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Background: The current AHA guidelines recommend (class IIb) advanced cardiac imaging in embolic stroke of unknown source (ESUS). We aim to better characterize the role of cardiac CTA (cCTA) in the evaluation of stroke patients. Method: A retrospective review of stroke patients at a comprehensive stroke center, who had cCTA between 12/2016 and 11/2020 was conducted using institutional registries. Ischemic stroke patients with ESUS, cryptogenic (with ESUS as a competing etiology) and cardio-embolic etiologies were included. Only cardioembolic etiologies in which a suspicion of intracardiac thrombus with either a known diagnosis of atrial fibrillation or presence of LVAD were included. Cases with TIA, large vessel disease, small vessel disease, dissection or hemodynamic etiologies were excluded. TTE and cCTA results from all cases were reviewed for remarkable findings, most notably intracardiac thrombus, and analyzed if a change in anti-thrombotic therapy was directly attributable to cCTA results. Results: As per our criteria, 96 cases (Female 42.7%, Black 37.5%, Age mean: 63.7 years) were included, of whom 45 (46.9%) were ESUS, 21 (21.9%) were cryptogenic, and 30 (31.2%) were cardioembolic. cCTA revealed intracardiac thrombus in 5 (5.2%) cases, all with LA thrombus. Of these, 3 (60%) had escalation of anti-thrombotic therapy. Interestingly, in one patient who had both cMRI and cCTA imaging, the cMRI revealed an apical LV thrombus which was not detected on cCTA. Conclusion: In this retrospective analysis of 96 select stroke cases, escalation of anti-thrombotic therapy from anti-platelets to full dose anti-coagulation was indicated in 3 patients (3.1%) with addition of cCTA. Compared to a similar cohort of patients from the same institutional registry using cMRI as the advanced cardiac imaging modality, cCTA did not reveal any LV thrombi and even missed a case of LV thrombus seen on cMRI suggesting lower sensitivity for cCTA to detect LV thrombus. Further analysis of data is in process to determine the subset of stroke patients who would benefit the most from cCTA.

Intro: Incidence of intracerebral hemorrhage (ICH) in the young is increasing but risk factors and outcomes are not well characterized. Methods: Using a stroke-specific bioinformatics pipeline across a 7-hospital certified stroke healthcare system, we identified adult non-traumatic ICH cases between 05/16 and 08/22 and flagged young ICH patients (YIP) aged 18 – 45. We compared sociodemographic, comorbidity, clinical, imaging, and treatment characteristics, and outcomes between YIP and non-YIP using logistic regression. Results: Among 1 869 ICH patients, 187 (10%) were YIP. YIP (vs. Non-YIP) were predominantly privately insured (71.1 % vs. 29.8 %), non-Hispanic Black (33.7% vs. 22.2%), Hispanic (26.7% vs. 21.7%), and single (41.2% vs. 20.5%). A higher proportion of YIP were obese and a lower proportion had pre-existing comorbidities (Figure). A lower proportion of YIP were on statins, antiplatelets, or anticoagulants prior to ICH. A significantly smaller proportion of YIP had large hemorrhage volumes (> 30 ml) and experienced lower rates of in-hospital complications such as delirium and SIRS. A significantly greater proportion of YIP underwent craniotomy and had longer lengths of stay. After adjusting for important clinical and sociodemographic correlates of in-hospital mortality, YIP had a 59% lower likelihood of in-hospital mortality or hospice discharge OR (CI): 0.41 (0.20 – 0.82). Additionally, for outcome assessment, YIP were more likely to be contacted [2.9 (1.26, 8.08)], consented [3.7 (1.8, 7.8)], and complete follow-up survey [1.9 (1.0, 3.8)] than non-YIP. Though 50.5% of YIP had a 90-day mRS >3, there was a 51% lower likelihood of severe disability or death in YIP vs. non-YIP. Conclusion: YIP poses a high morbidity burden and understanding long-term functional and cognitive outcomes is important. High follow-up rates provide an opportunity for engaging this often overlooked and underrepresented cohort of critically ill patients in future research.

Mycobacterial pathogens, including nontuberculous mycobacteria (NTM) and Mycobacterium tuberculosis, are pathogens of significant worldwide interest owing to their inherent drug resistance to a wide variety of FDA-approved drugs as well as causing a broad range of serious infections. Identifying new antibiotics active against mycobacterial pathogens is an urgent unmet need, especially those antibiotics that can bypass existing resistance mechanisms. In this study, we demonstrate that gepotidacin, a first-in-class triazaacenapthylene topoisomerase inhibitor, demonstrates potent activity against M. tuberculosis and M. fortuitum, as well as against other clinically relevant NTM species, including fluoroquinolone-resistant M. abscessus. Furthermore, gepotidacin exhibits concentration-dependent bactericidal activity against various mycobacterial pathogens, synergizes with several drugs utilized for their treatment, and reduces bacterial load in macrophages in intracellular killing assays comparably to amikacin. Additionally, M. fortuitum ATCC 6841 was unable to generate resistance to gepotidacin in vitro. When tested in a murine neutropenic M. fortuitum infection model, gepotidacin caused a significant reduction in bacterial load in various organs at a 10-fold lower concentration than amikacin. Taken together, these findings show that gepotidacin possesses a potentially new mechanism of action that enables it to escape existing resistance mechanisms. Thus, it can be projected as a potent novel lead for the treatment of mycobacterial infections, particularly for NTM, where present therapeutic interventions are extremely limited.

