Reaching for 90:90:90 in Correctional Facilities in South Africa and Zambia: Virtual Cross-Section of Coverage of HIV Testing and Antiretroviral Therapy During Universal Test and Treat Implementation.

BACKGROUND: People in correctional settings are a key population for HIV epidemic control. We sought to demonstrate scale-up of universal test and treat in correctional facilities in South Africa and Zambia through a virtual cross-sectional analysis. METHODS: We used routine data on 2 dates: At the start of universal test and treat implementation (time 1, T1) and 1 year later (time 2, T2). We obtained correctional facility census lists for the selected dates and matched HIV testing and treatment data to generate virtual cross-sections of HIV care continuum indicators. RESULTS: In the South African site, there were 4193 and 3868 people in the facility at times T1 and T2; 43% and 36% were matched with HIV testing or treatment data, respectively. At T1 and T2, respectively, 1803 (43%) and 1386 (36%) had known HIV status, 804 (19%) and 845 (21%) were known to be living with HIV, and 60% and 56% of those with known HIV were receiving antiretroviral therapy (ART). In the Zambian site, there were 1467 and 1366 people in the facility at times T1 and T2; 58% and 92% were matched with HIV testing or treatment data, respectively. At T1 and T2, respectively, 857 (59%) and 1263 (92%) had known HIV status, 277 (19%) and 647 (47%) were known to be living with HIV, and 68% and 68% of those with known HIV were receiving ART. CONCLUSIONS: This virtual cross-sectional analysis identified gaps in HIV testing coverage, and ART initiation that was not clearly demonstrated by prior cohort-based studies.

Co-design of an intervention to optimize mammographic screening participation in women with obesity and/or physical disabilities.

BACKGROUND: Mammographic breast screening/rescreening rates are suboptimal for women with obesity and/or physical disabilities. This study describes development of an intervention framework targeting obesity- and disability-related barriers to improve participation. METHODS: Mixed methods combined a systematic review with first-person perspectives to optimise screening engagement among women with obesity and/or physical disabilities. Phase 1 (systematic review) was conducted following the PRISMA framework. Phase 2 involved in-depth interviews with n = 8 women with lived experience of obesity and/or physical disabilities. An inductive coding approach was applied to the data which was then combined with Phase 1 results to develop the intervention framework. RESULTS: Six studies were included in the systematic review. Tailored education based on individual risk increased willingness to undergo mammographic screening. Recommendations to improve the screening experience included partnerships with consumers, targeted messaging, and enhanced professional development for breast screening staff. Participants also identified strategies to improve the uptake of screening and the experience itself. CONCLUSION: Development and evaluation of interventions informed by frameworks like the one developed in this study are needed to improve engagement in screening to promote regular participation among women with physical disabilities and/or obesity. IMPLICATIONS FOR PRACTICE: Successful implementation of practice interventions co-designed by women with obesity and/or physical disabilities are likely to improve their breast screening participation. Enhanced training of radiographers aimed at upskilling in empathetic communication around required manoeuvring and potentially longer screening times for clients with obesity and/or physical disabilities may encourage more positive client practitioner interactions. Client information aimed at women with obesity should include information on how to prepare for the appointment and explain there may be equipment limitations compromising imaging which may not be completed at an initial appointment.

Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer (PRAGMATIC): quality of life and service use results.

PURPOSE: To describe trends and explore factors associated with quality of life (QoL) and psychological morbidity and assess breast cancer (BC) health service use over a 12-month period for patients joining the supported self-management (SSM)/patient-initiated follow-up (PIFU) pathway. METHODS: Participants completed questionnaires at baseline, 3, 6, 9 and 12 months that measured QoL (FACT-B, EQ 5D-5L), self-efficacy (GSE), psychological morbidity (GHQ-12), roles and responsibilities (PRRS) and service use (cost diary). RESULTS: 99/110 patients completed all timepoints; 32% (35/110) had received chemotherapy. The chemotherapy group had poorer QoL; FACT-B total score mean differences were 8.53 (95% CI: 3.42 to 13.64), 5.38 (95% CI: 0.17 to 10.58) and 8.00 (95% CI: 2.76 to 13.24) at 6, 9 and 12 months, respectively. The odds of psychological morbidity (GHQ12 >4) were 5.5-fold greater for those treated with chemotherapy. Financial and caring burdens (PRRS) were worse for this group (mean difference in change at 9 months 3.25 (95% CI: 0.42 to 6.07)). GSE and GHQ-12 scores impacted FACT-B total scores, indicating QoL decline for those with high baseline psychological morbidity. Chemotherapy patients or those with high psychological morbidity or were unable to carry out normal activities had the highest service costs. Over the 12 months, 68.2% participants phoned/emailed breast care nurses, and 53.3% visited a hospital breast clinician. CONCLUSION: The data suggest that chemotherapy patients and/or those with heightened psychological morbidity might benefit from closer monitoring and/or supportive interventions whilst on the SSM/PIFU pathway. Reduced access due to COVID-19 could have affected service use.

