The impact of male infertility faculty on urology residency training.

The objective of this study was to determine the impact of having male infertility on urology residents' infertility training experience, surgical confidence, and In-Service-Exam Infertility/Sexual Medicine subscores. We electronically surveyed urology residents throughout the United States querying exposure to infertility faculty and fertility knowledge. Univariable and multivariable analysis was performed to determine predictors of higher In-Service Exam Infertility/Sexual Medicine sub-scores and self-rated infertility competency. Fifty-four of 72 respondents (75%) reported that male infertility comprises ≤10% of their training. Of the 63 residents who have a reproductive urologist on faculty, 66.7%, 47.6%, and 49.2% have scrubbed/observed a microsurgical varicocelectomy, vasectomy reversal and testicular sperm extraction, respectively. Residents exposed to infertility faculty are more likely to self-rate their infertility understanding as "excellent" or "good" (p = 0.04 and p = 0.02, respectively), and 14.4× more likely to feel confident performing infertility procedures, versus residents lacking faculty (p < 0.001). Residents having formal microsurgical training have better self-rated infertility understanding (p < 0.001), non-obstructive azoospermia management (p = 0.01), and competency performing infertility procedures (p < 0.001). Residents exposed to fertility faculty are more likely to feel confident performing fertility procedures after residency (p = 0.001). In conclusion, infertility comprises a minority of residency training. Most residents anticipate performing infertility procedures in practice, despite two-thirds lacking confidence performing these. Having an infertility faculty and formal microsurgical training improves residents' surgical confidence, non-obstructive azoospermia management, and global male infertility understanding. A structured educational curriculum may improve resident infertility training.

Sperm granulomas: Predictive factors and impacts on patency post vasectomy reversal.

The objective of this study was to identify factors that predict for sperm granuloma formation and the impact of sperm granuloma presence and quantity on vasectomy reversal (VR) outcomes. A cross sectional retrospective review of prospectively collected data, on the impact of granuloma on VR outcomes from a single academic center was performed. The impact of age, obstructive interval, intraoperative vasal fluid findings, anastomosis type, body mass index, tobacco use and total motile count (TMC) was determined. A total of 1550 men underwent VR between January 2000 and August 2019. Granulomas were present unilaterally in 23.3% (n = 361) and bilaterally in 14.2% (n = 220). On univariate analysis, increasing patient age negatively correlated with a larger number of granulomas (p = .011). Granuloma presence was associated with finding intact and motile sperm from the vasal stump intraoperatively (p = .001), and vasoepididymostomy anastomosis (p < .001). However, granuloma presence (and quantity) did not correlate with obstructive interval or maximum TMC. Tobacco use and body mass index (BMI) were not associated with granuloma presence. On multivariate analysis, granuloma quantity was not associated with TMC. Obstructive interval and vasovasostomy anastomosis were associated with higher TMC, while BMI was negatively associated with TMC. In conclusion, increasing age was negatively correlated with granuloma formation. Granuloma presence was associated with more favourable intraoperative fluid findings and anastomosis type, but not post-VR TMC, suggesting men with and without granulomas undergoing skilled microsurgery will have similar patency rates. Heavier men should be encouraged for weight loss prior to vasectomy reversal as increasing BMI was associated with lower TMC.

Determining the gas composition for the growth of BNNTs using a thermodynamic approach.

