Andrew J. Hale

Preliminary aggregate safety and immunogenicity results from three trials of a purified inactivated Zika virus vaccine candidate: phase 1, randomised, double-blind, placebo-controlled clinical trials

BACKGROUNDnA safe, effective, and rapidly scalable vaccine against Zika virus infection is needed. We developed a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate that showed protection in mice and non-human primates against viraemia after Zika virus challenge. Here we present the preliminary results in human beings.nnnMETHODSnWe did three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 μg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. We recorded adverse events and Zika virus envelope microneutralisation titres up to day 57. These trials are registered at ClinicalTrials.gov, numbers NCT02963909, NCT02952833, and NCT02937233.nnnFINDINGSnWe enrolled 68 participants between Nov 7, 2016, and Jan 25, 2017. One was excluded and 67 participants received two injections of Zika vaccine (n=55) or placebo (n=12). The vaccine caused only mild to moderate adverse events. The most frequent local effects were pain (n=40 [60%]) or tenderness (n=32 [47%]) at the injection site, and the most frequent systemic reactogenic events were fatigue (29 [43%]), headache (26 [39%]), and malaise (15 [22%]). By day 57, 52 (92%) of vaccine recipients had seroconverted (microneutralisation titre ≥1:10), with peak geometric mean titres seen at day 43 and exceeding protective thresholds seen in animal studies.nnnINTERPRETATIONnThe ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults.nnnFUNDINGnDepartments of the Army and Defense and National Institute of Allergy and Infectious Diseases.

Fatal spontaneous Clostridium bifermentans necrotizing endometritis: a case report and literature review of the pathogen

Clostridium bifermentans is a rare pathogen in humans. A fatal case of fulminant endometritis with toxic shock and capillary leak secondary to C bifermentans infection in a young woman is described, and this is compared to all 13 previously described cases of C bifermentans infection.

The Effects of Resident Peer- and Self-Chart Review on Outpatient Laboratory Result Follow-up.

Purpose Performing and teaching appropriate follow-up of outpatient laboratory results (LRs) is a challenge. The authors tested peer-review among residents as a potentially valuable intervention. Method Investigators assigned residents to perform self-review (n = 27), peer-review (n = 21), or self- + peer-review (n = 30) of outpatient charts. They also compared residence performance with that of historical controls (n = 20). In September 2012, residents examined 10 LRs from April 2012 onward. A second review in November 2012 ascertained whether performing chart review improved residents’ practice behaviors. Results Initially, the least-square (LS) mean number of LRs without documentation of follow-up per resident in the self-, peer-, and self- + peer-review group was, respectively, 0.5 (SD 1.0), 1.0 (SD 1.7), and 0.9 (SD 1.3), and post intervention, this was 1.0 (SD 0.2), 0.3 (SD 0.2), and 0.6 (SD 0.2) (self- versus peer-review P = .03). Initially the LS mean follow-up time per resident in the self-, peer-, and self- + peer-review group was, respectively, 4.2 (SD 1.2), 6.9 (SD 1.4), and 5.9 (SD 1.2) days, and after the intervention, LS mean time was 5.0 (SD 0.5), 2.5 (SD 0.6), and 3.9 (SD 0.5) days (self- versus peer-review P < .01). Self-review was not associated with significant improvements in practice. Conclusions In this comparison of self- and peer-review, only residents who performed peer-review demonstrated significant improvements in their documentation practices. These findings support the use of resident peer-review in improving LR follow-up, and potentially, in other, broader resident quality improvement initiatives.

Meeting the needs of the resident trainee during an elective subspecialty rotation.

