Australian interdisciplinary healthcare providers' perspectives on the effects of broader pre-exposure prophylaxis (PrEP) access on uptake and service delivery: a qualitative study.

Background The addition of pre-exposure prophylaxis (PrEP) for HIV prevention to the Australian Government-subsidised Pharmaceutical Benefits Scheme (PBS) enables any doctor or nurse practitioner to prescribe it and has increased accessibility options. However, understanding of Australian healthcare providers' (HCP) knowledge and preparedness to prescribe PrEP remains limited. METHODS: Semistructured interviews, conducted before PBS listing (October 2016-April 2017), explored PrEP knowledge and prescription experiences of 51 multidisciplinary HCPs involved with the Queensland Pre-Exposure Prophylaxis Demonstration study. RESULTS: Thematic analysis revealed that participants viewed PrEP as a necessary HIV prevention option, but there was concern about confusing prevention messages and potential risk compensation. Clinical capacity, stigma, cultural norms, rural access and PrEP-associated costs were identified as barriers to access and uptake. Some of these barriers may be addressed by the PBS listing; nonetheless, there was strong specialist concern about the preparedness of general practitioners without sexual health experience to prescribe PrEP. Participants identified a need to educate all HCPs, implement multidisciplinary supply models and provide timely access to PrEP for vulnerable populations and those ineligible for Medicare (Australia's universal healthcare insurance system). CONCLUSIONS: Although PrEP listing on the PBS addressed structural barriers to access, this study highlights the role of nurses and other interdisciplinary healthcare workers in the provision of PrEP in addressing the sociocultural barriers that still affect the access of certain populations to HIV prevention measures. These findings will inform further professional training as PrEP is more widely accessed and requested outside specialist sexual health services. Future work is needed to ensure that the primary healthcare workforce is prepared to provide competent and safe access to PrEP across diverse locations and population groups.

A novel xenograft mouse model for testing approaches targeting human kappa light-chain diseases.

Patients with immunoglobulin (Ig) light-chain (LC) diseases such as LC light-chain amyloidosis die with organ failure and need new therapies. We sought a model to test anti-LC siRNA delivery to human plasma cells, requiring circulating LC, in vivo indicators of tumor presence, and capacity for multiple injections of delivery vehicle. The JJN-3 human myeloma reporter cell line expressing firefly luciferase (FFL) implanted intraperitoneally (IP) in the NOD scid γ (NSG) mouse has a 90% prompt tumor-take, rapid LC production, and in vivo indicators of tumor measurable on day 5 post-implant (κ LC, bioluminescent signal, and soluble B-cell maturation antigen [sBCMA]) with median day 5 serum levels of κ LC of 1482 ng/mL (range, 255-4831) and robust correlations with all in vivo indicators. In preliminary attempts to deliver siRNA against κ LC constant region mRNA, we identified the 306-O18B3 lipidoid nanoparticle (LNP) as promising, safe and efficient in vitro. In vivo in the JJN-3 NSG IP model, after daily IP 306-O18B3:siRNA injections on days 5-10, a reduction in κ LC was observed on day 8 between control and test groups that continued through day 12 at sacrifice. This model is potentially useful as a platform for refining anti-LC therapies.

Online HIV Self-Testing (HIVST) Dissemination by an Australian Community Peer HIV Organisation: A Scalable Way to Increase Access to Testing, Particularly for Suboptimal Testers.

HIV self-testing (HIVST) introduces opportunities for screening in non-conventional settings, and addresses known testing barriers. This study involved the development and evaluation of a free online HIVST dissemination service hosted by a peer-led, community-based organisation with on-site, peer-facilitated HIV testing, and established referral and support programs for people newly diagnosed with HIV to determine whether this model was feasible and acceptable for engaging MSM, particularly among infrequent and naive HIV-testers, or those living in remote and rural areas. Between December 2016 and April 2018, 927 kits were ordered by 794 individuals, the majority of whom were men who have sex with men (MSM) (62%; 494), having condomless sex (50%; 392), or living outside a major city (38%; 305). Very few (5%; 39) sought the available pre-test peer contact, despite 45% (353) being naive HIV-testers. This study demonstrates that online HIVST dissemination is acceptable and feasible for engaging at-risk suboptimal testers, including those unwilling to test elsewhere (19%; 47/225). With half (50%; 403) unwilling to buy a kit, our study suggests that HIVST will need to be subsidized (cost-neutral to users) to enhance population coverage and access.

Daratumumab binds to mobilized CD34+ cells of myeloma patients in vitro without cytotoxicity or impaired progenitor cell growth.