High-yield production of high-quality boron-nitride nanotubes (BNNTs) has been reported recently in several publications. A boron-rich material is evaporated using a laser or plasma in a nitrogen-rich atmosphere to supply precursor gaseous species for nucleation and growth of BNNTs. Either hydrogen was added or pressure was increased in the system to achieve high yield and high purity of the synthesized nanotubes. According to the widely-accepted "root grow" mechanism, upon gas cooling, boron droplets form first, then they adsorb nitrogen from the surrounding gas species, and BNNTs grow on their surfaces. However, what are the precursor species that provide nitrogen for the growth is still an open question. To answer this question, we performed thermodynamic calculations for determining the B-N mixture composition considering a broad set of gas species. For the first time, condensation of boron was taken into account and was shown to have a drastic effect on thegas chemical composition. B2N molecules were identified to be a major source of nitrogen for the growth of BNNTs. The presence of B2N molecules in a B-N gas mixture was verified by our spectroscopic measurements during laser ablation of boron-rich targets in nitrogen. It was shown that the increase of pressure has a quantitative effect on the mixture composition yielding an increase of the precursor density. Hydrogen addition might open an additional channel of nitrogen supply to support the growth of BNNTs. The nitrogen atoms react with abundant H2 molecules to form NH2 and then NH3 precursor species, instead of just recombining back to inert N2 molecules, as in the no-hydrogen case. In addition, thermodynamics was applied in conjunction with agglomeration theory to predict the size of the boron droplets upon growth of BNNTs. Analytical relations for the identification of crucial species densities were derived.

POTASSIUM CITRATE DECREASES BONE RESORPTION IN POSTMENOPAUSAL WOMEN WITH OSTEOPENIA: A RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL.

OBJECTIVE: Diets rich in animal protein, such as the typical American diet, are thought to create a high acid load. An association between acid load and bone loss has led to the idea that providing positive alkaline salt therapy could have beneficial effects on bone metabolism. The objective of this study was to investigate the effects of potassium citrate (K-citrate), 40 mEq daily, over 1 year on bone resorption and formation. METHODS: A randomized, double-blind, placebo-controlled trial of 83 women with postmenopausal osteopenia. Levels of bone turnover markers, specifically urinary N-telopeptide of collagen type 1 (u-NTX), amino-terminal propeptide of type 1 procollagen (P1NP), bone-specific alkaline phosphatase (BSAP), and osteocalcin (OC) were compared. Changes in bone mineral density (BMD) were also examined. RESULTS: K-citrate decreased both u-NTX (P = .005) and serum P1NP (P<.001) starting at month 1 and continuing through month 12. No significant change was seen in BSAP or OC. No significant change was seen in lumbar or hip BMD between the 2 groups. CONCLUSION: In women with postmenopausal osteopenia, treatment with K-citrate for 1 year resulted in a significant decrease in markers of turnover. The effect on markers of bone formation was not consistent. K-citrate may serve as a potential treatment for bone loss that is well tolerated and without any significant known long-term consequences.

Mindfulness-Based Stress Reduction for Posttraumatic Stress Disorder Among Veterans: A Randomized Clinical Trial.

