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Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

BackgroundEndovascular thrombectomy (EVT) is efficacious for appropriately selected patients with large vessel occlusions (LVO) up to 24 hours from symptom onset. There is limited information on outcomes of nonagenarians, selected with computed tomography perfusion (CTP) imaging.MethodsWe retrospectively analyzed data from a large academic hospital between December 2017 and October 2019. Patients receiving EVT for anterior circulation LVO were stratified into nonagenarian (≥90 years) and younger (ResultsOverall, 214 consecutive patients (26 nonagenarians, 188 younger) underwent EVT. Nonagenarians were aged 92.8±2.9 years and younger patients were 74.5±13.5 years. Mortality rate was significantly greater in nonagenarians compared with younger patients (43.5% vs 10.4%, OR 9.33, 95% CI 2.88 to 47.97, PConclusionsNonagenarians were noted to have greater mortality and sICH rates following EVT compared with matched younger patients, which may be ameliorated by selecting patients with smaller CTP core volumes. Nonagenarians undergoing EVT had similar rates of successful reperfusion and functional independence compared with the younger cohort.

Background The rapid spread of the coronavirus disease 2019 (COVID-19) with high mortality rate necessitates disease characterization and accurate prognostication for prompt clinical decision-making. The aim of this study is to study clinical characteristics and predictors of mortality in hospitalized patients with COVID-19 in India. Methods Retrospective cohort study was conducted in a tertiary care hospital in northern India. All consecutive confirmed hospitalized COVID-19 cases aged 15 years and older from 13 Apr till 31 Aug 2020 are included. Primary end point was 30-day mortality. Results Of 1622 patients ,1536 cases were valid. Median age was 36 years, 88.3% were men and 58.1% were symptomatic. Fever (37.6%) was commonest presenting symptom. Dyspnea was reported by 15.4%. Primary hypertension (8.5%) was commonest comorbidity, followed by diabetes mellitus (6.7%). Mild, moderate, and severe hypoxemia were seen in 3.4%, 4.3%, and 0.8% respectively. Logistic regression showed greater odds of moderate/severe disease in patients with dyspnea, hypertension, Chronic Kidney Disease (CKD), and malignancy. Seventy six patients died (4.9%). In adjusted Cox proportional hazards model for mortality, patients with dyspnea (hazard ratio [HR]: 14.449 [5.043-41.402]), altered sensorium (HR: 2.762 [1.142-6.683]), Diabetes Mellitus (HR: 1.734 [1.001-3.009]), malignancy (HR:10.443 [4.396-24.805]) and Chronic Liver Disease (CLD) (HR: 14.432 [2.321-89.715]) had higher risk. Rising respiratory rate (HR: 1.098 [1.048-1.150]), falling oxygen saturation (HR: 1.057 per unit change 95% CI: 1.028-1.085) were significant predictors. Conclusion Analysis suggests that age, dyspnea, and malignancy were associated with both severe disease and mortality. Diabetes Mellitus and Chronic Liver Disease were associated with increased the risk of fatal outcome. Simple clinical parameters such as respiratory rate and oxygen saturation are strong predictors and with other risk factors at admission can be effectively used to triage patients.

Objective Indian data on cancer patients with coronavirus disease 2019 (COVID-19) infection and its outcome are limited. Infectivity and outcome among cancer patients staying in large congregations are not known. We conducted this study to address this lacuna in literature.Methods This was a retrospective–prospective, observational study of hospitalized cancer patients with proven COVID-19 infection, conducted at tertiary care hospital in New Delhi after ethical approval. We analyzed clinical, laboratorial parameters, and outcomes in these patients.Results All 32 admitted male patients became COVID-19 positive and 10 (31%) patients were symptomatic. Median age was 37.5 years (range: 16–64). Sixteen health-care workers (HCWs) were working in the cancer ward (paramedical staff: 4, nurses: 6, residents: 4, and consultants: 2). Among HCWs, two nursing staff and three paramedical staff contracted asymptomatic COVID-19. Eighteen (56%) and 14 (44%) patients were on curative and palliative treatment, respectively. Leukopenia (total leukocyte count Conclusion Seventy percent of cancer patients were asymptomatic. Cancer patients living in congregation areas are susceptible to COVID-19 with 3% mortality rate. Recent chemotherapy and associated cytopenias may not increase the risk in cancer patients with COVID-19 treated with curative intent. Palliative intended patients are at increased risk of death. N-95, personal protective equipment, and adherence to infection control measures should be encouraged.

Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy, however, such strategies are limited. Autophagy promotes resistance to cancer therapy, however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.

Introduction: Data remains scarce on which telestroke related sub-events (component parts/time intervals) are associated with delays in door-to-needle (DTN) time and goals for each telestroke sub-event. We aimed to assess the telestroke sub-events that contribute to DTN. After establishing set goals for each sub-event, we further evaluated the odds of DTN within 45 minutes if sub-event goals were achieved. Methods: We retrospectively analyzed prospectively collected data from a hub-and-spoke model telestroke network from January 2017 to September 2019. To determine which sub-events significantly contributed to DTN time, a sequential multiple regression analysis was performed. We entered covariates (age, sex, time of telestroke [day or night], NIHSS, average number of telestroke consults at a given site) in the first block followed by sub-events (door-to-telestroke request, door-to-CT, request-to-page, stroke physician response time, telestroke phone-to-video, video duration prior to needle and video completion-to-needle) in the second block. Logistic regression models were performed to estimate the odds of achieving a DTN within 45 minutes if sub-event goals were achieved. Results: During the study, 3361 telestrokes were completed and 306 (9.1%) patients received IV thrombolytics. After exclusions, 253 patients treated with IV thrombolytics were included. Five sub-events contributed to DTN time above and beyond the nuisance variables: door-to-telestroke request, stroke physician response time, telestroke phone-to-video, video duration prior to needle, and video completion-to-needle; each p Conclusions: Telestroke sub-events involving door-to-telestroke request, stroke physician response, telestroke phone-to-video, video duration prior to needle, and video completion-to-needle significantly contribute to DTN time. Successful achievement of sub-event goals was related to greater likelihood of administration of thrombolytic therapy within 45 minutes.

Introduction: Prior studies have demonstrated the importance of measuring and monitoring telestroke sub-events of door-to-needle time (DTN) such as door-to-telestroke request, but there is limited data on educational efforts to reduce sub-events contributing to DTN. We educated spoke coordinators, nurses and physicians at our telestroke sites on tips to reduce sub-events of DTN, developed a reference pocket card and reviewed sub-event metrics during monthly telestroke quality meetings with spoke sites. We aimed to evaluate if our educational activities and monthly data review affected door-to-telestroke request within 10 minutes of arrival, completion-of-video to needle within 1 minute and DTN within 60 minutes. Methods: Prospectively collected data was analyzed retrospectively from a hub-and-spoke model telestroke network. Education of the spokes was completed between January 2019 and April 2019. We compared data for one year prior to education (January 2018 - December 2018) and one year after education (May 2019 - April 2020). Logistic regression analyses were performed to determine the odds of achieving a door-to-telestroke request within 10 minutes, DTN within 60 minutes and completion-of-video to needle within 1 minute in treated patients. We entered possible confounding variables (EMS arrival; NIHSS; posterior symptoms) in the first block followed by the pre/post education groups in the second block. Results: Overall, telestroke was requested 2574 times during the study (1338 pre-education; 1236 post-education). A Chi square test suggested a trend towards more thrombolytic and thrombectomy treatments occurred after education compared to before education (14.6% vs. 12%), OR = 1.25 (95%CI 0.99 - 1.56), p=0.06. Door-to-telestroke request Conclusions: Education and regular review of sub-events data reduced door-to-telestroke request and door-to-needle time in our telestroke network.