Delivery Models and Health Economics of Supportive Care Services in England: A Multicentre Analysis.

AIMS: Improvements in cancer treatment have led to more people living with and beyond cancer. These patients have symptom and support needs unmet by current services. The development of enhanced supportive care (ESC) services may meet the longitudinal care needs of these patients, including at the end of life. This study aimed to determine the impact and health economic benefits of ESC for patients living with treatable but not curable cancer. MATERIALS AND METHODS: A prospective observational evaluation was undertaken over 12 months across eight cancer centres in England. ESC service design and costs were recorded. Data relating to patients' symptom burden were collected using the Integrated Palliative Care Outcome Scale (IPOS). For patients in the last year of life, secondary care use was compared against an NHS England published benchmark. RESULTS: In total, 4594 patients were seen by ESC services, of whom 1061 died during follow-up. Mean IPOS scores improved across all tumour groups. In total, £1,676,044 was spent delivering ESC across the eight centres. Reductions in secondary care usage for the 1061 patients who died saved a total of £8,490,581. CONCLUSIONS: People living with cancer suffer with complex and unmet needs. ESC services appear to be effective at supporting these vulnerable people and significantly reduce the costs of their care.

Allogeneic CD20-targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B-cell lymphoma models.

OBJECTIVES: Autologous chimeric antigen receptor (CAR) αß T-cell therapies have demonstrated remarkable antitumor efficacy in patients with haematological malignancies; however, not all eligible cancer patients receive clinical benefit. Emerging strategies to improve patient access and clinical responses include using premanufactured products from healthy donors and alternative cytotoxic effectors possessing intrinsic tumoricidal activity as sources of CAR cell therapies. γδ T cells, which combine innate and adaptive mechanisms to recognise and kill malignant cells, are an attractive candidate platform for allogeneic CAR T-cell therapy. Here, we evaluated the manufacturability and functionality of allogeneic peripheral blood-derived CAR+ Vδ1 γδ T cells expressing a second-generation CAR targeting the B-cell-restricted CD20 antigen. METHODS: Donor-derived Vδ1 γδ T cells from peripheral blood were ex vivo-activated, expanded and engineered to express a novel anti-CD20 CAR. In vitro and in vivo assays were used to evaluate CAR-dependent and CAR-independent antitumor activities of CD20 CAR+ Vδ1 γδ T cells against B-cell tumors. RESULTS: Anti-CD20 CAR+ Vδ1 γδ T cells exhibited innate and adaptive antitumor activities, such as in vitro tumor cell killing and proinflammatory cytokine production, in addition to in vivo tumor growth inhibition of B-cell lymphoma xenografts in immunodeficient mice. Furthermore, CD20 CAR+ Vδ1 γδ T cells did not induce xenogeneic graft-versus-host disease in immunodeficient mice. CONCLUSION: These preclinical data support the clinical evaluation of ADI-001, an allogeneic CD20 CAR+ Vδ1 γδ T cell, and a phase 1 study has been initiated in patients with B-cell malignancies (NCT04735471).

A Short Report Examining the Introduction of Routine Use of Patient-Reported Outcome Measures in a Mixed Oncology Population.

AIMS: People living with treatable but not curable cancer often experience a range of symptoms related to their cancer and its treatment. During the COVID-19 pandemic, face-to-face consultations were reduced and so remote monitoring of these needs was necessary. University Hospitals Sussex implemented the routine use of electronic remote patient-reported outcome measures (PROMs) in a mixed oncology population, focusing on those with treatable but not curable cancers. MATERIALS AND METHODS: Over a 9-month period, patients were invited to register with My Clinical Outcomes (MCO) - a secure online platform for the collection of electronic PROMs. They were prompted by e-mail to complete assessments (EORTC QLQ-C30, EQ-5D-3L and EQ-5D VAS) routinely every 2 weeks. The team monitored patient scores and changes in these prompted clinical interventions. RESULTS: In total, 324 patients completed at least one assessment. The median number of assessments completed by each patient was eight. The most represented tumour groups were secondary breast (28%), prostate (25%) and other (32%). Median scores for the assessments did not deteriorate in a clinically or numerically significant way for patients living with non-curable conditions for the majority of patients monitored. CONCLUSION: Routine collection of electronic remote PROMs is an effective and useful strategy to provide real-time clinical feedback to teams. With integration into existing systems, online platforms (such as MCO) could provide efficient and patient-centred information for those providing care for people with cancer.

