New Ameloblastoma Cell Lines Enable Preclinical Study of Targeted Therapies.

Ameloblastoma (AB) is an odontogenic tumor that arises from ameloblast-lineage cells. Although relatively uncommon and rarely metastatic, AB tumors are locally invasive and destructive to the jawbone and surrounding structures. Standard-of-care surgical resection often leads to disfigurement, and many tumors will locally recur, necessitating increasingly challenging surgeries. Recent genomic studies of AB have uncovered oncogenic driver mutations, including in the mitogen-activated protein kinase (MAPK) and Hedgehog signaling pathways. Medical therapies targeting those drivers would be a highly desirable alternative or addition to surgery; however, a paucity of existing AB cell lines has stymied clinical translation. To bridge this gap, here we report the establishment of 6 new AB cell lines-generated by "conditional reprogramming"-and their genomic characterization that reveals driver mutations in FGFR2, KRAS, NRAS, BRAF, PIK3CA, and SMO. Furthermore, in proof-of-principle studies, we use the new cell lines to investigate AB oncogene dependency and drug sensitivity. Among our findings, AB cells with KRAS or NRAS mutation (MAPK pathway) are exquisitely sensitive to MEK inhibition, which propels ameloblast differentiation. AB cells with activating SMO-L412F mutation (Hedgehog pathway) are insensitive to vismodegib; however, a distinct small-molecule SMO inhibitor, BMS-833923, significantly reduces both downstream Hedgehog signaling and tumor cell viability. The novel cell line resource enables preclinical studies and promises to speed the translation of new molecularly targeted therapies for the management of ameloblastoma and related odontogenic neoplasms.

Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Placental characteristics and risks of maternal mortality 50 years after delivery.

INTRODUCTION: Adverse pregnancy outcomes such as preterm delivery and preeclampsia are associated with a higher maternal risk for subsequent cardiovascular disease (CVD) and all-cause mortality. While such pregnancy conditions are related to abnormal placentation, little research has investigated whether pathologic placental measures could serve as a risk factor for future CVD mortality in mothers. METHODS: Longitudinal study of 33,336 women from the Collaborative Perinatal Project (CPP; 1959-1966) linked to mortality information through December 2016. Pathologists took extensive morphological and histopathological measures. Apart from assessing associations with morphological features, we derived an overall composite score and specific inflammation-related, hemorrhage-related, and hypoxia-related pathologic placenta index scores. Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for mortality adjusting for covariates. RESULTS: Thirty-nine percent of women died with mean (standard deviation, SD) time to death of 39 (12) years. Mean (SD) placental weight and birthweight were 436 g (98) and 3156 g (566), respectively. Placenta-to-birthweight ratio was associated with all-cause mortality (adjusted HR 1.03: 1.01, 1.05 per SD in ratio). In cause-specific analyses, it was significantly associated with respiratory (HR 1.06), dementia (HR: 1.10) and liver (HR 1.04) related deaths. CVD, cancer, diabetes and kidney related deaths also tended to increase, whereas infection related deaths did not (HR 0.94; 0.83, 1.06). Placental measures of thickness, diameters, and histopathological measures grouped by inflammatory, hemorrhagic, or hypoxic etiology were not associated with mortality. DISCUSSION: Placental weight in relation to birthweight was associated with long-term maternal mortality but other histopathologic or morphologic features were not.

Markers of vitamin D metabolism and premenstrual symptoms in healthy women with regular cycles.

