Automated Assessment of the DWI-FLAIR Mismatch in Patients with Acute Ischemic Stroke: Added Value to Routine Clinical Practice.

BACKGROUND AND PURPOSE: The DWI-FLAIR mismatch is used to determine thrombolytic eligibility in patients with acute ischemic stroke when the time since stroke onset is unknown. Commercial software packages have been developed for automated DWI-FLAIR classification. We aimed to use e-Stroke software for automated classification of the DWI-FLAIR mismatch in a cohort of patients with acute ischemic stroke and in a comparative analysis with 2 expert neuroradiologists. MATERIALS AND METHODS: In this retrospective study, patients with acute ischemic stroke who had MR imaging and known time since stroke onset were included. The DWI-FLAIR mismatch was evaluated by 2 neuroradiologists blinded to the time since stroke onset and automatically by the e-Stroke software. After 4 weeks, the neuroradiologists re-evaluated the MR images, this time equipped with automated predicted e-Stroke results as a computer-assisted tool. Diagnostic performances of e-Stroke software and the neuroradiologists were evaluated for prediction of DWI-FLAIR mismatch status. RESULTS: A total of 157 patients met the inclusion criteria. A total of 82 patients (52%) had a time since stroke onset of ≤4.5 hours. By means of consensus reads, 81 patients (51.5%) had a DWI-FLAIR mismatch. The diagnostic accuracy (area under the curve/sensitivity/specificity) of e-Stroke software for the determination of the DWI-FLAIR mismatch was 0.72/90.0/53.9. The diagnostic accuracy (area under the curve/sensitivity/specificity) for neuroradiologists 1 and 2 was 0.76/69.1/84.2 and 0.82/91.4/73.7, respectively; both significantly (P < .05) improved to 0.83/79.0/86.8 and 0.89/92.6/85.5, respectively, following the use of e-Stroke predictions as a computer-assisted tool. The interrater agreement (κ) for determination of DWI-FLAIR status was improved from 0.49 to 0.57 following the use of the computer-assisted tool. CONCLUSIONS: This automated quantitative approach for DWI-FLAIR mismatch provides results comparable with those of human experts and can improve the diagnostic accuracies of expert neuroradiologists in the determination of DWI-FLAIR status.

Overestimation of ischemic core on baseline MRI in acute stroke.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke (AIS), overestimation of ischemic core on MRI-DWI has been described primarily in regions with milder reduced diffusion. We aimed to assess the possibility of ischemic core overestimation on pretreatment MRI despite using more restricted reduced diffusion (apparent diffusion coefficient (ADC) ≤620 × 10-6 mm2/s) in AIS patients with successful reperfusion. MATERIALS AND METHODS: In this retrospective single institutional study, AIS patients who had pretreatment MRI underwent successful reperfusion and had follow-up MRI to determine the final infarct volume were reviewed. Pretreatment ischemic core and final infarction volumes were calculated. Ghost core was defined as overestimation of final infarct volume by baseline MRI of >10 mL. Baseline clinical, demographic, and treatment-related factors in this cohort were reviewed. RESULTS: A total of 6/156 (3.8%) patients had overestimated ischemic core volume on baseline MRI, with mean overestimation of 65.6 mL. Three out of six patients had pretreatment ischemic core estimation of >70 mL, while the final infarct volume was <70 mL. All six patients had last known well-to-imaging <120 min, median (IQR): 65 (53-81) minutes. CONCLUSIONS: Overestimation of ischemic core, known as ghost core, is rare using severe ADC threshold (≤620 × 10-6 mm2/s), but it does occur in nearly 1 of every 25 patients, confined to hyperacute patients imaged within 120 min of symptom onset. Awareness of this phenomenon carries implications for treatment and trial enrollment.

CTP-based estimated ischemic core: A comparative multicenter study between Olea and RAPID software.