Digital Medicine in Men with Advanced Prostate Cancer - A Feasibility Study of Electronic Patient-reported Outcomes in Patients on Systemic Treatment.

AIMS: Electronic patient-reported outcome (ePRO) measures have the potential to improve patient care, both at an individual level by detecting symptoms and at an organisational level to rationalise follow-up. The introduction of ePROs has many challenges, including funding, institutional rigidity and acceptability for both patients and clinicians. There are multiple examples of successful ePRO programmes but no specific feasibility studies in those who are less digitally engaged. Prostate cancer is predominantly a disease of older men and digital exclusion is associated with increased age. We assessed the feasibility of ePRO completion in older men receiving treatment for advanced prostate cancer both within the clinic and from home. MATERIALS AND METHODS: Men receiving palliative systemic treatment were asked to complete ePROs on a tablet computer in the outpatient department at 0 and 3 months. Participants were also offered optional completion from home. Feasibility was assessed via a mixed methods approach. RESULTS: On-site ePRO completion was acceptable to most patients, with 90% finding it easy or straightforward and 80% preferring electronic over paper. Remote completion was more challenging, even for those who accessed e-mail daily and owned a tablet, with only 20% of participants successfully completing ePROs. Barriers to electronic completion can be categorised as technical, attitudinal and medical. Quality of life and symptom ePRO results were comparable with published data. CONCLUSIONS: On-site completion is achievable in this population with limited staff support. However, remote completion requires further work to improve systems and acceptability for patients. Remote completion is critical to add significantly to current clinical care by detecting symptoms or stratifying follow-up.

Premature or early bilateral oophorectomy: a 2021 update.

In this invited review, we discuss some unresolved and controversial issues concerning premature (<40 years) or early (40-45 years) bilateral oophorectomy. First, we clarify the terminology. Second, we summarize the long-term harmful consequences of bilateral oophorectomy. Third, we discuss the restrictive indications for bilateral oophorectomy in premenopausal women to prevent ovarian cancer that are justified by the current scientific evidence. Fourth, we explain the importance of estrogen replacement therapy when bilateral oophorectomy is performed. Hormone replacement therapy is indicated after bilateral oophorectomy until the age of expected natural menopause like in premature or early primary ovarian insufficiency. Fifth, we discuss the relationship between adverse childhood experiences, adverse adult experiences, mental health, gynecologic symptoms and bilateral oophorectomy. The acceptance and popularity of bilateral oophorectomy over several decades, and its persistence even in the absence of supporting scientific evidence, suggest that non-medical factors related to sex, gender, reproduction, cultural beliefs and socioeconomic structure are involved. We discuss some of these non-medical factors and the need for more research in this area.

Universal test-and-treat in Zambian and South African correctional facilities: a multisite prospective cohort study.