STUDY QUESTION: Are insufficient 25-hydroxyvitamin D (25(OH)D) concentrations, and other markers of vitamin D metabolism, associated with premenstrual symptoms in healthy women with regular menstrual cycles? SUMMARY ANSWER: 25(OH)D insufficiency was associated with specific physical premenstrual symptoms, while no associations were observed with psychological symptoms or with other markers of vitamin D metabolism. WHAT IS KNOWN ALREADY: Prior studies evaluating vitamin D and premenstrual symptoms have yielded mixed results, and it is unknown whether 25(OH)D insufficiency and other markers of vitamin D metabolism are associated with premenstrual symptoms. STUDY DESIGN, SIZE, DURATION: We used two cohorts of women with regular menstrual cycles; 1191 women aged 18-40 years in EAGeR (cross-sectional analysis of a prospective cohort within a randomized trial) and 76 women aged 18-44 years in BioCycle (prospective cohort). In EAGeR, premenstrual symptoms over the previous year were assessed at baseline, whereas in BioCycle, symptoms were assessed prospectively at multiple points over two menstrual cycles with symptoms queried over the previous week. In both cohorts, symptomatology was assessed via questionnaire regarding presence and severity of 14 physical and psychological symptoms the week before and after menses. Both studies measured 25(OH)D in serum. We also evaluated the association of additional markers of vitamin D metabolism and calcium homeostasis, including intact parathyroid hormone (iPTH), calcium (Ca), fibroblast growth factor 23 (FGF23), and 1,25 dihydroxyvitamin D (1,25(OH)2D) with premenstrual symptoms in the BioCycle cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: One cohort of women actively seeking pregnancy (Effects of Aspirin in Gestation and Reproduction (EAGeR)) and one cohort not seeking pregnancy (BioCycle) were evaluated. Log-binomial regression was used to estimate risk ratios (RR) and 95% CIs for associations between insufficient 25(OH)D (<30 ng/ml) and individual premenstrual symptoms, adjusting for age, BMI, race, smoking, income, physical activity, and season of blood draw. MAIN RESULTS AND THE ROLE OF CHANCE: 25(OH)D insufficiency was associated with increased risk of breast fullness/tenderness (EAGeR RR 1.27, 95% CI 1.03, 1.55; BioCycle RR 1.37, 95% CI 0.56, 3.32) and generalized aches and pains (EAGeR RR 1.33, 95% CI 1.01, 1.78; BioCycle 1.36, 95% CI 0.41, 4.45), though results were imprecise in the BioCycle study. No associations were observed between insufficient 25(OH)D and psychological symptoms in either cohort. In BioCycle, iPTH, Ca, FGF23, and 1,25(OH) 2D were not associated with any premenstrual symptoms. LIMITATIONS, REASONS FOR CAUTION: Results from the EAGeR study were limited by the study design, which assessed both 25(OH)D at baseline and individual premenstrual symptoms over the past year at the baseline. As such, reverse causality is a potential concern. Though premenstrual symptoms were assessed prospectively in the BioCycle cohort, the power was limited due to small sample size. However, results were fairly consistent across both studies. WIDER IMPLICATIONS OF THE FINDINGS: Serum 25(OH)D may be associated with risk and severity of specific physical premenstrual symptoms. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract nos. HHSN267200603423, HHSN267200603424, and HHSN267200603426). JG.R. and D.L.K. have been funded by the NIH Medical Research Scholars Program, a public-private partnership jointly supported by the NIH and generous contributions to the Foundation for the NIH by the Doris Duke Charitable Foundation (Grant #2014194), the American Association for Dental Research, the Colgate Palmolive Company, Genentech, and other private donors. For a complete list, visit the foundation website at http://www.fnih.org. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.

Parity associated with telomere length among US reproductive age women.