BACKGROUND: The monoclonal antibody daratumumab, approved for treating myeloma, targets CD38, a protein on myeloma and also on CD34+ hematopoietic progenitor cells. Because mobilized CD34+ cells are critical for stem cell transplant, we investigated the in vitro activity of daratumumab on mobilized CD34+ cells from myeloma patients with no prior exposure to daratumumab. METHODS: We determined the number of CD38 molecules per CD34+ cell, and whether daratumumab bound to CD34+ cells, whether C1q bound to daratumumab-coated CD34+ cells and whether daratumumab-related complement-dependent cytotoxicity (CDC) occurred. We also examined CD34+ cell progenitor cell colony capacity in assays with pre-plating incubation of CD34+ cells with daratumumab alone or with daratumumab and the CD59 inhibitory antibody BRIC229, and also assessed CD34+ cell responses to increasing doses of daratumumab in caspase 3/7 activity assays. RESULTS: Although 75% of mobilized CD34+ cells co-express CD38, CD38 was minimally present on CD34+ cells compared to Daudi and KG-1 controls, C1q did not bind to daratumumab-coated CD34+ cells, and CDC did not occur. CD34+ cells incubated in complement-rich human serum with daratumumab alone or with daratumumab and BRIC229, and then plated in progenitor cell assays, produced similar numbers of colonies as controls. In progenitor cell assays with cryopreserved or fresh unselected or CD34-selected cells, daratumumab did not affect progenitor cell capacity, and in caspase 3/7 activity assays CD34+ cells were not affected by increasing doses of daratumumab. CONCLUSION: In vitro, daratumumab is not toxic to mobilized CD34+ progenitor cells from myeloma patients.

Outcome of Patients With Newly Diagnosed Systemic Light-Chain Amyloidosis Associated With Deletion of 17p.

INTRODUCTION: Deletion 17p (del 17p) portends a poor prognosis in myeloma, but its significance in light-chain amyloidosis is unknown. PATIENTS AND METHODS: We identified patients with light-chain amyloidosis and del 17p at diagnosis, and analyzed presenting characteristics, treatments, and clinical outcomes. All had baseline biopsy results showing amyloid and serologic and marrow studies, including standard fluorescence in-situ hybridization determinations of del 17p using commercial probes. Consensus criteria for hematologic and organ involvement, progression, and response were used. Kaplan-Meier (log rank) analyses and Cox regression analysis of baseline variables were used to identify predictors of overall and progression-free survival (PFS). Six-month landmark analyses were performed to assess the impact of treatment-related variables. RESULTS: We identified 44 patients from 7 countries with median marrow and del 17p plasma cells of 22% (range, 3%-100%) and 30% (2%-93%). Ninety-five percent had cardiac involvement, including 44% stage III. Two-thirds of the patients initially received bortezomib-based therapy. Forty-nine percent of patients experienced complete response or very good partial response, with median time to best response of 4 months (range, 1-28 months). Median overall survival and PFS were 49 and 32 months. Cardiac stage and hematologic response were the key predictors of outcomes. Patients with > 50% and ≤ 50% del 17p in clonal plasma cells had median survivals of 28 and 52 months, respectively (P = .08). In landmark analyses, only hematologic response predicted both overall survival and PFS. CONCLUSION: Cardiac stage, hematologic response, and del 17p percentage impact outcomes in these cases. Emphasis should be placed on optimizing supportive care and achieving a deep hematologic response.

Primary Amyloidosis With Renal Involvement: Outcomes in 77 Consecutive Patients at a Single Center.

BACKGROUND: Outcomes in primary amyloid renal patients are of interest as the era of monoclonal antibody therapies begins. PATIENTS AND METHODS: We studied 77 consecutive primary amyloid renal patients (58% men) for renal progression (end stage renal disease [ESRD]), renal response (RR), and overall survival (OS). RESULTS: At diagnosis median age was 63 (range, 35-81) years, estimated glomerular filtration rate 70 mL/min (range, 5-114), difference between involved and uninvolved free light chains 127 mg/L (range, 1-9957), ESRD 4%, renal stage 2 and 3 78%, and cardiac stage 2 and 3 56%. Ninety-six percent received bortezomib and 44% stem cell transplantation as well as bortezomib, 68% achieved complete or very good partial hematologic response (CR/VGPR), 34% had ESRD, and 39% RR. Median times to ESRD and RR were 18 (range, 3-81) and 12 (range, 2-30) months, respectively. Median OS was not reached in this cohort and was not reached from onset of ESRD. More than two-thirds of patients with ESRD also achieved CR/VGPR. In those without ESRD at diagnosis, baseline creatinine and absent RR predicted progression to ESRD in multivariate Cox regression analysis, whereas CR/VGPR predicted RR. In multivariate Cox regression analysis, cardiac stage and achievement of CR/VGPR predicted OS, enabling construction of a prognostic model. CONCLUSION: Anti-plasma cell therapies provide a definite albeit limited benefit and new approaches to amyloid-related organ dysfunction are needed.

Stakeholder Analysis of Community Distribution of Misoprostol in Lao PDR: A Qualitative Study.