BACKGROUND: Despite the global scale-up of antiretroviral therapy (ART), incarcerated people have not benefited equally from test-and-treat recommendations for HIV. To improve access to ART for incarcerated people with HIV, we introduced a universal test-and-treat (UTT) intervention in correctional facilities in South Africa and Zambia, and aimed to assess UTT feasibility and clinical outcomes. METHODS: Treatment as Prevention (TasP) was a multisite, mixed methods, implementation research study done at three correctional complexes in South Africa (Johnannesburg and Breede River) and Zambia (Lusaka). Here, we report the clinical outcomes for a prospective cohort of incarcerated individuals who were offered the TasP UTT intervention. Incarcerated individuals were eligible for inclusion if they were aged 18 years or older, with new or previously diagnosed HIV, not yet on ART, and were expected to remain incarcerated for 30 days or longer. To enable the implementation of UTT at the included correctional facilities, we first strengthened on-site HIV service delivery. All participants were offered same-day ART initiation, and had two study-specific follow-up visits scheduled to coincide with routine clinic visits at 6 and 12 months. The main outcomes were ART uptake, time from cohort enrolment to ART initiation, and retention in care and viral suppression at 6 and 12 months. We estimated the association between baseline demographic characteristics and time to ART initiation using Cox proportional hazard models, and, in a post-hoc analysis, we used logistic regression models to assess the association between demographic and clinical variables, including time to ART initiation, and the proportion of participants with a composite poor outcome (defined as viral load >50 copies per mL, or for participants with a missing viral load, lack of retention in care in the on-site ART programme) at 6 months. This study is registered at ClinicalTrials.gov, NCT02946762. FINDINGS: Between June 23, 2016, and Dec 31, 2017, we identified 1562 incarcerated people with HIV, of whom 1389 (89%) were screened, 1021 (74%) met eligibility criteria, and 975 (95%) were enrolled and followed up to March 31, 2018. At the end of follow-up, 835 (86%) of 975 participants had started ART. Median time from enrolment to ART initiation was 0 days (IQR 0-8). Of 346 participants who remained incarcerated at 6 months, 327 (95%) were retained in care and 269 (78%) had a documented viral load, of whom 262 (97%) achieved viral suppression (<1000 copies per mL). The mortality rate among the 835 participants who had initiated ART was 1·9 per 100 person-years (95% CI 0·9-3·9). No statistically significant associations were identified between any baseline characteristics and time to ART initiation or composite poor outcome. INTERPRETATION: UTT implementation is feasible in correctional settings, and can achieve levels of same-day ART uptake, retention in care, and viral suppression among incarcerated people with HIV that are comparable to those observed in community settings. FUNDING: UK Department for International Development, Swedish International Development Cooperation Agency, Norwegian Agency for Development Cooperation.

A 12-month extension study to evaluate the safety and efficacy of asoprisnil in women with heavy menstrual bleeding and uterine fibroids.

