The PEARL study: a prospective two-group pilot PrEP promotion intervention for cisgender female sex workers living in Baltimore, MD, U.S.

HIV remains elevated among female sex workers (FSW) globally, with a number of structural (e.g., poverty, access to care) factors driving these persistently high rates. Pre-exposure prophylaxis (PrEP), a user-controlled prevention method, is a promising means of empowering vulnerable populations to protect themselves and enhance agency. Yet there is a dearth of PrEP research and interventions targeting cisgender women in the United States, and even fewer aimed to reach FSW. We developed and implemented a multifaceted PrEP pilot intervention, the Promoting Empowerment And Risk Reduction (PEARL) study, to meet this gap. This paper describes the development process and nature of a community-informed intervention for tenofovir/emticitrabine (TDF/FTC) pre-exposure prophylaxis engagement among street-based cisgender FSW in Baltimore, Maryland, U.S. In the course of the study's implementation, structural, programmatic, and medical barriers have already posed significant barriers to full engagement. PEARL implemented a number of strategies in an effort to counter barriers and facilitate increased success of PrEP uptake and maintenance. The study will provide critical insights into the nature of intervention components that could help FSW to initiate PrEP and reduce PrEP care cascade gaps.

A multipronged, nutritional-based strategy for managing Alzheimer's disease.

A nutritional-based strategy has been proposed in order to improve cognitive performance of Alzheimer's disease (AD) patients. The strategy requires daily dietary supplementation with magnesium (Mg), folic acid, and vitamins B6 and B12, daily consumption of silicic acid-rich mineral water in order to lower the body burden of Al, and several plasma exchange procedures in order to replace Aß-bound albumin with fresh albumin. Evidence suggests that the deteriorating cognitive performance associated with AD may be improved by supplementation with either Mg alone or with the combination of the above three B vitamins (B vitamin combo), or by drinking silicic acid-rich mineral water, or by undergoing plasma exchange. However, for the following reasons the combination of all four therapeutic approaches may have a synergistic effect on improving cognitive performance of AD patients.

Risk factors associated with resistance to HIV testing among transwomen in Brazil.

Transwomen are a high-risk population for HIV/AIDS worldwide. However, many transwomen do not test for HIV. This study aimed to identify factors associated with resistance to HIV testing among transwomen in Fortaleza/CE. A cross-sectional study was conducted between August and December 2008 with a sample of 304 transwomen recruited through respondent-driven sampling. Data analysis utilized Respondent-Driven Sampling Analysis Tool and SPSS 11.0. Univariate, bivariate, and multivariate analyses examined risk factors associated with resistance to HIV testing. Less than 18 years of age (OR = 4.221; CI = 2.419-7.364), sexual debut before 10 years of age (OR = 6.760; CI = 2.996-15.256), using illegal drugs during sex (OR = 2.384; CI = 1.310-4.339), experience of discrimination (OR = 3.962; CI = 1.540-10.195) and a belief that the test results were not confidential (OR = 3.763; CI = 2.118-6.688) are independently associated with resistance to testing. Intersectoral and targeted strategies aimed at encouraging the adoption of safer sexual behaviors and testing for HIV among transwomen are required.

Conjunctivitis outbreak among divers.

In March 2006, an outbreak of conjunctivitis that occurred over a six day period among twenty-nine individuals who partook in recreational scuba diving trips on two boats off Vitu Levu Island, Fiji. We investigated the likelihood that a communal container used to store diving masks facilitated the spread of conjunctivitis among individuals. The diagnosis of conjunctivitis was based on clinical assessment by a physician. Transmission of conjunctivitis from person to person was documented with eventual identification of the index case, the dive master, a Fijian resident. Topical antibiotics were dispensed accordingly and detergent and bleach were used as mask cleaning agents in an effort to control the outbreak. Follow up surveys were mailed to all twenty-nine participants. Ultimately, fourteen cases of conjunctivitis were documented (46.7%). Eleven cases were verified during the six days in Fiji, two upon arrival back in the U.S., and one case of familial transmission in the U.S. All but two cases resolved within one week. Unknown to these divers was a coincidental, generalized outbreak of acute haemorrhagic conjunctivitis among the Fijian Residents. The communal container used to store diving masks was the likely vector for the spread of infectious conjunctivitis, the first such documented outbreak involving communal diving equipment.

First--select the target: better choice of adjuvant treatments for breast cancer patients.

