Assessment of phototoxicity in pigmented Long-Evans rat: sparfloxacin and 8-methoxypsoralen.

The aim of the present work was to evaluate the effects of photo-activated toxicity induced after administration of two known melanin-binding phototoxic compounds, sparfloxacin (SPX) and 8-methoxypsoralen (8-MOP), followed or not by UVA/Vis exposure, in pigmented rats (Long Evans: LE) and albino rats (Sprague Dawley: SD). Groups of three rats were treated with SPX or 8-MOP by oral gavage for six consecutive days. Irradiated animals were submitted to a UVA/Vis light dose standardized to 10 J/cm2 UVA daily. Clinical signs, cutaneous reactions and body weight were monitored throughout the study period. Ear biopsy weight, lymph node weight and lymph node cell count were determined at necropsy. Ophthalmologic examinations were performed before the first treatment and on the day of sacrifice. Microscopic examinations were performed on skin biopsies and eyes. Phototoxicity was demonstrated for both SPX and 8-MOP in the pigmented and albino strains, in terms of auricular irritation, lymph node weight and proliferation index, cutaneous reactions and ocular histopathology. LE rats were less sensitive than SD rats, especially at the ocular level, supporting the notion that pigmentation may provide protection against photo-activation. The pigmented rat may be a more relevant model than the albino rat for human safety evaluation.

Using Value Stream Mapping to improve quality of care in low-resource facility settings.

QUALITY PROBLEM OR ISSUE: Jacaranda Health (JH) is a Kenya-based organization that attempts to provide affordable, high-quality maternal and newborn healthcare through a chain of private health facilities in Nairobi. INITIAL ASSESSMENT: JH needed to adopted quality improvement as an organization-wide strategy to optimize effectiveness and efficiency. CHOICE OF SOLUTION: Value Stream Mapping, a Lean Management tool, was used to engage staff in prioritizing opportunities to improve clinical outcomes and patient-centered quality of care. IMPLEMENTATION: Implementation was accomplished through a five-step process: (i) leadership engagement and commitment; (ii) staff training; (iii) team formation; (iv) process walkthrough; and (v) construction and validation. EVALUATION: The Value Stream Map allowed the organization to come together and develop an end-to-end view of the process of care at JH and to select improvement opportunities for the entire system. LESSONS LEARNED: The Value Stream Map is a simple visual tool that allows organizations to engage staff at all levels to gain commitment around quality improvement efforts.

Optimized synthesis, polymer conjugation, and proof-of-concept studies of the gd-IgA1 epitope for antibody-scavenging therapies in IgA nephropathy.

IgA nephropathy (IgAN) is the most common glomerular autoimmune disease and has severe long-term consequences for patients, with 40% of the patients eventually progressing to end-stage renal disease. Despite the severity, no causal treatment is currently available. While the pathogenesis of IgAN is complex, disease severity is linked to autoantibodies against the gd-IgA1 epitope, a stretch in the hinge region of IgA1 that lacks O-glycans and is found in the characteristic immune complexes deposited in the kidneys of IgAN patients. One elegant, causal approach would be to remove the anti-gd-IgA1 autoantibodies and consequently reduce the immune complex burden on the kidneys. The administration of synthetic polymers that present autoantigens in a multivalent manner have been established as promising therapeutic strategies in other autoimmune diseases and may be applied to IgAN. We here present an improved protocol for the synthesis of the gd-IgA1 epitope, its successful coupling to a poly-L-lysine polymer and proof-of-concept experiments that the polymer-bound synthetic glycopeptide is able to capture the IgAN autoantibodies, making this approach a promising way forward for developing a targeted treatment option for IgAN patients.

Scenario-based design for a hospital setting: An exploratory study of opportunities and barriers for personal health records usage.

Personal health records (PHRs) offer patients the opportunity to be more actively involved in their own care. There is limited research into the application during hospital admissions for elective or emergency presentations. We used techniques from scenario-based design to test the opportunities and boundaries of a commercially available PHR in a simulated environment. Scenarios included a patient in his 80s admitted for hip surgery with his son, and a younger patient admitted with pneumonia. A catastrophic deterioration was demonstrated with a mannequin in a high-fidelity simulation. Workflows were summarised in swim-lane diagrams. The PHR allowed patients to file information prior to the interaction with the clinical team. This led to shorter time requirements for acquisition of data. The elderly patient required assistance from a relative but this aided verification of history prior to the encounter with the clinical team. Ward rounds could be prepared by the patient with specific 'what matters' questions. Documentation in the PHR environment during a simulated life-threatening emergency did not result in information that was unintelligible or useful for the 'patient'. Usage of a commercially available PHR during hospital admission is feasible and might aid workflow. Documentation of emergencies might require different documentation formats.