COVID-19 has been associated with a hypercoagulable state causing cardiovascular and neurovascular complications. To further characterize cerebrovascular disease (CVD) in COVID-19, we review the current literature of published cases and additionally report the clinical presentation, laboratory and diagnostic testing results of 12 cases with COVID-19 infection and concurrent CVD from two academic medical centers in Houston, TX, USA, between March 1 and May 10, 2020. To date, there are 12 case studies reporting 47 cases of CVD in COVID-19. However, only 4 small case series have described the clinical and laboratory findings in patients with COVID-19 and concurrent stroke. Viral neurotropism, endothelial dysfunction, coagulopathy and inflammation are plausible proposed mechanisms of CVD in COVID-19 patients. In our case series of 12 patients, 10 patients had an ischemic stroke, of which 1 suffered hemorrhagic transformation and two had intracerebral hemorrhage. Etiology was determined to be embolic without a clear cause identified in 6 ischemic stroke patients, while the remaining had an identifiable source of stroke. The majority of the patients had elevated inflammatory markers such as D-dimer and interleukin-6. In patients with embolic stroke of unclear etiology, COVID-19 may have played a direct or indirect role in the processes that eventually led to the strokes while in the remaining cases, it is unclear if infection contributed partially or was an incidental finding.

Background: The current AHA guidelines recommend (class IIb) advanced cardiac imaging in an embolic stroke of unknown source (ESUS). We aim to better characterize the role of cardiac MRI (cMRI) in the evaluation of stroke patients and determine patient characteristics that may increase the positive predictive value of cMRI. Method: A retrospective review of stroke patients at a comprehensive stroke center, who had cMRI between 12/2016 and 11/2020 was conducted using institutional registries. Ischemic stroke patients with ESUS, cryptogenic (with ESUS as a competing etiology), and cardioembolic etiologies were included. Cases with TIA, large vessel, small vessel, or hemodynamic etiologies were excluded. Cardioembolic etiology was defined as newly diagnosed Afib patients with TTE abnormalities including wall motion abnormalities and/or reduced LVEF Results: As per our criteria, 250 cases (Female 44.4%, Black 29.6%, Age mean: 65.2 years) were included, of whom 146 (58.4%) were ESUS, 86 (34.4%) were cryptogenic, and 18 (7.2%) were cardioembolic. Sixteen (6.4%) revealed intracardiac thrombus, of which 10 had LV thrombus, 5 had LA thrombus, and 1 had RA thrombus along with questionable PFO on cMRI. Of these, 14 (87.5%) had an escalation of anti-thrombotic therapy. For the other 2 cases, despite cMRI obtained due to low LVEF and revealing LA thrombus, antithrombotic regimen was not changed. Eight (3.2%) additional patients were placed on anticoagulation secondary to incidental findings. Conclusion: In this large retrospective analysis of 250 select stroke cases, escalation of anti-thrombotic therapy from anti-platelets to full dose anti-coagulation was indicated in 14 patients (5.6%) with addition of cMRI. Further analysis of data is in process to determine the subset of stroke patients who would benefit the most from cMRI.

Background: The role of neighborhood socioeconomic disadvantage as a barrier to utilization of thrombolytic therapies among acute ischemic strokes (AIS) patients is not well characterized. Methods: Using data from 7 comprehensive and primary stroke centers across a diverse metropolitan, we analyzed intravenous tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) utilization rates among AIS patients across various levels of Area Deprivation Index (ADI). Exact patient addresses were geocoded, and state-level ADI ranks (1 - 10) were calculated. Multivariable logistic regression models were fitted to evaluate the association between high ADI and thrombolytic therapy (tPA and/or MT vs no tPA or MT). Among the treated, Last Known Well to Treatment Time (LKNW-TT) across ADI ranks was analyzed. Odds ratios (OR) and 95% confidence intervals (CI) are reported. Results: Between May 2016 and Apr 2021, a total of 2,900 AIS patients with complete data were included (mean age: 68.5 years, 49.9% female, 58.4% White, 12.9% Hispanic, median [IQR] ADI rank: 4 [2-7]). The overall treatment utilization rate was 35% (tPA only: 16.7%; MT with/without tPA: 18.3%). In a fully adjusted model, higher ADI was independently associated with lower likelihood of overall treatment (OR, CI: 0.93, 0.89-0.96), treatment with tPA alone (OR: 0.95, CI: 0.91-0.99) and utilization of MT (OR: 0.90, CI: 0.85-0.95) (Figure). LKNW-TT among tPA-treated patients was longer for those residing in top 50% of ADI neighborhoods (highest vs lowest 50 th percentile ADI rank) - median [IQR] minutes: 135 [86-179] vs 122 [90-180]. No differences for MT were observed: 268 [188-544] vs 270 [199-460] minutes. Conclusion: Socioeconomic disadvantage may lead to lower utilization of thrombolytic therapies among AIS patients, potentially driven by delayed presentation or treatment. Targeted educational and awareness efforts are needed among disadvantaged populations to equitably improve stroke outcomes.