IMPORTANCE: Mindfulness-based interventions may be acceptable to veterans who have poor adherence to existing evidence-based treatments for posttraumatic stress disorder (PTSD). OBJECTIVE: To compare mindfulness-based stress reduction with present-centered group therapy for treatment of PTSD. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 116 veterans with PTSD recruited at the Minneapolis Veterans Affairs Medical Center from March 2012 to December 2013. Outcomes were assessed before, during, and after treatment and at 2-month follow-up. Data collection was completed on April 22, 2014. INTERVENTIONS: Participants were randomly assigned to receive mindfulness-based stress reduction therapy (n = 58), consisting of 9 sessions (8 weekly 2.5-hour group sessions and a daylong retreat) focused on teaching patients to attend to the present moment in a nonjudgmental, accepting manner; or present-centered group therapy (n = 58), an active-control condition consisting of 9 weekly 1.5-hour group sessions focused on current life problems. MAIN OUTCOMES AND MEASURES: The primary outcome, change in PTSD symptom severity over time, was assessed using the PTSD Checklist (range, 17-85; higher scores indicate greater severity; reduction of 10 or more considered a minimal clinically important difference) at baseline and weeks 3, 6, 9, and 17. Secondary outcomes included PTSD diagnosis and symptom severity assessed by independent evaluators using the Clinician-Administered PTSD Scale along with improvements in depressive symptoms, quality of life, and mindfulness. RESULTS: Participants in the mindfulness-based stress reduction group demonstrated greater improvement in self-reported PTSD symptom severity during treatment (change in mean PTSD Checklist scores from 63.6 to 55.7 vs 58.8 to 55.8 with present-centered group therapy; between-group difference, 4.95; 95% CI, 1.92-7.99; P=.002) and at 2-month follow-up (change in mean scores from 63.6 to 54.4 vs 58.8 to 56.0, respectively; difference, 6.44; 95% CI, 3.34-9.53, P < .001). Although participants in the mindfulness-based stress reduction group were more likely to show clinically significant improvement in self-reported PTSD symptom severity (48.9% vs 28.1% with present-centered group therapy; difference, 20.9%; 95% CI, 2.2%-39.5%; P = .03) at 2-month follow-up, they were no more likely to have loss of PTSD diagnosis (53.3% vs 47.3%, respectively; difference, 6.0%; 95% CI, -14.1% to 26.2%; P = .55). CONCLUSIONS AND RELEVANCE: Among veterans with PTSD, mindfulness-based stress reduction therapy, compared with present-centered group therapy, resulted in a greater decrease in PTSD symptom severity. However, the magnitude of the average improvement suggests a modest effect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01548742.

Factors Associated With Dysphagia in Patients Undergoing Tracheal Resection.

Importance: Patients undergoing tracheal resection commonly experience dysphagia postoperatively, and the patient factors that predict severity and duration of symptoms are currently unclear. Objective: To determine the association of patient and surgical factors on postoperative dysphagia in adult patients undergoing tracheal resection. Design, Setting, and Participants: This was a retrospective cohort study of patients undergoing tracheal resection at 2 tertiary academic centers from February 2014 to May 2021. The centers included LAC+USC (Los Angeles County + University of Southern California) Medical Center and Keck Hospital of USC, both tertiary care academic institutions. Patients involved in the study underwent a tracheal or cricotracheal resection. Exposures: Tracheal or cricotracheal resection. Main Outcomes and Measures: The main outcome was dysphagia symptoms as measured by the functional oral intake scale (FOIS) on postoperative days (PODs) 3, 5, and 7, on the day of discharge, and at the 1-month follow-up visit. Demographics, medical comorbidities, and surgical factors were evaluated for association with FOIS scores at each time period using Kendall rank correlation and Cliff delta. Results: The study cohort consisted of 54 patients, with a mean (SD) age of 47 (15.7) years old, of whom 34 (63%) were male. Length of resection segment ranged from 2 to 6 cm, with a mean (SD) length of 3.8 (1.2) cm. The median (range) FOIS score was 4 (1-7) on PODs 3, 5, 7. On the day of discharge and at 1-month postoperative follow-up, the median (range) FOIS score was 5 (1-7) and 7 (1-7), respectively. Increasing patient age was moderately associated with decreasing FOIS scores at all measured time points (τ = -0.33; 95% CI, -0.51 to -0.15 on POD 3; τ = -0.38; 95% CI, -0.55 to -0.21 on POD 5; τ = -0.33; 95% CI, -0.58 to -0.08 on POD 7; τ = -0.22; 95% CI, -0.42 to -0.01 on day of discharge; and τ = -0.31; 95% CI, -0.53 to -0.09 at 1-month follow-up visit). History of neurological disease, including traumatic brain injury and intraoperative hyoid release, was not associated with FOIS score at any of the measured time points (δ = 0.03; 95% CI, -0.31 to 0.36 on POD 3; δ = 0.11; 95% CI, -0.28 to 0.47 on POD 5, δ = 0.3; 95% CI, -0.25 to 0.70 on POD 7; δ = 0.15; 95% CI, -0.24 to 0.51 on the day of discharge, and δ = 0.27; 95% CI, -0.05 to 0.53 at follow-up). Resection length was also not correlated with FOIS score with τ ranging from -0.04 to -0.23. Conclusions and Relevance: In this retrospective cohort study, most patients undergoing tracheal or cricotracheal resection experienced full resolution of dysphagia symptoms within the initial follow-up period. During preoperative patient selection and counseling, physicians should consider that older adult patients will experience greater severity of dysphagia throughout their postoperative course and delayed resolution of symptoms.