BACKGROUND AND PURPOSE: CTP is increasingly used to assess eligibility for endovascular therapy (EVT) in patients with large vessel occlusions (LVO). There remain variability and inconsistencies between software packages for estimation of ischemic core. We aimed to use heterogenous data from four stroke centers to perform a comparative analysis for CTP-estimated ischemic core between RAPID (iSchemaView) and Olea (Olea Medical). METHODS: In this retrospective multicenter study, patients with anterior circulation LVO who underwent pretreatment CTP, successful EVT (defined TICI ≥ 2b), and follow-up MRI included. Automated CTP analysis was performed using Olea platform [rCBF < 25% and differential time-to-peak (dTTP)>5s] and RAPID (rCBF < 30%). The CTP estimated core volumes were compared against the final infarct volume (FIV) on post treatment MRI-DWI. RESULTS: A total of 151 patients included. The CTP-estimated ischemic core volumes (mean ± SD) were 18.7 ± 18.9 mL on Olea and 10.5 ± 17.9 mL on RAPID significantly different (p < 0.01). The correlation between CTP estimated core and MRI final infarct volume was r = 0.38, p < 0.01 for RAPID and r = 0.39, p < 0.01 for Olea. Both software platforms demonstrated a strong correlation with each other (r = 0.864, p < 0.001). Both software overestimated the ischemic core volume above 70 mL in 4 patients (2.6%). CONCLUSIONS: Substantial variation between Olea and RAPID CTP-estimated core volumes exists, though rates of overcalling of large core were low and identical. Both showed comparable core volume correlation to MRI infarct volume.

Repeat breeding: prevalence and potential causes in dairy cows at different milk pocket areas of Bangladesh.

The objective of this study was to figure out the prevalence and probable causes of repeat breeding (RB) in dairy cows. Hence, a cross-sectional study was conducted on randomly selected 265 dairy farms in Sirajganj, Bogura, Rangpur, Satkhira, and Munshiganj districts of Bangladesh from December 2018 to February 2019. Data were collected through a direct interview method using a survey questionnaire. The reproductive organs of repeat breeder cows were examined for pathological, infectious, and functional reasons, and genital tract abnormalities. Additionally, the influence of nutrition, season, and age on the frequency of RB was recorded. The prevalence of RB was 28% among the 3824 cows investigated. Among the total repeat breeder cases, 72.54% of RB cases were found in Holstein-Friesian crossbred, 23.90% in Jersey crossbred, 1.50% in Sahiwal crossbred, and 2.06% in indigenous cows. The prevalence of RB was significantly highest (P < 0.01) in Satkhira (44.35%) and lowest in the Munshiganj district (15.87%). Data indicated that a major proportion of cows significantly (P < 0.05) faced RB problems due to functional causes (34.18%), followed by pathological causes (28.01%), genital tract abnormalities (21.32%), and infectious causes (16.49%). Furthermore, the cows were remarkably (P < 0.001) affected in RB during the summer season and nutritional deficient diseases like milk fever (70%). Age (3-7 years) had a significant (P < 0.001) effect on the RB occurrence (90%) in crossbred cows. However, particular focus should be given to systematic breeding, balanced nutrition, artificial inseminator efficiency, and hygienic inseminating tools to reduce RB incidence in high-yielding crossbred cows.

Molecular and phenotypic characterization of two cryptic species of the predatory genus Mononchoides Rahm, 1928 (Rhabditida: Diplogastridae) and their congeneric affinities.

Based on morphometric, morphological and molecular characterization using partial small subunit 18S ribosomal DNA (rDNA) and the D2/D3 domain of large subunit 28S rDNA, we described a new species Mononchoides kanzakii collected from manure, and the known species Mononchoides composticola Steel, Moens, Scholaert, Boshoff, Houthoofd and Bert, 2011, isolated from the dung beetle Oniticellus cinctus (Fabricius, 1775). Phylogenetic trees based on the evolutionary model (GTR + I + G) were inferred by Bayesian inference algorithms. Mononchoides kanzakii sp. n. is characterized by 28-32 longitudinal ridges, discontinuous at level of stoma; amphidial apertures inconspicuous; metastegostom armed with thorn-shaped dorsal tooth; a flattened, claw-like right subventral tooth, and left subventral denticulate ridge with 12-14 fine denticles delimited by a group of five denticles in females vs. triangular, flattened right subventral tooth, 5-8 prominent denticles at left subventral sector in males; cloacal lips with a distinct rim; and gubernaculum with cuticularized, proximal and distal extensions of equal length, each constituting half of the length of the wider part of gubernaculum.