Introduction: Perfusion based imaging aids in patient selection for endovascular therapy (EVT). Appropriate selection of patients for EVT is an important component of telestroke programs. Thus, telestroke sites could be ideal locations for perfusion imaging. Despite the advantages of perfusion imaging, there is the concern that advanced imaging may delay door to needle time (DTN). We implemented CT perfusion (CTP) using RAPID software at three large primary stroke centers within our telestroke network in December 2017. We aimed to evaluate the proportion of transfers for EVT, door in door out time (DIO) and DTN at telestroke sites before and after CTP implementation. Methods: Data was prospectively collected and retrospectively analyzed as part of our telestroke quality database. We compared data for one year before and one year after implementing CTP at the telestroke sites. We hypothesized that the addition of CTP would not delay DTN. Additionally we hypothesized that a greater proportion of transfers for possible EVT would receive a stroke thrombectomy and that DIO would be reduced after utilizing CTP. Results: Five hundred and forty patients were evaluated via telestroke and completed CT head and/or CT angiography head and neck imaging prior to CTP implementation. Seven hundred and thirteen telestroke patients received CT head, CTA head and neck and CTP imaging after CTP implementation. Of the 1253 patients, 101 (8.1%) were transferred for a possible EVT. Patients receiving CTP had a significantly shorter DIO time (median 109 minutes) compared to patients without CTP (median 122 minutes), U = 425, p = 0.04, r = 0.26. There was no difference in DTN in the 63 IV alteplase treated patients without CTP (median 66 minutes) and 58 IV alteplase treated patients who received CTP (median 63 minutes), U = 1672, p = 0.42, r = 0.07. There was no significant difference in the proportion of patients transferred for a possible EVT that received a stroke thrombectomy in the patients without CTP 28 (74%) compared to patients with CTP 38 (84%), p = 0.23. Conclusions: In conclusion, automated perfusion maps and calculated ischemic penumbra size in CTP allowed telestroke physicians to make quicker transfer decisions, without delaying DTN.

Creutzfeldt–Jakob disease (CJD) is a well-described disease. It is characterized by rapidly progressive dementia, myoclonus, ataxia, pyramidal, and extrapyramidal signs. There are well-defined electroencephalogram and magnetic resonance imaging (MRI) findings, and markers found in the cerebrospinal fluid (CSF). The gold standard for diagnosing CJD remains brain biopsy. We present a case of a patient with a family history of biopsy-proven CJD who initially presented with symptoms of peripheral neuropathy. A month later, he developed ataxia, ophthalmoparesis, and then dysarthria. His initial workup was relatively unrevealing, showing an elevated protein in his CSF. He was thought to have Miller Fisher syndrome variant of Guillain–Barré syndrome. He neither, however, responded to plasmapheresis nor IVIG. He later started to develop progressive dementia. Repeated MRI showed restricted diffusion in the caudate and putamen, as well as in the cortex (cortical ribboning). Lumbar puncture was then found to be positive for 14-3-3 protein, total-tau protein, and real-time quaking-induced conversion assay, which are highly suggestive of CJD. We present a case of CJD with an unusual presentation resulting in misdiagnosis, prolonged workup, and potentially harmful treatment modalities. This case highlights the importance of broadening our definition of CJD to encompass more cases with unusual presentations.

Allergic bronchopulmonary mycosis (ABPM) is most commonly seen in cystic fibrosis and bronchial asthma. Most of patients are misdiagnosed at initial outpatient department visit due to low suspicion, lack of awareness of entity and similarity in clinical symptoms and radiological findings with other common pulmonary diseases. Pulmonary tuberculosis is the most common entity diagnosed, and anti-tubercular treatment is the most commonly abused chemotherapy. Careful history taking, astute initial examination and awareness may help in curbing wrong diagnosis and treatment. This article present two cases of ABPM who were initially misdiagnosed as pulmonary tuberculosis and carcinoma lung, respectively.

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 - now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ∼3.5-fold and ∼65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average >2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy.

