Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte.

Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs). Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5-E11.5, including genome-wide loss of 5-methylcytosine. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro. Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro.

Physicochemical properties of otic products for Canine Otitis Externa: comparative analysis of marketed products.

BACKGROUND: Otitis externa is a commonly diagnosed dermatological disorder in canines. The pathogens primarily involved in canine otitis externa (COE) include Staphylococcus pseudintermedius, Pseudomonas aeruginosa, Proteus mirabilis, and Malassezia pachydermatis. As COE tends to be superficial, medications delivered topically are often effective and practical in managing the condition. As such, there is a wide variety of approved topical products currently available in the market. The efficacy of topical dosage forms can be dependent on various factors such as the pharmacology of active constituents and the physicochemical properties of the formulation, including pH, viscosity, spreadability, and bio-adhesion. Currently, there is a lack of published literature available on the optimal properties of topical COE products. In this study, we compared the physicochemical properties of nine commercially available otic veterinarian products in Australia used clinically to manage COE. RESULTS: Based on our comparative analysis, the pH (6.26 ± 0.04) of an aqueous-based product was similar to a healthy dog's external auditory canal. Products containing polymers exhibited higher viscosity and bio-adhesion. Spreadability was inversely related to viscosity and Osurnia ® a product with high viscosity demonstrated the lowest spreadability. Aqueous-based otic products showed better syringebility whereas oil-based systems required higher force to expel the products. Variability in droplet size was noted. Derm Otic, Baytril Otic, and Aurizon Ear Drops had the lower standard deviation which indicates they would give a more consistent dose. CONCLUSIONS: Findings from this work provide considerations for industry researchers or formulation scientists working in the area of otic dosage formulations.

Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.

The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of histone deposition in the absence of DNA replication, we deleted the H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is dynamic and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. Our study thus unequivocally shows the importance of continuous histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in a non-replicative system in vivo.

Patient Trajectories Among Persons Hospitalized for COVID-19 : A Cohort Study.

BACKGROUND: Risk factors for progression of coronavirus disease 2019 (COVID-19) to severe disease or death are underexplored in U.S. cohorts. OBJECTIVE: To determine the factors on hospital admission that are predictive of severe disease or death from COVID-19. DESIGN: Retrospective cohort analysis. SETTING: Five hospitals in the Maryland and Washington, DC, area. PATIENTS: 832 consecutive COVID-19 admissions from 4 March to 24 April 2020, with follow-up through 27 June 2020. MEASUREMENTS: Patient trajectories and outcomes, categorized by using the World Health Organization COVID-19 disease severity scale. Primary outcomes were death and a composite of severe disease or death. RESULTS: Median patient age was 64 years (range, 1 to 108 years); 47% were women, 40% were Black, 16% were Latinx, and 21% were nursing home residents. Among all patients, 131 (16%) died and 694 (83%) were discharged (523 [63%] had mild to moderate disease and 171 [20%] had severe disease). Of deaths, 66 (50%) were nursing home residents. Of 787 patients admitted with mild to moderate disease, 302 (38%) progressed to severe disease or death: 181 (60%) by day 2 and 238 (79%) by day 4. Patients had markedly different probabilities of disease progression on the basis of age, nursing home residence, comorbid conditions, obesity, respiratory symptoms, respiratory rate, fever, absolute lymphocyte count, hypoalbuminemia, troponin level, and C-reactive protein level and the interactions among these factors. Using only factors present on admission, a model to predict in-hospital disease progression had an area under the curve of 0.85, 0.79, and 0.79 at days 2, 4, and 7, respectively. LIMITATION: The study was done in a single health care system. CONCLUSION: A combination of demographic and clinical variables is strongly associated with severe COVID-19 disease or death and their early onset. The COVID-19 Inpatient Risk Calculator (CIRC), using factors present on admission, can inform clinical and resource allocation decisions. PRIMARY FUNDING SOURCE: Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.

Tangible Experiences of Grace: A Qualitative Investigation of Divine Grace in Roman Catholics.

According to Catholic theology, God offers a gift of love, known as divine grace, to all of humanity. This gift of divine grace is the gift of redemption and forgiveness of sins from God that is offered to everyone who decides to acknowledge and accept it. Grace is central to the lived experience of many Christians. This qualitative study examined how Catholics perceive and experience divine grace using interviews that assessed perceptions of divine grace in 29 practicing adult Catholics. A grounded theory analysis resulted in themes indicating that these Catholics view God's divine grace as a tangible gift that is undeserved though continuously offered. The participants' experience of God's grace is not just an abstract theological concept but an embodied aspect of religious life with which believers can interact in many powerful ways. Three characteristics of God's divine grace (i.e., salvific grace, cooperation through free will, primacy of conscience and the afterlife) and three mechanisms to experiencing God's grace (i.e., sacraments, prayer and meditation, saints) are presented.