Risk Association, Clinical Presentation and Management of Uterine Leiomyoma.

Uterine leiomyoma is a common gynecological problem throughout the world. As 50% hysterectomies in black and 40% in Australians are performed due to fibroid, in our country also it is assumed that about 40%-50% hysterectomies are done due to fibroid uterus. Thus leiomyoma constitute a major public health cost to the community in terms of outpatient attendance and hospital cost for surgery. This is a descriptive type of cross sectional study among 50 patients having leiomyoma of uterus in the department of Obs and Gynae, BSMMU hospital from March 2011 to August 2011. The objective of the study is to find out the risk associated with leiomyoma, to find out the common presenting features of uterine leiomyoma and to find out best options for management. Study results showed that 62% patients were in the age group 36-45 years, 48%patients were in para1-2 group, 32% patients used combined oral contraceptive pill for contraception. Sixty percent (60%) patients presented with progressive menorrhagia and palpable mass was found in 62% cases. About 46% patients had associated medical conditions like hypertension, diabetes, obesity. Total abdominal hysterectomy was done in 32% cases. TAH with unilateral or bilateral salpingoophorectomy was done in 40% cases. Myomectomy was done in 20% cases. There is a scope for large scale study about risk factors of uterine leiomyoma like obesity, diabetes mellitus, hypertension, use of hormonal contraceptive, racial differences, different treatment modalities etc. Treatment should be individualized. However in this connection a good referral system and good communication has got a tremendous contribution in the proper management of such problems.

Potential role of flavonoids against SARS-CoV-2 induced diarrhea.

COVID-19, caused by the SARS-CoV-2 virus, can lead to massive inflammation in the gastrointestinal tract causing severe clinical symptoms. SARS-CoV-2 infects lungs after binding its spike proteins with alveolar angiotensin-converting enzyme 2 (ACE2), and it also triggers inflammation in the gastrointestinal tract. SARS-CoV-2 invades the gastrointestinal tract by interacting with Toll-like receptor-4 (TLR4) that induces the expression of ACE2. The influx of ACE2 facilitates cellular binding of more SARS-CoV-2 and causes massive gastrointestinal inflammation leading to diarrhea. Diarrhea prior to COVID-19 infection or COVID-19-induced diarrhea reportedly ends up in a poor prognosis for the patient. Flavonoids are part of traditional remedies for gastrointestinal disorders. Preclinical studies show that flavonoids can prevent infectious diarrhea. Recent studies show flavonoids can inhibit the multiplication of SARS-CoV-2. In combination with vitamin D, flavonoids possibly activate nuclear factor erythroid-derived-2-related factor 2 that downregulates ACE2 expression in cells. We suggest that flavonoids have the potential to prevent SARS-CoV-2 induced diarrhea.

Sodium MR Neuroimaging.

Sodium MR imaging has the potential to complement routine proton MR imaging examinations with the goal of improving diagnosis, disease characterization, and clinical monitoring in neurologic diseases. In the past, the utility and exploration of sodium MR imaging as a valuable clinical tool have been limited due to the extremely low MR signal, but with recent improvements in imaging techniques and hardware, sodium MR imaging is on the verge of becoming clinically realistic for conditions that include brain tumors, ischemic stroke, and epilepsy. In this review, we briefly describe the fundamental physics of sodium MR imaging tailored to the neuroradiologist, focusing on the basics necessary to understand factors that play into making sodium MR imaging feasible for clinical settings and describing current controversies in the field. We will also discuss the current state of the field and the potential future clinical uses of sodium MR imaging in the diagnosis, phenotyping, and therapeutic monitoring in neurologic diseases.

Obstetric Outcome of Multiple Pregnancy in a Medical College Hospital.

