Trends, patterns, and factors associated with HIV infection among males diagnosed with syphilis, 2014-2019, Hawaii.

OBJECTIVE: This study describes HIV infection and associated risk factors among males diagnosed with syphilis in Hawaii. METHODS: Hawaii sexually transmitted infection (STI) registry records of males diagnosed with syphilis, 2014-2019, were crossmatched with Hawaii HIV surveillance registry records through 2020 using CDC's Registry Plus Link Plus software. HIV status from the STI registry was validated by matching results. Logistic regression was used to examine demographic and behavioral factors associated with HIV infection. RESULTS: Among the 947 male syphilis cases, 257 (27.1%) had both syphilis and HIV infections. Dual infection rates were higher in earlier years (39.5% in 2015), among older patients (41.6% among persons ≥45 years old), males who have sex with males (MSM, 36.6%), and cases with repeated syphilis events (59.5%). The overall agreement on HIV status between the STI registry and matching results was 95.7%. CONCLUSIONS: Over a quarter (27.1%) of male syphilis cases were living with HIV. HIV infection rates were higher among older patients, MSM, and males with repeated syphilis events. Periodic matching between STI and HIV registries provides opportunities for quality control to both registries and opportunities to identify patients not linked to HIV care or who have fallen out of HIV care.

Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques.

BACKGROUND: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. METHODS: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). FINDINGS: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively. INTERPRETATION: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. FUNDING: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.

Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives.

This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (Ci) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (Ci-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked Ci-polyvinyl alcohol-boric acid (Ci-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to Ci gelling properties) on vaginal application (at acidic pH of ~3.5-4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7-8 of seminal fluid, thereby acting as a physical barrier to motile sperm. The gels were characterized for dynamic rheology, physicochemical properties, and impact on sperm functionality (motility, viability, penetration). The rheology data confirmed that the Ci-PBA gel was formed by ionic interactions whereas Ci-PVA-BA gel was chemically cross-linked and became more elastic at basic pH. Based on the screening data, lead gels were selected for in vitro sperm functionality testing. The in vitro results confirmed that the Ci-PBA and Ci-PVA-BA gels created a barrier at the sperm-gel interface, providing sperm blocking properties. For preclinical proof-of-concept, the Ci-PBA gels were applied vaginally and tested for contraceptive efficacy in rabbits, demonstrating only partial efficacy (40-60%). Overall, the in vitro and in vivo results support the development and further optimization of cross-linked gels using commercially available materials as vaginal contraceptives.

Microwave Ablation of Renal Cell Carcinoma.

Management options for small renal masses include active surveillance, partial nephrectomy, radical nephrectomy, and thermal ablation. For tumors typically ≤3 cm in size, thermal ablation is a good option for those desiring an alternative to surgery or active surveillance, especially in patients who are considered high surgical risk. We favor microwave ablation because of the more rapid heating, higher temperatures that overcome the heat sink effect of vessels, reproducible cell kill, and a highly visible ablation zone formed by water vapor that corresponds well to the zone of necrosis. For central tumors, we favor cryoablation because of the slower formation of the ablation zone and less likelihood of damage to the collecting system. With microwaves, it is important to monitor the ablation zone in real time (ultrasound is the best modality for this purpose), avoid direct punctures of the collecting system, and to place probes tangential to the collecting system to avoid burning open a persistent tract between the urothelium and extrarenal spaces or causing strictures. The surgical steps described in this video cover our use of high-frequency jet ventilation with general anesthesia to minimize organ motion, initial imaging and targeting, probe insertion, hydrodissection (a technique that enables displacement of adjacent structures), the ablation itself, and finally our dressing. Postoperative cares typically consist of observation with a same-day discharge or an overnight stay. Follow-up includes a magnetic resonance imaging abdomen with and without contrast, chest X-ray, and laboratories (basic metabolic panel, complete blood count, and C-reactive protein) 6 months postablation. Overall, percutaneous microwave ablation is an effective and safe treatment option for renal cell carcinoma in both T1a and T1b tumors in selected patients with multiple studies showing excellent oncologic outcomes when compared with partial and radical nephrectomy.

Incident Cases of Sexually Transmitted Infections among Users of Pre-Exposure Prophylaxis for HIV Prevention in Honolulu, Hawai'i.

