Improving the Infectious Diseases Physician Scientist Workforce From the View of Junior Investigators: Vision, Transparency, and Reproducibility.

Shortcomings in the current pipeline of infectious disease physician scientists are well documented. With a focus on the transition of early stage investigators to research independence, we outline challenges in existing training pathways for physician scientists. We urge leaders of infectious disease societies, divisions, and governmental and nongovernmental funding organizations to reinvigorate a vision for nurturing trainees with interests in research, to seek transparency in physician scientist funding mechanisms, and to encourage efforts to improve the reproducibility of outcomes for talented junior investigators. We feel that the alternative to making these changes will lead to further drop-off in the physician scientist pipeline in a field that has a perpetual need for research.

Hepatitis C Management and the Infectious Diseases Physician: A Survey of Current and Anticipated Practice Patterns.

This query of North American infectious diseases physicians reviews current and anticipated practice patterns related to hepatitis C virus (HCV) care. Less than 20% of survey respondents evaluated and/or treated >10 HCV-infected individuals in the past year. We review HCV practice patterns, barriers to management, and education among infectious diseases physicians.

Contributing factors to disease outbreaks associated with untreated groundwater.

Disease outbreaks associated with drinking water drawn from untreated groundwater sources represent a substantial proportion (30.3%) of the 818 drinking water outbreaks reported to CDC's Waterborne Disease and Outbreak Surveillance System (WBDOSS) during 1971 to 2008. The objectives of this study were to identify underlying contributing factors, suggest improvements for data collection during outbreaks, and inform outbreak prevention efforts. Two researchers independently reviewed all qualifying outbreak reports (1971 to 2008), assigned contributing factors and abstracted additional information (e.g., cases, etiology, and water system attributes). The 248 outbreaks resulted in at least 23,478 cases of illness, 390 hospitalizations, and 13 deaths. The majority of outbreaks had an unidentified etiology (n = 135, 54.4%). When identified, the primary etiologies were hepatitis A virus (n = 21, 8.5%), Shigella spp. (n = 20, 8.1%), and Giardia intestinalis (n = 14, 5.7%). Among the 172 (69.4%) outbreaks with contributing factor data available, the leading contamination sources included human sewage (n = 57, 33.1%), animal contamination (n = 16, 9.3%), and contamination entering via the distribution system (n = 12, 7.0%). Groundwater contamination was most often facilitated by improper design, maintenance or location of the water source or nearby waste water disposal system (i.e., septic tank; n = 116, 67.4%). Other contributing factors included rapid pathogen transport through hydrogeologic formations (e.g., karst limestone; n = 45, 26.2%) and preceding heavy rainfall or flooding (n = 36, 20.9%). This analysis underscores the importance of identifying untreated groundwater system vulnerabilities through frequent inspection and routine maintenance, as recommended by protective regulations such as Environmental Protection Agency's (EPA's) Groundwater Rule, and the need for special consideration of the local hydrogeology.

Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy.

Immune checkpoint inhibitors such as ipilimumab and targeted BRAF inhibitors have dramatically altered the landscape of melanoma therapeutics over the past few years. Agents targeting the programmed cell death-1/ligand (PD-1/PD-L1) axis are now being developed and appear to be highly active clinically with favorable toxicity profiles. We report two patients with BRAF V600E mutant melanoma who were treated with anti-PD-1 agents as first-line therapy without significant toxicity, followed by vemurafenib at disease progression. Both patients developed severe hypersensitivity drug eruptions with multi-organ injury early in their BRAF inhibitor treatment course. One patient subsequently developed acute inflammatory demyelinating polyneuropathy (AIDP) and the other developed anaphylaxis upon low-dose vemurafenib rechallenge. Further investigation of the immune response during combination or sequences of melanoma therapeutics is warranted. Furthermore, clinicians should maintain a high index of suspicion for these toxicities when vemurafenib is administered following an anti-PD-1 agent.

Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria.

The aggregation of abnormally folded proteins is a defining feature of neurodegenerative disease, but it has not previously been possible to assess the conformation of these proteins in a physiologically relevant context, before they form morphologically recognizable aggregates. We now describe FRET-based reporters for the conformation of alpha-synuclein, a protein central to the pathogenesis of Parkinson's disease (PD). Characterization in vitro shows that alpha-synuclein adopts a relatively "closed" conformation in solution that converts to "open" on membrane binding. In living cells, the closed conformation predominates. In neurons, however, cell bodies contain a much larger proportion of the open conformation than synaptic boutons. To account for these differences, we also used the reporters to characterize the interaction with native membranes. We find that the conformation of alpha-synuclein responds selectively to mitochondria, indicating a direct link between alpha-synuclein and an organelle strongly implicated in the pathogenesis of PD.