Introduction: Timeliness of a response to page by telestroke physicians is an important component in a telestroke network. Accrediting organizations such as the Joint Commission require telemedicine to be available within 20 minutes of the request. We implemented a secure messaging system to improve physician communication. We hypothesized that implementation of a secure messaging system would improve communication, reduce telestroke physician response to page and reduce door-to-needle (DTN) times compared to the previous pager-based system. Methods: We reviewed data collected as part of our telestroke quality program. We compared response to page times for one year before and after initiation of the secure messaging system. Additionally, we compared DTN times during the same epochs. Results: Seven hundred and sixty-five telestroke consults were completed in the year prior to implementation of the secure messaging system and 941 telestroke consults were completed in the year following implementation. Telestroke response to page time decreased significantly between pre ( mean rank 1005; median 4 min) and post ( mean rank 731 ; median 2 min) implementation of the secure messaging system ( U = 244,240 , p < .001, r = .28). A significantly greater percentage of telestroke neurologist response times occurred within 20 minutes when using secure messaging 936/941 (99.5%) compared to pagers, 751/765 (98.2%), χ 2 (1, N = 1706) = 6.46, p = .01, φ = .06. DTN was lower when using secure messaging (64 min) compared to the prior paging system (66 min), but this difference was not statistically significant ( p = .74). Conclusions: In conclusion, implementation of a secure messaging system improved communication in our telestroke network and reduced telestroke response to page compared to our prior paging system. Implementation of the secure messaging system did not significantly reduce DTN times.

Background Rapid arterial occlusion evaluation (RACE) scale is a valid prehospital tool used to predict large vessel occlusion of major cerebral arteries in patients with suspected acute stroke. RACE scale administered by Emergency medicine services (EMS) technicians in the prehospital setting correlates well with NIH Stroke Scale score after patient arrival at a hospital. Despite this, the RACE scale is often characterized as too difficult for EMS technicians to accurately utilize. There are no data examining RACE scale accuracy in the prehospital setting comparing EMS technicians with neurologists. We sought to examine agreement between RACE scores calculated by EMS technicians and stroke neurologists in the prehospital setting during telestroke consultation. Methods Data for this observational cohort study were prospectively collected and retrospectively analyzed. EMS technicians in person and stroke specialized neurologists via televideo connection independently assessed suspected stroke patients and calculated RACE scores in the prehospital setting. We used a linearly weighted Cohen's kappa (kw) to estimate the extent of agreement for RACE score between EMS technicians and stroke neurologists. Results Thirty-one patients with stroke symptoms were independently examined and assessed with the RACE scale by EMS technicians and stroke neurologists in the prehospital setting. Exact agreement on the RACE score was found in 24 of 31 (77%) patients. We found very good agreement between EMS technicians and stroke neurologists, kw = .818 (95% CI, .677-.960), P Conclusions EMS technicians provide reliable RACE assessments in patients with suspected stroke, with agreement similar to stroke specialized neurologists in the prehospital setting.

Introduction: Implementation of telestroke in community hospitals and primary stroke centers has resulted in reduced door to needle times. Mobile stroke units equipped with CT scanners, also utilizing telestroke have demonstrated a further reduction in door to needle times. Despite the benefits of mobile stroke units, the cost of producing and maintaining these units may be a limiting factor in system-wide adoption of the concept. There is little data examining continuous telestroke support provided by neurologists in the EMS setting. We tested this lower-cost alternative, by providing 24/7 telestroke access to two local EMS providers. We hypothesized that telestroke in the EMS setting would be safe, feasible and reduce door to needle times. Methods: Stroke-specialized neurologists provided continuous (24/7) video-based telestroke access to two local EMS agencies from December 2015 through May 2017 as part of the REACHOUT project. Data were prospectively collected and retrospectively analyzed. Intravenous (IV) tPA door to needle times were compared between patients who were assessed via EMS telestroke to patients assessed by hospital based telestroke in one of the nine hospitals within our telestroke network, during the same time period. Results: Fifty-eight telestroke requests were registered with 52 (89.7%) successful consultations during the study period. The initial telestroke impression in 42/52 (80.8%) cases was a possible acute stroke or TIA. There were 142 patients treated with IV tPA via hospital based telestroke encounters and 4 patients were treated with IV tPA after being evaluated via EMS telestroke. A comparison of door to needle times suggested shorter door to needle times in the EMS telestroke group (mean rank 12.8; median 39.5 min) compared to the hospital based telestroke group (mean rank 74.2; median 65.5 min), U = 41, p = .004, r = .24. Conclusions: Despite isolated connectivity issues, we found EMS based telestroke encounters to be safe and feasible. Pre-hospital evaluation of patients by a stroke-specialized neurologist provided a comprehensive clinical picture to emergency department physicians upon arrival to the hospital. Reduced door to needle times were reported in EMS based telestroke compared to hospital based telestroke.