Effectiveness of Glaucoma Screening and Factors Associated with Follow-up Adherence among Glaucoma Suspects in a Safety-Net Teleretinal Screening Program.

PURPOSE: To evaluate rates and risk factors associated with follow-up adherence to in-person glaucoma evaluations and confirmed glaucoma diagnosis in glaucoma suspects identified through teleretinal diabetic retinopathy screening (TDRS). DESIGN: Retrospective cohort study SUBJECTS: Patients with diabetes identified through teleretinal screening to have large or asymmetric cup-to-disc ratios in a Los Angeles County safety-net primary care-based TDRS program. METHODS: Retrospective chart review was performed to obtain demographic and clinical information for patients with cup-to-disc ratios concerning for glaucoma on TDRS. Patients who completed an in-person follow-up appointment within 1 year of teleretinal screening were adherent. Factors associated with follow-up adherence and diagnosis of glaucoma were analyzed with chi-square and independent t tests along with multivariable logistic regressions. MAIN OUTCOME MEASURES: The proportion of patients with suspected glaucoma who adhered with in-person follow-up examination, proportion of patients with confirmed glaucoma diagnosis, and factors associated with follow-up adherence and glaucoma diagnosis. RESULTS: Eight-hundred seventeen patients with optic discs suspicious for glaucoma were included. Five-hundred thirty-four (65.4%) patients successfully completed an in-person glaucoma evaluation. Among these patients, 62.9% and 24.5% received a diagnosis of glaucoma suspect and glaucomatous optic neuropathy, respectively. Compared with patients aged < 50 years, patients aged 50 to 64 years had 1.57 times higher odds of being adherent with in-person visits (P = 0.036), whereas no difference was seen in those aged ≥ 65 years. For every $10 000 increase in the zip code median income, patients had 11% lower odds of being adherent (P = 0.031). Compared with Latino patients, Black patients had 3.52 times (P < 0.001) higher odds of having confirmed glaucoma. CONCLUSION: The majority of patients referred as glaucoma suspects on TDRS completed a follow-up examination, and nearly a quarter of those examined received a confirmed glaucoma diagnosis. Patients aged ≥ 50 and < 65 years along with those from lower-income neighborhoods were more likely to follow up for an in-person evaluation. Compared with Latino patients, Black patients had a higher risk for a confirmed glaucoma diagnosis. This demonstrates the effectiveness of glaucoma detection in a large-scale TDRS program for a safety-net patient population. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Early outcomes of lung transplantation with lung allografts from coronavirus disease 2019 (COVID-19)-positive donors.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) can be detected for extended periods of time with nucleic acid amplification test even after transmissibility becomes negligible. Lung allografts from COVID-19-positive donors have been used for transplantation in highly selected cases. This study aimed to clarify the early outcomes of lung transplantation with COVID-19-positive donors. METHODS: The Organ Procurement and Transplantation Network/United Network for Organ Sharing database between April 2020 and June 2022 was retrospectively analyzed. RESULTS: In the study period, 1297 COVID-19-positive donors were identified and the lungs were transplanted from 47 donors (3.6%). Of 47 donors, 44 donors were positive for COVID-19 NAT with nasopharyngeal swabs and the other 3 were positive with bronchoalveolar lavage. The COVID-19-positive lung donors were younger than the COVID-19-negative donors (28.4 ± 11.6 years vs 35.4 ± 13.6 years, P < .001). Recipients of the COVID-19-positive lungs (n = 47) were more likely have a greater lung allocation score (57.1 ± 22.9 vs 50.5 ± 19.7, P = .057) than recipients of COVID-19-negative lungs (n = 5501). The posttransplant length of hospital stay (39.8 ± 43.6 days vs 30.6 ± 34.5 days, P = .181), need for extracorporeal membrane oxygenation support at 72 hours after transplantation (2.6% [1/38] vs 10.4% [541/5184], P = .18), and 1-year overall survival rate (85.6% vs 87.1%, P = .63) were comparable between the 2 groups. CONCLUSIONS: Carefully selected lung allografts from COVID-19-positive donors had comparable early posttransplant outcomes to lung allografts from COVID-19-negative donors.