Building a sustainable rural physician workforce.

CHAPTER 1: CHARACTERISING AUSTRALIA'S RURAL SPECIALIST PHYSICIAN WORKFORCE: THE PROFESSIONAL PROFILE AND PROFESSIONAL SATISFACTION OF JUNIOR DOCTORS AND CONSULTANTS: Objective: To assess differences in the demographic characteristics, professional profile and professional satisfaction of rural and metropolitan junior physicians and physician consultants in Australia. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional, population level national survey of the Medicine in Australia: Balancing Employment and Life longitudinal cohort study (collected 2008-2016). Participants were specialist physicians from four career stage groups: pre-registrars (physician intent); registrars; new consultants (< 5 years since Fellowship); and consultants. MAIN OUTCOME MEASURES: Level of professional satisfaction across various job aspects, such as hours worked, working conditions, support networks and educational opportunities, comparing rural and metropolitan based physicians. RESULTS: Participants included 1587 pre-registrars (15% rural), 1745 physician registrars (9% rural), 421 new consultants (20% rural) and 1143 consultants (13% rural). Rural physicians of all career stages demonstrated equivalent professional satisfaction across most job aspects, compared with metropolitan physician counterparts. Some examples of differences in satisfaction included rural pre-registrars being less likely to agree they had good access to support and supervision from qualified consultants (odds ratio [OR], 0.6; 95% CI, 0.3-0.9) and rural consultants being more likely to agree they had a poorer professional support network (OR, 1.9; 95% CI, 1.2-2.9). In terms of demographics, relatively more rural physicians had a rural background or were trained overseas. Although most junior physicians were women, female consultants were less likely to be working in a rural location (OR, 0.6; 95% CI, 0.4-0.8). CONCLUSION: Junior physicians in metropolitan or rural settings have a similar professional experience, which is important in attracting future trainees. Increased opportunities for rural training should be prioritised, along with addressing concerns about the professional isolation and poorer support network of those in rural areas, not only among junior doctors but also consultants. Finally, making rural practice more attractive to female junior physicians could greatly improve the consultant physician distribution. CHAPTER 2: GENERAL PHYSICIANS AND PAEDIATRICIANS IN RURAL AUSTRALIA: THE SOCIAL CONSTRUCTION OF PROFESSIONAL IDENTITY: Objective: To explore the construction of professional identity among general physicians and paediatricians working in non-metropolitan areas. DESIGN, SETTING AND PARTICIPANTS: In-depth qualitative interviews were conducted with general physicians and paediatricians, plus informants from specialist colleges, government agencies and academia who were involved in policy and programs for the training and recruitment of specialists in rural locations across three states and two territories. This research is part of the Training Pathways and Professional Support for Building a Rural Physician Workforce Study, 2018-19. MAIN OUTCOME MEASURES: Individual and collective descriptors of professional identity. RESULTS: We interviewed 36 key informants. Professional identity for general physicians and paediatricians working in regional, rural and remote Australia is grounded in the breadth of their training, but qualified by location - geographic location, population served or specific location, where social and cultural context specifically shapes practice. General physicians and paediatricians were deeply engaged with their local community and its economic vulnerability, and they described the population size and dynamics of local economies as determinants of viable practice. They often complemented their practice with formal or informal training in areas of special interest, but balanced their practice against subspecialist availability, also dependent on demographics. While valuing their professional roles, they showed limited inclination for industrial organisation. CONCLUSION: Despite limited consensus on identity descriptors, rural general physicians and paediatricians highly value generalism and their rural engagement. The structural and geographic bias that preferences urban areas will need to be addressed to further develop coordinated strategies for advanced training in rural contexts, for which collective identity is integral. CHAPTER 3: SUSTAINABLE RURAL PHYSICIAN TRAINING: LEADERSHIP IN A FRAGILE ENVIRONMENT: Objectives: To understand Royal Australasian College of Physicians (RACP) training contexts, including supervisor and trainee perspectives, and to identify contributors to the sustainability of training sites, including training quality. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional mixed-methods design was used. A national sample of RACP trainees and Fellows completed online surveys. Survey respondents who indicated willingness to participate in interviews were purposively recruited to cover perspectives from a range of geographic, demographic and training context parameters. MAIN OUTCOME MEASURES: Fellows' and trainees' work and life satisfaction, and their experiences of supervision and training, respectively, by geographic location. RESULTS: Fellows and trainees reported high levels of satisfaction, with one exception - inner regional Fellows reported lower satisfaction regarding opportunities to use their abilities. Not having a good support network was associated with lower satisfaction. Our qualitative findings indicate that a culture of undermining rural practice is prevalent and that good leadership at all levels is important to reduce negative impacts on supervisor and trainee availability, site accreditation and viability. Trainees described challenges in navigating training pathways, ensuring career development, and having the flexibility to meet family needs. The small number of Fellows in some sites poses challenges for supervisors and trainees and results in a blurring of roles; accreditation is an obstacle to provision of training at rural sites; and the overlap between service and training roles can be difficult for supervisors. CONCLUSION: Our qualitative findings emphasise the distinctive nature of regional specialist training, which can make it a fragile environment. Leadership at all levels is critical to sustaining accreditation and support for supervisors and trainees. CHAPTER 4: PRINCIPLES TO GUIDE TRAINING AND PROFESSIONAL SUPPORT FOR A SUSTAINABLE RURAL SPECIALIST PHYSICIAN WORKFORCE: Objective: To draw on research conducted in the Building a Rural Physician Workforce project, the first national study on rural specialist physicians, to define a set of principles applicable to guiding training and professional support action. DESIGN: We used elements of the Delphi approach for systematic data collection and codesign, and applied a hybrid participatory action planning approach to achieve consensus on a set of principles. RESULTS: Eight interconnected foundational principles built around rural regions and rural people were identified: FP1, grow your own "connected to" place; FP2, select trainees invested in rural practice; FP3, ground training in community need; FP4, rural immersion - not exposure; FP5, optimise and invest in general medicine; FP6, include service and academic learning components; FP7, join up the steps in rural training; and FP8, plan sustainable specialist roles. CONCLUSION: These eight principles can guide training and professional support to build a sustainable rural physician workforce. Application of the principles, and coordinated action by stakeholders and the responsible organisations, are needed at national, state and local levels to achieve a sustainable rural physician workforce.