Aim: Primary lateral sclerosis (PLS) is a form of motor neuron disease involving only upper motor neurons. In some patients presenting as PLS, the disease progresses to involve lower motor neurons and thereby converting to amyotrophic lateral sclerosis (ALS). However, pure forms of PLS do exist. Our aim was to study epidemiological and clinical characteristics of pure PLS patients treated at our neuromuscular clinic. Methods: We retrospectively reviewed 15 patients from July 2011 to October 2014 with PLS treated at the neuromuscular disorder clinic at our hospital. Data collection included patient demographics, age and site of onset, duration of symptoms and duration of follow-up. We also studied clinical features such as bulbar involvement; pseudobulbar affect; depression; spasms/pain; bladder involvement; diagnostic work up, in other words, MRI; brain/electromyography findings; clinical course, namely years to wheelchair; and need for gastrostomy tube requirement baclofen pump placement. We also tried to find a correlation between PLS and environmental factors such as urban/suburban/rural living, consumption of well water, socioeconomic status/occupation and history of trauma. Results: Male-to-female ratio was 1:2, mean age at onset of symptoms was 58.6 years, with the oldest patient being an 84-year-old female at the time of onset of symptoms. Mean duration of follow-up was 51 months. Mean duration of symptoms was 77.4 months. About eight (53%) patients presented with bulbar symptoms in the form of spastic speech and dysphagia, pseudobulbar affect, developed depression and had bladder involvement. Seven (47%) patients presented with symmetric spasticity in the extremities. A third of the patients required baclofen for spasticity and a third required gastrostomy tube placement for dysphagia. None of them had abnormal neuroimaging or electrodiagnostic testing. Only one patient had history of trauma. About half of the patients were from lower socioeconomic status as well as middle class. One of the patients had consumed well water during younger years and three (20%) patients lived in the rural area. Conclusion: Though on review of literature there is no clear consensus about the existence of PLS as a distinct disease entity, we believe that there are rare cases of motor neuron disease with progressive upper motor neuron symptoms that throughout their course never convert to ALS. Our series highlights the demographic and clinical features of these patients and underscores the longer survival of these patients when compared with ALS.

Background: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these BclxL/ Bcl-2 inhibitors showed promise in pre-clinical studies, resistance to several Bcl-xL inhibitors was observed, when used alone. This is attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins. Indeed, Mcl-1 is highly amplified in numerous cancers, suggesting that it may contribute to malignant cell growth and evasion of apoptosis. Therefore, significant efforts have been made toward the development of direct Mcl-1 inhibitors for cancer therapy. Methods: Following an extensive search of peer-reviewed articles on the development of Mcl-1-selective inhibitors, the literature retrieved is chronologically arranged and discussed in this review article. Results: We have included 147 articles in this review; including articles that describe the development of stapled peptides with improved binding affinity as Mcl-1-selective BH3 mimetics, those describing fragment-based and structure-based design of small molecule Mcl-1 inhibitors by various research groups, and those detailing the use of natural products and their derivatives as potential Mcl-1 inhibitors. Conclusion: The therapeutic potential of targeting the Mcl-1 protein for cancer drug discovery is vast. Stapling BH3 peptides, as well as the development of small molecule inhibitors as BH3 mimetics, are viable strategies to develop selective Mcl-1 inhibitors. With no clinically approved candidate in hand, additional modes of perturbing the biological function of this protein will aid drug discovery efforts.

