aberdeen Menorrhagia Clinical Outcomes Questionnaire (AMCOQ), Visual Analog Scale for pain (VAS), McGill Pain Questionnaire (MPQ), Endometriosis Health Profile (EHP-30), Female Sexual Function Index (FSFI) and the Fibroid Symptom Quality of Life (UFS-QOL) symptom severity and health-related quality of life (HRQL) subscores. Scores were compared between baseline and 9 months using the Wilcoxon signed rank test. RESULTS: Mean age of participants was 44.8 years. About 77.8% reported PBLAC scores >250 and 68.4% reported moderate to severe pain at baseline. Compared with baseline, women had lower 9-month scores (median [interquartile range] for all) on PBLAC (baseline 349 [292-645] vs 9-month 233 [149-515], P = 0.003), VAS (5.0 [4-8.3] vs 2.5 [0-4.5], P < 0.001), EHP Core Pain (15.9 [9.1-50.0] vs 3.4 [2.3-34.1], P = 0.029), EHP Core Self-image (41.7 [16.7-58.3] vs 25 [0-5], P = 0.048) and Symptom Severity Score (60 [44-72] vs 44 [25-56], P < 0.001) and higher HRQL scores (57 [37-63] vs 72 [51-85], P < 0.001) following bromocriptine treatment. Other EHP core parameters and FSFI were not significantly different. CONCLUSIONS: Significant improvement in menstrual bleeding, pain and quality of life after vaginal bromocriptine treatment suggests a novel therapeutic agent for adenomyosis.

Using a muscle pump activator device to stimulate healing for non-healing lower leg wounds in long-term care residents.

Chronic non-healing wounds are a burden in the Long-Term Care (LTC) sector, increasing costs, morbidity, and mortality and causing pain and suffering. The objective of this LTC Innovation pilot was to test the value of a promising new neuromuscular stimulation device in elevating the experience and satisfaction of the residents, engaging and empowering the nursing staff, and improving healing and/or reducing costs. Small, wireless, and worn at the knee, this muscle pump activator is self-contained, wearable, and battery-powered to increase lower-leg blood circulation (up to 60% of that achieved by walking). It has no wires, weighs just 10 g, and is easy to use. Nurses in four LTC homes identified residents with non-healing lower leg wounds. Consent was obtained, and on-site training was delivered. Eleven residents were recruited. Only seven met the inclusion criteria for venous/mixed or diabetic foot ulcers. Of the seven who met the criteria and were adherent with best practices and the muscle pump activator, four healed 100%, and one healed 90%. Two patients with other aetiologies, who were also adherent, healed. All adherent residents had an average weekly decrease in wound size of 9.75% and were extremely happy with the results. Three residents who were non-adherent had a 9.25% increase in wound size per week. One patient with diabetic foot ulcers developed skin changes at the end of life and passed away. Nursing staff and cognisant residents can easily adjust the pulse of muscle pump activator, and application and removal are simple. Most residents feel engaged with the therapy "because they feel it working". The LTC corporation feels that it is a great adjunctive solution for many types of lower-leg wounds (venous, mixed, diabetic, pressure) in addition to best practices in the LTC and Retirement home sectors.

Risk of ESRD and Mortality in Kidney and Bladder Stone Formers.