STUDY QUESTION: What is the safety and efficacy profile during long-term (12-24 months) uninterrupted treatment with the selective progesterone receptor modulator asoprisnil, 10 and 25 mg in women with heavy menstrual bleeding (HMB) associated with uterine fibroids? SUMMARY ANSWER: Uninterrupted treatment with asoprisnil should be avoided due to endometrial safety concerns and unknown potential long-term consequences. WHAT IS KNOWN ALREADY: Asoprisnil was well tolerated in shorter-term studies and effectively suppressed HMB and reduced fibroid volume. STUDY DESIGN SIZE DURATION: Women with uterine fibroids who had previously received placebo (n = 87) or asoprisnil 10 mg (n = 221) or 25 mg (n = 215) for 12 months in two double-blind studies entered this randomized uncontrolled extension study and received up to 12 additional months of treatment followed by 6 months of post-treatment follow-up. Women who previously received placebo were re-randomized to either asoprisnil 10 or 25 mg for the extension study. This report focuses on the 436 women who received asoprisnil in the double-blind studies and this extension study. Results for women who previously received placebo in the double-blind studies are not described. PARTICIPANTS/MATERIALS SETTING METHODS: Women ≥18 years of age who completed a 12-month, double-blind, placebo-controlled study, had estradiol levels indicating that they were not menopausal and had no endometrial hyperplasia or other significant endometrial pathology were eligible. The safety endpoints were focused on endometrial assessments. The composite primary efficacy endpoint was the proportion of women who demonstrated a response to treatment by meeting all three of the following criteria at the final month for participants who prematurely discontinued or at month 12 for those who completed the study: a reduction from initial baseline to final visit of ≥50% in the menstrual pictogram score, hemoglobin concentration ≥11 g/dl or an increase of ≥1 g/dl from initial baseline at the final visit, and no surgical or invasive intervention for uterine fibroids. Other efficacy endpoints included rates for amenorrhea and suppression of bleeding, changes in fibroid and uterine volume and changes in hematologic parameters. No statistical tests were planned or performed for this uncontrolled study. MAIN RESULTS AND ROLE OF CHANCE: Imaging studies revealed a progressive increase in endometrial thickness and cystic changes that frequently prompted invasive diagnostic procedures. Endometrial biopsy results were consistent with antiproliferative effects of asoprisnil. Two cases of endometrial cancer were diagnosed. At the final month of this extension study (total duration of uninterrupted treatment up to 24 months), the primary efficacy endpoint was achieved in 86 and 92% of women in the asoprisnil 10- and 25-mg groups, respectively. During each month of treatment, amenorrhea was observed in the majority of women (up to 77 and 94% at 10 and 25 mg, respectively). There was a progressive, dose-dependent decrease in the volume of the primary fibroid with asoprisnil 10 and 25 mg (-55.7 and -75.2% median decrease, respectively, from baseline [i.e. the beginning of the placebo-controlled study] to month 12 [cumulative months 12-24] of this extension study). These effects were associated with improvements in quality of life measures. LIMITATIONS REASONS FOR CAUTION: This study was uncontrolled, which limits the interpretation of safety and efficacy findings. The study also had multiple protocol amendments with the addition of diagnostic procedures and, because no active comparator was included, the potential place of asoprisnil in comparison to therapies such as GnRH agonists and surgery cannot be determined. WIDER IMPLICATIONS OF THE FINDINGS: Long-term, uninterrupted treatment with asoprisnil leads to prominent cystic endometrial changes that are consistent with the 'late progesterone receptor modulator' effects, which prompted invasive diagnostic procedures, although treatment efficacy is maintained. Although endometrial cancers were uncommon during both treatment and follow-up, these findings raise concerns regarding endometrial safety during uninterrupted long-term treatment with asoprisnil. This study shows that uninterrupted treatment with asoprisnil should be avoided due to safety concerns and unknown potential long-term consequences. STUDY FUNDING/COMPETING INTERESTS: AbbVie Inc. (prior sponsor, TAP Pharmaceutical Products Inc.) sponsored the study and contributed to the design and conduct of the study, data management, data analysis, interpretation of the data and the preparation and approval of the manuscript. Financial support for medical writing and editorial assistance was provided by AbbVie Inc. M. P. Diamond received research funding for the conduct of the study paid to the institution and is a consultant to AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution for Bayer and ObsEva. E. A. Stewart participated as a site investigator in the phase 2 study of asoprisnil and served as a consultant to TAP Pharmaceuticals during the time of design and conduct of the studies while on the faculty of Harvard Medical School and Brigham and Women's Hospital, Boston, MA. In the last 3 years, she has received support from National Institutes of Health grants HD063312, HS023418 and HD074711. She has served as a consultant for AbbVie Inc., Allergan, Bayer HealthCare AG and Myovant for consulting related to uterine leiomyoma and to Welltwigs for consulting related to infertility. She has received royalties from UpToDate and the Med Learning Group. A.R.W. Williams has acted as a consultant for TAP Pharmaceutical Products Inc. and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr has served as consultant and received research funding from AbbVie Inc. and Synteract (Medicines360). E.R. Myers has served as consultant for AbbVie Inc., Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was a co-inventor of several patents related to asoprisnil.C. Mattia-Goldberg is a former employee of AbbVie Inc. and owns AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie Inc. and own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER: NCT00156195 at clinicaltrials.gov.

"It's Not Like Taking Chocolates": Factors Influencing the Feasibility and Sustainability of Universal Test and Treat in Correctional Health Systems in Zambia and South Africa.

BACKGROUND: Sub-Saharan African correctional facilities concentrate large numbers of people who are living with HIV or at risk for HIV infection. Universal test and treat (UTT) is widely recognized as a promising approach to improve the health of individuals and a population health strategy to reduce new HIV infections. In this study, we explored the feasibility and sustainability of implementing UTT in correctional facilities in Zambia and South Africa. METHODS: Nested within a UTT implementation research study, our qualitative evaluation of feasibility and sustainability used a case-comparison design based on data from 1 Zambian and 3 South African correctional facilities. Primary data from in-depth interviews with incarcerated individuals, correctional managers, health care providers, and policy makers were supplemented by public policy documents, study documentation, and implementation memos in both countries. Thematic analysis was informed by an empirically established conceptual framework for health system analysis. RESULTS: Despite different institutional profiles, we were able to successfully introduce UTT in the South Africa and Zambian correctional facilities participating in the study. A supportive policy backdrop was important to UTT implementation and establishment in both countries. However, sustainability of UTT, defined as relevant government departments' capacity to independently plan, resource, and administer quality UTT, differed. South Africa's correctional facilities had existing systems to deliver and monitor chronic HIV care and treatment, forming a "scaffolding" for sustained UTT despite some human resources shortages and poorly integrated health information systems. Notwithstanding recent improvements, Zambia's correctional health system demonstrated insufficient material and technical capacity to independently deliver quality UTT. In the correctional facilities of both countries, inmate population dynamics and their impact on HIV-related stigma were important factors in UTT service uptake. CONCLUSION: Findings demonstrate the critical role of policy directives, health service delivery systems, adequate resourcing, and population dynamics on the feasibility and likely sustainability of UTT in corrections in Zambia and South Africa.