Autotitrating external positive end-expiratory airway pressure to abolish expiratory flow limitation during tidal breathing in patients with severe COPD: a physiological study.

BACKGROUND: The optimal noninvasive application of external positive end-expiratory pressure (EPAP) to abolish tidal-breathing expiratory flow limitation (EFLT) and minimise intrinsic positive end-expiratory pressure (PEEPi) is challenging in COPD patients. We investigated whether auto-titrating EPAP, using the forced oscillation technique (FOT) to detect and abolish EFLT, would minimise PEEPi, work of breathing and neural respiratory drive (NRD) in patients with severe COPD. METHODS: Patients with COPD with chronic respiratory failure underwent auto-titration of EPAP using a FOT-based algorithm that detected EFLT. Once optimal EPAP was identified, manual titration was performed to assess NRD (using diaphragm and parasternal intercostal muscle electromyography, EMGdi and EMGpara, respectively), transdiaphragmatic inspiratory pressure swings (ΔP di), transdiaphragmatic pressure-time product (PTPdi) and PEEPi, between EPAP levels 2 cmH2O below to 3 cmH2O above optimal EPAP. RESULTS: Of 10 patients enrolled (age 65±6 years; male 60%; body mass index 27.6±7.2 kg.m-2; forced expiratory volume in 1 s 28.4±8.3% predicted), eight had EFLT, and optimal EPAP was 9 (range 4-13) cmH2O. NRD was reduced from baseline EPAP at 1 cmH2O below optimal EPAP on EMGdi and at optimal EPAP on EMGpara. In addition, at optimal EPAP, PEEPi (0.80±1.27 cmH2O versus 1.95± 1.70 cmH2O; p<0.05) was reduced compared with baseline. PTPdi (10.3±7.8 cmH2O·s-1 versus 16.8±8.8 cmH2O·s-1; p<0.05) and ΔP di (12.4±7.8 cmH2O versus 18.2±5.1 cmH2O; p<0.05) were reduced at optimal EPAP+1 cmH2O compared with baseline. CONCLUSION: Autotitration of EPAP, using a FOT-based algorithm to abolish EFLT, minimises transdiaphragmatic pressure swings and NRD in patients with COPD and chronic respiratory failure.

Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and autism spectrum disorder based upon expert consensus.