Background: Relationships between neighborhood socioeconomic deprivation (NSD) and Intracerebral hemorrhage (ICH) outcomes are not well characterized. We sought to evaluate the impact of NSD on ICH outcomes and assessed mediating pathways for association between NSD and poor outcomes. Methods: Clinical data were extracted from the electronic medical records and 90-day modified Rankin Scale (mRS) scores were obtained from a prospectively collected stroke registry at a large healthcare system. Presentation NIHSS score was used to assess ICH severity. Exact patient addresses were geocoded, and state-level Area Deprivation Index (ADI) was calculated, with high NSD (H-NSD) categorized as top 15% of ADI scores. The outcome was severe disability or death (SDD) (mRS ≥ 4). Age-adjusted logistic regression models were fitted, and mediation analyses were performed utilizing structured equation modeling. Odds ratios (OR) and 95% Confidence Intervals (CI) are reported. Results: Final analyses included 486 patients with complete data (mean age: 65.6 years, 45.9 % female, 28.8% non-Hispanic Black, 20.2% Hispanic, median presentation NIHSS: 10, and median 90-day mRS 4). In separate age-adjusted models, both high NIHSS scores (OR, CI: 1.24, 1.20 - 1.29) and H-NSD (OR, CI: 1.59, 1.02 - 2.46) were associated with SDD. In a mediation analysis, H-NSD significantly contributed to higher NIHSS scores (OR, CI: 14.30, 1.44 - 141.61) and in turn higher NIHSS scores were significantly associated with SDD (OR, CI: 1.03, 1.03 - 1.04). In this analysis, H-NSD did not retain a significant direct effect on SDD (OR, CI: 1.38, 0.96 - 1.12) and was instead fully mediated by high NIHSS scores (Figure 1). Discussion: Our analyses uniquely identify higher stroke severity as a potential causal pathway between NSD and poor ICH outcomes. These findings warrant comprehensive understanding of factors that may predispose the disadvantaged to experience higher ICH severity and greater neurological deficit.

Background: Only 20-30% of Intracerebral Hemorrhage (ICH) survivors achieve functional independence. We investigated if neighborhood socioeconomic disadvantage (NSD) mediated by cerebral small vessel disease (CSVD) is associated with post-ICH functional outcomes. Methods: Clinical and imaging data were extracted from electronic medical records and 90-day modified Rankin Score (mRS) was obtained from prospectively collected stroke registry at a large hospital system. CSVD was assessed based on MRI markers from 1-year before to 30 days after the ICH event and was scored from 0-4 with severe CSVD (S-CSVD) ≥ 2. Exact patient addresses were geocoded, and state-level Area Deprivation Index (ADI) was calculated, with high NSD (H-NSD) categorized as the top 15% of ADI scores. The outcome was severe disability or death (SDD) categorized as 90-day mRS score ≥4. Multivariate logistic regression models were fitted, and mediation was evaluated by structural equation modeling. Odds ratios (OR) and 95% confidence intervals (CI) are reported. Results: Final analysis included 367 patients (mean age: 65 years, 49.7% female, median presentation ICH Score: 1) with complete data. We found significant associations between older age, Black race, S-CSVD, H-NSD, hematoma volume, presence of ventricular hemorrhage, presentation systolic blood pressure (SBP), and ICH score with SDD (P Discussion: In addition to known clinical factors, NSD, as measured by the ADI, and CSVD were independently associated with poor ICH outcomes. Potential causal pathways between H-NSD and poor ICH outcomes need to be further evaluated.