St Gallen Expert Consensus meetings update evidence on treatment of early breast cancer every 2 years and interpret its significance for treatment of individual patients. Such interpretation is controversial. Clinical decisions cannot, however, be postponed, and the harms of failing to tailor treatment must be balanced against those of overinterpretation. Since the ninth meeting in January 2005, an extraordinary year of progress has significantly changed the landscape in breast cancer therapy. The panel in January recommended a fundamental change in selection of adjuvant systemic therapy, giving prime attention to endocrine responsiveness. Primarily, three categories were acknowledged: endocrine responsive in which the primary treatment should be endocrine, endocrine non-responsive in which endocrine therapy should not be used, and an intermediate group for which both endocrine and other therapies should be offered. Secondarily, three risk groups were defined: low, intermediate, and high, slightly modifying the previous classification. In June 2005, three trials, supported in December by a fourth, demonstrated the additional contribution of targeted therapy with trastuzumab in appropriately selected patients. Reports from several trials strengthened the evidence supporting the inclusion of taxanes, though controversy persists concerning their use in endocrine-responsive disease. This commentary midway between St Gallen meetings, therefore, emphasizes how new information influences algorithms for selecting adjuvant therapy in a rapidly changing environment.

Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005.

The ninth St Gallen (Switzerland) expert consensus meeting in January 2005 made a fundamental change in the algorithm for selection of adjuvant systemic therapy for early breast cancer. Rather than the earlier approach commencing with risk assessment, the Panel affirmed that the first consideration was endocrine responsiveness. Three categories were acknowledged: endocrine responsive, endocrine non-responsive and tumors of uncertain endocrine responsiveness. The three categories were further divided according to menopausal status. Only then did the Panel divide patients into low-, intermediate- and high-risk categories. It agreed that axillary lymph node involvement did not automatically define high risk. Intermediate risk included both node-negative disease (if some features of the primary tumor indicated elevated risk) and patients with one to three involved lymph nodes without additional high-risk features such as HER 2/neu gene overexpression. The Panel recommended that patients be offered chemotherapy for endocrine non-responsive disease; endocrine therapy as the primary therapy for endocrine responsive disease, adding chemotherapy for some intermediate- and all high-risk groups in this category; and both chemotherapy and endocrine therapy for all patients in the uncertain endocrine response category except those in the low-risk group.

Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer.

We performed an economic analysis of data from 180 women in a clinical trial of conventional-dose chemotherapy vs high-dose chemotherapy plus stem-cell transplantation for metastatic breast cancer responding to first-line chemotherapy. Data on resource use, including hospitalizations, medical procedures, medications, and diagnostic tests, were abstracted from subjects' clinical trial records. Resources were valued using the Medicare Fee Schedule for inpatient costs at one academic medical center and average wholesale prices for medications. Monthly costs were calculated and stratified by treatment group and clinical phase. Mean follow-up was 690 days in the transplantation group and 758 days in the conventional-dose chemotherapy group. Subjects in the transplantation group were hospitalized for more days (28.6 vs 17.8, P=0.0041) and incurred higher costs (US dollars 84055 vs US dollars 28169) than subjects receiving conventional-dose chemotherapy, with a mean difference of US dollars 55886 (95% CI, US dollars 47298-US dollars 63666). Sensitivity analyses resulted in cost differences between the treatment groups from US dollars 36528 to US dollars 75531. High-dose chemotherapy plus stem-cell transplantation resulted in substantial additional morbidity and costs at no improvement in survival. Neither the survival results nor the economic findings support the use of this procedure outside of the clinical trial setting.

Cloning and localization of the cGMP-specific phosphodiesterase type 9 in the rat brain.

In this study, we report the cloning of the rat cGMP-specific phosphodiesterase type 9 (PDE9A) and its localization in rat and mouse brain by non-radioactive in situ hybridization. Rat PDE9A was 97.6% identical to mouse PDE9A1 and showed 92.1% similarity on the amino acid level to the human homologue. PDE9A mRNA was widely distributed throughout the rat and mouse brain, with the highest expression observed in cerebellar Purkinje cells. Furthermore, strong staining was detected in areas such as cortical layer V, olfactory tubercle, caudate putamen and hippocampal pyramidal and granule cells. Comparison of PDE9A mRNA expression by double staining with the cellular markers NeuN and glial fibrillary acidic protein demonstrated that PDE9A expression was mainly detected in neurons and in a subpopulation of astrocytes. Using cGMP-immunocytochemistry, the localization of cGMP was investigated in the cerebellum in which the highest PDE9 expression was demonstrated. Strong cGMP immunoreactivity was detected in the molecular layer in the presence of the non-selective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). After treatment with soluble guanylyl cyclase activators the granular layer also showed cGMP staining, whereas no clear immunostaining was detected in Purkinje cells under all conditions investigated, which might be due to the presence of the IBMX-insensitive PDE9A in these cells. The present findings indicate that PDE9A is highly conserved between species and is widely distributed throughout the rodent brain. PDE9A is probably involved in maintenance of low cGMP levels in cells and might play an important role in a variety of brain functions involving cGMP-mediated signal transduction.