The Incidence of twin and high order multiple gestation has increased significantly over the past 15 years primarily because of the availability and increased use of ovulation inducing drugs and assisted reproductive technology. Both maternal and perinatal mortality and morbidity is higher in multiple pregnancy than in singleton pregnancy. Proposed study is designed to determine the incidence and obstetric outcome of multiple pregnancy which is a high-risk pregnancy in a tertiary referral hospital. The purpose of this study is to evaluate obstetric outcome of multiple pregnancy. This prospective observational study was carried out in the Department of Obs and Gynae, Mymensingh Medical College Hospital, Mymensingh from December 2011 to May 2012. Patients were selected by purposive way. In this study it was observed that incidence of twin pregnancy was 1.66% common age group 30-35 years (48%), common in multipara (74%), no pregnancy crossed EDD. Family history of twin was 32% and unknown etiology 58%. Most common maternal complication was preterm labour (60%). Commonest mode of delivery was LSCS (64%), incidence of perinatal mortality 15%, 36% baby had birth weight in between 2.1-2.5kg, all the baby requiring admission in neonatal unit. This prospective observational study revealed that perinatal mortality was high in our center, there was no maternal mortality.

In silico screening of Allium cepa phytochemicals for their binding abilities to SARS and SARS-CoV-2 3C-like protease and COVID-19 human receptor ACE-2.

Corona virus SARS-CoV-2-induced viral disease (COVID-19) is a zoonotic disease that was initially transmitted from animals to humans. The virus surfaced towards the end of December 2019 in Wuhan, China where earlier SARS (Severe Acute Respiratory Syndrome) had also surfaced in 2003. Unlike SARS, SARS-CoV-2 (a close relative of the SARS virus) created a pandemic, and as of February 24 2021, caused 112,778,672 infections and 2,499,252 deaths world-wide. Despite the best efforts of scientists, no drugs against COVID-19 are yet in sight; five vaccines have received emergency approval in various countries, but it would be a difficult task to vaccinate twice the world population of 8 billion. The objective of the present study was to evaluate through in silico screening a number of phytochemicals in Allium cepa (onion) regarding their ability to bind to the main protease of COVID-19 known as the 3C-like protease or 3CLpro, (PDB ID: 6LU7), 3CLpro of SARS (PDB ID: 3M3V), and human angiotensin converting enzyme-2 (ACE-2), [PDB ID: 1R42], which functions as a receptor for entry of the virus into humans. Molecular docking (blind docking, that is docking not only against any target pocket) were done with the help of AutoDockVina. It was observed that of the twenty-two phytochemicals screened, twelve showed good binding affinities to the main protease of SARS-CoV-2. Surprisingly, the compounds also demonstrated good binding affinities to ACE-2. It is therefore very likely that the binding affinities shown by these compounds against both 3CLpro and ACE-2 merit further study for their potential use as therapeutic agents.

Effect of Amniotomy on Outcome of Spontaneous Labour.

Intentional artificial rupture of the amniotic membranes during labour, called amniotomy or 'breaking of the water's, is one of the most commonly performed procedures in modern obstetric and midwifery practice. The primary aim of amniotomy is to speed up uterine contractions and therefore shorten the length of labour. However there are concerns regarding unintended adverse effects on the woman and baby. A prospective observational study was conducted to determine the effectiveness and safety of routine procedure of amniotomy to shorten the duration of labour (prolonged or not) in Mymensingh Medical College & Hospital, Mymensingh, Bangladesh from July 2011 to December 2011. One hundred low-risk women with spontaneous onset of labour at term with singleton fetus in cephalic presentation and intact amniotic membranes and a cervical dilatation between 4 and 5cm were conventionally assigned to have amniotomy during the course of labour. Maternal demographics, duration of labour (prolonged or not), maternal and perinatal outcome were considered as major outcome. Majority (49.0%) of the patients belonged to 21-25 years age group and primigravida was predominant and most of them had middle socio-economic conditions. More the three-fourth (89.0%) of the patients had head engaged. Rh-positive and negative were found 96.0% and 4.0% respectively. The primigravidae required 10.07±2.17 hours in 1st stage of labour and had 1.51±0.5 hours duration of 2nd stage of labour. In case of multi-gravidae it was 6.07±2.06 hours in 1st stage of and 1±0.5 hours in 2nd stage of labour. There was a marked reduction of amniotomy-delivery interval time in this study, which was 3 hours 40 minutes and whereas mean cervical dilatation was 4cm during amniotomy. Almost three fourth (72.0%) cases delivered vaginally among which, with episiotomy in 49.0% and without episiotomy in 23.0%. Instrumental delivery was in 9.0% of which 4.0% by forceps, 5.0% by vaccum extraction and 14.0% underwent LUCS. Still birth was found 2.0%, asphyxiated 3.0% and prenatal death 1.0%. In terms of referral to neonatal care unit it was found that 7.0% were asphyxiated. Asphyxia and low APGAR score was 4.0%, low birth weight 9.0%, instrumental delivery was 5.0%, Rh incompatibility was 2.0%. Only 1.0% babies needed admission to neonatal care unit and were intubated. So, Amniotomy significantly reduced the duration of the first stage of labour without affecting the oxytocin requirement, the rate of caesarean section and newborn outcome.