Objective To examine and compare perceptions between resident-trainees and faculty-educators on goals and reasons why resident trainees choose certain subspecialty elective rotations. Methods In June 2013 residents and faculty-educators at a large tertiary care academic medical center were surveyed regarding perceived resident goals for subspecialty electives. Each group was sent a different electronic survey of parallel questions assessing agreement on an ordered scale with statements about which factors impacted resident choice. Results The survey was sent to 154 residents and had 75 (49%) respondents, as well as 20 faculty-educators with 12 (60%) respondents. Residents and faculty did not differ in their responses that electives were chosen to fill perceived knowledge gaps (exact Cochran-Armitage p = .51). However, educators and residents significantly varied in the degree to which they thought resident choice was based on networking within the field (exact Cochran-Armitage p = .01), auditioning for fellowship (exact Cochran-Armitage p < .01), or exploring career options (exact Cochran-Armitage p = .01), with educators overestimating the degree to which these impacted resident choice. Conclusions Resident trainees and faculty educators agree that subspecialty electives are most frequently chosen in order to meet resident educational goals, highlighting the importance of developing and delivering high quality subspecialty curricular content for the internal medicine resident learner during electives. Many residents choose electives for career development reasons, but faculty educators overestimate this motivation.

Fatal purpura fulminans and Waterhouse-Friderichsen syndrome from fulminant Streptococcus pneumoniae sepsis in an asplenic young adult.

Asplenic patients are at increased risk for sepsis and fulminant infection. Sepsis in these patients is typically secondary to encapsulated bacteria, with Streptococcus pneumoniae being the most frequent pathogen. Rare complications of severe sepsis include purpura fulminans and bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome). We present the case of a 36-year-old woman, healthy except for splenectomy years prior for idiopathic thrombocytopenic purpura treatment, who presented with fever. Upon presentation to our hospital, three hours after symptoms onset, she had purpura fulminans and shock. Despite timely antimicrobials and maximal resuscitative efforts, her disease progressed and she expired 12 hours after symptoms onset. Autopsy revealed bilateral adrenal hemorrhage; acute adrenal crisis likely contributed to her refractory shock. Prior to her presentation, she had not received guideline-based post-splenectomy care. Sepsis in asplenic patients can be fulminant and rapidly fatal. Streptococcus pneumoniae remains the most frequent cause, despite decreasing rates in recent years related to widespread pneumococcal vaccination. Guideline-based vaccinations and “pill-in-pocket” therapy can be life-saving for asplenic patients. Purpura fulminans represents an extreme manifestation of disseminated intravascular coagulation, is more common in asplenic patients, and portends a poor prognosis. Waterhouse-Friderichsen syndrome can be seen concurrently with purpura fulminans and further portends a poor prognosis; pre-mortem diagnosis requires a high index of suspicion.

Mindset theory in medical education

1 Carl J Shapiro Institute for Education and Research, Boston, Massachusetts, USA 2 Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA 4 Division of Infectious Disease, University of Vermont Medical Center, Burlington, Vermont, USA 5 Division of Infectious Disease, University of Vermont Larner College of Medicine, Burlington, Vermont, USA

Adapting Maslow's Hierarchy of Needs as a Framework for Resident Wellness.

ABSTRACT Issue: Burnout in graduate medical education is pervasive and has a deleterious impact on career satisfaction, personal well-being, and patient outcomes. Interventions in residency programs have often addressed isolated contributors to burnout; however, a more comprehensive framework for conceptualizing wellness is needed. Evidence: In this article the authors propose Maslows hierarchy of human needs (physiologic, safety, love/belonging, esteem, and self-actualization) as a potential framework for addressing wellness initiatives. There are numerous contributors to burnout among physician-trainees, and programs to combat burnout must be equally multifaceted. A holistic approach, considering both the trainees personal and professional needs, is recommended. Maslows Needs can be adapted to create such a framework in graduate medical education. The authors review current evidence to support this model. Implications: This work surveys current interventions to mitigate burnout and organizes them into a scaffold that can be used by residency programs interested in a complete framework to supporting wellness.

When are Oral Antibiotics a Safe and Effective Choice for Bacterial Bloodstream Infections? An Evidence-Based Narrative Review.