STUDY QUESTION: Is telomere length related to parity among a nationally representative sample of US reproductive age women? SUMMARY ANSWER: History of live birth was associated with shorter telomere length. WHAT IS KNOWN ALREADY: Shorter telomeres have been linked with a range of chronic health conditions and mortality and parity has been associated with health indicators. However, there is a lack of research on how parity relates to telomere length. STUDY DESIGN, SIZE, DURATION: This nationally representative, cross-sectional study included 1954 women from the National Health and Nutrition Examination Survey, 1999-2002, the only survey period which includes measurement of telomere length. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 20-44 were included. Parity, defined as number of previous live births, was ascertained by questionnaire. Leukocyte telomere length was measured by polymerase chain reaction and reported as a ratio in relation to standard reference DNA (T/S ratio). The relationship between leukocyte T/S ratio and parity was examined using survey weighted linear regression. Models were adjusted for race/ethnicity, age, BMI, income-to-poverty ratio, education, early age at menarche and smoking status. MAIN RESULTS AND THE ROLE OF CHANCE: Among reproductive age women in the US, the adjusted mean leukocyte T/S ratio was 4.2% (95% CI: 0.9, 7.3) shorter in parous compared with nulliparous women. Parity was associated with 116 fewer base pairs (95% CI: 26, 204) on average, using estimated coefficients from the adjusted linear regression models and mean covariate values. LIMITATIONS REASONS FOR CAUTION: This study was cross-sectional and therefore was unable to establish temporality. The dataset lacked information on social factors, stress and fertility status, which may help explain these findings. Only two previous studies have examined this question and our findings should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: These findings in a nationally representative sample of US reproductive age women suggest that history of live birth may be associated with accelerated cellular aging. The magnitude of the observed association was greater than that of the impact of smoking or obesity on telomere length, suggesting that parity may have an independent influence on cellular aging and warrant further study. STUDY FUNDING/COMPETING INTEREST(S): The study was funded in part by the Undergraduate Research Scholars Program at George Mason University. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.

Aflibercept as a Second Line Therapy for Neovascular Age Related Macular Degeneration in Israel (ASLI) study.

PurposeThe purpose of this study is to evaluate an early switch to aflibecept in eyes with neovascular age-related macular degeneration (nvAMD) showing partial or lack of response for initial therapy with bevacizumab.MethodsThe Aflibercept as a Second Line Therapy for Neovascular Age Related Macular Degeneration in Israel (ASLI) was a prospective, multicenter, single-arm clinical trial. Eyes with nvAMD having incomplete response to 3-9 prior bevacizumab injections were recruited. Three monthly intravitreal aflibercept (2 mg) injections were administered, followed by two bi-monthly injections and a final examination at week 28. An optional injection was allowed at week 20.ResultsForty-seven eyes of 46 patients (mean±SD age 76±8 years) were recruited. The mean number of prior bevacizumab injections was 5.5±2.9. The mean visual acuity improved from 60.3±10 ETDRS letters at baseline to 63.1±15 letters at week 28 (P=0.02, paired t-test). The central subfield thickness (CST) reduced from 409±127 micron at baseline to 330±110 microns at week 4 (P=0.0002; paired t-test), and 277±70 microns at week 28 (P=0.00002; paired t-test). Twenty-two eyes had three to five prior bevacizumab injections (mean 5.1±0.7), and 25 eyes had six to nine prior injections (7.32±1.2). Both groups had reduced CST from baseline to week 28 (P=0.0004 and P=0.0007; paired t-test, respectively). Thirty-five (75%) eyes required the optional additional aflibercept injection at week 20.ConclusionsThe ASLI study demonstrated improved BCVA and reduced CST following an early switch to aflibercept therapy in eyes with prior incomplete response to initial therapy with three to nine bevacizumab injections.

Primary health care for people with an intellectual disability: an exploration of consultations, problems identified, and their management in Australia.

BACKGROUND: People with an intellectual disability (ID) have more complex and different patterns of health care needs than the general population. They experience a greater burden of multi-morbidity, high levels of undetected and unmanaged health issues, and premature mortality than the general population. Primary care has a key role in the health care of people with an ID. Currently, very little is known about the consultation type and length, problems managed, and how general practitioners (GPs) manage these problems for people with an ID compared with the general population. This information would provide valuable insights into how GPs are achieving the health guidelines and facilitating people with an ID to achieve the highest attainable standard of health. METHODS: A secondary analysis of data was collected from January 2003 to December 2012 from the Bettering the Evaluation and Care of Health (BEACH) programme. Consultation type, consultation length in minutes, problem(s) managed during the consultation, medications, treatments provided, and referrals made, pre and post age-sex standardisation, at all GP encounters with people identified in the encounter record as having an ID ('ID' encounters, n = 690) were compared with those at 'non-ID' encounters (n = 970 641). Statistical significance was tested with 95% confidence intervals. RESULTS: This study identified significant differences in consultation types, consultation length, problem(s) managed during the consultation, medications, treatments provided, and referrals made at 'ID' encounters compared with 'non-ID' encounters. 'ID' encounters had more indirect encounters, longer consultations, more problems managed, but an under management of common health conditions in people with an ID. Administrative rather than medically related actions dominated clinical treatments for people at 'ID' encounters, and they received fewer procedural treatments, referrals to specialists, and medications compared with those at 'non-ID' encounters. CONCLUSION: The significant differences in consultations, problems identified and managed suggest that GPs may require additional support to (1) identify and manage common medical conditions experienced by people with an ID; (2) manage the increased time required for consultations; and (3) directly consult with people with an ID. Further research is required to determine why GPs managed problems in a significantly different way for people with an ID.