Can Costus afer be used for co-treatment of COVID-19, its symptoms and comorbidities? A novel approach for combating the pandemic and implications for sub-Saharan Africa.

Despite the huge loss of lives and massive disruption of the world economy by the COVID -19 pandemic caused by SARS -CoV-2, scientists are yet to come out with an effective therapeutic against this viral disease . Several vaccines have obtained 'emergency approval ', but difficulties are being faced in the even distribution of vaccines amongst high- and low- income countries . On top of it, comorbidities associated with COVID -19 like diabetes, hypertension and malaria can seriously impede the treatment of the main disease, thus increasing the fatality rate . This is more so in the context of sub -Saharan African and south Asian countries . Our objective was to demonstrate that a single plant containing different phytoconstituents may be used for treatment of COVID -19 and comorbidities . Towards initial selection of a plant, existing scientific literature was scanned for reported relevant traditional uses, phytochemicals and pharmacological activities of a number of plants and their phytoconstituents pertaining to treatment of COVID-19 symptoms and comorbidities. Molecular docking studies were then performed with phytochemicals of the selected plant and SARS-CoV-2 components - Mpro, and spike protein receptor binding domain and hACE2 interface using AutoDock V ina. We showed that crude extracts of an indigenous African plant, Costus afer having traditional antidiabetic and antimalarial uses, has phytochemicals with high binding affinities for Mpro, and /or spike protein receptor binding domain and hACE2 interface; the various phytochemicals with predicted high binding energies include aferoside C, dibutyl phthalate, nerolidol, suginal, and ± -terpinene, making them potential therapeutics for COVID -19. The results suggest that crude extracts and phytochemicals of C. afer can function as a treatment modality for COVID -19 and comorbidities like especially diabetes and malaria .

Can Costus afer be used for co-treatment of COVID-19, its symptoms and comorbidities? A novel approach for combating the pandemic and implications for sub-Saharan Africa

@#Despite the huge loss of lives and massive disruption of the world economy by the COVID-19 pandemic caused by SARS-CoV-2, scientists are yet to come out with an effective therapeutic against this viral disease. Several vaccines have obtained ‘emergency approval’, but difficulties are being faced in the even distribution of vaccines amongst high- and lowincome countries. On top of it, comorbidities associated with COVID-19 like diabetes, hypertension and malaria can seriously impede the treatment of the main disease, thus increasing the fatality rate. This is more so in the context of sub-Saharan African and south Asian countries. Our objective was to demonstrate that a single plant containing different phytoconstituents may be used for treatment of COVID-19 and comorbidities. Towards initial selection of a plant, existing scientific literature was scanned for reported relevant traditional uses, phytochemicals and pharmacological activities of a number of plants and their phytoconstituents pertaining to treatment of COVID-19 symptoms and comorbidities. Molecular docking studies were then performed with phytochemicals of the selected plant and SARS-CoV-2 components – Mpro, and spike protein receptor binding domain and hACE2 interface using AutoDock Vina. We showed that crude extracts of an indigenous African plant, Costus afer having traditional antidiabetic and antimalarial uses, has phytochemicals with high binding affinities for Mpro, and/or spike protein receptor binding domain and hACE2 interface; the various phytochemicals with predicted high binding energies include aferoside C, dibutyl phthalate, nerolidol, suginal, and ±-terpinene, making them potential therapeutics for COVID-19. The results suggest that crude extracts and phytochemicals of C. afer can function as a treatment modality for COVID-19 and comorbidities like especially diabetes and malaria.