Providing support to pregnant women and new mothers through moderated WhatsApp groups: a feasibility study.

BACKGROUND: Group-based health services can improve maternal and newborn health outcomes. Group antenatal care and participatory learning and action cycles (PLA) with women's groups have been cited by the WHO as health systems interventions that can lead to improvements in adherence to care and health outcomes in pregnancy and the postpartum period. METHODS: We used a mixed-methods approach to assess the feasibility of a light touch group-based support intervention using the WhatsApp text-messaging platform. Pregnant women were enrolled at Jacaranda Health (JH), a maternity center in peri-urban Kiambu County, Kenya. Their phone numbers were added to WhatsApp groups consisting of participants with similar estimated due dates. The WhatsApp group administrator was a JH employee. Acceptability, demand, implementation, and practicality of this service were evaluated through in-depth interviews (IDIs), surveys, chart review, and analysis of group chats. Limited analysis of program efficacy (ANC visits, any PNC, and post-partum family planning uptake) was assessed by comparing participant data collected through chart review using a concurrent comparison of the general JH patient population. RESULTS: Fifty women (88%) of 57 eligible women who were approached to participate enrolled in the study. Five WhatsApp groups were created. A total of 983 messages were exchanged over 38 weeks. No harms or negative interactions were reported. Participants reported several benefits. Participants had differing expectations of the level of the group administrator's activity in the groups. ANC and PNC attendance were in line with the hospital's metrics for the rest of JH's patient population. Higher rates of postpartum long acting reversible contraception (LARC) uptake were observed among participants relative to the general patient population. CONCLUSIONS: A moderated mobile-based support group service for pregnant women and new mothers is safe and feasible. Additional research using experimental designs to strengthen evidence of the effectiveness of the support intervention is warranted.

In Vitro Human Placental Studies to Support Adenovirus-Mediated VEGF-DΔNΔC Maternal Gene Therapy for the Treatment of Severe Early-Onset Fetal Growth Restriction.

Severe fetal growth restriction (FGR) affects 1 in 500 pregnancies, is untreatable, and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) is one cause. Transduction of uterine arteries in normal and FGR animal models using an adenovirus (Ad) encoding VEGF isoforms increases UBF and improves fetal growth in utero. Understanding potential adverse consequences of this therapy before first-in-woman clinical application is essential. The aims of this study were to determine whether Ad.VEGF-DΔNΔC (1) transfers across the human placental barrier and (2) affects human placental morphology, permeability and primary indicators of placental function, and trophoblast integrity. Villous explants from normal term human placentas were treated with Ad.VEGF-DΔNΔC (5 × 107-10 virus particles [vp]/mL), or virus formulation buffer (FB). Villous structural integrity (hematoxylin and eosin staining) and tissue accessibility (LacZ immunostaining) were determined. Markers of endocrine function (human chorionic gonadotropin [hCG] secretion) and cell death (lactate dehydrogenase [LDH] release) were assayed. Lobules from normal and FGR pregnancies underwent ex vivo dual perfusion with exposure to 5 × 1010 vp/mL Ad.VEGF-DΔNΔC or FB. Perfusion resistance, para-cellular permeability, hCG, alkaline phosphatase, and LDH release were measured. Ad.VEGF-DΔNΔC transfer across the placental barrier was assessed by quantitative polymerase chain reaction in DNA extracted from fetal-side venous perfusate, and by immunohistochemistry in fixed tissue. Villous explant structural integrity and hCG secretion was maintained at all Ad.VEGF-DΔNΔC doses. Ad.VEGF-DΔNΔC perfusion revealed no effect on placental permeability, fetoplacental vascular resistance, hCG secretion, or alkaline phosphatase release, but there was a minor elevation in maternal-side LDH release. Viral vector tissue access in both explant and perfused models was minimal, and the vector was rarely detected in the fetal venous perfusate and at low titer. Ad.VEGF-DΔNΔC did not markedly affect human placental integrity and function in vitro. There was limited tissue access and transfer of vector across the placental barrier. Except for a minor elevation in LDH release, these test data did not reveal any toxic effects of Ad.VEGF-DΔNΔC on the human placenta.