Kinetic interpretation of the classical Rayleigh-Taylor instability.

Rayleigh-Taylor (RT) instabilities are prevalent in many physical regimes ranging from astrophysical to laboratory plasmas and have primarily been studied using fluid models, the majority of which have been ideal fluid models. This work presents a five-dimensional (two spatial dimensions, three velocity space dimensions) simulation using the continuum-kinetic model to study the effect of the collisional mean free path and transport on the instability growth. The continuum-kinetic model provides noise-free access to the full particle distribution function permitting a detailed investigation of the role of kinetic physics in hydrodynamic phenomena such as the RT instability. For long mean free path, there is no RT instability growth, but as collisionality increases, particles relax towards the Maxwellian velocity distribution, and the kinetic simulations reproduce the fluid simulation results. An important and novel contribution of this work is in the intermediate collisional cases that are not accessible with traditional fluid models and require kinetic modeling. Simulations of intermediate collisional cases show that the RT instability evolution is significantly altered compared to the highly collisional fluidlike cases. Specifically, the growth rate of the intermediate collisionality RT instability is lower than the high collisionality case while also producing a significantly more diffused interface. The higher moments of the distribution function play a more significant role relative to inertial terms for intermediate collisionality during the evolution of the RT instability interface. Particle energy flux is calculated from moments of the distribution and shows that transport is significantly altered in the intermediate collisional case and deviates much more so from the high collisionality limit of the fluid regime.

Improving Lentiviral Transduction of Human Adipose-Derived Mesenchymal Stem Cells.

Lentiviral transduction of human mesenchymal stem cells (MSCs) induces long-term transgene expression and holds great promise for multiple gene therapy applications. Polybrene is the most commonly used reagent to improve viral gene transfer efficiency in laboratory research; however, it is not approved for human use and has also been shown to impair MSC proliferation and differentiation. Therefore, there is a need for optimized transduction protocols that can also be adapted to clinical settings. LentiBOOST (LB) and protamine sulfate are alternative transduction enhancers (TEs) that can be manufactured to current Good Manufacturing Practice standards, are easily applied to existing protocols, and have been previously studied for the transduction of human CD34+ hematopoietic stem cells. In this study, we investigated these reagents for the enhancement of lentiviral transduction of adipose-derived MSCs. We found that the combination of LB and protamine sulfate could yield comparable or even superior transduction efficiency to polybrene, with no dose-dependent adverse effects on cell viability or stem cell characteristics. This combination of TEs represents a valuable clinically compatible alternative to polybrene with the potential to significantly improve the efficiency of lentiviral transduction of MSCs for gene therapy applications.

Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants.

Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C(24)) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (C(max)) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.

Factors Influencing the Decision for Fresh vs Cryopreserved Microdissection Testicular Sperm Extraction for Non-Obstructive Azoospermia.

