Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).

Antiprotozoal agents: How have they changed over a decade?

Neglected tropical diseases are a diverse group of communicable diseases that are endemic in low- or low-to-middle-income countries located in tropical and subtropical zones. The number and availability of drugs for treating these diseases are low, the administration route is inconvenient in some cases, and most of them have safety, efficacy, or adverse/toxic reaction issues. The need for developing new drugs to deal with these issues is clear, but one of the most drastic consequences of this negligence is the lack of interest in the research and development of new therapeutic options among major pharmaceutical companies. Positive changes have been achieved over the last few years, although the overall situation remains alarming. After more than one decade since the original work reviewing antiprotozoal agents came to light, now it is time to question ourselves: How has the scenario for the treatment of protozoal diseases such as malaria, leishmaniasis, human African trypanosomiasis, and American trypanosomiasis changed? This review covers the last decade in terms of the drugs currently available for the treatment of these diseases as well as the clinical candidates being currently investigated.

Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products.

To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients.

BACKGROUND: Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety. METHODS: The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy. RESULTS: The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy. CONCLUSION: The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema.

The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.

The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. Acute evaluation with blood, imaging and electroencephalographic monitoring will be performed and then patients will be tracked for 2 years to determine the incidence of PTE. Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies.

De novo gastroesophageal reflux disease after sleeve gastrectomy: role of preoperative silent reflux.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become the most frequently performed bariatric procedure to date. However, LSG is known to worsen pre-operative and result in de novo gastroesophageal reflux disease (GERD). Pre-operative evaluation reveals a high percentage of silent GERD of so far unknown influence on post-operative GERD. METHODS: Prospective data of patients undergoing primary LSG between 01/2012 and 12/2015 were evaluated. Pre-operative GERD-specific evaluation consisted of validated questionnaires, upper endoscopy, 24 h-pH-manometry, and esophagograms. Patients were followed-up with questionnaires every 6 months, upper endoscopies after 1 year and 24 h-pH-metry after 2 years. Silent GERD was defined as esophagitis grade > B and/or abnormal esophageal acid exposure in absence of symptoms. LSG was performed over a 32F bougie, hiatal hernias > 1 cm were addressed with posterior hiatoplasty. Excluded were patients with hiatal hernias > 4 cm, patients with incorrect anatomy (stenosis, fundus too large) and conversion to RYGB for early leaks. RESULTS: 222 patients were included. Mean follow-up was 32 ± 16 months, mean preoperative body mass index 49.6 ± 7.2 kg/m2. 116 patients (52%) presented with post-operative GERD-symptoms, of which 85 (73%) had de novo symptoms. Of those, 48 (of 85, 56%) had no preoperative GERD and 37 (of 85, 44%) silent GERD. 57 patients (26%) had neither pre- nor post-operative GERD, 7 (3%) had silent pre-operative and no postop GERD, and in 19 patients (9%) GERD was cured with LSG. 31 patients (14%) stayed symptomatic. Of 56 patients (25%) with pre-operative silent GERD, 37 (of 54, 66%) became symptomatic. CONCLUSION: LSG leads to a considerable rate of post-operative GERD. De novo-GERD consist of around half of pre-operative silent GERD and completely de novo-GERD. Most patients with pre-operative silent GERD became symptomatic.

Evaluation of a New Catheter for Simultaneous Intracranial Pressure Monitoring and Cerebral Spinal Fluid Drainage: A Pilot Study.

OBJECTIVES: Intracranial pressure (ICP) monitoring is a common practice when treating intracranial pathology with risk of elevated ICP. External ventricular drain (EVD) insertion is a standard approach for both monitoring ICP and draining cerebrospinal fluid (CSF). However, the conventional EVD cannot serve these two purposes simultaneously because it cannot accurately measure ICP and its pulsatile waveform while the EVD is open to CSF drainage. A new Integra® Camino® FLEX Ventricular Catheter (Integra Lifesciences, County Offaly, Ireland) with a double-lumen construction has been recently introduced into the market, and it can monitor ICP waveforms even during CSF drainage. The aim of this study was to evaluate and validate this new FLEX catheter for ICP monitoring in a neurological intensive care unit. METHODS: Six patients with 34 EVD open/close episodes were retrospectively analyzed. Continuous ICP was detected in two ways: through the FLEX sensor at the tip (ICPf) and through a fluid-coupled manometer within the FLEX catheter, functioning as a conventional EVD (ICPe). The morphologies of ICPf and ICPe pulses were extracted using Morphological Clustering and Analysis of ICP algorithm, an algorithm that has been validated in previous publications. The mean ICP and waveform shapes of ICP pulses detected through the two systems were compared. Bland-Altman plots were used to assess the agreement of the two systems. RESULTS: A significant linear relationship existed between mean ICPf and mean ICPe, which can be described as: mICPf = 0.81 × mICPe + 1.67 (r = 0.79). The Bland-Altman plot revealed that no significant difference existed between the two ICPs (average of [ICPe-ICPf] was - 1.69 mmHg, 95% limits of agreement: - 7.94 to 4.56 mmHg). The amplitudes of the landmarks of ICP pulse waveforms from the two systems showed strong, linear relationship (r ranging from 0.89 to 0.94). CONCLUSIONS: This study compared a new FLEX ventricular catheter with conventional fluid-coupled manometer for ICP waveform monitoring. Strong concordance in ICP value and waveform morphology between the two systems indicates that this catheter can be used for reliability for both clinical and research applications.