RATIONALE & OBJECTIVES: Kidney stones have been associated with increased risk for end-stage renal disease (ESRD). However, it is unclear whether there is also an increased risk for mortality and if these risks are uniform across clinically distinct categories of stone formers. STUDY DESIGN: Historical matched-cohort study. SETTING & PARTICIPANTS: Stone formers in Olmsted County, MN, between 1984 and 2012 identified using International Classification of Diseases, Ninth Revision codes. Age- and sex-matched individuals who had no codes for stones were the comparison group. PREDICTOR: Stone formers were placed into 5 mutually exclusive categories after review of medical charts: incident symptomatic kidney, recurrent symptomatic kidney, asymptomatic kidney, bladder only, and miscoded (no stone). OUTCOMES: ESRD, mortality, cardiovascular mortality, and cancer mortality. ANALYTICAL APPROACH: Cox proportional hazards models with adjustment for baseline comorbid conditions. RESULTS: Overall, 65 of 6,984 (0.93%) stone formers and 102 of 28,044 (0.36%) non-stone formers developed ESRD over a mean follow-up of 12.0 years. After adjusting for baseline hypertension, diabetes mellitus, dyslipidemia, gout, obesity, and chronic kidney disease, risk for ESRD was higher in recurrent symptomatic kidney (HR, 2.34; 95% CI, 1.08-5.07), asymptomatic kidney (HR, 3.94; 95% CI, 1.65-9.43), and miscoded (HR, 6.18; 95% CI, 2.25-16.93) stone formers, but not in incident symptomatic kidney or bladder stone formers. The adjusted risk for all-cause mortality was higher in asymptomatic kidney (HR, 1.40; 95% CI, 1.18-1.67) and bladder (HR, 1.37; 95% CI, 1.12-1.69) stone formers. Chart review of asymptomatic and miscoded stone formers suggested increased risk for adverse outcomes related to diagnoses including urinary tract infection, cancer, and musculoskeletal or gastrointestinal pain. CONCLUSIONS: The higher risk for ESRD in recurrent symptomatic compared with incident symptomatic kidney stone formers suggests that stone events are associated with kidney injury. The clinical indication for imaging in asymptomatic stone formers, the correct diagnosis in miscoded stone formers, and the cause of a bladder outlet obstruction in bladder stone formers may explain the higher risk for ESRD or death in these groups.

Preeclampsia and ESRD: The Role of Shared Risk Factors.

BACKGROUND: Several registry-based studies, using diagnostic codes, have suggested that preeclampsia is a risk factor for end-stage renal disease (ESRD). However, because the 2 diseases share risk factors, the true nature of their association remains uncertain. Our goals were to conduct a population-based study to determine the magnitude of the association between preeclampsia and ESRD and evaluate the role of shared risk factors. STUDY DESIGN: Population-based nested case-control study. SETTING & PARTICIPANTS: The US Renal Data System was used to identify women with ESRD from a cohort of 34,581 women who gave birth in 1976 to 2010 in Olmsted County, MN. 44 cases of ESRD were identified and each one was matched to 2 controls based on year of birth (±1 year), age at first pregnancy (±2 years), and parity (±1 or ≥4). PREDICTOR: Preeclamptic pregnancy, confirmed by medical record review. OUTCOME: ESRD. MEASUREMENTS: Prepregnancy serum creatinine and urine protein measurements were recorded. Comorbid conditions existing prior to pregnancy were abstracted from medical records and included kidney disease, obesity, diabetes, and hypertension. RESULTS: There was evidence of kidney disease prior to the first pregnancy in 9 of 44 (21%) cases and 1 of 88 (<1%) controls. Per chart review, 8 of 44 (18%) cases versus 4 of 88 (5%) controls had preeclamptic pregnancies (unadjusted OR, 4.0; 95% CI, 1.21-13.28). Results were similar after independent adjustment for race, education, diabetes, and hypertension prior to pregnancy. However, the association was attenuated and no longer significant after adjustment for obesity (OR, 3.25; 95% CI, 0.93-11.37). LIMITATIONS: The limited number of ESRD cases and missing data for prepregnancy kidney function. CONCLUSIONS: Our findings confirm that there is a sizable association between preeclampsia and ESRD; however, obesity is a previously unexplored confounder. Pre-existing kidney disease was common, but not consistently coded or diagnosed.

Periprocedural outcomes comparing fibroid embolization and focused ultrasound: a randomized controlled trial and comprehensive cohort analysis.