OBJECTIVE: To determine reproductive urologists' (RU) practice patterns for microdissection testicular sperm extraction (microTESE) and factors associated with use of fresh vs frozen microTESE for non-obstructive azoospermia. MATERIALS AND METHODS: We electronically surveyed Society for Study of Male Reproduction members with a 21-item questionnaire. Our primary outcomes were to determine RU preference for fresh or frozen microTESE and to understand barriers to performing microTESE. Pearson's chi-square and Fisher's exact tests were used to analyze categorical outcomes and candidate predictor variables. Firth logistic regression was performed to identify the predictors for preferring and performing fresh vs frozen microTESE. RESULTS: A total of 208 surveys were sent with 76 responses. Most (63.0%) primarily perform frozen microTESE for non-obstructive azoospermia, while 37.0% primarily perform fresh. However, in an ideal practice, 59.3% prefer fresh microTESE, 22.2% prefer frozen microTESE, and 18.5% had no preference. MicroTESE is performed most often (61.1%) at surgical centers not affiliated with a fertility practice. The most commonly reported barriers for both fresh and frozen microTESE are cost (42.6%), scheduling (33.3%), and andrologist unavailability (16.7%). There are no statistically significant differences between these barriers and performing fresh vs frozen microTESE. On multivariable analysis, reproductive endocrinology and infertility-based surgical center (OR 22.9; 95% CI 1.1-467.2; P = 0.04) and professional fee $2,500-$4,999 (OR 20.7; 95% CI 1.27-337.9; P = 0.03) are significant predictors of performing fresh microTESE. CONCLUSION: Frozen microTESE is performed more commonly than fresh, despite most RU preferring fresh microTESE in an ideal setting. Both fresh and frozen microTESE have a role in reproductive care. Barriers to performing fresh microTESE include cost, scheduling and andrologist availability.

Total and active rabbit antithymocyte globulin (rATG;Thymoglobulin) pharmacokinetics in pediatric patients undergoing unrelated donor bone marrow transplantation.

Rabbit antithymocyte globulin (rATG; Thymoglobulin) is currently used to prevent or treat graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation (HSCT). The dose and schedule of rATG as part of the preparative regimen for unrelated donor (URD) bone marrow transplantation (BMT) have not been optimized in pediatric patients. We conducted a prospective study of 13 pediatric patients with hematologic malignancies undergoing URD BMT at St. Jude Children's Research Hospital from October 2003 to March 2005, to determine the pharmacokinetics and toxicities of active and total rATG. The conditioning regimen comprised total body irradiation (TBI), thiotepa, and cyclophosphamide (Cy); cyclosporine (CsA) and methotrexate (MTX) were administered as GVHD prophylaxis. Patients received a total dose of 10 mg/kg rATG, and serial blood samples were assayed for total rATG by enzyme linked immunosorbent assay (ELISA) and active rATG by florescein activated cell sorting (FACS). We found that our weight-based dosing regimen for rATG was effective and well tolerated by patients. The half-lives of total and active rATG were comparable to those from previous studies, and despite high doses our patients had low maximum concentrations of active and total rATG. There were no occurrences of grade iii-iv GVHD even in patients having low peak rATG levels, and the overall incidence of grade II GVHD was only 15%. None of the patients had serious infections following transplantation. These data support the use of a 10 mg/kg dose of rATG in children with hematologic malignancies because it can be administered without increasing the risk of graft rejection, or serious infection in pediatric patients with a low rate of GVHD. These conclusions may not apply to patients with nonmalignant disorders.

Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy.

BACKGROUND: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). METHODS: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants > or =14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 microg/mL and area under the curve (AUC) <170 microg hr/mL. RESULTS: Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. CONCLUSIONS: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.

Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors.

Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m(2) orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m(2) p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m(2) p.o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years (range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of >0.75 log(10), with a median maximal decrease in viral load of -1.57 log(10) copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 (range, 62.8 to 305.5) microg x h/ml and median LPV trough concentration (C(trough)) of 10.8 (range, 4.1 to 25.3) microg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) microg x h/ml and the median SQV C(trough) was 2.1 (range, 0.2 to 4.1) microg/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach.