BACKGROUND: Individuals with co-occurring hyperactivity disorder/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) can have complex presentations that may complicate diagnosis and treatment. There are established guidelines with regard to the identification and treatment of ADHD and ASD as independent conditions. However, ADHD and ASD were not formally recognised diagnostically as co-occurring conditions until the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) was published in 2013. Hence, awareness and understanding of both conditions when they co-occur is less established and there is little guidance in the clinical literature. This has led to uncertainty among healthcare practitioners when working with children, young people and adults who present with co-existing ADHD and ASD. The United Kingdom ADHD Partnership (UKAP) therefore convened a meeting of professional experts that aimed to address this gap and reach expert consensus on the topic that will aid healthcare practitioners and allied professionals when working with this complex and vulnerable population. METHOD: UK experts from multiple disciplines in the fields of ADHD and ASD convened in London in December 2017. The meeting provided the opportunity to address the complexities of ADHD and ASD as a co-occurring presentation from different perspectives and included presentations, discussion and group work. The authors considered the clinical challenges of working with this complex group of individuals, producing a consensus for a unified approach when working with male and female, children, adolescents and adults with co-occurring ADHD and ASD. This was written up, circulated and endorsed by all authors. RESULTS: The authors reached a consensus of practical recommendations for working across the lifespan with males and females with ADHD and ASD. Consensus was reached on topics of (1) identification and assessment using rating scales, clinical diagnostic interviews and objective supporting assessments; outcomes of assessment, including standards of clinical reporting; (2) non-pharmacological interventions and care management, including psychoeducation, carer interventions/carer training, behavioural/environmental and Cognitive Behavioural Therapy (CBT) approaches; and multi-agency liaison, including educational interventions, career advice, occupational skills and training, and (3) pharmacological treatments. CONCLUSIONS: The guidance and practice recommendations (Tables 1, 4, 5, 7, 8 and 10) will support healthcare practitioners and allied professionals to meet the needs of this complex group from a multidisciplinary perspective. Further research is needed to enhance our understanding of the diagnosis, treatment and management of individuals presenting with comorbid ADHD and ASD.

Primary health care contributions to universal health coverage, Ethiopia.

Many global health institutions, including the World Health Organization, consider primary health care as the path towards achieving universal health coverage (UHC). However, there remain concerns about the feasibility and effectiveness of this approach in low-resource countries. Ethiopia has been implementing the primary health-care approach since the mid-1970s, with primary health care at the core of the health system since 1993. Nevertheless, comprehensive and systemic evidence on the practice and role of primary health care towards UHC is lacking in Ethiopia. We made a document review of publicly available qualitative and quantitative data. Using the framework of the Primary Health Care Performance Initiative we describe and analyse the practice of primary health care and identify successes and challenges. Implementation of the primary health-care approach in Ethiopia has been possible through policies, strategies and programmes that are aligned with country priorities. There has been a diagonal approach to disease control programmes along with health-systems strengthening, community empowerment and multisectoral action. These strategies have enabled the country to increase health services coverage and improve the population's health status. However, key challenges remain to be addressed, including inadequate coverage of services, inequity of access, slow health-systems transition to provide services for noncommunicable diseases, inadequate quality of care, and high out-of-pocket expenditure. To resolve gaps in the health system and beyond, the country needs to improve its domestic financing for health and target disadvantaged locations and populations through a precision public health approach. These challenges need to be addressed through the whole sustainable development agenda.

De nombreux organismes sanitaires internationaux, dont l'Organisation mondiale de la Santé, considèrent que les soins de santé primaires représentent un jalon essentiel du cheminement vers une couverture maladie universelle (CMU). Néanmoins, des inquiétudes subsistent quant à la faisabilité et à l'efficacité de cette approche dans les pays à faible revenu. L'Éthiopie a adopté cette approche depuis le milieu des années 1970, et les soins de santé primaires figurent au cœur du système sanitaire depuis 1993. Pourtant, rares sont les preuves exhaustives et généralisées concernant la pratique et le rôle des soins de santé primaires dans l'évolution vers une CMU en Éthiopie. Nous avons donc procédé à un examen des documents contenant des données qualitatives et quantitatives accessibles au public. À l'aide du cadre instauré par l'initiative PHCPI (Primary Health Care Performance Initiative), nous avons décrit et analysé la pratique des soins de santé primaires; nous avons également identifié les réussites et les défis. C'est grâce à des politiques, stratégies et programmes en adéquation avec les priorités nationales que cette méthode axée sur les soins de santé primaires a pu être mise en œuvre en Éthiopie. Le pays a emprunté une approche diagonale vis-à-vis des programmes de contrôle des maladies, tout en renforçant les systèmes de santé, l'autonomie des communautés et l'action multisectorielle. Ces stratégies lui ont permis d'augmenter la prise en charge des services de santé et d'améliorer l'état de santé de la population. Il reste cependant d'importants défis à relever: couverture insuffisante des services, inégalités d'accès, lenteur de transition entre systèmes sanitaires pour la fourniture de prestations liées aux maladies non transmissibles, qualité médiocre des soins et frais non remboursables élevés. Afin de combler les lacunes au sein et en dehors du système de santé, le pays doit revoir le montant du financement octroyé aux soins de santé à la hausse, mais aussi cibler les régions et populations défavorisées par le biais d'une approche de précision en matière de santé publique. Ces défis doivent être abordés tout au long du programme de développement durable.