Potential role of flavonoids against SARS-CoV-2 induced diarrhea

@#COVID-19, caused by the SARS-CoV-2 virus, can lead to massive inflammation in the gastrointestinal tract causing severe clinical symptoms. SARS-CoV-2 infects lungs after binding its spike proteins with alveolar angiotensin-converting enzyme 2 (ACE2), and it also triggers inflammation in the gastrointestinal tract. SARS-CoV-2 invades the gastrointestinal tract by interacting with Toll-like receptor-4 (TLR4) that induces the expression of ACE2. The influx of ACE2 facilitates cellular binding of more SARS-CoV-2 and causes massive gastrointestinal inflammation leading to diarrhea. Diarrhea prior to COVID-19 infection or COVID-19-induced diarrhea reportedly ends up in a poor prognosis for the patient. Flavonoids are part of traditional remedies for gastrointestinal disorders. Preclinical studies show that flavonoids can prevent infectious diarrhea. Recent studies show flavonoids can inhibit the multiplication of SARS-CoV-2. In combination with vitamin D, flavonoids possibly activate nuclear factor erythroid-derived-2-related factor 2 that downregulates ACE2 expression in cells. We suggest that flavonoids have the potential to prevent SARS-CoV-2 induced diarrhea.

In silico screening of Allium cepa phytochemicals for their binding abilities to SARS and SARS-CoV-2 3C-like protease and COVID-19 human receptor ACE-2

@# Corona virus SARS-CoV-2-induced viral disease (COVID-19) is a zoonotic disease that was initially transmitted from animals to humans. The virus surfaced towards the end of December 2019 in Wuhan, China where earlier SARS (Severe Acute Respiratory Syndrome) had also surfaced in 2003. Unlike SARS, SARS-CoV-2 (a close relative of the SARS virus) created a pandemic, and as of February 24 2021, caused 112,778,672 infections and 2,499,252 deaths world-wide. Despite the best efforts of scientists, no drugs against COVID-19 are yet in sight; five vaccines have received emergency approval in various countries, but it would be a difficult task to vaccinate twice the world population of 8 billion. The objective of the present study was to evaluate through in silico screening a number of phytochemicals in Allium cepa (onion) regarding their ability to bind to the main protease of COVID-19 known as the 3C-like protease or 3CLpro, (PDB ID: 6LU7), 3CLpro of SARS (PDB ID: 3M3V), and human angiotensin converting enzyme-2 (ACE-2), [PDB ID: 1R42], which functions as a receptor for entry of the virus into humans. Molecular docking (blind docking, that is docking not only against any target pocket) were done with the help of AutoDockVina. It was observed that of the twenty-two phytochemicals screened, twelve showed good binding affinities to the main protease of SARS-CoV-2. Surprisingly, the compounds also demonstrated good binding affinities to ACE-2. It is therefore very likely that the binding affinities shown by these compounds against both 3CLpro and ACE-2 merit further study for their potential use as therapeutic agents.

Association of Serum Vitamin D (25OHD) Level with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Acute exacerbations of COPD is characterized by a change in the patients baseline dyspnoea, cough and/or sputum that is beyond normal day to day differences and guides to a change in standard medications in a patient with COPD. Vitamin D influences the innate & adaptive immune system, and exerts pleiotropic antimicrobial and anti-inflammatory responses. Vitamin D deficiency is frequent among COPD patients but its contributory role in disease exacerbations is widely debated. This study was aimed to assess relationship between reduced serum vitamin D (25-OHD) level with COPD severity and acute exacerbation. This observational cross-sectional study was carried out in the department of Respiratory Medicine, NIDCH, Mohakhali, Dhaka, Bangladesh from October 2016 to September 2017. Consecutive 80 hospital admitted patients with acute exacerbation of chronic obstructive pulmonary disease diagnosed on the basis of clinical history & pulmonary function tests and 78 age & sex matched controls were investigated for serum vitamin D (25-OHD) level. Among the COPD patients, 37% had Vitamin D deficiency (<20ng/ml) and 28.75% had Vitamin D insufficiency (20-29ng/ml). Mean vitamin D (25-OHD) level of COPD patients (25.82±10.62ngm/ml) was found to be significantly lower than healthy controls (32.57±11.32ngm/ml). Vitamin D deficiency was found, by Pearson correlation test, to be significantly associated with severity of COPD. Multivariate analysis showed that age (in years), FEV1 (percent predicted), frequent exacerbators (≥2 in the last year), and smoking (>40 pack year) were significantly associated with Vitamin D deficiency. Acute exacerbation of chronic obstructive pulmonary disease patients was found to have vitamin D deficiency and vitamin D deficiency was significantly associated with severity of COPD. Vitamin D deficiency was also associated with frequent disease exacerbation.