Safety and efficacy of the selective progesterone receptor modulator asoprisnil for heavy menstrual bleeding with uterine fibroids: pooled analysis of two 12-month, placebo-controlled, randomized trials.

STUDY QUESTION: Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER: Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY: In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION: In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE: In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66-78% in the asoprisnil 10-mg group and 83-93% in the asoprisnil 25-mg group, significantly higher than with placebo (3-12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to -48% and -28%, respectively) and 25 mg (median changes up to -63% and -39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION: Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS: Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women's Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER: NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT'S ENROLMENT: 12 September 2002; 6 September 2002.

PEDOT doped with algal, mammalian and synthetic dopants: polymer properties, protein and cell interactions, and influence of electrical stimulation on neuronal cell differentiation.

Poly(3,4-ethylenedioxythiophene) (PEDOT) films were electrochemically polymerised with several synthetic (dodecylbenzosulfonic acid (DBSA)) and biological (dextran sulphate (DS), chondroitin sulphate (CS), alginic acid (ALG) and ulvan (ULV)) dopant anions, and their physical, mechanical and electrochemical properties characterised. PEDOT films incorporating the biological dopants ALG and ULV produced films of the greatest surface roughness (46 ± 5.1 and 31 ± 1.9 nm, respectively), and demonstrated significantly lower shear modulus values relative to all other PEDOT films (2.1 ± 0.1 and 1.2 ± 0.2 MPa, respectively). Quartz crystal microgravimetry was used to study the adsorption of the important extracellular matrix protein fibronectin, revealing protein adsorption to be greatest on PEDOT doped with DS, followed by DBSA, ULV, CS and ALG. Electrical stimulation experiments applying a pulsed current using a biphasic waveform (250 Hz) were undertaken using PEDOT doped with either DBSA or ULV. Electrical stimulation had a significant influence on cell morphology and cell differentiation for PEDOT films with either dopant incorporated, with the degree of branching per cell increased by 10.5× on PEDOT-DBSA and 6.5× on PEDOT-ULV relative to unstimulated cells, and mean neurite length per cell increasing 2.6× and 2.2× on stimulated vs. unstimulated PEDOT-DBSA and PEDOT-ULV, respectively. We demonstrate the cytocompatibility of synthetic and biologically doped PEDOT biomaterials, including the new algal derived polysaccharide dopant ulvan, which, along with DBSA doped PEDOT, is shown to significantly enhance the differentiation of PC12 neuronal cells under electrical stimulation.

Seasonal variations in tuberculosis diagnosis among HIV-positive individuals in Southern Africa: analysis of cohort studies at antiretroviral treatment programmes.

OBJECTIVES: Seasonal variations in tuberculosis diagnoses have been attributed to seasonal climatic changes and indoor crowding during colder winter months. We investigated trends in pulmonary tuberculosis (PTB) diagnosis at antiretroviral therapy (ART) programmes in Southern Africa. SETTING: Five ART programmes participating in the International Epidemiology Database to Evaluate AIDS in South Africa, Zambia and Zimbabwe. PARTICIPANTS: We analysed data of 331 634 HIV-positive adults (>15 years), who initiated ART between January 2004 and December 2014. PRIMARY OUTCOME MEASURE: We calculated aggregated averages in monthly counts of PTB diagnoses and ART initiations. To account for time trends, we compared deviations of monthly event counts to yearly averages, and calculated correlation coefficients. We used multivariable regressions to assess associations between deviations of monthly ART initiation and PTB diagnosis counts from yearly averages, adjusted for monthly air temperatures and geographical latitude. As controls, we used Kaposi sarcoma and extrapulmonary tuberculosis (EPTB) diagnoses. RESULTS: All programmes showed monthly variations in PTB diagnoses that paralleled fluctuations in ART initiations, with recurrent patterns across 2004-2014. The strongest drops in PTB diagnoses occurred in December, followed by April-May in Zimbabwe and South Africa. This corresponded to holiday seasons, when clinical activities are reduced. We observed little monthly variation in ART initiations and PTB diagnoses in Zambia. Correlation coefficients supported parallel trends in ART initiations and PTB diagnoses (correlation coefficient: 0.28, 95% CI 0.21 to 0.35, P<0.001). Monthly temperatures and latitude did not substantially change regression coefficients between ART initiations and PTB diagnoses. Trends in Kaposi sarcoma and EPTB diagnoses similarly followed changes in ART initiations throughout the year. CONCLUSIONS: Monthly variations in PTB diagnosis at ART programmes in Southern Africa likely occurred regardless of seasonal variations in temperatures or latitude and reflected fluctuations in clinical activities and changes in health-seeking behaviour throughout the year, rather than climatic factors.