Varias instituciones sanitarias mundiales, incluida la Organización Mundial de la Salud, opinan que la atención primaria de salud es la vía hacia el logro de la cobertura sanitaria universal (CSU). Sin embargo, persisten las preocupaciones acerca de la viabilidad y la eficacia de este enfoque en los países de bajos recursos. Etiopía aplica el enfoque de la atención primaria de salud desde mediados del decenio de 1970, por lo que la atención primaria de salud es el núcleo del sistema de salud desde 1993. No obstante, Etiopía carece de pruebas integrales y generales sobre la práctica y la función de la atención primaria de salud orientada a la CSU. Se realizó un análisis documental de los datos cualitativos y cuantitativos a disposición del público. Se describe y analiza la práctica de la atención primaria de salud y se determinan los éxitos y los desafíos por medio del marco de la Iniciativa sobre el desempeño de la atención primaria de salud. La aplicación del enfoque de la atención primaria de salud en Etiopía fue posible gracias a las políticas, las estrategias y los programas que se adaptaron a las prioridades del país. Existe un enfoque diagonal de los programas de control de enfermedades sumado al fortalecimiento de los sistemas sanitarios, a la participación de la comunidad y a las medidas multisectoriales. Gracias a estas estrategias, el país ha logrado aumentar la cobertura de los servicios sanitarios y mejorar el estado de salud de la población. Sin embargo, aún quedan por resolver algunos desafíos fundamentales, como la cobertura insuficiente de los servicios, la falta de equidad en el acceso, la lentitud de la transición de los sistemas sanitarios para prestar los servicios correspondientes a las enfermedades no transmisibles, la calidad deficiente de la atención y los elevados gastos de bolsillo. Para resolver las deficiencias del sistema sanitario y otros aspectos, el país debe mejorar su financiamiento nacional para la salud y centrarse en los lugares y las poblaciones desfavorecidos a través de un enfoque preciso de la salud pública. Se debe abordar estos desafíos en todo el programa de desarrollo sostenible.

The Effect of Kidney Biopsy on Glomerular Filtration Rate: A Frequent Patient Concern.

The effect of percutaneous kidney biopsy on glomerular filtration rate has never been identified, though it is frequently a concern raised by patients. Following a clinical interaction with an inquisitive patient undergoing her fifth biopsy, we attempted to estimate the effect using retrospective data. In a cohort of patients with stable kidney function undergoing transplant biopsy without clinical indication (as part of a surveillance programme) the effect of biopsy was observed as a step change in glomerular filtration rate. Reassuringly, the loss of glomerular filtration rate resulting from a biopsy, has a 1-sided 95% confidence interval of <1.4 mL/min.

Females with ADHD: An expert consensus statement taking a lifespan approach providing guidance for the identification and treatment of attention-deficit/ hyperactivity disorder in girls and women.

BACKGROUND: There is evidence to suggest that the broad discrepancy in the ratio of males to females with diagnosed ADHD is due, at least in part, to lack of recognition and/or referral bias in females. Studies suggest that females with ADHD present with differences in their profile of symptoms, comorbidity and associated functioning compared with males. This consensus aims to provide a better understanding of females with ADHD in order to improve recognition and referral. Comprehensive assessment and appropriate treatment is hoped to enhance longer-term clinical outcomes and patient wellbeing for females with ADHD. METHODS: The United Kingdom ADHD Partnership hosted a meeting of experts to discuss symptom presentation, triggers for referral, assessment, treatment and multi-agency liaison for females with ADHD across the lifespan. RESULTS: A consensus was reached offering practical guidance to support medical and mental health practitioners working with females with ADHD. The potential challenges of working with this patient group were identified, as well as specific barriers that may hinder recognition. These included symptomatic differences, gender biases, comorbidities and the compensatory strategies that may mask or overshadow underlying symptoms of ADHD. Furthermore, we determined the broader needs of these patients and considered how multi-agency liaison may provide the support to meet them. CONCLUSIONS: This practical approach based upon expert consensus will inform effective identification, treatment and support of girls and women with ADHD. It is important to move away from the prevalent perspective that ADHD is a behavioural disorder and attend to the more subtle and/or internalised presentation that is common in females. It is essential to adopt a lifespan model of care to support the complex transitions experienced by females that occur in parallel to change in clinical presentation and social circumstances. Treatment with pharmacological and psychological interventions is expected to have a positive impact leading to increased productivity, decreased resource utilization and most importantly, improved long-term outcomes for girls and women.