Cerebral Vascular Changes During Acute Intracranial Pressure Drop.

OBJECTIVE: This study applied a new external ventricular catheter, which allows intracranial pressure (ICP) monitoring and cerebral spinal fluid (CSF) drainage simultaneously, to study cerebral vascular responses during acute CSF drainage. METHODS: Six patients with 34 external ventricular drain (EVD) opening sessions were retrospectively analyzed. A published algorithm was used to extract morphological features of ICP recordings, and a template-matching algorithm was applied to calculate the likelihood of cerebral vasodilation index (VDI) and cerebral vasoconstriction index (VCI) based on the changes of ICP waveforms during CSF drainage. Power change (∆P) of ICP B-waves after EVD opening was also calculated. Cerebral autoregulation (CA) was assessed through phase difference between arterial blood pressure (ABP) and ICP using a previously published wavelet-based algorithm. RESULTS: The result showed that acute CSF drainage reduced mean ICP (P = 0.016) increased VCI (P = 0.02) and reduced ICP B-wave power (P = 0.016) significantly. VCI reacted to ICP changes negatively when ICP was between 10 and 25 mmHg, and VCI remained unchanged when ICP was outside the 10-25 mmHg range. VCI negatively (r = - 0.44) and VDI positively (r = 0.82) correlated with ∆P of ICP B-waves, indicating that stronger vasoconstriction resulted in bigger power drop in ICP B-waves. Better CA prior to EVD opening triggered bigger drop in the power of ICP B-waves (r = - 0.612). CONCLUSIONS: This study demonstrates that acute CSF drainage reduces mean ICP, and results in vasoconstriction which can be detected through an index, VCI. Cerebral vessels actively respond to ICP changes or cerebral perfusion pressure (CPP) changes in a certain range; beyond which, the vessels are insensitive to the changes in ICP and CPP.

Diagnostic Approach to Health Care- and Device-Associated Central Nervous System Infections.

Health care- and device-associated central nervous system (CNS) infections have a distinct epidemiology, pathophysiology, and microbiology that require a unique diagnostic approach. Most clinical signs, symptoms, and tests used to diagnose community-acquired CNS infections are insensitive and nonspecific in neurosurgical patients due to postsurgical changes, invasive devices, prior antimicrobial exposure, and underlying CNS disease. The lack of a standardized definition of infection or diagnostic pathway has added to this challenge. In this review, we summarize the epidemiology, microbiology, and clinical presentation of these infections, discuss the issues with existing microbiologic tests, and give an overview of the current diagnostic approach.

Synthesis and biological evaluation of isoxazolyl-sulfonamides: A non-cytotoxic scaffold active against Trypanosoma cruzi, Leishmania amazonensis and Herpes Simplex Virus.

In this study we report the synthesis, characterization, biological evaluation, and druglikeness assessment of a series of 20 novel isoxazolyl-sulfonamides, obtained by a four-step synthetic route. The compounds had their activity against Trypanosoma cruzi, Leishmania amazonensis, Herpes Simplex Virus type 1 and cytotoxicity evaluated in phenotypic assays. All compounds have drug-like properties, showed low cytotoxicity and were promising regarding all other biological activities reported herein, especially the inhibitory activity against T. cruzi. The compounds 8 and 16 showed significant potency and selectivity against T. cruzi (GI50 = 14.3 µM, SI > 34.8 and GI50 = 11.6 µM, SI = 29.1, respectively). These values, close to the values of the reference drug benznidazole (GI50 = 10.2 µM), suggest that compounds 8 and 16 represent promising candidates for further pre-clinical development targeting Chagas disease.

Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as analogues of natural lignans with antiparasitic activity.

Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against Trypanosoma cruzi amastigotes. Thirty-seven compounds were active, and eight of them had GI50 values lower than 100 µM (GI50 88.4-12.2 µM). A qualitative structure activity relationship study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compounds. Compound 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole (31) was the most active in the series (GI50 12.2 µM), showing, in vitro, low toxicity and potency similar to benznidazole (GI50 10.2 µM). These results suggest that this compound can be a promising scaffold for the design of new trypanocidal compounds.

Treatment options for posttraumatic epilepsy.