Context: Although worldwide studies are available regarding the prevalence of COPD in CAD patients, data from India are sparse. Aims: The purpose of this study was to determine the prevalence of undiagnosed and therefore, untreated COPD in patients suffering from CAD. It would also attempt to establish the need for screening of patients diagnosed with CAD for COPD. Settings and Design: A cross-sectional, observational study carried out at the respiratory out patients department (OPD) of a tertiary care centre of armed forces over a period of one year. Methods and Material: 79 patients with angiographically proven CAD underwent spirometry to assess the prevalence of COPD. Statistical Analysis Used: Data analysis was done using SPSS (Statistical Package for Social Sciences) version 21.0. Results: The mean age of the patients was 62.49 years (±8.77). Mean smoking index was 235.88. Nine patients (11.39 %) were diagnosed to have COPD. All the patients diagnosed as COPD were male, >60 years old and had normal BMI. 88.9 % patients with COPD were smokers. On comparing the patients with and without COPD, a significant co-relation was found with LVEF (%) (P = 0.044). 44.4% patients had never been diagnosed with COPD. Conclusions: The prevalence of missed diagnosis of COPD is significant in our study. We recommend that at the time of diagnosis of CAD, the initial evaluation should include a detailed history, clinical examination and evaluation of lung function by spirometry.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare delayed complication of cerebral radiation therapy. A 53-year-old female initially presented with headache, confusion and left homonymous hemianopia. Her medical history was notable for cerebellar hemangioblastoma, which was treated with radiation in 1987. Her initial brain MRI (magnetic resonance imaging) revealed cortical enhancement in the right temporo-parieto-occipital region. She improved spontaneously in 2 weeks and follow-up scan at 4 weeks revealed no residual enhancement or encephalomalacia. She presented 6 weeks later with aphasia. Her MRI brain revealed similar contrast-enhancing cortical lesion but on the left side. Repeat CSF studies was again negative other than elevated protein. She was treated conservatively and recovered completely within a week. Before diagnosing SMART syndrome, it is important to rule out tumor recurrence, encephalitis, posterior reversible encephalopathy syndrome (PRES) and stroke. Typically the condition is self-limiting, and gradually resolves.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease presenting with weakness and numbness in a remitting or chronic progressive course. It is known to have several clinical presentations and several associated diseases. CIDP has been associated with multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), and other paraproteinemias. We present a case of refractory CIDP in which the initial workup for multiple myeloma was negative, and multiple myeloma was then diagnosed two and half years later. Treatment of the multiple myeloma led to clinical improvement. This case is instructive in that perhaps more frequent surveillance for paraproteinemia in patients with CIPD, even after a negative initial workup, could lead to a better clinical outcome.

Background and Aims: Face mask ventilation of the edentulous patient is often difficult as ineffective seating of the standard mask to the face prevents attainment of an adequate air seal. The efficacy of nasal ventilation in edentulous patients has been cited in case reports but has never been investigated. Material and Methods: Consecutive edentulous adult patients scheduled for surgery under general anesthesia with endotracheal intubation, during a 17-month period, were prospectively evaluated. After induction of anesthesia and administration of neuromuscular blocker, lungs were ventilated with a standard anatomical face mask of appropriate size, using a volume controlled anesthesia ventilator with tidal volume set at 10 ml/kg. In case of inadequate ventilation, the mask position was adjusted to achieve best-fit. Inspired and expired tidal volumes were measured. Thereafter, the face mask was replaced by a nasal mask and after achieving best-fit, the inspired and expired tidal volumes were recorded. The difference in expired tidal volumes and airway pressures at best-fit with the use of the two masks and number of patients with inadequate ventilation with use of the masks were statistically analyzed. Results: A total of 79 edentulous patients were recruited for the study. The difference in expiratory tidal volumes with the use of the two masks at best-fit was statistically significant (P = 0.0017). Despite the best-fit mask placement, adequacy of ventilation could not be achieved in 24.1% patients during face mask ventilation, and 12.7% patients during nasal mask ventilation and the difference was statistically significant. Conclusion: Nasal mask ventilation is more efficient than standard face mask ventilation in edentulous patients.