Leaving no one behind: lessons from implementation of policies for universal HIV treatment to universal health coverage.

BACKGROUND: The third Sustainable Development Goal (SDG - 3) aims to ensure healthy lives and promote well-being for all at all ages. SDG-3 has a specific target on universal health coverage (UHC), which emphasizes the importance of all people and communities having access to quality health services without risking financial hardship. The objective of this study is to review progress towards UHC using antiretroviral treatment (ART) as a case study. METHODS: We used a mixed-methods design including qualitative and quantitative approaches. We reviewed and synthesised the evidence on the evolution of the WHO HIV treatment guidelines between 2002 and 2019. We calculated ART coverage over time by gender, age group, and location. We also estimated ART coverage differences and ratios. FINDINGS: ART guidelines have evolved from "treating the sickest" to "treating all". ART coverage increased globally from under 7% in 2005 to 62% in 2018. There have been successes in increasing ART coverage in all populations and locations. However, progress varies by population and location in many regions. There is inequity in ART coverage: women (68%) versus men (55%), and adults (62%) versus children (54%). This inequity has widened over time, and with expanded ART eligibility criteria. On the other hand, data from at least one high-burden country (Ethiopia) shows that inequity among regions has narrowed over time due to the improvements in the primary health care systems and implementation of the public health approach in the country. CONCLUSION: ART coverage has increased at global, regional and national levels to all population groups. However, the gains have not been equitable among locations and populations. Policies towards universality may widen the inequity in resource-limited settings unless countries take precautions and "put the last first". We argue that primary health care and public health approaches, with multi-sectoral actions and community engagement, are vital to minimize inequity, achieve UHC and leave no one behind.

Biology, diagnosis and treatment of Malassezia dermatitis in dogs and cats Clinical Consensus Guidelines of the World Association for Veterinary Dermatology.

BACKGROUND: The genus Malassezia is comprised of a group of lipophilic yeasts that have evolved as skin commensals and opportunistic cutaneous pathogens of a variety of mammals and birds. OBJECTIVES: The objective of this document is to provide the veterinary community and other interested parties with current information on the ecology, pathophysiology, diagnosis, treatment and prevention of skin diseases associated with Malassezia yeasts in dogs and cats. METHODS AND MATERIAL: The authors served as a Guideline Panel (GP) and reviewed the literature available prior to October 2018. The GP prepared a detailed literature review and made recommendations on selected topics. The World Association of Veterinary Dermatology (WAVD) Clinical Consensus Guideline committee provided guidance and oversight for this process. The document was presented at two international meetings of veterinary dermatology societies and one international mycology workshop; it was made available for comment on the WAVD website for a period of six months. Comments were shared with the GP electronically and responses incorporated into the final document. CONCLUSIONS AND CLINICAL IMPORTANCE: There has been a remarkable expansion of knowledge on Malassezia yeasts and their role in animal disease, particularly since the early 1990's. Malassezia dermatitis in dogs and cats has evolved from a disease of obscurity and controversy on its existence, to now being a routine diagnosis in general veterinary practice. Clinical signs are well recognised and diagnostic approaches are well developed. A range of topical and systemic therapies is known to be effective, especially when predisposing factors are identified and corrected.

In vitro antimicrobial activity of narasin and monensin in combination with adjuvants against pathogens associated with canine otitis externa.