Background: Delirium in-hospital (DIH) is common among the critically ill. However, DIH incidence and outcomes are not well characterized among ischemic stroke (IS) patients, particularly those treated with intravenous tissue plasminogen activator (tPA) and / or mechanical thrombectomy (MT). Methods: Utilizing data from a healthcare system with standardized delirium screening protocols, DIH was determined by a positive 4AT / CAM-ICU screen or diagnosis codes. IS patients with tPA or MT were flagged and a subset with available 90-day modified Rankin Scale (mRS) were analyzed for shifts in mRS scores associated with DIH, via ordinal logistic regression models adjusted for age, stroke severity, tPA or MT, Charlson Comorbidity Index [CCI], prior stroke and sepsis / infections. Common odds ratios (OR) and 95% confidence intervals (CI) are reported. Results: Between May 2016 and June 2021, IS was the primary discharge diagnosis in 12,415 encounters (10,878 unique patients). DIH was documented in 41.6% of IS encounters, compared to 20.0% of non-IS encounters. Stroke-DIH patients (vs no-DIH Stroke) were older (median: 75 vs 65 years), more frequently female (53.3% vs 48.7%), with higher comorbidity burden (median CCI: 7 vs 5), longer hospital stays (median: 6 vs 3 days), higher in-hospital mortality (3.1% vs 0.5%), and fewer home discharges (36.2% vs 75.2%). Among a sub-cohort of 2,785 IS patients with 90-day mRS, fully adjusted model indicated lower mRS (OR, CI: 0.48, 0.41-0.57) for those with tPA or MT, and worse outcomes for DIH patients (OR, CI: 2.70, 2.26-3.23). Among 948 treated IS patients, DIH remained a significant risk for worse outcomes (OR, CI: 2.54, 1.89-3.43). Conclusion: Delirium was twice as common in IS patients and was a negative prognostic indicator of short and long-term outcomes among non-treated and treated IS patients. Active screening and management of DIH is critically important to improve stroke outcomes.

Background: Impact of socioeconomic disadvantage on outcomes among acute ischemic stroke (AIS) patients has not been well characterized. Methods: Clinical data on AIS patients were extracted from electronic medical records and 90-day modified Rankin Scale (mRS) scores were collected as a part of prospective stroke registry. Exact patient addresses were geocoded, and state-level Area Deprivation Index (ADI) ranks were categorized as low, medium, high. Patients with a 90-day mRS score ≥ 4 were categorized as severe disability or death (SDD). Logistic regression models (adjusted for treatment with intravenous tissue plasminogen activator or mechanical thrombectomy, age, sex, race/ethnicity, insurance, prior stroke, vascular risk factors) were fitted to compute odds ratios (OR) and 95% confidence intervals (CI) for total effect of high ADI on SDD. Structural equation modeling was used to assess mediation effects of stroke severity as measured by National Institutes of Health Stroke Scale (NIHSS). Results: Between May 2016 and Apr 2021, a total of 2,900 AIS patients (mean age: 68.5 years; 50.1% male; 28.4% non-Hispanic Black; 12.9% Hispanic) with complete outcomes data were included. In an adjusted model, high ADI was significantly associated with SDD (OR, CI: 1.14, 1.02-1.28). In the mediation analysis, patients in higher ADI neighborhoods had a 28% increased likelihood of having higher NIHSS (OR: 1.28, CI: 1.15-1.44). Likewise, higher NIHSS was associated with SDD (OR: 7.10, CI: 5.96-8.51). The effect of neighborhood disadvantage on SDD was fully mediated by NIHSS (average causal mediation effect of ADI on SDD: P=0.002), with 77% of the total effect pathway mediated through NIHSS. The proportions of 90-day mRS by ADI categories are reported (Figure). Conclusion: Neighborhood disadvantage leads to poor stroke outcomes mediated via stroke severity. Tracking social determinants of health may identify opportunities for reducing stroke related disability.

DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolone class of antibacterials. However, owing to increasing drug resistance as well as a concomitant reduction in the availability of newer classes of antibiotics, fluoroquinolones are increasingly being over-utilized in order to treat serious infections, including multi-drug resistant tuberculosis. This, in turn, increases the probability of resistance to fluoroquinolones, which is mediated by a single amino acid change in gyrA, leading to class-wide resistance. In this review, we provide an overview of the recent progress in identifying novel scaffolds which target DNA gyrase and provide an update on their discovery and development status.