Simultaneous measurement of intracellular triphosphate metabolites of zidovudine, lamivudine and abacavir (carbovir) in human peripheral blood mononuclear cells by combined anion exchange solid phase extraction and LC-MS/MS.

All nucleoside reverse transcriptase inhibitors (NRTI) must first be metabolized to their triphosphate forms in order to be active against HIV. Zidovudine (ZDV), abacavir (ABC) and lamivudine (3TC) have proven to be an efficacious combination. In order simultaneously to measure intracellular levels of the triphosphates (-TP) of ZDV, ABC (carbovir, CBV) and 3TC, either together or individually, we have developed a cartridge-LC-MS/MS method. The quantitation range was 2.5-250 pg/microl for 3TC-TP, 0.1-10.0 pg/microl for ZDV-TP and 0.05-5.00 pg/microl for CBV-TP. This corresponds to 0.1-11.0 pmol 3TC-TP per million cells, 4-375 fmol ZDV-TP per million cells and 2-200 fmol CBV-TP per million cells, extracted from 10 million cells. Patient samples demonstrated measured levels in the middle regions of our standard curves both at pre-dose and 4h post-dose times.

Examining Burnout, Depression, and Self-Compassion in Veterans Affairs Mental Health Staff.

OBJECTIVES: Burnout, a state of emotional exhaustion associated with negative personal and occupational outcomes, is prevalent among healthcare providers. A better understanding of the psychological factors that may be associated with resilience to burnout is essential to develop effective interventions. Self-compassion, which includes kindness toward oneself, recognition of suffering as part of shared human experience, mindfulness, and nonjudgment toward inadequacies and failures, may be one such factor. The purpose of this study was to examine the relationships between burnout, depression, and self-compassion in Veterans Affairs (VA) mental health staff. DESIGN: Cross-sectional study. SETTING: VA medical center and affiliated community-based clinics. PARTICIPANTS: VA mental health staff. OUTCOME MEASURES: The 19-item Copenhagen Burnout Inventory, the 26-item Self-Compassion Scale, and the Patient Health Questionnaire 2-item depression screen. Demographic information included age, sex, years worked in current position, and number of staff supervised. RESULTS: One hundred and twenty-eight of a potential 379 individuals (33.8%) responded. Clerical support, nursing, social work, psychology, and psychiatry were the major professions represented. Self-compassion was inversely correlated with burnout (r = -0.41, p < 0.001), and inversely correlated with depression (rpb = -0.39, p < 0.001). The inverse relationship between self-compassion and burnout remained significant even after accounting for depressive symptoms and demographic variables in a multiple linear regression model. Of all the variables examined, self-compassion was the strongest predictor of burnout. CONCLUSIONS: The results of this study support the hypothesis that self-compassion may be associated with resilience to burnout. Alternatively, decreased self-compassion may be a downstream effect of increased burnout. Prospective, longitudinal studies are needed to determine the directional relationship between these factors, and whether interventions that cultivate self-compassion may decrease burnout and/or protect against its negative personal and professional outcomes.

Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age.

BACKGROUND: Few data are available regarding clinical outcomes or dosing requirements for the protease inhibitor ritonavir in human immunodeficiency virus (HIV)-infected children younger than under 24 months of age. METHODS: This prospective, multicenter phase I/II open label treatment trial used ritonavir, zidovudine and lamivudine to treat protease inhibitor-naive, HIV-infected infants between the ages of 4 weeks and 24 months. Two sequential dosing cohorts were treated with 350 or 450 mg/m(2) ritonavir every 12 hours; this report includes results of pharmacokinetics, safety, tolerability and efficacy through 104 weeks of follow-up of all subjects. RESULTS: Fifty HIV-infected children were treated. By week 16, 36 had achieved HIV-1 RNA <400 copies/mL (72% intent-to-treat, 84% as-treated analysis); by week 104, 18 maintained durable viral suppression (36% intent-to-treat, 46% as-treated). Poor medication adherence by caregiver report contributed to virologic failure. Few subjects experienced treatment-limiting toxicity: emesis or ritonavir refusal in 6 (12%); and severe but reversible anemia or elevated serum hepatic transaminases in 1 (4%) each. Apparent oral clearance was higher and the median predose concentrations were substantially lower than those found in adults. Median z scores for weight and height for age/gender were below normal at baseline but improved by week 104. CONCLUSIONS: A combination regimen of ritonavir, zidovudine and lamivudine was generally safe and produced sustained viral suppression in more than one-third of infants who initiated therapy before 2 years of age. Improved palatability of liquid preparations of protease inhibitors, supporting infrastructure and behavioral approaches to improve medication adherence with antiretrovirals will likely be necessary to further improve efficacy.

