Molecular insights into virulence regulation in MRSA using mass-spectrometry based metabolomics

Drug resistant infections are an increasing problem world-wide, with an annual estimate of 300,000 infections a year, 10,000 deaths, and 1.7 billion dollars in costs in the US alone. Current treatment modalities to combat infections of this type rely on antibiotics. Unfortunately, the use of antibiotics accelerates the development of resistance. Severe drug resistant infections such as methicillin-resistant Staphylococcus aureus (MRSA) are often managed with “last resort treatments”, which have side effects similar to chemotherapy, including, but not limited to, loss of appetite for months at a time, increased hospital stays, and extreme fatigue. MRSA produces a host of toxins that are responsible for its virulence, causing inflammation, skin lesions and, in extreme cases, septic shock and even death. One potential alternative strategy for treating drug resistant bacterial infections would be to inhibit the production of these toxins, thereby making the bacteria less harmful to the host; a so called “anti-virulence” approach. A major advantage of anti-virulence therapeutics would be the ability to reduce the damage caused by bacterial infections without selecting for the development of resistance. The long-term goal of our research is to develop new anti-virulence strategies against MRSA. With this dissertation, we undertook three projects towards this goal. With Project 1, we developed analytical methodologies to better understand and track virulence in MRSA by measuring molecules that are regulated by and regulate the quorum sensing system. With Project 2, we sought to identify new secondary metabolites produced by MRSA, with a particular focus on those regulated by the quorum sensing system. Lastly, with Project 3, we employed new informatic approaches to identify antimicrobial compounds from the plant Rumex crispus. This third project also included a significant training component and was carried out collaboratively with an undergraduate student. A central goal of this dissertation in addition to benchwork science was to recruit and retain a diverse body of students in chemistry. This goal was carried out through effective mentorship and training, as evidenced by the outcomes of Project 3

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

It’s Not Only Rents: Explaining the Persistence and Change of Neopatrimonialism in Indonesia

Indonesia has long been associated with neopatrimonialism, corruption, collusion, and nepotism as the main modi operandi of politics, economics and public administration. Despite various measures and initiatives to fight these practises, little evidence for a significant decline can be found over the years. Rather, longitudinal analysis points to changes in the character of neopatrimonialism. Based on more than 60 in-depth interviews, focus-group discussions, and the analysis of both primary and secondary data, the aim of this article is, first, to describe the changes that have taken place, and, second, to investigate what accounts for these changes. Political economy concepts posit the amount and development of economic rents as the explanatory factor for the persistence and change of neopatrimonialism. This study's findings, however, indicate that rents alone cannot explain what has taken place in Indonesia. Democratisation and decentralisation exert a stronger impact

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Variation in general supportive and preventive intensive care management of traumatic brain injury: a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study

Abstract Background General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. Methods We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. Results The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36–40 mmHg (4.8–5.3 kPa) in case of controlled intracranial pressure (ICP) < 20 mmHg (n = 45, 69%) and PaCO2 target of 30–35 mmHg (4–4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%). Conclusions Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome

Ruptured Ectopic Pregnancy with an Intrauterine Device: Case Report and Sonographic Considerations

Introduction: Ectopic pregnancy carries a high morbidity and mortality; patients are at risk for rupture and life-threatening hemorrhage.Case Report: We present a rare case of ruptured abdominal ectopic pregnancy in a patient with a well-positioned intrauterine device (IUD) and discuss the diagnostic utility that transabdominal point-of-care ultrasound (POCUS) can have when performed at the bedside.Conclusion: While pregnancy with an IUD in place is rare, when it is encountered the emergency provider should maintain a high degree of suspicion for extrauterine pregnancy and perform prompt evaluation for hemorrhagic shock using diagnostic POCUS

Ruptured Ectopic Pregnancy with an Intrauterine Device: Case Report and Sonographic Considerations

Introduction: Ectopic pregnancy carries a high morbidity and mortality; patients are at risk for rupture and life-threatening hemorrhage.Case Report: We present a rare case of ruptured abdominal ectopic pregnancy in a patient with a well-positioned intrauterine device (IUD) and discuss the diagnostic utility that transabdominal point-of-care ultrasound (POCUS) can have when performed at the bedside.Conclusion: While pregnancy with an IUD in place is rare, when it is encountered the emergency provider should maintain a high degree of suspicion for extrauterine pregnancy and perform prompt evaluation for hemorrhagic shock using diagnostic POCUS