Aims β casein fragment peptide (54–59) downregulates Basic Transcription factor 3a (BTF3a) in macrophages and exhibits enhanced clearance of M. bovis BCG and several other intracellular pathogens. However, the direct effect of BTF3a downregulation on Mycobacterium tuberculosis (Mtb) survival and the probable pathways involved have not yet been studied. Therefore, the present study was undertaken to deduce the antimycobacterial significance of BTF3a in human macrophages. Main methods CRISPR/Cas 9 gRNA was designed to downregulate BTF3a in THP1 derived macrophages. Fold change in BTF3a, p62 and Lamp 1 expression was evaluated through immune blot analysis. CFU assay was done to enumerate the intracellular burden of Mtb H37Rv. LC3B-II turnover and Lamp 1 expression was checked through immunoblotting and also visualized through confocal microscopy. Colocalization of Mtb H37Rv with LC3B, Lysotracker and Rab 7 was visualized through confocal microscopy. Key findings The current study identifies BTF3a as a critical host factor assisting intracellular survival of Mtb. In THP1 derived macrophages, infection with Mtb H37Rv resulted in upregulation of BTF3a and targeted depletion of BTF3a resulted in augmented Mtb clearance. Furthermore, BTF3a knockdown demonstrated increased autophagy flux and ameliorated the lysosomal targeting of Mtb containing autophagosomes for lysosomal degradation. Significance Deep understanding of macrophage-Mtb interactions and their roles in the pathogenesis can offer exciting new therapeutic targets for alternative host-specific adjunct therapies in tuberculosis treatment. The present study highlights a novel and significant role of BTF3a in curbing the intracellular survival of Mtb through modulation of autophagy and lysosome biogenesis.

Background and purpose: The study aims to identify the characteristics and neurological outcomes of the left ventricular-assist device (LVAD)-associated cerebrovascular events (CVE) and infections, particularly in the setting of infectious intracranial aneurysms (IIA). Methods: A single-center retrospective review of patients having undergone LVAD implantation between 2011 and 2017 was conducted using institutional registries and screened for CVE. Patients with CVE were assessed for concurrent bacteremia; neurovascular imaging was then used to isolate patients with IIA. A review of comorbidities, imaging characteristics, and management were performed to determine predictors of neurological outcomes, as defined by the 90-day modified Rankin scale (mRS) scores. Results: Of the 383 HeartMate II LVAD implantations performed, 43 all-cause stroke events were identified across 35 (9%) patients. The majority of the events were hemorrhagic CVE (n=28) with 21 events complicated by bacteremia. Of patients with hemorrhagic CVE and bacteremia, Staphylococcus aureus (n=10) and Pseudomonas aeruginosa (n= 8) infection were the most frequently associated organisms. Severe disability or death (90-day mRS > 4) was observed in 15 patients (63%). Seven patients had confirmed findings of IIA on diagnostic cerebral angiogram and were associated with distal middle cerebral artery (MCA) territory involvement (n=6; 86%) with concurrent Staphylococcus (n=5, 71%) and/or Pseudomonas (n=4, 57%) infections. Overall, a higher incidence of acute and chronic bacteremia was observed in the hemorrhagic CVE subgroup compared to the ischemic CVE subgroup (74% vs 36% & 71% vs 29%, respectively; p

Introduction: Stroke and infection are among the more common complications of LVAD therapy related to higher rates of mortality. The characteristics and disability outcomes of LVAD-associated cerebrovascular events and infections, particularly in the setting of infectious intracranial aneurysms (IIA), have not been defined. Methods: A single-center retrospective review of patients having undergone LVAD implantation between 2011-2017 was conducted using institutional registries and screened for hemorrhagic and ischemic strokes. Patients with hemorrhagic stroke were assessed for concurrent bacteremia; neurovascular imaging was then used to isolate patients with associated IIA. Review of comorbidities, imaging characteristics, and management were performed to determine predictors of disability outcomes, as defined by 90-day modified Rankin scales (mRS). Results: Of 383 patients with HeartMate II LVAD implantation, 46 all-cause stroke events were identified across 38 (12%) patients. 31 ICH events were identified, with 22 complicated by bacteremia (evidenced by chronic driveline infection and/or positive blood cultures on admission). Of patients with ICH and bacteremia, Staphylococcus aureus (n=12, 54.5%) and Pseudomonas aeruginosa (n= 10, 45.5%) infection were the highest associated causal organisms; severe disability or death (90-day mRS > 4) was seen in 16 (72.7%) patients. 7 (31.8 %) patients had confirmed findings of IIA on diagnostic cerebral angiogram, and were associated with distal MCA territory involvement (100%), concurrent Pseudomonas infection (83.3%), and INR > 3.0 (66.7%). Despite endovascular intervention in patients with IIA, 4 patients failed management and were withdrawn from care. Conclusion: Our results indicate Pseudomonas aeruginosa and Staphylococcus aureus bacteremia are associated with greater incidence of hemorrhage and neurological disability. Further investigation is warranted to better define management of these patients. Future considerations may include pre-implantation cerebrovascular imaging to assess for vascular pathology as a screen for higher risk patients, as well as more aggressive antibiotic therapy at bacteremia onset.

Relapse of anti-NMDA receptor (NMDAR) encephalitis should be considered in all patients with history of anti-NMDAR encephalitis presenting with new acute-onset encephalopathy or psychosis.