Metabolism of tenofovir and didanosine in quiescent or stimulated human peripheral blood mononuclear cells.

OBJECTIVE: As tenofovir disoproxil fumarate substantially increases plasma concentrations of didanosine in patients with human immunodeficiency virus-1 infection, we sought to determine whether tenofovir and didanosine showed a similar intracellular interaction in human peripheral blood mononuclear cells (PBMCs). DESIGN: Comparative in vitro incubation of two antiretrovirals in lymphocytes. SETTING: Clinical research laboratory. MATERIAL: Radiolabeled tenofovir and didanosine in human PBMCs. MEASUREMENTS AND MAIN RESULTS: Phosphorylation of 2 and 20 microM didanosine to dideoxyadenosine triphosphate (ddATP) was determined in quiescent and stimulated PBMCs in the presence or absence of 5 microM tenofovir. Similarly, phosphorylation of 5 microM tenofovir to tenofovir diphosphate (TFVpp) was examined in the presence or absence of 2 and 20 microM didanosine. Intracellular amounts of ddATP and TFVpp were determined by incubating PBMCs with radiolabeled tenofovir or didanosine alone and together for up to 16 hours and then separating the anabolites by high-performance liquid chromatography for quantitation. The presence of tenofovir did not affect the amount of ddATP in quiescent or stimulated PBMCs with 2 or 20 microM didanosine. In addition, didanosine did not alter the amount of TFVpp that formed. The amount of ddATP was modestly (1.5-3-fold) but consistently higher in stimulated than in quiescent PBMCs, but the amount of TFVpp did not differ. CONCLUSION: There is no significant interaction between tenofovir and didanosine in human PBMCs as determined by the extent of formation of the phosphorylated anabolites. This suggests that adjusting didanosine dosage, when given with tenofovir, to achieve similar didanosine plasma concentrations, may be sufficient to accommodate the systemic drug interaction.

Renal function after ifosfamide, carboplatin and etoposide (ICE) chemotherapy, nephrectomy and radiotherapy in children with Wilms tumour.

We prospectively evaluated tumour response and renal function in 12 newly diagnosed children with high-risk Wilms tumour receiving ifosfamide, carboplatin and etoposide (ICE) chemotherapy. Two cycles of ICE were followed by 5 weeks of vincristine, dactinomycin and doxorubicin (Adriamycin) (VDA), and nephrectomy, radiotherapy, additional VDA, and a third ICE cycle. Carboplatin dosage was based on glomerular filtration rate (GFR) to achieve targeted systemic exposure (6mg/ml min). Mean GFR (measured by technetium 99m-DTPA clearance) declined by 7% after 2 cycles of ICE and by 38% after nephrectomy; the mean carboplatin dose was reduced 32% after nephrectomy. Mean GFR remained stable after the third ICE cycle. Although urinary beta(2)-microglobulin excretion increased during therapy, no patient had clinically significant renal tubular dysfunction at the end of treatment. Treatment with ICE, nephrectomy and radiotherapy significantly reduces GFR, largely as the result of nephrectomy. Adjustment of carboplatin dosage on the basis of GFR and careful monitoring of renal function may alleviate nephrotoxicity.