Mammographic image quality in relation to positioning of the breast: A multicentre international evaluation of the assessment systems currently used, to provide an evidence base for establishing a standardised method of assessment.

INTRODUCTION: Optimum mammography positioning technique is necessary to maximise cancer detection. Current criteria for mammography appraisal lack reliability and validity with a need to develop a more objective system. We aimed to establish current international practice in assessing image quality (IQ), of screening mammograms then develop and validate a reproducible assessment tool. METHODS: A questionnaire sent to centres in countries undertaking population screening identified practice, participants for an expert panel (EP) of radiologists/radiographers and a testing panel (TP) of radiographers. The EP developed category criteria and descriptors using a modified Delphi process to agree definitions. The EP scored 12 screening mammograms to test agreement then a main set of 178 cases. Weighted scores were derived for each descriptor enabling calculation of numerical parameters for each new category. The TP then scored the main set. Statistical analysis included ANOVA, t-tests and Kendall's coefficient. RESULTS: 11 centres in 8 countries responded forming an EP of 7 members and TP of 44 members. The EP showed moderate agreement when the scoring the mini test set W = 0.50 p < 0.001 and the main set W = 0.55 p < 0.001, 'posterior nipple line' being the most difficult descriptor. The weighted total scores differentiated the 4 new categories Perfect, Good, Adequate and Inadequate (p < 0.001). CONCLUSION: We have developed an assessment tool by Delphi consensus and weighted consensus criteria. We have successfully tabulated a range of numerical scores for each new category providing the first validated and reproducible mammography IQ scoring system.

Limited impact of awareness-raising campaigns on hepatitis C testing practices among general practitioners.

The global hepatitis strategy calls for increased effort to diagnose those infected, with a target of 90% diagnosed by 2030. Scotland's Action Plan on Hepatitis C included awareness-raising campaigns, undertaken during 2008-2011, to promote testing by general practitioners. We examined hepatitis C virus (HCV) testing practice among general practitioners before and following these campaigns. Scottish general practitioners were surveyed, using Dillman's method, in 2007 and 2013; response rates were 69% and 60%, respectively. Most respondents offer testing when presented with a risk history (86% in 2007, 88% in 2013) but only one-fifth actively sought out risk factors (19% in 2007, 21% in 2013). Testing was reportedly always/almost always/usually offered to people who inject drugs (84% in 2007, 87% in 2013). Significant improvements in the offer of testing were reported in patients with abnormal LFTs (41% in 2007, 65% in 2013, P<.001) and who had received medical/dental treatment in high prevalence countries (14% in 2007, 24% in 2013, P=.001). In 2013, 25% of respondents had undertaken HCV-related continued professional development. This group was significantly more likely to actively seek out risk factors (P=.009) but only significantly more likely to offer a test to patients who had received medical/dental treatment in high prevalence countries (P=.001). Our findings suggest that government-led awareness raising campaigns have limited impact on general practitioners' testing practices. If the majority of the HCV-infected population are to be diagnosed, practitioner-based or physician-centred interventions should be considered alongside educational initiatives targeted at professionals.

Epidemiology of uterine fibroids: a systematic review.