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.

Correlation between Clinical Outcomes and Baseline CT and CT Angiographic Findings in the SWIFT PRIME Trial.

BACKGROUND AND PURPOSE: Patient selection for endovascular therapy remains a great challenge in clinic practice. We sought to determine the effect of baseline CT and angiography on outcomes in the Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial and to identify patients who would benefit from endovascular stroke therapy. MATERIALS AND METHODS: The primary end point was a 90-day modified Rankin Scale score of 0-2. Subgroup and classification and regression tree analysis was performed on baseline ASPECTS, site of occlusion, clot length, collateral status, and onset-to-treatment time. RESULTS: Smaller baseline infarct (n = 145) (ASPECTS 8-10) was associated with better outcomes in patients treated with thrombectomy versus IV tPA alone (66% versus 41%; rate ratio, 1.62) compared with patients with larger baseline infarcts (n = 44) (ASPECTS 6-7) (42% versus 21%; rate ratio, 1.98). The benefit of thrombectomy over IV tPA alone did not differ significantly by ASPECTS. Stratification by occlusion location also showed benefit with thrombectomy across all groups. Improved outcomes after thrombectomy occurred in patients with clot lengths of ≥8 mm (71% versus 43%; rate ratio, 1.67). Outcomes stratified by collateral status had a benefit with thrombectomy across all groups: none-fair collaterals (33% versus 0%), good collaterals (58% versus 44%), and excellent collaterals (82% versus 28%). Using a 3-level classification and regression tree analysis, we observed optimal outcomes in patients with favorable baseline ASPECTS, complete/near-complete recanalization (TICI 2b/3), and early treatment (mean mRS, 1.35 versus 3.73), while univariate and multivariate logistic regression showed significantly better results in patients with higher ASPECTS. CONCLUSIONS: While benefit was seen with endovascular therapy across multiple subgroups, the greatest response was observed in patients with a small baseline core infarct, excellent collaterals, and early treatment.

Mechanical Thrombectomy for Isolated M2 Occlusions: A Post Hoc Analysis of the STAR, SWIFT, and SWIFT PRIME Studies.

BACKGROUND AND PURPOSE: Mechanical thrombectomy is beneficial for patients with acute ischemic stroke and a proximal anterior occlusion, but it is unclear if these results can be extrapolated to patients with an M2 occlusion. The purpose of this study was to examine the technical aspects, safety, and outcomes of mechanical thrombectomy with a stent retriever in patients with an isolated M2 occlusion who were included in 3 large multicenter prospective studies. MATERIALS AND METHODS: We included patients from the Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR), Solitaire With the Intention For Thrombectomy (SWIFT), and Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) studies, 3 large multicenter prospective studies on thrombectomy for ischemic stroke. We compared outcomes and technical details of patients with an M2 with those with an M1 occlusion. All patients were treated with a stent retriever. Imaging data and outcomes were scored by an independent core laboratory. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score of 2b/3. RESULTS: We included 50 patients with an M2 and 249 patients with an M1 occlusion. Patients with an M2 occlusion were older (mean age, 71 versus 67 years; P = .04) and had a lower NIHSS score (median, 13 versus 17; P < .001) compared with those with an M1 occlusion. Procedural time was nonsignificantly shorter in patients with an M2 occlusion (median, 29 versus 35 minutes; P = .41). The average number of passes with a stent retriever was also nonsignificantly lower in patients with an M2 occlusion (mean, 1.4 versus 1.7; P = .07). There were no significant differences in successful reperfusion (85% versus 82%, P = .82), symptomatic intracerebral hemorrhages (2% versus 2%, P = 1.0), device-related serious adverse events (6% versus 4%, P = .46), or modified Rankin Scale score 0-2 at follow-up (60% versus 56%, P = .64). CONCLUSIONS: Endovascular reperfusion therapy appears to be feasible in selected patients with ischemic stroke and an M2 occlusion.