Background: Pain is a complex unpleasant phenomenon composed of sensory experiences originating from damaged tissue or abnormal physiological condition. The objective of this study was to evaluate the analgesic activity of resveratrol in different doses in animal model. Methods: Albino mice of either sex weighing 20-30 gms were selected for the study. Mice were divided into 4 groups of 6 animals each. The control group received 0.9% normal saline (10 ml/kg), standard group received indomethacin (10 mg/kg) and test groups received resveratrol (50 mg/kg and 100 mg/kg). The drugs were given orally 1 hour prior to the tests. The animals were tested for analgesia activity 30, 60, 90, 120 minutes after drug administration using tail flick method and 1% acetic acid was given intraperitoneally to induce writhing in the other method. Delay in the reaction time in tail flick method and decrease in total number of writhes in acetic acid induced writhing model denoted analgesic activity. Data analysis was done using one way ANOVA followed by Tukey’s HSD test. P

Background: As we know primary open angle glaucoma need lifelong treatment. It possess financial burden to patient. We have done this study to compare the monthly cost and cost effectiveness of brimonidine /timolol fixed combi-nation and Travoprost 0.004% eye drops in patients of primary open angle glaucoma. Methods: Drops were dispensed at room temperature from 2.5-mL bottles of Travoprost, and 5ml of Brimonidine/Timolol. Two determinations of drop count were taken, each made from bottles held vertically and at a 45-degree angle. The total volumes of medication dispensed from each bottle were measured. Drops in five new bottles were counted and averaged for each drug. Drugs given to patients and asked them to come back with empty bottles for follow up after 2, 4, 8, 12 wks. IOP was measured and another bottle of drug is given. Average retail price was determined by survey of different brands available in market. Drop count, average retail price, and IOP reduction data were used to compute annual cost and cost effectiveness (annual cost per mmHg of IOP reduction) of both of the drugs. Results: Drops per 2.5ml bottle averaged 83 for Travoprost 0.004% and 100 drops per 5ml bottle for Brimonidine/Timolol. Average retail cost per bottle was 498 for Travoprost 0.004% and 204 for Brimonidine/Timolol. Annual re-tail cost was 3545 for Brimonidine/Timolol and 4910 for Travoprost 0.004%. Cost effectiveness ranges were 328 to 361 for Brimoni-dine/Timolol and 629 to 637 for Travoprost 0.004%. Conclusions: Brimonidine/Timolol had the lower monthly cost and annual cost and it is more cost effective than Travoprost 0.004%.

We report a case of a 60-year-old right-handed woman with hypertension, hyperlipidemia, and hypothyroidism who presented with a three-week history of recurrent thunderclap headaches accompanied by photophobia, phonophobia, nausea, and vomiting. She reported one brief episode of slurred speech, expressive aphasia, right facial droop, and right hemiparesis suggestive of a TIA. Family history was remarkable for primary angiitis of the CNS (PACNS) in the mother. Neurologic examination was unremarkable. CT of the head was negative; CT angiography (CTA) of the head and neck suggested fibromuscular dysplasia in bilateral cervical internal carotid arteries and distal right vertebral artery. MRI of the brain showed no correlating abnormalities. A digital subtraction angiography (DSA) revealed multivessel intracranial medium and large vessel narrowing and fusiform dilatations, suggestive of reversible cerebral vasoconstriction syndrome (RCVS) vs vasculitis. Subsequent MR intracranial vessel wall imaging (IVWI) showed multifocal concentric vessel wall thickening and enhancement consistent with vasculitis (figure). Transcranial Doppler showed no evidence of elevated intracranial velocities. CSF studies were unremarkable with an opening pressure of 10 cm H2O, 2 white blood cells (normal 0–5/mm3), 2 red blood cells (normal 0–1/mm3), 58 mg/dL glucose (normal 40–70, serum glucose 87), 41 mg/dL protein (normal 15–45), normal Q-albumin ratio, normal IgG synthetic rate, and IgG index. Serum inflammatory and infectious studies had been negative thus far. Empiric high-dose IV steroids lead to complete symptom resolution. Final infectious workup revealed strongly positive serum Bartonella IgM titer of 1:256 and negative IgG, consistent with her reported cat exposure. She was started on an outpatient two-week course of doxycycline, rifampin, and oral steroids. Four weeks later, repeat vessel wall MRI and Bartonella serologies (IgM titer 1:80) showed improvement. The authors thank Dr. Gadhia for his mentorship.