BACKGROUND: Uterine fibroids (UFs) are the most common neoplasm affecting women that can cause significant morbidity and may adversely impact fertility. OBJECTIVES: To examine UF epidemiology and to evaluate the relative strengths of putative risk factors. SEARCH STRATEGY: MEDLINE and Embase were searched for studies published in English between January 1995 and April 2015. SELECTION CRITERIA: Publications reporting relevant data from registries and other observational studies with over 1000 patients and single-centre studies with over 100 patients were selected. DATA COLLECTION AND ANALYSIS: Data on UF incidence, prevalence and associated risk factors were extracted from 60 publications. MAIN RESULTS: Wide ranges were reported in both UF incidence (217-3745 cases per 100 000 women-years) and prevalence (4.5-68.6%), depending on study populations and diagnostic methods. Black race was the only factor that was recurrently reported to increase UF risk, by two-threefold compared with white race. Eleven other factors affected UF risk to a magnitude similar to or greater than race. Age, premenopausal state, hypertension, family history, time since last birth, and food additive and soybean milk consumption increased UF risk; use of oral contraceptives or the injectable contraceptive depot medroxyprogesterone acetate, smoking in women with low body mass index and parity reduced UF risk. CONCLUSIONS: We identified 12 risk factors that play an important role in UF epidemiology. The UF risk factor with the strongest evidence is black race. High-quality prospective observational data are needed to improve our understanding of UF epidemiology, and thus its aetiology and optimal management. TWEETABLE ABSTRACT: Uterine fibroids occur in about 70% of women. Black race and 11 other factors affect uterine fibroid risk.

Medical therapies for heavy menstrual bleeding in women with uterine fibroids: a retrospective analysis of a large commercially insured population in the USA.

OBJECTIVES: To report patterns and patient characteristics associated with initiation of and persistence with medical therapies for uterine fibroid-related heavy menstrual bleeding. DESIGN: Retrospective cohort study. SETTING: US commercial insurance claims database. POPULATION: 41 561 women aged 18-54 years with uterine fibroids and heavy menstrual bleeding who initiated medical therapies from January 2000 through December 2013. METHOD: Multinomial logistic regression was used to assess patient characteristics associated with initiation and persistence. Cox proportional hazards regression was used on propensity score-matched cohorts to examine change from index medication. MAIN OUTCOMES MEASURES: Initiation of and persistence with four first-line medical therapies: short- and long-acting reversible contraceptive steroids, leuprolide acetate, and tranexamic acid. RESULTS: Most women (79.4%) took short-acting reversible contraceptive steroids as first-line therapy (index medication), whereas 9.5%, 8.5%, and 2.7% used long-acting reversible contraceptive steroids, leuprolide acetate, and tranexamic acid, respectively. During follow-up, 16 594 women (39.9%) switched to nonindex medication (18.4%) or procedural treatment (81.6%). In comparison with women taking short-acting steroids, those receiving long-acting steroids were less likely to switch [hazard ratio (HR) 0.84, 95% CI 0.79-0.91], whereas women taking leuprolide acetate (HR 2.44, 95% CI 2.27-2.62) or tranexamic acid (HR 1.44, 95% CI 1.26-1.65) were more likely to switch. Older age, emergency department visits, anaemia, and inflammatory disease diagnoses at baseline were associated with increased probability of discontinuing the index medication or switching to another therapy. CONCLUSIONS: Women with uterine fibroid-related heavy menstrual bleeding were more likely to persist with their initial therapy of long-acting reversible contraceptive steroid compared with other medical options. TWEETABLE ABSTRACT: 80% women with fibroid-related heavy menstrual bleeding use SARC, but LARC users are more persistent.

Dexamethasone reverses the effects of high glucose on human retinal endothelial cell permeability and proliferation in vitro.

Diabetic macular oedema (DMO), a leading cause of preventable visual loss in the working population, is caused by an increase in microvascular endothelial cell permeability, and its prevalence is on the increase in parallel with the rising worldwide prevalence of diabetes. It is known that retinal vascular leakage in DMO is contributed to by VEGF upregulation as well as non-VEGF dependent inflammatory pathways, and the potential use of anti-inflammatory agents such as the glucocorticoids, including dexamethasone are being extensively studied. However, the mechanisms of action of dexamethasone in DMO reduction are not fully understood. Using human primary retinal endothelial cells (REC) the in vitro effect of dexamethasone in modulating the proliferation, permeability and gene expression of key tight and adheren junction components, and the expression of angiopoietins (Ang) 1 and 2 in high (25 mM) glucose conditions were investigated. High glucose decreased REC proliferation, an effect that was reversed by dexamethasone. High glucose conditions significantly increased REC permeability and decreased claudin-5, occludin and JAM-A gene expression; dexamethasone was effective in partially reversing these changes, restoring EC permeability to the normal or near normal state. High glucose levels resulted in reduction of Ang1 secretion, although Ang2 levels were consistently high. DEX increased Ang1 and decreased Ang2, indicating that the balance of Ang1/Ang2 may be important in determining functional changes in REC under high glucose conditions.