Primary health care for people with an intellectual disability: an exploration of demographic characteristics and reasons for encounters from the BEACH programme.

BACKGROUND: People with an intellectual disability (ID) have complex and different patterns of healthcare needs. Poor participation in primary health care contributes to the high levels of undetected and unmanaged health issues and premature deaths of people with an ID. Limited research is available on the characteristics of people with an ID, their reasons for consulting general practitioners (GPs), and if these differ to people without an ID. Gaining such insights may provide an avenue to better understand patterns of primary care use and potential gaps in usage by people with an ID given their complex health profile compared with people without an ID. METHOD: A secondary analysis of data collected January 2003 to December 2012 from The Bettering the Evaluation and Care of Health programme was used. Participant characteristics and their reasons for encounter, pre- and post-age-sex standardisation, at all GP encounters with people identified in the encounter record as having an ID ('ID' encounters, n = 690) were compared with those at 'non-ID' encounters (n = 970 641). Statistical significance was tested with chi-squared statistics or 95% confidence intervals as appropriate. RESULTS: This study identified significant differences in participant characteristics and their reasons for consulting GPs at ID encounters compared with non-ID encounters. Participants at ID encounters had a skewed demography, an over-representation of presentations for psychological, social and 'general and unspecified' reasons, and an under-representation of presentations for core physical health and preventive health measures. Administrative rather than medically related reasons dominated presentations to general practice at ID encounters. CONCLUSION: There are significant differences in the characteristics of participants and their reasons for presentation to general practice in Australia for participants at ID encounters compared with non-ID encounters. This work suggests that there is a difference in service use patterns between these two groups. These findings may suggest that people with an ID experience barriers to participating in essential primary healthcare services.

Atlantic bluefin tuna Thunnus thynnus feeding ecology in the northern Gulf of Mexico: a preliminary description of diet from the western Atlantic spawning grounds.

A combination of stomach contents, nitrogen stable-isotope and tissue C:N values are presented to demonstrate feeding activity of Atlantic bluefin tuna Thunnus thynnus on the Gulf of Mexico (GOMEX) spawning grounds. Diets include teleosts, cephalopods, crustaceans and a pelagic tunicate (Pyrosoma atlanticum). Results reveal the need to classify the GOMEX as a T. thynnus feeding ground.

Bisphenol A, benzophenone-type ultraviolet filters, and phthalates in relation to uterine leiomyoma.

Bisphenol A, benzophenone-type UV filters, and phthalates are chemicals in high production and use including in a range of personal care products. Exposure of humans to these chemicals has been shown to affect endocrine function. Although short-lived, widespread exposure may lead to continual opportunity for these chemicals to elicit health effects in humans. The association of these chemicals with incident uterine leiomyoma, an estrogen sensitive disease, is not known. Urinary concentrations of bisphenol A (BPA), five benzophenone-type UV filters (2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4OH-BP), 2,2׳-dihydroxybenzophenone (2,2׳OH-4MeO-BP), 2,2׳4,4׳-tetrahydroxybenzophenone (2,2׳4,4׳OH-BP), and 4-hydroxybenzophenone (4OH-BP), and 14 phthalate monoesters were quantified in 495 women who later underwent laparoscopy/laparotomy at 14 clinical sites for the diagnosis of fibroids. Significantly higher geometric mean creatinine-corrected concentrations of BPA, 2,4OH-BP, and 2OH-4MeO-BP were observed in women with than without fibroids [BPA: 2.09µg/g vs. 1.46µg/g p=0.004; 2,4OH-BP:11.10µg/g vs. 6.71µg/g p=0.01; 2OH-4MeO-BP: 11.31µg/g vs. 6.10µg/g p=0.01]. Mono-methyl phthalate levels were significantly lower in women with than without fibroids (1.78µg/g vs. 2.40µg/g). However, none of the exposures were associated with a significant odds ratio even when adjusting for relevant covariates. There was a lack of an association between select nonpersistent chemicals and the odds of a fibroid diagnosis.