Hip arthroscopy. The lateral approach.

The lateral approach provides an easy and safe access to the hip joint. The line from skin to the joint itself is a straight, downward drop (Fig. 18). The vital arteries and nerves are a safe distance from the portal sites. The potential problems that can arise from this procedure are from the traction applying a compression force on the branches of the pudendal nerve as they cross the ischium (Fig. 19) and traction force on the sciatic nerve. I have always maintained that traction should be treated like a tourniquet; that is, it should be applied for no more then 2 hours. [figure: see text] Furthermore, the amount of traction should not exceed 75 pounds. I use a tensiometer, but it is not mandatory because the major issue with traction is the duration of application. I have monitored the sciatic nerve using both evoke potentials and, in some cases, motor potentials in over 50 cases in the past year, and the poundage and time limits of the traction (75 pounds and 2 hours) were verified. In addition, if the fracture [figure: see text] table has a vertical post as well as a peroneal post, set the vertical post in the back of the patient, and not in the front. Flexing the hip around that post will greatly increase the traction and at the same time will place an extreme stretch on the sciatic nerve, setting up the chance of a significant sciatic nerve neuropraxia. To protect the pudendal nerve, Lyon et al suggest that the perineal post be at least 9 cm in diameter to distribute the forces in a wide area on the ischium and make sure that the pelvis is well supported so the pressure of the post is not placed directly on the this nerve. The perineal posts on most fracture tables are only 3 cm in diameter. These can be made larger by wrapping them with padding. In some fracture tables, the slats that support the lower leg can be removed, and consequently the support on the pelvis is lost. For hip arthroscopy, the slats do not have to be removed. The lateral approach provides a safe and simple way of performing hip arthroscopy. The instruments can be manipulated easily so that the entire confines of the joint can be visualized with the arthroscope and reached with operative instruments.

Bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone (BLEO-CCVPP) in patients with Hodgkin's disease who relapsed after radiotherapy alone: a long-term follow-up study of the Eastern Cooperative Oncology Group (E3481).

Thirty-three evaluable patients with Hodgkin's disease who failed radiotherapy were treated on this phase II study with bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone given every 28 days for a minimum of eight courses. Twenty-five patients (76%; 95% CI=55.6-87.1%) achieved a complete remission, the median duration of which cannot yet be determined, but the probability of remaining in continuous complete remission at 10 years is.64. The median survival from entry on this study for all evaluable patients is 10 years, and 12 patients were alive at the time of this analysis with a median follow-up for them of 15.5 years. Of the 22 patients who died, 11 died of progressive or recurrent Hodgkin's disease and 11 died of other causes including 7 second primary neoplasms and at least one myocardial infarction. Both are now well known late complications of Hodgkin's disease treatment.

The impact of a multidisciplinary breast cancer center on recommendations for patient management: the University of Pennsylvania experience.