Emtricitabine/tenofovir disoproxil fumarate [FTC-TDF] is a daily oral medication taken by HIV-negative individuals for pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus (HIV) infection. A higher incidence of sexually transmitted infections (STIs) among PrEP users has been reported compared to STI incidence before PrEP use. Asymptomatic incident STI rates were investigated among 78 patients presenting for PrEP in Honolulu, Hawai'i, from April 2018 to May 2019. Testing for oropharyngeal gonorrhea, urethral gonorrhea and chlamydia, rectal gonorrhea and chlamydia, and syphilis was performed. Incident STI percentages were calculated at each follow-up visit. Ninety-seven percent of patients were men who have sex with men (MSM). Forty-seven percent of patients had follow-up data 6 months after initiation and 28% after 1 year. Thirty-two percent of patients self-reported an STI before initiating PrEP. More than half reported anonymous partners. There were 35 positive STI tests during the study period, and 25% of patients had one or more positive tests during this time. At initiation, 17% of patients were found to have an STI, followed by 16% at 3 months, 14% at 6 months, 8% at 9 months, and 5% at 12 months. At all visits, chlamydia was the most common STI detected; at 6 months, 18% of all rectal tests were positive for chlamydia. There were inconsistent condom use and high STI rates from screening during PrEP initiation and follow-up, offering an opportunity to identify asymptomatic STIs in this population. This study is the first report in Hawai'i of STI rates among PrEP users.

Patient and provider characteristics associated with retention in HIV medical care and viral suppression among in care patients in Hawaii.

The percentages of retention in care and viral suppression among persons living with HIV (PLWH) in the United States from 2015 to 2018 were far below the 2020 national goals. This study aims to examine disparities in retention in care and viral suppression. The study population included PLWH diagnosed through 2016, residing in Hawaii at year-end 2016 and 2017, and who were in care in 2017 defined as having ≥1 CD4/viral load tests in 2017. Care providers were categorized as "very frequent" (≥50 patients), "frequent" (25-49 patients), "occasional" (10-24 patients), and "infrequent" (<10 patients). Among the 1752 patients included, 28.0% were not retained in care in 2017 (i.e., <2 CD4/VL tests performed at least 3 months apart), of whom 89.2% had only a single viral load test. Patients receiving care from the "infrequent" group of providers were less likely to be retained in care (adjusted odds ratio (aOR) = 0.48; 95% CI = 0.33, 0.69) or virally suppressed (aOR = 0.39; 95% CI = 0.24, 0.63), than patients receiving care from the "very frequent" group of providers. Percentages of three-year (2016-2018) in care and viral suppression were lowest among patients receiving care from "infrequent" care providers. Patients <45 years old were less likely to be retained in care (aOR = 0.53; 95% CI = 0.41, 0.68) or be virally suppressed (aOR = 0.59; 95% CI = 0.40, 0.86) than those 45 years or older. Patients of multiple races were less likely to be virally suppressed than whites (aOR = 0.38, 95% CI = 0.23, 0.64). Establishing a long-term relationship with an experienced HIV provider appears beneficial to achieve sustainable viral suppression and provision of uninterrupted HIV medical care.

Microwave Ablation of Adrenal Tumors in Patients With Continuous Intra-Arterial Blood Pressure Monitoring Without Prior Alpha-Adrenergic Blockade: Safety and Efficacy.