INTERGROWTH-21st Gestational Dating and Fetal and Newborn Growth Standards in Peri-Urban Nairobi, Kenya: Quasi-Experimental Implementation Study Protocol.

BACKGROUND: The burden of preterm birth, fetal growth impairment, and associated neonatal deaths disproportionately falls on low- and middle-income countries where modern obstetric tools are not available to date pregnancies and monitor fetal growth accurately. The INTERGROWTH-21st gestational dating, fetal growth monitoring, and newborn size at birth standards make this possible. OBJECTIVE: To scale up the INTERGROWTH-21st standards, it is essential to assess the feasibility and acceptability of their implementation and their effect on clinical decision-making in a low-resource clinical setting. METHODS: This study protocol describes a pre-post, quasi-experimental implementation study of the standards at Jacaranda Health, a maternity hospital in peri-urban Nairobi, Kenya. All women with viable fetuses receiving antenatal and delivery services, their resulting newborns, and the clinicians caring for them from March 2016 to March 2018 are included. The study comprises a 12-month preimplementation phase, a 12-month implementation phase, and a 5-month post-implementation phase to be completed in August 2018. Quantitative clinical and qualitative data collected during the preimplementation and implementation phases will be assessed. A clinician survey was administered eight months into the implementation phase, month 20 of the study. Implementation outcomes include quantitative and qualitative analyses of feasibility, acceptability, adoption, appropriateness, fidelity, and penetration of the standards. Clinical outcomes include appropriateness of referral and effect of the standards on clinical care and decision-making. Descriptive analyses will be conducted, and comparisons will be made between pre- and postimplementation outcomes. Qualitative data will be analyzed using thematic coding and compared across time. The study was approved by the Amref Ethics and Scientific Review Committee (Kenya) and the Harvard University Institutional Review Board. Study results will be shared with stakeholders through conferences, seminars, publications, and knowledge management platforms. RESULTS: From October 2016 to February 2017, over 90% of all full-time Jacaranda clinicians (26/28) received at least one of the three aspects of the INTERGROWTH-21st training: gestational dating ultrasound, fetal growth monitoring ultrasound, and neonatal anthropometry standards. Following the training, implementation and evaluation of the standards in Jacaranda Health's clinical workflow will take place from March 2017 through March 5, 2018. Data analysis will be finalized, and results will be shared by August 2018. CONCLUSIONS: The findings of this study will have major implications on the national and global scale up of the INTERGROWTH-21st standards and on the process of scaling up global standards in general, particularly in limited-resource settings. REGISTERED REPORT IDENTIFIER: RR1-10.2196/10293.

Biodistribution and predictive hepatic gene expression of intravenous iron sucrose.

INTRODUCTION: We have examined iron biodistribution and hepatic gene expression in rats following administration of the generic Iron Sucrose Azad (ISA) or the reference iron sucrose drug Venofer®. METHODS: ISA and Venofer® were administered intravenously to normal, non-anemic, male rats at 15 mg/kg (a supra-therapeutic dose-level). To evaluate biodistribution, tissue iron levels were determined over 28 days for plasma, liver, spleen, bone marrow, heart, kidney, lung and stomach using a validated ICP-MS method. Hepatic gene expression was evaluated by microarray analysis of mRNA from samples taken 24 h after drug administration. RESULTS: Iron concentration/time profiles for plasma and tissues were quantitatively similar for ISA and Venofer. Following administration, circulating iron levels briefly exceeded transferrin binding capacity and there was a transient increase in hepatic iron. Bone marrow iron levels remained elevated throughout the study. No increases in tissue iron levels were observed in the heart, stomach or lungs. Spleen iron levels increased over the course of the study in treated and control rats. Small, transient increases were recorded in the kidneys of treated rats. The effects of ISA and Venofer® on hepatic gene transcription were similar. Principal components analysis showed that there was no systematic effect of either treatment on transcriptional profiles. Only a small number of genes showed significant modulation of expression. No transcriptional pattern matches with toxicity pathways were found in the ToxFX database for either treatment. No modulation of key genes in apoptosis, inflammation or oxidative stress pathways was detected. DISCUSSION: These findings demonstrated that the biodistribution of administered iron is essentially similar for Iron Sucrose Azad and Venofer®, that iron sucrose partitions predominantly into the liver, spleen and bone marrow, and that hepatic gene expression studies did not provide any evidence of toxicity in animals treated at a supra-therapeutic dose-level.