BACKGROUND: Advances in the diagnosis and treatment of breast carcinoma have led to a multidisciplinary approach to management for patients with breast carcinoma. To assess the effect of this approach, the authors performed an evaluation for a cohort of patients examined in a multidisciplinary breast cancer center. METHODS: An analysis was performed for the records of 75 consecutive women with 77 breast lesions examined in consultation in a multidisciplinary breast cancer center between January and June 1998. Each patient's case was evaluated by a panel consisting of a medical oncologist, surgical oncologist, radiation oncologist, pathologist, diagnostic radiologist, and, when indicated, plastic surgeon. A comprehensive history and physical examination was performed, and the relevant mammograms, pathology slides, and medical records were reviewed. Treatment recommendations made before this evaluation were compared with the consensus recommendations made by the panel. RESULTS: For the 75 patients, the multidisciplinary panel disagreed with the treatment recommendations from the outside physicians in 32 cases (43%), and agreed in 41 cases (55%). Two patients (3%) had no treatment recommendation before consultation. For the 32 patients with a disagreement, the treatment recommendations were breast-conservation treatment instead of mastectomy (n = 13; 41%) or reexcision (n = 2; 6%); further workup instead of immediate definitive treatment (n = 10; 31%); treatment based on major change in diagnosis on pathology review (n = 3; 9%); addition of postmastectomy radiation treatment (n = 3; 9%); or addition of hormonal therapy (n = 1; 3%). CONCLUSIONS: The multidisciplinary breast cancer evaluation program provided an integrated program in which individual patients were evaluated by a team of physicians and led to a change in treatment recommendation for 43% (32 of 75) of the patients examined. This multidisciplinary program provided important second opinions for many patients with breast carcinoma.

Phenotypic correction of lipid storage and growth arrest in wolman disease fibroblasts by gene transfer of lysosomal acid lipase.

Wolman disease is a lethal lysosomal storage disease due to deficiency of lysosomal acid lipase (LAL). Wolman disease is characterized by pronounced hepatic involvement while neurological symptoms are uncommon, making Wolman disease an attractive candidate for liver-directed gene therapy. This study was performed to test the effects of gene replacement in fibroblasts lacking LAL, using a recombinant adenovirus encoding the human LAL cDNA (AdhLAL). Human fibroblasts from a Wolman disease patient were infected with AdhLAL and showed a dose-dependent increase in LAL protein and activity up to 5-fold above levels in control fibroblasts. Furthermore, 72 hr after infection with AdhLAL there was a dose-dependent correction of the severe lipid storage phenotype of Wolman disease fibroblasts. Electron microscopy confirmed significant correction of the lysosomal lipid storage in AdhLAL-infected Wolman disease fibroblasts at the ultrastructural level. Intravenous injection of AdhLAL into wild-type mice resulted in a 13.5-fold increase in hepatic LAL activity, and overexpression of LAL was not associated with toxic side effects. These data demonstrate high-level lysosomal expression of recombinant LAL in vitro and in vivo and show the feasibility of gene therapeutic strategies for the treatment of Wolman disease.

Arthroscopically assisted excision of osteoid osteoma involving the hip.

Two cases of arthroscopically assisted excision of osteoid osteoma involving the femoral neck and acetabulum are presented. This technique allows for percutaneous excision of this benign bone lesion in those rare circumstances when it occurs in an intra-articular location. The approach enables direct visualization of the tumor as well as histologic confirmation. There was minimal morbidity, excellent relief of symptoms, and rapid functional restoration.

Sterol carrier protein 2 gene transfer changes lipid metabolism and enterohepatic sterol circulation in mice.

BACKGROUND & AIMS: Sterol carrier protein 2 (SCP-2) enhances sterol cycling and facilitates cholesterol translocation between intracellular organelles and plasma membrane in cultured cells, including hepatocytes. We examined the role of SCP-2 in hepatic cholesterol and lipid trafficking through the sinusoidal and canalicular secretory pathways of the liver in vivo. METHODS: Recombinant adenovirus-mediated SCP-2 gene transfer was used to obtain hepatic overexpression of SCP-2 in C57BL/6 mice. RESULTS: SCP-2 overexpression in the mouse liver resulted in an 8-fold increase of SCP-2 protein levels and determined various effects on lipid metabolism. It decreased high-density lipoprotein cholesterol and increased low-density lipoprotein (LDL) cholesterol concentrations. The expressions of hepatic LDL receptor, apolipoprotein (apo) A-I, apoB, and apoE were decreased. SCP-2 overexpression also increased hepatic cholesterol concentration, associated with decreased cholesterol neosynthesis. Increased biliary cholesterol and bile acid secretion, bile acid pool size, and intestinal cholesterol absorption were also observed. CONCLUSIONS: These results indicate that modulation of SCP-2 expression in the liver determines important modifications on lipoprotein metabolism, hepatic cholesterol synthesis and storage, biliary lipid secretion, bile acid metabolism, and intestinal cholesterol absorption.

Effects of overexpression of the amino-terminal fragment of apolipoprotein B on apolipoprotein B and lipoprotein production.