PURPOSE: Evaluate the safety and efficacy of adrenal microwave ablation performed with continuous intra-arterial blood pressure monitoring (IABPM) and without alpha-adrenergic blockade (AAB) as pretreatment. MATERIAL AND METHODS: A single-center, retrospective review of all percutaneous adrenal microwave ablation performed between 2011 and 2018. Microwave ablation was completed on 11 patients, with a total of 15 adrenal tumors with a mean size of 3.3 cm (1.4-6.9 cm) treated metastatic RCC, HCC, esophageal carcinoma, adrenal adenoma. Cases were performed without prior AAB, but with continuous IABPM and rapid intervention using short-acting antihypertensive medications. RESULTS: There were no post-procedural episodes of hypertension, no neurological or cardiovascular complications, and no SIR moderate or worse adverse event complications. Mean intraprocedural maximum systolic blood pressure (SBP) was 211 mmHg (range: 132-288), with an average increase in SBP of 100 mmHg (range: 23-180). A hypertensive crisis (SBP ≥ 180 and/or DBP ≥ 120) occurred in 9 of the 15 procedures (60%) with a mean length of 3.0 min (range: 1-12). The technical success rate was 100% (15/15 procedures). The mean follow-up time was 2.4 years (range: 0.9-7.7 years), with primary and secondary efficacy rates of 77% and 87%, respectively, and an overall survival of 82%. CONCLUSION: In this single-center retrospective study, microwave ablation of adrenal tumors without AAB was safe and effective when performed with continuous arterial line monitoring of vital signs and the use of short-acting, rapid-onset antihypertensive medications. LEVEL OF EVIDENCE: Level 4, Case Series.

Perioperative Multimodal Analgesia Reduces Opioid Use Following Skin Grafting in Nonintubated Burn Patients.

Hundreds of patients are treated for burn injuries each year at University of Wisconsin School of Medicine and Public Health. Pain management is particularly challenging during dressing changes and following skin grafting procedures. We performed a retrospective chart review from January 2011 through June 2018 to evaluate the effect of nonopioid analgesic medications on opioid use in nonintubated patients. Our primary outcome was the change in opioid use following the procedure. We found that most patients (69%) report severe pain (Numeric Rating Scale ≥7) immediately after autologous skin grafting. On average, patients required an additional 52 mg of oral morphine equivalents (ME) in the 24 h after the procedure compared with the 24 h before. The use of perioperative nonopioid analgesia varied between patients (acetaminophen 29%, gabapentin 29%, ketamine 35%, and all three 8%). Patients who received either gabapentin or a combination of acetaminophen, gabapentin, and ketamine had a smaller increase in their opioid use than patients who did not receive the medications (-25 ME, 95% confidence interval [-46, -4]; P = .018 and -47 ME, [-81, -11]; P = .010, respectively). These results support using a combination of acetaminophen, gabapentin, and ketamine for perioperative analgesia in burn patients undergoing autologous skin grafting.

Trends and Racial Disparities of Late-Stage HIV Diagnosis: Hawaii, 2010-2016.

OBJECTIVES: To examine racial/ethnic disparities in Hawaii in stage 3 classification at HIV diagnosis and trends in such disparities from 2010 through 2016. METHODS: We analyzed data including patients' demographic information, behavioral risk factors, residential county at HIV diagnosis, and type of facility where HIV was diagnosed. Multivariable logistic regression modeling was used to examine racial/ethnic disparities in late-stage diagnoses after adjustment for known or possible confounders. RESULTS: About 30% of HIV diagnoses were classified as late-stage (stage 3) diagnoses, and there were significant racial/ethnic disparities in stage 3 classification at diagnosis. Relative to Whites, the odds of being diagnosed at stage 3 were 3.7 times higher among Native Hawaiians and other Pacific Islanders (NHPIs; odds ratio [OR] = 3.69; 95% confidence interval [CI] = 1.89, 7.22) and more than twice as high among Asians (OR = 2.46; 95% CI = 1.16, 5.20). Older age and being diagnosed in an inpatient setting were associated with stage 3 classification. CONCLUSIONS: Targeted preventive services need to be strengthened for Asians and NHPIs in Hawaii.

Differential Effects of In Vitro Treatment with Cinobufotalin on Three Types of Ovarian Cancer Cells.

BACKGROUND/AIM: Cinobufotalin (CINO), a cardiotonic steroid, has been used as an anticancer agent. This study assessed the cell-specific effect of CINO on SK-OV-3, CRL-1978 and CRL-11731 ovarian cancer cells which differ in terms of their respective karyotypes. MATERIALS AND METHODS: Cell cultures were treated with CINO (0.1, 1, 5 and 10 µM) for 24, 48, and 72 h. Cell proliferation, migration, and invasion were measured using CellTiter, Cytoselect, and FluoroBlock assays, respectively. Expression of proliferating cell nuclear antigen (PCNA) was evaluated by western blot analysis. Cell viability was determined by fluorescence-activated cell sorting. Immunofluorescence was performed using Annexin-V staining and fluorescein isothiocyanate (FITC). Mitochondrial membrane potential (MMP) was measured using MitoTracker™ Red. RESULTS: CINO at 0.5 µM inhibited SK-OV-3, CRL-1978, and CRL-11731 proliferation, migration, and invasion. Each cell type differed in response to CINO doses for PCNA, Annexin-V expression and MMP. CONCLUSION: The antineoplastic property of CINO is consistent, but its mode of action varies among cell lines.

Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women.

To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20µg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94-100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing. Trial registration ClinicalTrials.gov #NCT02235662.

3,4',7-O-trimethylquercetin Inhibits Invasion and Migration of Ovarian Cancer Cells.

BACKGROUND/AIM: Methylquercetin, 3,4',7-O-trimethylquercetin (34'7TMQ), has been reported to inhibit metastasis. Recently, we demonstrated that 34'7TMQ inhibited the in vitro melanoma B16 cell metastatic activity. We evaluated the effect of 34'7TMQ on three ovarian cancer cells (SK-OV-3, CRL11731 and CRL1978). MATERIALS AND METHODS: Proliferation, migration and invasion were measured in 34'7TMQ-treated ovarian cancer cells by commercially available kits. We also evaluated the expression of proliferating cell nuclear antigen (PCNA), urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and matrix metalloproteinase (MMP)-2 by western blot analysis. RESULTS: 34'7TMQ inhibited ovarian cancer cell migration and invasion without effecting proliferation. Furthermore, 34'7TMQ inhibited the expression of uPA and MMP-2; however, it had no effect on PAI-1 and PCNA. CONCLUSION: 34'7TMQ significantly regulates the expressions of protein to inhibit metastasis in ovarian cancers, while the regulatory effects of 34'7TMQ vary between different ovarian cancer cell lines.

Spectroscopic evidence for a type II Weyl semimetallic state in MoTe2.

In a type I Dirac or Weyl semimetal, the low-energy states are squeezed to a single point in momentum space when the chemical potential µ is tuned precisely to the Dirac/Weyl point. Recently, a type II Weyl semimetal was predicted to exist, where the Weyl states connect hole and electron bands, separated by an indirect gap. This leads to unusual energy states, where hole and electron pockets touch at the Weyl point. Here we present the discovery of a type II topological Weyl semimetal state in pure MoTe2, where two sets of Weyl points (, ) exist at the touching points of electron and hole pockets and are located at different binding energies above EF. Using angle-resolved photoemission spectroscopy, modelling, density functional theory and calculations of Berry curvature, we identify the Weyl points and demonstrate that they are connected by different sets of Fermi arcs for each of the two surface terminations. We also find new surface 'track states' that form closed loops and are unique to type II Weyl semimetals. This material provides an exciting, new platform to study the properties of Weyl fermions.

Vaginal birth after caesarean section prediction models: a UK comparative observational study.

OBJECTIVE: Primarily, to assess the performance of three statistical models in predicting successful vaginal birth in patients attempting a trial of labour after one previous lower segment caesarean section (TOLAC). The statistically most reliable models were subsequently subjected to validation testing in a local antenatal population. STUDY DESIGN: A retrospective observational study was performed with study data collected from the Northern Ireland Maternity Service Database (NIMATs). The study population included all women that underwent a TOLAC (n=385) from 2010 to 2012 in a regional UK obstetric unit. Data was collected from the Northern Ireland Maternity Service Database (NIMATs). Area under the curve (AUC) and correlation analysis was performed. RESULTS: Of the three prediction models evaluated, AUC calculations for the Smith et al., Grobman et al. and Troyer and Parisi Models were 0.74, 0.72 and 0.65, respectively. Using the Smith et al. model, 52% of women had a low risk of caesarean section (CS) (predicted VBAC >72%) and 20% had a high risk of CS (predicted VBAC <60%), of whom 20% and 63% had delivery by CS. The fit between observed and predicted outcome in this study cohort using the Smith et al. and Grobman et al. models were greatest (Chi-square test, p=0.228 and 0.904), validating both within the population. CONCLUSION: The Smith et al. and Grobman et al. models could potentially be utilized within the UK to provide women with an informed choice when deciding on mode of delivery after a previous CS.