BACKGROUND Non-tuberculous mycobacteria are emerging pathogens of significant worldwide interest because they have inherent drug resistance to a wide variety of FDA-approved drugs and cause a broad range of serious infections. In order to identify new drugs active against non-tuberculous mycobacteria, we identified disulfiram, utilized for treatment of alcohol dependence, as exhibiting potent growth-inhibitory activity against non-tuberculous mycobacteria. METHODS Whole-cell growth inhibition assays were used to screen and identify novel inhibitors. The hit compounds were tested against Vero cells to determine the selectivity index, and this was followed by determining time-kill kinetics against Mycobacterium fortuitum and Mycobacterium abscessus. Disulfiram's ability to synergize with several approved drugs utilized for the treatment of M. fortuitum and M. abscessus was determined using fractional inhibitory concentration indexes followed by determining its ability to reduce mycobacterial infections ex vivo. Finally, disulfiram's in vivo potential was determined in a neutropenic murine model mimicking mycobacterial infection. RESULTS We identified disulfiram as possessing potent antimicrobial activity against non-tuberculous mycobacteria. Disulfiram exhibited concentration- and time-dependent bactericidal activity against M. fortuitum as well as against M. abscessus and synergized with all drugs utilized for their treatment. Additionally, disulfiram reduced bacterial load in macrophages in an intracellular killing assay better than amikacin. When tested in a murine neutropenic M. fortuitum infection model, disulfiram caused significant reduction in bacterial load in kidneys. CONCLUSIONS Disulfiram exhibits all properties required for it to be repositioned as a novel anti-mycobacterial therapy and possesses a potentially new mechanism of action. Thus, it can be considered as a potent structural lead for the treatment of non-tuberculous mycobacterial infections.

Nontuberculous mycobacteria (NTM) or mycobacteria other than tuberculosis (MOTT) are opportunistic environmental pathogens capable of causing different kinds of infections to humans starting from hospital acquired to pulmonary and soft tissue infections. They share the common genera Mycobacterium tuberculosis (Mtb) and Mycobacterium leprae, the causative agents of two major diseases, tuberculosis (TB) and leprosy, respectively. Although NTMs or MOTT are similar to Mtb and M. leprosy in terms of mycolic acid-containing cell wall, acid fastness and their capability of causing pulmonary and extrapulmonary diseases, they are highly dissimilar in terms of growth rate and their antibiotic resistance profile. Several clinically relevant NTM strains are inherently resistant to different classes of antibiotics including the first line of drugs (e.g. isoniazid, rifampicin and pyrazinamide) used for treatment of TB. Currently, NTM infections have become a major concern to mankind in terms of mortality and morbidity in immunocompromised individuals. In addition, lack of antibacterial molecules, specific diagnostic tools and their intrinsic resistance to common antibiotics have turned these historically neglected pathogens to serious threats. In this chapter, we have discussed about infections caused by different NTMs, their laboratory identification and the antibiotics available to treat these infections.

A 50-year-old woman with a recent diagnosis of poorly differentiated nonteratomatous cervicouterine cancer presented to our hospital for breath-holding episodes resulting in perioral cyanosis. Her medical history was significant for chickenpox at age 8 and shingles at age 15. Before her admission and 10 days after her cancer diagnosis, she was admitted to an outside hospital for confusion and intermittent catatonia. Workup at the outside hospital was unremarkable, and she was diagnosed with adjustment disorder. At home, she continued to decompensate and ultimately became incomprehensible, anorexic, and bedbound, prompting admission to our hospital. The authors thank Dr. Jennifer Chu for her invaluable help in interpreting the patient's EEG studies.

Background: Low back pain is one of the most common health problems in society which leads to considerable disability, loss of work days, and puts a huge burden on socioeconomic and healthcare system. It is often associated with musculoskeletal spasm. The aim of the study was to compare the efficacy and safety of tolperisone and thiocolchicoside in combination with etodolac in patients of acute low back pain associated with musculoskeletal spasm.Methods: it was a prospective, randomized, open label study which included patients of either sex between age 18-50 years of acute low back pain with musculoskeletal spasm. Patients were allocated in two groups. Patients in ‘Group A’ were given tolperisone 150 mg + etodolac 400 mg twice a day and patients in ‘Group B’ were given thiocolchicoside 4 mg + etodolac 400 mg twice a day. Efficacy of two drugs was assessed by decrease in finger to floor distance (FFD), decrease in pain as per visual analog scale (VAS) and global assessment of efficacy of treatment by physician. Follow-up of the patients was done on day 3 and 7 of treatment. Various side effects reported by patients in both the groups were also recorded and compared.Results: Both tolperisone and thiocolchicoside caused significant decrease in FFD, reduced pain score thus indicating decrease in pain and spasm. Side effects reported in both groups were mild and did not result in discontinuation of therapy.Conclusions: Tolperisone was found to have efficacy similar to that of thiocolchicoside though number of side effects reported was more with tolperisone.