This communication presents a current mode universal biquad filter using voltage differencing current conveyor (VDCC). The proposed filter employs all grounded passive elements. The pole frequency (ω 0 ) and quality factor (Q) can be tuned independently in the present filter structure. The validity of the proposed biquad is verified by PSPICE simulations using 0.18µm TSMC CMOS technology parameters.

Data clustering is the most popular data analysis method in data mining. It is the method that parts the data object to meaningful groups. It has been applied into many areas such as image processing, pattern recognition and machine learning where the data sets are of many shapes and sizes. The most popular K-means and other classical algorithms suffer from drawback of their initial choice of centroid selection and local optima. This paper presents a new improved algorithm named as Boundary Restricted Adaptive Particle Swam Optimization (BR-APSO) algorithm with boundary restriction strategy. The proposed BR-APSO algorithm is tested on nine data sets, and its results are compared with those of PSO, NM-PSO, K-PSO and K-means clustering algorithms. It has been found that the proposed algorithm is robust, generates more accurate results and its convergence speed is also fast compared to other algorithms.

Data clustering is one of the most popular techniques in data mining. It is a method of grouping data into clusters, in which each cluster must have data of great similarity and high dissimilarity with other cluster data. The most popular clustering algorithm K-mean and other classical algorithms suffer from disadvantages of initial centroid selection, local optima, low convergence rate problem etc. Particle Swarm Optimization (PSO) is a population based globalized search algorithm that mimics the capability (cognitive and social behavior) of swarms. PSO produces better results in complicated and multi-peak problems. This paper presents a literature survey on the PSO application in data clustering. PSO variants are also described in this paper. An attempt is made to provide a guide for the researchers who are working in the area of PSO and data clustering.

A significant obstacle in the successful management of colon cancer (CRC) patients remains intrinsic or acquired drug resistance. Addressing these obstacles remain priority for reducing CRC-associated deaths. Autophagy is a survival-promoting program and upregulated in cancers to sustain metabolism and survive microenvironmental stress. In preclinical cancer models, inhibition of autophagy can restore chemosensitivity and enhance tumor cell death. However, clinical applicability of the currently available autophagy inhibitors is problematic due to potential toxicity as these inhibitors primarily interfere with lysosomal trafficking program, implicated in essential cellular processes. To overcome this limitation, we examined the effects of inhibiting VPS34, a class III PI-3 Kinase implicated in autophagy initiation, to overcome resistance to therapy by inhibiting autophagy. Notably, #36-077, the inhibitor used in our studies was synthesized based on the recently described novel VPS34 inhibitor, SAR405. Using colon cancer cells and colon tumoroids from APCmin mice, we confirmed marked upregulation of autophagy. Tumoroids exposure to #36-077 inhibited autophagy (LC-3I/II and P-62 expression) and induced apoptosis (Cleaved caspase-3 expression), and thus confirmed survival role for autophagy in CRC. We further examined efficacy of using #36-077 for adjuvant therapy. Combinatorial treatment efficacy of #36-077with 5-Fluorouracil (5-FU) and Erlotinib (anti-EGFR therapy) was tested. SW480 (highly tumorigenic) and HCT116 (Highly Metastatic) cells were used. MTT-assay helped determine cell viability. We found synergy between #36-077 and 5-FU in the killing CRC cells, and the EC50 was 4.9µm, 4.7µm and 2.40µm for 5-FU, #36-077 and 5-FU+#36-077, respectively. Combinatorial use of the #36-077 also boosted the cancer cell killing effects of Erlotinib, and the EC50 was 25.05µm ,5.59µm and 4.09 µm for Erlotinib, #36-077 and Erlotinib+#36-077, respectively. In further studies, we focused on the β-catenin regulation due to its role in promoting Wnt-signaling and autophagy. Indeed, in both, colon cancer cells and tumoroids, combinatorial treatment with 5FU+#36-077 resulted in sharp increases in phospho-β-catenin (Ser33) expression. Of note, phosphorylation of β-catenin at Ser33 by GSK-3β leads to its destabilization and degradation. TOP-FLASH reporter analysis (p Citation Format: Balawant Kumar, Rizwan Ahmad, Sandeep Rana, Amarnath Natarajan, Punita Dhawan, Amar B. Singh. Inhibiting VPS34 suppresses Wnt/beta-catenin signaling and promotes chemotherapeutic efficacy in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1350.