BACKGROUND: Uterine fibroids are a common problem for reproductive-aged women, yet little comparative effectiveness research is available to guide treatment choice. Uterine artery embolization and magnetic resonance imaging-guided focused ultrasound surgery are minimally invasive therapies approved by the US Food and Drug Administration for treating symptomatic uterine fibroids. The Fibroid Interventions: Reducing Symptoms Today and Tomorrow study is the first randomized controlled trial to compare these 2 fibroid treatments. OBJECTIVE: The objective of the study was to summarize treatment parameters and compare recovery trajectory and adverse events in the first 6 weeks after treatment. STUDY DESIGN: Premenopausal women with symptomatic uterine fibroids seen at 3 US academic medical centers were enrolled in the randomized controlled trial (n = 57). Women meeting identical criteria who declined randomization but agreed to study participation were enrolled in a nonrandomized parallel cohort (n = 34). The 2 treatment groups were analyzed by using a comprehensive cohort design. All women undergoing focused ultrasound and uterine artery embolization received the same postprocedure prescriptions, instructions, and symptom diaries for comparison of recovery in the first 6 weeks. Return to work and normal activities, medication use, symptoms, and adverse events were captured with postprocedure diaries. Data were analyzed using the Wilcoxon rank sum test or χ2 test. Multivariable regression was used to adjust for baseline pain levels and fibroid load when comparing opioid medication, adverse events, and recovery time between treatment groups because these factors varied at baseline between groups and could affect outcomes. Adverse events were also collected. RESULTS: Of 83 women in the comprehensive cohort design who underwent treatment, 75 completed postprocedure diaries. Focused ultrasound surgery was a longer procedure than embolization (mean [SD], 405 [146] vs 139 [44] min; P <.001). Of women undergoing focused ultrasound (n = 43), 23 (53%) underwent 2 treatment days. Immediate self-rated postprocedure pain was higher after uterine artery embolization than focused ultrasound (median [interquartile range], 5 [1-7] vs 1 [1-4]; P = .002). Compared with those having focused ultrasound (n = 39), women undergoing embolization (n = 36) were more likely to use outpatient opioid (75% vs 21%; P < .001) and nonsteroidal antiinflammatory medications (97% vs 67%; P < .001) and to have a longer median (interquartile range) recovery time (days off work, 8 [6-14] vs 4 [2-7]; P < .001; days until return to normal, 15 [10-29] vs 10 [10-15]; P = .02). There were no significant differences in the incidence or severity of adverse events between treatment arms; 86% of adverse events (42 of 49) required only observation or nominal treatment, and no events caused permanent sequelae or death. After adjustment for baseline pain and uterine fibroid load, uterine artery embolization was still significantly associated with higher opioid use and longer time to return to work and normal activities (P < .001 for each). Results were similar when restricted to the randomized controlled trial. CONCLUSION: Women undergoing uterine artery embolization have longer recovery times and use more prescription medications, but women undergoing focused ultrasound have longer treatment times. These findings were independent of baseline pain levels and fibroid load.

Evaluation of the Good Start Program: a healthy eating and physical activity intervention for Maori and Pacific Islander children living in Queensland, Australia.

BACKGROUND: Reducing the prevalence of obesity and chronic disease are important priorities. Maori and Pacific Islander communities living in Australia have higher rates of obesity and chronic disease than the wider Australian population. This study aims to assess the effectiveness of the Good Start program, which aims to improve knowledge, attitudes and practices related to healthy eating and physical activity amongst Maori and Pacific Islander communities living in Queensland. METHODS: The intervention was delivered to children aged 6-19 years (N = 375) in schools by multicultural health workers. Class activities focused on one message each term related to healthy eating and physical activity using methods such as cooking sessions and cultural dance. The evaluation approach was a quantitative uncontrolled pre-post design. Data were collected each term pre- and post-intervention using a short questionnaire. RESULTS: There were significant increases in knowledge of correct servings of fruit and vegetables, knowledge of sugar and caffeine content of common sugar-sweetened drinks, recognition of the consequences of marketing and upsizing, and the importance of controlling portion size (all P < 0.05). There was also increases in knowledge of physical activity recommendations (P < 0.001), as well as the importance of physical activity for preventing heart disease (P < 0.001) and improving self-esteem (P < 0.001). In terms of attitudes, there were significant improvements in some attitudes to vegetables (P = 0.02), and sugar-sweetened drinks (P < 0.05). In terms of practices and behaviours, although the reported intake of vegetables increased significantly (P < 0.001), the proportion of children eating discretionary foods regularly did not change significantly, suggesting that modifying the program with an increased emphasis on reducing intake of junk food may be beneficial. CONCLUSION: The study has shown that the Good Start Program was effective in engaging children from Maori and Pacific Island backgrounds and in improving knowledge, and some attitudes and practices, related to healthy eating and physical activity. The evaluation contributes valuable information about components and impacts of this type of intervention, and considerations relevant to this population in order to successfully change behaviours and reduce the burden of chronic disease.