The influence of sporadic anovulation on hormone levels in ovulatory cycles.

STUDY QUESTION: Do ovulatory hormone profiles among healthy premenopausal women differ between women with and without sporadic anovulation? SUMMARY ANSWER: Women with one anovulatory cycle tended to have lower estradiol, progesterone and LH peak levels during their ovulatory cycle. WHAT IS KNOWN ALREADY: Anovulation occurs sporadically in healthy premenopausal women, but the influence of hormones in a preceding cycle and the impact on a subsequent cycle's hormone levels is unknown. STUDY DESIGN, SIZE, DURATION: The BioCycle Study was a prospective cohort including 250 healthy regularly menstruating women, 18-44 years of age, from Western New York with no history of menstrual or ovulation disorders. The women were followed with up to eight study visits per cycle for two cycles, most of which were consecutive. PARTICIPANTS/MATERIALS, SETTING AND METHODS: All study visits were timed to menstrual cycle phase using fertility monitors and located at the University at Buffalo women's health research center from 2005 to 2007. The main outcomes measured were estradiol, progesterone, LH and follicle-stimulating hormone levels in serum at up to 16 visits over two cycles. Anovulation was defined as peak serum progesterone concentrations ≤5 ng/ml and no serum LH peak detected during the mid- or late-luteal phase visit. MAIN RESULTS AND THE ROLE OF CHANCE: Reproductive hormone concentrations were lower during anovulatory cycles, but significant reductions were also observed in estradiol (-25%, P = 0.003) and progesterone (-22%, P = 0.001) during the ovulatory cycles of women with one anovulatory cycle compared with women with two ovulatory cycles. LH peak concentrations were decreased in the ovulatory cycle of women with an anovulatory cycle (significant amplitude effect, P = 0.004; geometric mean levels 38% lower, P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Follow-up was limited to two menstrual cycles, and no ultrasound assessment of ovulation was available. Data were missing for a total of 168 of a possible 4072 cycle visits (4.1%), though all women had at least five visits per cycle (94% had seven or more per cycle). WIDER IMPLICATIONS OF THE FINDINGS: These results suggest a possible underlying cause of anovulation, such as a longer-term subclinical follicular, ovarian or hypothalamic/pituitary dysfunction, even among healthy, regularly menstruating women.

Bone mineral density and blood metals in premenopausal women.

Exposure to metals, specifically cadmium, lead, and mercury, is widespread and is associated with reduced bone mineral density (BMD) in older populations, but the associations among premenopausal women are unclear. Therefore, we evaluated the relationship between these metals in blood and BMD (whole body, total hip, lumbar spine, and non-dominant wrist) quantified by dual energy X-ray absorptiometry in 248 premenopausal women, aged 18-44. Participants were of normal body mass index (mean BMI 24.1), young (mean age 27.4), 60% were white, 20% non-Hispanic black, 15% Asian, and 6% other race group, and were from the Buffalo, New York region. The median (interquartile range) level of cadmium was 0.30 µg/l (0.19-0.43), of lead was 0.86 µg/dl (0.68-1.20), and of mercury was 1.10 µg/l (0.58-2.00). BMD was treated both as a continuous variable in linear regression and dichotomized at the 10th percentile for logistic regression analyses. Mercury was associated with reduced odds of decreased lumbar spine BMD (0.66, 95% confidence interval: 0.44, 0.99), but overall, metals at environmentally relevant levels of exposure were not associated with reduced BMD in this population of healthy, reproductive-aged women. Further research is needed to determine if the blood levels of cadmium, lead, and mercury in this population are sufficiently low that there is no substantive impact on bone, or if effects on bone can be expected only at older ages.