Objective Yttrium-90 (Y-90) radioembolization is an emerging treatment option for unresectable neuroendocrine liver metastases (NELM). However, the data regarding this treatment are currently limited. This study evaluates the efficacy and tolerability of Y-90 radioembolization and identifies prognostic factors for radiographic response and survival. Methods and materials Thirty-eight patients underwent Y-90 radioembolization for NELM at our institution between April 2004 and February 2012. Patients were assessed radiographically (RECIST criteria, enhancement), serologically, and clinically at 1 month, and then at every 3 months after treatment for tumor response, toxicity, and survival outcomes. Results Median length of follow-up was 17.0 months (IQR, 9.0–37.0). Median survival was 29.2 months. Three patients (9%) had a radiographic complete response to treatment, 6 (17%) had a partial response, 21 (60%) had stable disease, and 5 (14%) developed progressive disease. Two factors were significantly associated with a good radiographic response (complete/partial response): islet cell histological subtype (p = 0.043) and hepatic tumor burden ≥ 33% (p = 0.031). Multivariate analysis revealed that patients requiring multiple Y-90 treatments (HR 2.9, p = 0.035) and patients who had previously failed systemic therapy with octreotide/chemotherapy (HR 4.4, p = 0.012) had worse survival. Grade 3 serologic toxicity was observed in 2 patients (5%; hyperbilirubinemia, elevated alkaline phosphatase) after treatment. Grade 3 non-serologic toxicities included abdominal pain (11%), fatigue (11%), nausea/vomiting (5%), ascites (5%), dyspnea (3%), diarrhea (3%), and peripheral edema (3%). No grade 4 or 5 toxicity was reported. Conclusions Y-90 radioembolization is a promising treatment option for inoperable NELM and is associated with low rates of grade ≥ 3 toxicity.

Lymphopenia is a common consequence of chemoradiation therapy yet is seldom addressed clinically. This study was conducted to determine if patients with locally advanced pancreatic cancer (LAPC) treated with definitive chemoradiation develop significant lymphopenia and if this affects clinical outcomes.A retrospective analysis of patients with LAPC treated with chemoradiation at a single institution from 1997 to 2011 was performed. Total lymphocyte counts (TLCs) were recorded at baseline and then monthly during and after chemoradiation. The correlation between treatment-induced lymphopenia, established prognostic factors, and overall survival was analyzed using univariate Cox regression analysis. Important factors identified by univariate analysis were selected as covariates to construct a multivariate proportional hazards model for survival.A total of 101 patients met eligibility criteria. TLCs were normal in 86% before chemoradiation. The mean reduction in TLC per patient was 50.6% (SD, 40.6%) 2 months after starting chemoradiation (P0.00001), and 46% had TLC500 cells/mm. Patients with TLC500 cells/mm 2 months after starting chemoradiation had inferior median survival (8.7 vs. 13.3 mo, P=0.03) and PFS (4.9 vs. 9.0 mo, P=0.15). Multivariate analysis revealed TLC500 cells/mm to be an independent predictor of inferior survival (HR=2.879, P=0.001) along with baseline serum albumin (HR=3.584, P=0.0002), BUN (HR=1.060, P=0.02), platelet count (HR=1.004, P=0.005), and radiation planning target volume (HR=1.003, P=0.0006).Severe treatment-related lymphopenia occurs frequently after chemoradiation for LAPC and is an independent predictor of inferior survival.

Root cause analysis (RCA) is a class of problem solving methods aimed at identifying the root causes of problems/ incidents. By directing corrective measures at core causes, it is hoped that the chances of problem recurrence will be minimized. Thus, RCA is frequently considered to be an iterative process, and is frequently viewed as a tool of continuous improvement. RCA, initially is a reactive method of problem detection & solving. This means that, the analysis is done after an incident has occurred. By gaining proficiency in RCA it becomes a pro-active method. This means that RCA is able to estimate the possibility of an incident even before it could occur. Root cause analysis mainly consists of three steps A): Define the problem. B): Analyze the problem. C): Find the solutions for the problem. In view of the accident which took place recently i.e. Gulf of Mexico oil spill 2010, there were eight catastrophic failures which led to the explosion that destroyed the Deepwater Horizon drilling rig in the Gulf of Mexico. These failures included the sending of unofficial cement by specialist cementing services, no indications of testing done on the surface by drilling rig provider company before deploying it, pressure test which would have revealed problems in the drill was incorrectly deemed as a success by operator company and drilling rig provider company rig personnel. A complex and interlinked succession of mechanical failures, human judgments, engineering design, operational implementation and team interfaces caused this tragedy. Consequences of these plain errors were quite hazardous. It affected the humanity, environment, economy and also the settlements. The core objective of the paper is to bring about a detailed analysis so as to throw light on new techniques and how they can be utilised to prevent such disasters. To achieve this objective we acknowledged all the possible solutions for this issue so that the most excellent solutions can be selected and the challenges that are to be faced are studied thoroughly and examined to prevent future errors. However, it is recognized that complete prevention of reappearance by a single intrusion is not always possible. On the belief that problems are best solved by attempting to correct or eliminate root causes, as opposed to merely addressing the immediately obvious symptoms.