Differential and convergent utilization of autophagy components by positive-strand RNA viruses.

Many viruses interface with the autophagy pathway, a highly conserved process for recycling cellular components. For three viral infections in which autophagy constituents are proviral (poliovirus, dengue, and Zika), we developed a panel of knockouts (KOs) of autophagy-related genes to test which components of the canonical pathway are utilized. We discovered that each virus uses a distinct set of initiation components; however, all three viruses utilize autophagy-related gene 9 (ATG9), a lipid scavenging protein, and LC3 (light-chain 3), which is involved in membrane curvature. These results show that viruses use noncanonical routes for membrane sculpting and LC3 recruitment. By measuring viral RNA abundance, we also found that poliovirus utilizes these autophagy components for intracellular growth, while dengue and Zika virus only use autophagy components for post-RNA replication processes. Comparing how RNA viruses manipulate the autophagy pathway reveals new noncanonical autophagy routes, explains the exacerbation of disease by starvation, and uncovers common targets for antiviral drugs.

A Genome-Wide RNA Interference Screen Identifies a Role for Wnt/ß-Catenin Signaling during Rift Valley Fever Virus Infection.

UNLABELLED: Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of ß-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE: RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. These studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.

Nonlytic viral spread enhanced by autophagy components.

The cell-to-cell spread of cytoplasmic constituents such as nonenveloped viruses and aggregated proteins is usually thought to require cell lysis. However, mechanisms of unconventional secretion have been described that bypass the secretory pathway for the extracellular delivery of cytoplasmic molecules. Components of the autophagy pathway, an intracellular recycling process, have been shown to play a role in the unconventional secretion of cytoplasmic signaling proteins. Poliovirus is a lytic virus, although a few examples of apparently nonlytic spread have been documented. Real demonstration of nonlytic spread for poliovirus or any other cytoplasmic constituent thought to exit cells via unconventional secretion requires demonstration that a small amount of cell lysis in the cellular population is not responsible for the release of cytosolic material. Here, we use quantitative time-lapse microscopy to show the spread of infectious cytoplasmic material between cells in the absence of lysis. siRNA-mediated depletion of autophagy protein LC3 reduced nonlytic intercellular viral transfer. Conversely, pharmacological stimulation of the autophagy pathway caused more rapid viral spread in tissue culture and greater pathogenicity in mice. Thus, the unconventional secretion of infectious material in the absence of cell lysis is enabled by components of the autophagy pathway. It is likely that other nonenveloped viruses also use this pathway for nonlytic intercellular spread to affect pathogenesis in infected hosts.

The pitfalls of prescribing for family and friends.

In most of Australia there is no legislation prohibiting medical practitioners from prescribing for family and friends. In South Australia it is prohibited to prescribe Schedule 8 drugs for family members unless it is a verifiable emergency. The Medical Board of Australia states medical practitioners should avoid providing medical care to anyone with whom they have a close personal relationship. Medical defence organisations may exclude treatment of family members from doctors' insurance cover. Think very carefully before you prescribe for family and friends. It is only considered ethically and professionally appropriate to prescribe in exceptional circumstances, and there are potential risks to you and your family member or friend if you do.

How to write a medico-legal report.

BACKGROUND: The preparation and provision of medico-legal reports by the treating doctor is an inevitable but sometimes unwelcome part of general practice. OBJECTIVE: This article outlines the steps involved in preparing a 'good' medico-legal report, including some of the common pitfalls to avoid. DISCUSSION: General practitioners play an important role in providing medico-legal reports about their patients for a wide variety of purposes. A medico-legal report may be seen by a diverse, non-medical audience. Once prepared, the report may be used as evidence in court proceedings and subjected to close scrutiny. A structured and comprehensive medico-legal report may minimise the chances of having to give evidence in court.

Patients' use of social media: e-rating of doctors.

BACKGROUND: Patients are increasingly posting online reviews about their medical care, including rating their doctors. OBJECTIVE: This article discusses patients' use of social media to comment on and 'rate' their medical care, with a particular focus on what a general practitioner (GP) can do about a negative online review. DISCUSSION: The vast majority of online reviews about doctors are positive. However, the small proportion of negative online reviews can be a source of great distress to those doctors who are the subject of these reviews. GPs should seek advice before considering whether or not to respond to a negative online review.

Advance care planning.

BACKGROUND: Good Medical Practice: A Code of Conduct for Doctors in Australia states that in caring for patients towards the end of their life, good medical practice involves facilitating advance care planning. OBJECTIVE: This article discusses the role of advance care planning in end-of-life care, with an emphasis on the ethical and legal framework for advance care directives. DISCUSSION: There has been an increased focus on advanced care planning and advance care directives in Australia, partly driven by the ageing population and technological advances, as well as the principle of patient-centred care. General practitioners have an important role in initiating and facilitating advance care planning.

Genetic testing: medico-legal issues.

BACKGROUND: The availability and frequency of genetic testing is increasing. Genetic testing poses some unique ethical and legal issues for medical practitioners because of the potential to identify genetic variants that carry implications for the risk of disease in the future for the patient and their relatives. The regulatory framework within which genetic testing is provided in Australia is also changing. OBJECTIVE: This article examines some medico-legal issues associated with genetic testing that general practitioners (GPs) are likely encounter in their practices. DISCUSSION: There is inevitable involvement of the GP in the long term care of a patient (and possibly their family) following genetic testing, regardless of whether or not the GP has ordered the testing. Cases are presented to illustrate some of the medico-legal issues that may arise from direct-to-consumer genetic testing, information disclosure to genetic relatives and requests for parentage testing.