BACKGROUND: The emergence of antimicrobial resistance represents a serious human and animal health risk. Good antimicrobial stewardship is essential to prolong the lifespan of existing antibiotics, and new strategies are required to combat infections in man and animals. HYPOTHESIS/OBJECTIVES: To determine the in vitro interaction of ionophores (narasin or monensin) with antimicrobial adjuvants (N-acetylcysteine (NAC), Tris-EDTA or disodium EDTA) against bacterial strains representing pathogens associated with canine otitis externa (OE). ANIMAL/ISOLATES: American Type Culture Collection (ATCC) strains Staphylococcus aureus 29213, Pseudomonas aeruginosa 27853 and P. aeruginosa biofilm producer PAO1, and a clinical isolate of Proteus mirabilis from a case of canine OE were tested. METHODS AND MATERIALS: A 2D microdilution checkerboard method was used, allowing calculation of fractional inhibitory concentration index (FICI), dose reduction index (DRI) and plotting of isobolograms. RESULTS: The combination of narasin with either Tris-EDTA or disodium EDTA produced additive effects (FICI = 0.75) against P. aeruginosa ATCC 27853 and P. aeruginosa biofilm producer ATCC PAO1. An additive effect (FICI = 0.53-0.75) was found against S. aureus ATCC 29213 when narasin or monensin were combined with NAC. The highest DRI (32-fold) was found with monensin/NAC where the MIC of monensin was reduced from 4 to 0.125 µg/mL. CONCLUSIONS AND CLINICAL IMPORTANCE: The combination of narasin with Tris-EDTA or disodium EDTA is a promising strategy to inhibit the intrinsic resistance elements of Gram-negative bacteria. These novel combinations potentially could be useful as a multimodal approach to treat mixed infections in canine OE.

Assessing the Relationships Among Forgiveness by God, God Images, and Death Anxiety.

Previous research suggests that people who feel forgiven by God may experience lower levels of death anxiety. The purpose of the current study is to contribute to this work by assessing whether the relationship between forgiveness by God and death anxiety varies according to how people view God. Three images of God are assessed: a pantheistic view of God, a theistic view of God, and a deistic view of God. Data from nationwide survey that was conducted in 2014 (N = 2,650) suggest that the relationship between forgiveness by God and death anxiety is strongest among people with a theistic view of God, significantly weaker among people with a pantheistic view of God, and not significant among individuals with a deistic view of God. The findings point to the importance of taking views of God into account when assessing the relationship between forgiveness by God and death anxiety.

Reprogramming of cell fate: epigenetic memory and the erasure of memories past.

Cell identity is a reflection of a cell type-specific gene expression profile, and consequently, cell type-specific transcription factor networks are considered to be at the heart of a given cellular phenotype. Although generally stable, cell identity can be reprogrammed in vitro by forced changes to the transcriptional network, the most dramatic example of which was shown by the induction of pluripotency in somatic cells by the ectopic expression of defined transcription factors alone. Although changes to cell fate can be achieved in this way, the efficiency of such conversion remains very low, in large part due to specific chromatin signatures constituting an epigenetic barrier to the transcription factor-mediated reprogramming processes. Here we discuss the two-way relationship between transcription factor binding and chromatin structure during cell fate reprogramming. We additionally explore the potential roles and mechanisms by which histone variants, chromatin remodelling enzymes, and histone and DNA modifications contribute to the stability of cell identity and/or provide a permissive environment for cell fate change during cellular reprogramming.

Effectiveness and sustainability of a diagonal investment approach to strengthen the primary health-care system in Ethiopia.

Weakness of primary health-care (PHC) systems has represented a challenge to the achievement of the targets of disease control programmes (DCPs) despite the availability of substantial development assistance for health, in resource-poor settings. Since 2005, Ethiopia has embraced a diagonal investment approach to strengthen its PHC systems and concurrently scale up DCPs. This approach has led to a substantial improvement in PHC-system capacity that has contributed to increased coverage of DCPs and improved health status, although gaps in equity and quality in health services remain to be addressed. Since 2013, Ethiopia has had a decline in development assistance for health. Nevertheless, the Ethiopian Government has been able to compensate for this decline by increasing domestic resources. We argue that the diagonal investment approach can effectively strengthen PHC systems, achieve DCP targets, and sustain the gains. These goals can be achieved if a visionary and committed leadership coordinates its development partners and mobilises the local community, to ensure financial support to health services and improve population health. The lessons learnt from Ethiopia's efforts to improve its health services indicate that global-health initiatives should have a proactive and balanced investment approach to concurrently strengthen PHC systems, achieve programme targets, and sustain the gains, in resource-poor settings.

Urothelial carcinoma arising from the transplanted kidney: A single-center experience and literature review.

Urothelial carcinoma (UC) is a malignancy predominantly arising in the bladder. Upper tract UC (UUC) is uncommon, accounting only for 5-10% of the cases. High incidence of neoplasms is associated with immunosuppressive therapy; thus, UCs of the transplanted grafts often lead to a more aggressive treatment, in order to withdraw completely the immunosuppression. It significantly affects the patient quality of life, meaning return to dialysis, along with the worse life expectancy. We present our single-institution experience of this rare malignancy in two mid-age kidney transplant recipients, with UCs successfully treated with radical nephroureterectomy: G3 pT3 N0 + G3 pT1 N0 in the first patient and G3 pT2 N0 in the second one. We also review the previous literature focusing on stage of presentation and treatment for the affected kidney transplant patients.