First phase 1 double-blind, placebo-controlled, randomized rectal microbicide trial using UC781 gel with a novel index of ex vivo efficacy.

OBJECTIVES: Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. METHODS: HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1∶1∶1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. RESULTS: All 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1(BaL) showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. CONCLUSIONS: Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538).

Preclinical evaluation of UC781 microbicide vaginal drug delivery.

UC781 is a potent nonnucleoside reverse transcriptase inhibitor being investigated as a potential microbicide to prevent transmission of HIV-1 both vaginally and rectally. This study was designed to investigate the in vitro drug release, in vitro permeability/safety, and in vivo pharmacokinetics in rabbits of a vaginal gel prepared with micronized or nonmicronized UC781 (UC781m and UC781nm, respectively). Gels prepared with UC781m had greater in vitro release rates (Franz cells) and permeability/tissue-associated UC781 concentrations than gels prepared with UC781nm (EpiVaginal tissues). Both gels were well tolerated under in vitro conditions compared with controls using EpiVaginal tissues. Following intravaginal administration of both gels to rabbits, tissue concentrations typically ranged from 1,000 to over 10,000 ng/g regardless of dosing regimen (single dose or 7 days once daily dosing) and sampling times (2 and 24 h post-dose). Tissue-associated concentrations were highly variable, and no statistically significant differences were found between test conditions. Plasma levels were generally low after vaginal administration: following a single dose, the concentrations were between 0.5 and 1.0 ng/mL. After 7 days repeated once daily dosing, UC781 concentrations were slightly higher ranging from below 1.0 to about 2 ng/mL, although none of the differences were statistically significant. Based on these results, gels prepared with either form of UC781 led to tissue concentrations well in excess of UC781's EC50 under in vitro conditions (~3 ng/mL).

Aggressive small cell carcinoma of the ovary, hypercalcemic type with hypercalcemia in pregnancy, treated with conservative surgery and chemotherapy.

BACKGROUND: Small cell carcinoma of the ovary, hypercalcemic type is a rare and aggressive malignancy found in reproductive-age women. CASE: We report a 22-year-old pregnant woman found to have symptomatic paraneoplastic hypercalcemia associated with small cell carcinoma of the ovary, hypercalcemic type. She was primarily treated with conservative surgery and chemotherapy secondary to desired pregnancy. She died of the disease 10 months from primary diagnosis. CONCLUSIONS: Small cell carcinoma of the ovary, hypercalcemic type is a very aggressive type of ovarian malignancy with a poor prognosis.

Aligning risk management with patient safety.

There are four key components to the success of HCCI, a captive insurance company formed by five healthcare systems: Common and aligned goals. A commitment to ongoing education. Open and honest dialogue among member-owners. Easy-to-use technology to support information flow and decision making.

A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor.

GOAL: This study evaluated the effect of a single dose and 5 additional consecutive daily doses of UC781 gel at concentrations of 0.1%, 0.25%, 1.0%, and 0% on urogenital irritation. STUDY DESIGN: Forty-eight healthy sexually abstinent women were randomly assigned to 1 of 4 groups. METHODS: Urogenital irritation was assessed by pelvic examination, colposcopy, and reports of genital symptoms at baseline and after 1 and 6 doses. Vaginal health was assessed by wet mount and systemic safety by laboratory evaluation after 1 and 6 doses, and UC781 levels were assessed at baseline and after 6 doses. RESULTS: Some evidence of urogenital irritation was common in all treatment groups and was most often transient and mild. Colposcopic findings were infrequent in the placebo group (8%) and more common in the 3 treatment groups (24%-42%). Edema, which may indicate underlying inflammation, was observed in the vaginal fornix of 2 women exposed to UC781. There was no apparent increase in vaginal infection or clinically significant changes in laboratory values. Two of 12 participants randomized to 1% UC781 gel had detectable plasma levels that were less than the lower level of quantification. CONCLUSIONS: UC781 was well tolerated in this initial dose ranging safety study when used once daily for 6 days in sexually abstinent women. Five safety/pharmacokinetic studies of UC781 are currently underway in women and men, all utilizing UC781 concentrations less than 1%, with twice-daily dosing in some studies, and all involving careful monitoring of exposed epithelium.

In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials.

The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.