Correlated biomarker measurement error: an important threat to inference in environmental epidemiology.

Utilizing multiple biomarkers is increasingly common in epidemiology. However, the combined impact of correlated exposure measurement error, unmeasured confounding, interaction, and limits of detection (LODs) on inference for multiple biomarkers is unknown. We conducted data-driven simulations evaluating bias from correlated measurement error with varying reliability coefficients (R), odds ratios (ORs), levels of correlation between exposures and error, LODs, and interactions. Blood cadmium and lead levels in relation to anovulation served as the motivating example, based on findings from the BioCycle Study (2005-2007). For most scenarios, main-effect estimates for cadmium and lead with increasing levels of positively correlated measurement error created increasing downward or upward bias for OR > 1.00 and OR < 1.00, respectively, that was also a function of effect size. Some scenarios showed bias for cadmium away from the null. Results subject to LODs were similar. Bias for main and interaction effects ranged from -130% to 36% and from -144% to 84%, respectively. A closed-form continuous outcome case solution provides a useful tool for estimating the bias in logistic regression. Investigators should consider how measurement error and LODs may bias findings when examining biomarkers measured in the same medium, prepared with the same process, or analyzed using the same method.

Once-daily topical brimonidine tartrate gel 0·5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies.

BACKGROUND: Erythema of rosacea is thought to result from abnormal cutaneous vasomotor activity. Brimonidine tartrate (BT) is a highly selective α(2) -adrenergic receptor agonist with vasoconstrictive activity. OBJECTIVE: To determine the optimal concentration and dose regimen of topical BT gel for the treatment of erythema of rosacea and to evaluate its efficacy and safety. METHODS: In study A, 122 subjects were randomized to receive a single application of BT 0·07%, 0·18%, 0·5% or vehicle. In study B (4-week treatment and 4-week follow-up), 269 subjects were randomized to receive BT 0·5% once daily, BT 0·18% once daily, vehicle once daily, BT 0·18% twice daily or vehicle twice daily. Evaluations included Clinician's Erythema Assessment (CEA), Patient's Self-Assessment (PSA), Chroma Meter measurements and adverse events. RESULTS: In study A, a single application of topical BT gel reduced facial erythema in a dose-dependent fashion. A significant difference between BT 0·5% and vehicle in Chroma Meter redness value was observed from 30min to 12h after application. In study B, BT 0·5% once daily had a statistically superior success profile (defined as a two-grade improvement on both CEA and PSA over 12h) compared with vehicle once daily on days 1, 15 and 29 (all P<0·001). No tachyphylaxis, rebound of erythema or aggravation of other disease signs (telangiectasia, inflammatory lesions) was observed. All regimens were safe and well tolerated with similarly low incidence of adverse events. CONCLUSIONS: Once-daily BT gel 0·5% is well tolerated and provides significantly greater efficacy than vehicle gel for the treatment of moderate to severe erythema of rosacea.

Intermuscular and subcutaneous adipose tissue distributions differ in HIV+ versus HIV-men and women.

BACKGROUND: Loss of subcutaneous (SAT) with sparing of visceral (VAT) adipose tissue (AT) has been documented in HIV + men and women. Intermuscular AT (IMAT) rivals VAT in independent associations with cardiovascular risk. OBJECTIVE: To determine whether the size and distribution of IMAT differs in HIV+ vs. HIV- men and/or women. DESIGN: We used whole-body MRI to measure VAT, IMAT and four SAT compartments and compared them by HIV status using whole-body skeletal muscle (SM) or total AT (TAT) as co-variates in multi-ethnic groups of healthy HIV- (n=86) and stable HIV+ (n=76) men and women. RESULTS: The sizes of AT depots (adjusting for SM) did not differ by HIV status, except for smaller gluteal SAT (lower trunk, between L(4)-L(5) to greater trochanter) in both sexes (P<0.05). The AT distribution (adjusting for TAT) was significantly different, with larger VAT (P<0.05) and smaller gluteal and limb SAT (P<0.05) in both HIV+ sexes; IMAT increased more with TAT in HIV+ vs. HIV- men (P<0.05 for slope interaction) but there were no significant differences in women. There were significant race by HIV interactions in AT distribution with more pronounced VAT differences in non-Hispanic white men and larger trunk SAT in African Americans HIV+ vs. HIV-. CONCLUSION: The AT distribution differed markedly in HIV+ vs. HIV- with limb and lower body SAT representing a smaller proportion of TAT in HIV+ in both sexes and IMAT representing a larger proportion of TAT in HIV+ vs. HIV- men.