Cambodia's health professionals and the ASEAN Mutual Recognition Arrangements: registration, education and mobility.

BACKGROUND: From 2006, the Association of South East Asian Nations (ASEAN) has been developing Mutual Recognition Arrangements (MRAs) across key professions, including medicine, dentistry and nursing, that would facilitate the development of an ASEAN Economic Community, with shared regional standards and easier mobility of the workforce. This paper examines the interface between those agreements and the registration, professional education and mobility of health personnel in Cambodia. METHODS: This qualitative health policy analysis combined documentary and policy review with key informant interviews with 16 representatives of agencies relevant to the development and implementation of the MRAs in health. Thematic analysis identified three themes: registration, education and mobility. RESULTS: Cambodia is an active participant in the ASEAN MRA processes for doctors, dentists and nurses reporting progress annually. Education of health professionals has been increasingly formalised in the past 25 years, with nursing moving towards a 4-year bachelor degree. The private university sector has substantially increased, with English increasingly used as a language of instruction. Recent legislation provides for enforcement through fines and/or imprisonment to ensure all practising health professionals hold initial registration as a health professional and a renewable licence to practise as a health practitioner. Continuing Professional Development is a mandatory requirement for licence renewal. This is consistent with the MRA guidelines, though the capacity for enforcement appears limited. The Medical Council of Cambodia (MCC), and more recently, the Dental and Nursing Councils, have introduced continuing professional development initiatives, using them strategically as a positive reinforcer of registration. Midwifery education and registration in Cambodia does not conform with ASEAN guidelines. In education, course durations in medicine and dentistry are longer than regional counterparts, though anxiety around maintaining clinical standards has resulted in the introduction of a National Exit Examination and reluctance to abbreviate courses. The introduction of reforms appears to reference regional standards, though parity is still some way off. Mobility at present is infrequent and more likely to result from informal mechanisms than through the MRA mechanisms. CONCLUSION: The Royal Government of Cambodia is committed to the ASEAN MRA process. Developments in registration appear to use regional standards as benchmarks, as do reforms in the education of health professionals, though domestic factors appear to more directly impact on developments. Informal mechanisms facilitate the limited mobility currently occurring, with little formal application of the MRA provisions evident at this point.

Australia's overseas development aid commitment to health through the sustainable development goals: a multi-stakeholder perspective.

BACKGROUND: In 2018, the Australian Government, through a Senate-led Parliamentary Inquiry, sought the views of diverse stakeholders on Sustainable Development Goal (SDG) implementation both domestically and as part of Australia's Overseas Development Assistance (ODA) program. One hundred and sixty-four written submissions were received. The submissions offered perspective and guidance from a rich cross-section of those involved, and with keen interest in, Australia's ODA-SDG commitment. This article identifies and explores the submissions to that Inquiry which placed impetus on Australia's ODA-SDG and health and development nexus. It then compares how the synthesized views, concerns and priorities of selected Inquiry stakeholders align with and reflect the Australian Government's treatment of SDG 3 in its SDG Voluntary National Review (VNR), as well as with the final Inquiry report summarizing submission content. RESULTS: Four key themes were synthesized and drawn from the thirty-one stakeholder submissions included in our analysis. Disconnect was then found to exist between the selected stakeholder views and the Australian Government's SDG-VNR's treatment of SDG 3, as well as with the content of the Parliamentary Inquiry's final report with respect to the ODA-SDG and health and development nexus. CONCLUSIONS: We situate the findings of our analysis within the wider strategic context of the Australian Government's policy commitment to "step up" in the Pacific region. This research provides an insight into both multi-stakeholder and Federal Government views on ODA in the Indo-Pacific region, especially at a time when Australia's Pacific engagement has come to the forefront of both foreign and security policy. We conclude that the SDG agenda, including the SDG health and development agenda, could offer a unique vehicle for enabling a paradigm shift in the Australian Government's development approach toward the Pacific region and its diverse peoples. This potential is strongly reflected in stakeholder perspectives included in our analysis. However, study findings remind that the political determinants of health, and overlapping political determinants of SDG achievement, will be instrumental in the coming decade, and that stakeholders from different sectors need to be genuinely engaged in SDG-ODA policy-related decision-making and planning by governments in both developed and developing countries alike.