In vitro studies have shown that the binding site for microsomal triglyceride transfer protein (MTP) is within the first 17% of apoB (apoB-17). Expression of apoB-48 in McArdle cells decreases endogenous lipoprotein production; however, overexpression of human apoB in transgenic mice does not decrease endogenous mouse apoB expression. To assess this inconsistency, adenoviruses expressing human apoB-17 (AdB17) or apoB-17-beta (which contains apoB-17 plus a small lipid-binding beta-sheet region of apoB, AdB-17beta) were produced. Hepatoma cells were infected with AdB17 or AdB17-beta with AdLacZ, an adenovirus expressing beta-galactosidase, as a control. Overexpression of apoB-17 and apoB-17-beta in hepatoma cells to levels 2- to 3-fold greater than that of endogenous apoB did not alter endogenous apoB production. This was also true in the presence of oleic acid and N-acetyl-leucyl-leucyl-norleucinal. High levels of apoB-17 or beta-galactosidase expression reduced apoB-100 production; however, control protein production was also reduced. To assess the effects of apoB-17 expression in vivo, mice of three different strains were injected with AdB17. Two days after injection, plasma apoB-17 was approximately 24 times the amount of endogenous apoB in the C57BL/6 mice, 2 times the apoB-100 in human apoB transgenic mice, and 4 times the apoB-48 in apoE knockout mice. Overexpression of apoB-17 did not decrease apoB-100 or apoB-48 concentrations in mouse plasma as assessed by Western blot analysis. These results demonstrate that although the apoB-17 binds to MTP in vitro, it does not alter endogenous apoB expression in mice or in hepatoma cells.

Analysis of outcomes for high-risk breast cancer based on interval from surgery to postmastectomy radiation therapy.

PURPOSE: The success of adjuvant chemotherapy has prolonged the interval between surgery and postmastectomy radiation therapy for high-risk breast cancer patients. The purpose of this study is to determine whether a delay in radiation therapy after mastectomy results in an increased risk of local-regional recurrence of breast cancer. MATERIALS AND METHODS: A retrospective review was performed of the University of Pennsylvania database of 221 patients with high-risk breast cancer treated with postmastectomy radiation therapy between 1977 and 1992. The surgery to postmastectomy radiation therapy time interval was 2 months or less in 82 patients (37%), 2.1 to 6 months in 50 patients (23%), and greater than 6 months in 89 patients (40%). Adjuvant chemotherapy was utilized in 151 patients (68%). The median follow-up was 4.3 years after postmastectomy radiation therapy. RESULTS: Because the three groups showed significant differences for a number of prognostic factors, outcomes are reported in terms of local-regional recurrence only and not survival. The actuarial rate of local-regional recurrence at 8 years was 13% for patients with a surgery to radiation therapy interval of 2 months or less, 4% for those with an interval of 2.1 to 6 months, and 12% for those with an interval of greater than 6 months. A similar analysis performed for 4 months or less versus greater than 4 months between surgery and postmastectomy radiation therapy showed no difference in local-regional recurrence (11% versus 10%, respectively). CONCLUSIONS: A delay in the institution of postmastectomy radiation therapy in favor of the prolongation of chemotherapy for high-risk breast cancer patients does not adversely affect outcome for local-regional recurrence at 8 years.

Hepatic apolipoprotein E expression promotes very low density lipoprotein-apolipoprotein B production in vivo in mice.

In addition to its role in the uptake of apolipoprotein B (apoB)-containing lipoproteins, apoE promotes hepatic very low density lipoprotein-triglyceride (VLDL-TG) production in animal models. However, it is not known if apoE increases the amount of TG per VLDL particle or the number of VLDL particles secreted. VLDL-apoB production is a measure of the rate of VLDL particle secretion. We determined the effects of apoE deficiency and apoE overexpression on VLDL-apoB production in mice. [(35)S]methionine was injected into endogenously label VLDL-apoB and Triton WR-1339 was simultaneously injected to block the catabolism of VLDL. Compared with wild-type mice, the VLDL-apoB production rate was decreased by 33% in apoE-deficient mice. Conversely, VLDL-apoB production was increased by 48% in mice overexpressing apoE compared with controls. Nascent VLDL, obtained from post-Triton plasma, had a decreased, not increased, content of TG per apoB in the apoE-overexpressing group compared with the control group. This study demonstrates that hepatic apoE expression increases the output of VLDL triglyceride by increasing the production rate of VLDL-apoB, suggesting that hepatic apoE influences the number of VLDL particles secreted by the liver.