The diagnostic contribution of indocyanine green to fluorescein angiography in fellow drusen eyes of patients with wet age-related macular degeneration.

PURPOSE: To assess the contribution of indocyanine green angiography (ICGA) to fluorescein angiography (FA) in evaluating fellow drusen eyes of patients with wet age-related macular degeneration (AMD) in the other eye. METHODS: The records of paired FA and ICGA of patients with dry AMD in one eye and wet AMD in the other eye were retrospectively reviewed. Based on color fundus photographs, drusen were graded to low, moderate, or high grade of severity on FA. The FA and ICGA findings were compared. RESULTS: Fifty-two pairs of eyes were included. Fluorescein angiography showed drusen of low severity in 11 (21.2%) eyes, of moderate severity in 31 (59.6%), and of high severity in 10 (19.2%). Leakage on both FA and ICGA was not demonstrated in any case of drusen of low or moderate severity. Only in 2 out of 10 eyes from the high severity group, 3.8% of the eyes of the whole study population, did ICGA reveal occult choroidal neovascularization (CNV) that was not observed on FA. CONCLUSIONS: In selected eyes with drusen of high grade severity, ICGA may detect occult CNV, unrecognized clinically or by FA. ICGA had a small contribution to the diagnosis of occult CNV in fellow drusen eyes with any degree of severity.

Cervical cancer: a call for political will.

Cervical cancer kills over a quarter of a million women worldwide on an annual basis, with 80% of these deaths occurring in developing countries. Cytology-based screening programs, widely used in industrialized countries, are difficult to implement in low-resource settings. Non-cytological methods for screening and treatment have been developed and studied over the last decade. Given the barriers to widespread, good quality screening and early treatment, the most promising new prevention strategy will be the introduction of a vaccine to prevent human papillomavirus infection, the cause of cervical cancer. Understanding women's health-seeking behaviors is critical to successful dissemination and uptake of both screening and vaccine prevention strategies.

The course of surface deposits on a hydrophilic acrylic intraocular lens after implantation through a hexagonal cartridge.

AIM: To evaluate the outcome of surface deposits that occurred during implantation of hydrophylic acrylic intraocular lenses (IOLs) through a hexagonal cartridge. METHODS: Surface deposits were observed on the posterior surface of the ACR6D SE IOLs that were injected through a hexagonal cartridge filled with sodium hyaluronate 1%. All the patients were examined 1 day, 1 week, 1 month, 6 months and 1 year postoperatively. The location of the deposits was recorded and photographed. The patients were questioned about blurred vision, glare or halos. RESULTS: Linear or curly deposits were detected on the posterior surface of the IOL in six patients. In four patients, the deposits were peripheral and were observed 1 week postoperatively. In two patients, the deposits were noticed immediately after implantation. In one eye, they were misinterpreted as a crack in the IOL's optic and were left in the eye. In the second patient the deposits were removed immediately after implantation with forceps. The deposits that were left after implantation (five eyes) did not resolve during 1 year of follow-up. None of the eyes developed abnormal inflammatory reaction. In three eyes the best-corrected visual acuity (BCVA) was 6/6. In the other three eyes the BCVA was 6/12. None of the patients experienced any visual disturbance. CONCLUSIONS: Implantation of the ACR6D SE IOL through a hexagonal cartridge can lead to the formation of deposits on the posterior surface of the lens. The deposits do not resolve and may resemble a crack in the IOL. The deposits left on the IOL had no clinical relevance in our patients.