Bacterial bloodstream infections (BSIs) are a major cause of morbidity and mortality in the United States. Traditionally, BSIs have been managed with intravenous antimicrobials. However, whether intravenous antimicrobials are necessary for the entirety of the treatment course in BSIs, especially for uncomplicated episodes, is a more controversial matter. Patients that are clinically stable, without signs of shock, or have been stabilized after an initial septic presentation, may be appropriate candidates for treatment of BSIs with oral antimicrobials. There are risks and costs associated with extended courses of intravenous agents, such as the necessity for long-term intravenous catheters, which entail risks for procedural complications, secondary infections, and thrombosis. Oral antimicrobial therapy for bacterial BSIs offers several potential benefits. When selected appropriately, oral antibiotics offer lower cost, fewer side effects, promote antimicrobial stewardship, and are easier for patients. The decision to use oral versus intravenous antibiotics must consider the characteristics of the pathogen, the patient, and the drug. In this narrative review, the authors highlight areas where oral therapy is a safe and effective choice to treat bloodstream infection, and offer guidance and cautions to clinicians managing patients experiencing BSI.

Occam’s razor need not apply: Advanced HIV infection presenting with five simultaneous opportunistic infections and central nervous system lymphoma

Patients with Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS) are at risk for multiple infectious and oncologic complications. In such cases, Occam’s razor need not apply: multiple infections and malignancies are often present concurrently upon presentation to care. A patient off anti-retroviral therapy (ART) for several years developed advanced HIV infection (CD4 count 19 cells/uL) and presented with five simultaneous opportunistic infections including Pneumocystis jiroveci pneumonia (PJP), cytomegalovirus (CMV) retinitis, Mycobacterium avium complex (MAC) bloodstream infection, chronic hepatitis B virus (HBV), and Epstein-Barr virus (EBV) viremia. Simultaneously, he was found to have primary central nervous system (CNS) B-cell lymphoma. Treatment decisions for such patients are often complex, as ideal therapy for one disease may directly counter or interact with therapy for another. For instance, methotrexate for primary CNS lymphoma and trimethoprim/sulfamethoxazole for PJP is a strictly contraindicated medication combination. It is important to understand not just the management of any single opportunistic disease in patients with advanced HIV, but how to balance management for patients with a variety of concurrent processes. In an era when HIV care is becoming increasingly simplified, patients presenting with advanced infection highlight the lack of data on how best to manage patients with multiple concurrent disease processes. Significant further research is needed to clarify ideal comparative therapy.

Unilateral purpura resulting from deep vein thrombosis

A 72-year-old man presented with complaint of acute swelling and pain in his right leg. He had been in his usual state of health until 2 days prior, when he developed pain in the right upper thigh, which then spread down the right lower extremity and was associated with a new rash. His past medical history was notable for cirrhosis (Childs-Pugh class C) secondary to alcohol abuse, complicated by esophageal varices and chronic thrombocytopenia. On exam, he was noted to have a unilateral, painless, purpuric rash on the right thigh (1), and the right lower extremity was significantly larger than the left. Laboratory values were notable for a white blood cell count of 10.2 × 10 cells/μL, hemoglobin 9.8 g/dL, platelets 57 × 10/μL, INR 1.8, fibrinogen 189 mg/dL, creatinine 1.0 mg/dL, AST 32 u/L, ALT 25 u/L, and total bilirubin of 2.3 mg/dL. Ultrasonography revealed an extensive, proximal deep vein thrombosis (DVT) involving the right femoral vein. Purpura results from blood extravasating from small vessels. This can be due to coagulopathy, immunologic injury to vessels, or increased venous pressure due to stasis. These processes are typically generalized and thus, if the lower extremities are involved, a degree of symmetry is expected. Rare cases of unilateral linear capillaritis have been described but the mechanism of such cases is unclear. Other rare causes of asymmetric purpura have been attributed to unilateral Schamberg disease or lichen purpuricus. While DVT is associated with an acute increase in venous pressure, for unclear reasons it rarely causes purpura, having been described just once previously in the literature. In our patient, we hypothesize that the purpura in this case was due to a combination of acutely increased venous pressure from the large proximal DVT on a background of coagulopathy and thrombocytopenia from advanced liver disease. Unilateral purpura is a rare presenting sign of DVT. IMAGE 1 Asymmetric purpura of the right thigh Received: 10 August 2018 Revised: 20 August 2018 Accepted: 22 August 2018 DOI: 10.1002/ajh.25266