PURPOSE OF REVIEW: Posttraumatic seizures (PTS) and posttraumatic epilepsy (PTE) are common and debilitating consequences of traumatic brain injury (TBI). Early PTS result in secondary brain injury by raising intracranial pressure and worsening cerebral edema and metabolic crisis. PTE is a localization-related epilepsy strongly associated with TBI severity, but risk factors for PTE and epileptogenesis are incompletely understood and are active areas of research. Medical management of PTS in adults and children is reviewed. Surgical options for posttraumatic drug-resistant epilepsy are also discussed. RECENT FINDINGS: Continuous electroencephalography is indicated for children and adults with TBI and coma because of the high incidence of nonconvulsive seizures, periodic discharges, and associated secondary brain injury in this population. Neuroinflammation is a central component of secondary brain injury and appears to play a key role in epileptogenesis. Levetiracetam is increasingly used for seizure prophylaxis in adults and children, but variability remains. SUMMARY: PTS occur commonly after TBI and are associated with secondary brain injury and worse outcomes in adults and children. Current medical and surgical management options for PTS and PTE are reviewed.

Focal amyotrophy in multiple sclerosis.

INTRODUCTION: The assumption that multiple sclerosis (MS) is purely a white matter disease has been challenged in recent years by observations of axonal damage and neuronal loss in gray matter of the cortex, subcortex, and spinal cord. METHODS: We report the case of a 71-year-old man with primary progressive MS and longstanding right arm weakness who presented with intermittent right arm pain. RESULTS: Neurological examination showed atrophy, weakness, and hyporeflexia, and electromyography (EMG) showed acute and chronic partial denervation in multiple segments of the right arm. Magnetic resonance imaging (MRI) demonstrated asymmetric volume loss and increased T2 signal in the right anterior spinal cord from C3 to C7, with no evidence of nerve root compression. CONCLUSIONS: Lower motor neuron involvement of his right arm was caused by MS with involvement of either the anterior horn cells or the intraspinal motor nerve roots.

Simple text-messaging intervention is associated with improved door-to-needle times for acute ischemic stroke.

BACKGROUND AND PURPOSE: Timely administration of intravenous tissue-type plasminogen activator (IV tPA) is associated with improved outcomes for acute ischemic stroke; yet, developing processes to consistently provide prompt treatment remains a challenge. We developed and evaluated a simple quality improvement intervention designed to improve door-to-needle (DTN) times for resident-led Code Stroke teams at an academic medical center. METHODS: We evaluated a simple text-messaging based intervention with real-time feedback to improve DTN times for intravenous tissue-type plasminogen activator. We used the rank-sum test and linear regression to evaluate for a change in DTN times that was temporally associated with the rollout of the intervention. RESULTS: A total of 202 patients received intravenous tissue-type plasminogen activator; 94 preintervention and 108 postintervention. The median DTN time was significantly lower in the postintervention period (56 minutes [interquartile range 44-71] versus 82 minutes [IQR 68-103], P<0.0001) and a significantly higher proportion of patients were treated within 60 minutes (61% versus 16%, P<0.001). CONCLUSIONS: A simple real-time text-messaging intervention was associated with a significant improvements in DTN times for acute ischemic stroke.

Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives.

Two cucurbitacins, dihydrocucurbitacin B (1) and cucurbitacin B (2), which can be obtained in large amounts from the roots of Wilbrandia ebracteata and from the fruits of Luffa operculata, respectively, were used as starting materials for the preparation of a library of 29 semi-synthetic derivatives. The structural changes that were performed include the removal, modification or permutation of functional groups in rings A and B as well as in the side chain. All new semisynthetic compounds, as well as 1 and 2, were tested in vitro for their cytotoxic effects on non-small-cell lung cancer cells (A549 cells). Some of these compound displayed potent to moderate activity against A549 tumor cells, especially those cucurbitacin B derivatives which were modified at ring A.

Cytotoxic activity of semi-synthetic derivatives of elatol and isoobtusol.

In the present study, the in vitro cytotoxic effects of six semi-synthetic derivatives of elatol (1) and isoobtusol (2) were investigated. Chemical modifications were performed on the hydroxyl groups aiming to get derivatives of different polarity, namely the hemisuccinate, carbamate and sulfamate. The structural elucidation of the new derivatives was based on detailed NMR and MS spectroscopic analyses. The in vitro cytotoxicity of compounds 1 to 8 was evaluated against A459 and RD tumor cell lines with CC50 values ranging from 4.93 to 41.53 µM. These results suggest that the structural modifications performed on both compounds could be considered a good strategy to obtain more active derivatives.

New cytotoxic cucurbitacins from Wilbrandia ebracteata Cogn.

Chemical investigation of the roots of Wilbrandia ebracteata Cogn. (Cucurbitaceae) led to the isolation of two new (1- 2) and four known (3- 6) cucurbitacins. Their structures were elucidated by NMR and MS and compared with related compounds. The in vitro cytotoxicity of isolated compounds was evaluated against RD, KB, HCT-8, and A549 cell lines showing strong activity.