The duty of GPs to follow up patients.

A recent Supreme Court of Victoria judgement examined the legal obligations of a general practitioner to recall a patient who does not undergo a test that has been recommended by the GP or to return for a consultation, despite being asked to do so.

Managing professional boundaries.

The maintenance of boundaries in the doctor-patient relationship is central to good medical practice and the appropriate care of patients. This article examines the nature of boundaries in medical practice and outlines some strategies to minimise the risk of a boundary violation.

An intellectual property sharing initiative in agricultural biotechnology: development of broadly accessible technologies for plant transformation.

The Public Intellectual Property Resource for Agriculture (PIPRA) was founded in 2004 by the Rockefeller Foundation in response to concerns that public investments in agricultural biotechnology benefiting developing countries were facing delays, high transaction costs and lack of access to important technologies due to intellectual property right (IPR) issues. From its inception, PIPRA has worked broadly to support a wide range of research in the public sector, in specialty and minor acreage crops as well as crops important to food security in developing countries. In this paper, we review PIPRA's work, discussing the failures, successes, and lessons learned during its years of operation. To address public sector's limited freedom-to-operate, or legal access to third-party rights, in the area of plant transformation, we describe PIPRA's patent 'pool' approach to develop open-access technologies for plant transformation which consolidate patent and tangible property rights in marker-free vector systems. The plant transformation system has been licensed and deployed for both commercial and humanitarian applications in the United States (US) and Africa, respectively.

Consent to medical treatment: the mature minor.

Can children and young people consent to their own medical treatment? Consent issues involving children and young people are complex. This article examines the legal obligations of general practitioners when obtaining consent to medical treatment from patients who are less than 18 years of age.

Capacity to consent to treatment.

A competent adult patient has an ethical and legal right to give, or withhold, consent to an examination, investigation or treatment. Depending on the nature and complexity of an intervention, a patient with an intellectual disability may be capable of consenting to their own medical treatment. In circumstances in which an adult patient does not have the capacity to consent, there is specific guardianship legislation enacted in each state and territory which provides for valid consent by a substitute decision maker.

How to complete a death certificate - a guide for GPs.

This article discusses some questions that frequently arise in general practice with regard to the completion of death certificates.

Sickness certification.

This article forms part of our 'Paperwork' series for 2011, providing information about a range of paperwork that general practitioners complete regularly. The aim of the series is to provide information on the purpose of the paperwork, and hints on how to complete it accurately. This will allow the GP to be more efficient and the patient to have an accurately completed piece of paperwork for the purpose required. Sickness certificates are legal documents. Medical boards receive numerous complaints each year from patients, employers, insurers and other parties about the quality and accuracy of sickness certificates. General practitioners who deliberately issue a false, misleading or inaccurate certificate could face disciplinary action, or even a charge of fraud. This article provides some guidance for GPs about writing certificates certifying illness, and discusses common medicolegal issues associated with sickness certificates.

Child abuse - mandatory reporting requirements.

All Australian states and territories have legislation that requires medical practitioners to report cases of child abuse to the appropriate child protection service. This article outlines the obligations of medical practitioners to report child abuse and highlights the differences that exist in the legislative requirements in each state and territory.

Failure to use an interpreter.

Case studies are based on actual medical negligence claims or medicolegal referrals; however certain facts have been omitted or changed by the author to ensure the anonymity of the parties involved. This article discusses a Medical Board complaint involving an allegation of failure to use an interpreter, resulting in the death of a patient, aged 35 years.

Failure to diagnose: diabetic ketoacidosis.

A recent coronial inquest examined the death of a patient, 17 years of age, from fulminant diabetic ketoacidosis.1 The patient's presentation with diabetic ketoacidosis was the first manifestation of the onset of type 1 diabetes. This article examines the Coroner's findings and recommendations.

Mandatory reporting of health practitioners - notifiable conduct.

Case histories are based on actual medical negligence claims or medicolegal referrals; however certain facts have been omitted or changed by the author to ensure the anonymity of the parties involved. On 26 March 2008, the Council of Australian Governments signed an Intergovernmental Agreement for a National Registration and Accreditation Scheme for the Health Professions. The new scheme is scheduled to be introduced on 1 July 2010. As part of the scheme all registered health practitioners will be legally required to report any other registered health practitioner who has behaved in a manner that constitutes 'notifiable conduct'. The threshold to be met to trigger the requirement to report notifiable conduct in relation to a practitioner is high, and the practitioner or employer must have first formed a 'reasonable belief' that the behaviour constitutes notifiable conduct. This article discusses this new legislation, the circumstances in which a colleague's conduct must be reported and how a notification should be made.

Lost: loss of chance.

Loss of chance claims involve an allegation that a patient has lost the chance of a better medical outcome, in terms of treatment and/or prognosis, as a result of the negligence of the medical practitioner. A recent High Court of Australia judgment confirmed that monetary damages are not available for the loss of a chance of a better medical outcome. This article discusses the judgment and its implications for medical practitioners in Australia.