BACKGROUND: Globally, significant progress has been made in reducing maternal mortality, yet in many low-resource contexts it remains unacceptably high. Many of these deaths are due to postpartum haemorrhage and are preventable with access to essential obstetric care. Where there are barriers to access, maternal deaths could be prevented if community-level misoprostol was available. The purpose of this study was to explore perceptions of stakeholders regarding misoprostol use in the Lao People's Democratic Republic, a setting with high maternal mortality. METHODS: Semi-structured interviews were conducted with 35 stakeholders in the capital, Vientiane and in one northern province identified as a site for a possible intervention. The sample included international and national stakeholders involved in policy-making and providing maternal and reproductive health services. FINDINGS: Most stakeholders supported a pilot program for community distribution of misoprostol but levels of awareness of the drug's use in preventing postpartum haemorrhage and level of influence over policy direction varied considerably. Some international organizations, all identified as powerful in influencing policy, were ambivalent about the use of community distribution of misoprostol. Concerns related to the capacity of village health workers or lay people to safely administer misoprostol, whether its distribution would undermine efforts to improve access to safe delivery services and active management of the third stage of labour, the ease with which prescription drugs can be bought over the counter, and technical, logistical, and financial constraints. CONCLUSION: Access to appropriate oxytocic drugs is a matter of health equity. In settings without access to essential obstetrical care, misoprostol represents a viable solution for the prevention of postpartum haemorrhage. Understanding stakeholders' perspectives and their legitimate concerns on misoprostol can inform interventions in order to assuage these concerns and enable disadvantaged women to access misoprostol and its potentially life-saving benefits.

Pulse Electron Double Resonance Detected Multinuclear NMR Spectra of Distant and Low Sensitivity Nuclei and Its Application to the Structure of Mn(II) Centers in Organisms.

The ability to characterize the structure of metal centers beyond their primary ligands is important to understanding their chemistry. High-magnetic-field pulsed electron double resonance detected NMR (ELDOR-NMR) is shown to be a very sensitive approach to measuring the multinuclear NMR spectra of the nuclei surrounding Mn(II) ions. Resolved spectra of intact organisms with resonances arising from (55)Mn, (31)P, (1)H, (39)K, (35)Cl, (23)Na, and (14)N nuclei surrounding Mn(2+) centers were obtained. Naturally abundant cellular (13)C could be routinely measured as well. The amplitudes of the (14)N and (2)H ELDOR-NMR spectra were found to be linearly dependent on the number of nuclei in the ligand sphere. The evolution of the Mn(II) ELDOR-NMR spectra as a function of excitation time was found to be best described by a saturation phenomenon rather than a coherently driven process. Mn(II) ELDOR-NMR revealed details about not only the immediate ligands to the Mn(II) ions but also more distant nuclei, providing a view of their extended structures. This will be important for understanding the speciation and chemistry of the manganese complexes as well as other metals found in organisms.

New techniques for augmenting saliva collection: bacon rules and lozenge drools.

PURPOSE: Saliva is a reliable, noninvasive, and cost-effective alternative to biomarkers measured in other biological fluids. Within certain populations, saliva sampling may be difficult because of insufficient saliva flow, which may compromise disease diagnosis or research integrity. Methods to improve flow rates (eg, administering citric acid, chewing gum, or collecting cotton) may compromise biomarker integrity, especially if the methods involve the presence of a collection aid in the oral cavity. Anecdotal strategies (eg, looking at pictures of food or imagining food) have not been evaluated to date. In this study, we evaluate whether 2 novel collection techniques improve saliva flow or interfere with assay of common biomarkers (ie, cortisol, dehydroepiandrosterone, and testosterone). We evaluate an over-the-counter anhydrous crystalline maltose lozenge intended to increase saliva production for patients with xerostomia long after the lozenge dissolves. We then evaluate whether the smell of freshly cooked bacon stimulates a pavlovian-type reflex. METHODS: Saliva was collected from 27 healthy young adults (aged 20-34 years; 12 men) on a basal day and a lozenge day, providing 5 samples at 15-minute intervals. Twenty participants then returned for the bacon day condition, providing 2 saliva samples with an interval of 15 minutes between samples. Collection times required to generate 2 mL of saliva across collection strategies were recorded, and then saliva samples were assayed for cortisol, dehydroepiandrosterone, and testosterone. FINDINGS: Repeated analysis of variance measures revealed that both the lozenges and bacon significantly decreased collection time compared with the passive drool collection on the basal day. No significant effects were found related to the quantification of cortisol, testosterone, or dehydroepiandrosterone when comparing lozenge or bacon to the basal day. In addition, bivariate correlations revealed that concentrations from time-matched control samples correlated significantly with concentrations from the lozenge and bacon conditions. IMPLICATIONS: These results indicate that both the lozenge and smelling bacon improve saliva collection times and that neither technique interferes with salivary hormone concentrations. This study reveals new methods to augment saliva collection strategies.