In this paper, a wave active filter structure based on Voltage Differencing Buffered Amplifier (VDBA) is presented. The proposed structure uses a lower number of active building blocks for ladder simulation using grounded capacitors. The workability of the proposed structure is verified for a 4th order low pass Butterworth filter using PSPICE simulation with 0.18μm TSMC CMOS technology parameters.

Wide proliferation of low cost IoT sensing terminals require inexpensive energy harvesting circuits integrated with RFID. The main emphasis of this paper has been the design of a switching circuit to avoid the use of separate antennas for harvesting and backscatter operations. The use of single antenna presented here also enables a compact design. Since this design considers the requirement of matching the antenna with differential output to the tag chip with similar interface and the harvester circuit with a single-ended input, this approach may lead to compact and efficient ubiquitous deployment of IoT terminals.

Background: Fiberoptic bronchoscopy is very important tool for evaluating the profile of endobronchial lesion. Endobronchial profile provides important clue regarding likely pathology which is of immense help for clinician and pathologist to reach definitive diagnosis. Aim and Objectives: To study the clinical, radiological, and histopathological profile of endobronchial lesions detected during bronchoscopy. Materials and Methods: A cross-sectional prospective observational study was conducted at a tertiary respiratory center. Demographic, clinical, and radiological profile was prepared for all patients above 18 years of age, and relevant blood and radiological investigations were conducted. Patients detected to have endobronchial lesion during fiberoptic bronchoscopy were selected for the study. Bronchoalveolar lavage, bronchial biopsy, and bronchial brushing were done and sent for examination. Patients were observed postprocedure for any complication. Results: Male patients were more in number (70%) with most of patients above 40 years of age (80%). Most common symptom was cough (48%) with smoking history present in 48% patients. Mass lesion was most common radiological presentation (52%). Right lung was most commonly involved (52%), and upper lobe involvement was most common (50%). Exophytic growth was most common endobronchial lesion (46%) with carcinoma lung most common diagnosis (74%). Hemoptysis was most common complication (80%), which resolved on its own, followed by postprocedure hypoxemia (8%). Conclusion: Clinical, radiological, and bronchoscopic profile of endobronchial lesion is an important information which helps clinician and pathologist to reach final diagnosis. Carcinoma lung is most common diagnosis made in our study as most common endobronchial lesions at age of our patients are malignant as reported in literature.

Pulmonary embolism remains a disease which needs high clinical suspicion to prevent mortality and morbidity. More so in young healthy individuals, suspicion is very low as compared to old age individuals with multiple co-morbid conditions. Pulmonary embolism carries high mortality if not suspected and treatment initiated as early as possible. There are two case reports of young male individuals who presented as acute onset of breathlessness and later diagnosed and treated as a case of pulmonary thromboembolism.

Background/Aims: Environmental and occupational exposures are implicated as risk factors for amyotrophic lateral sclerosis (ALS), the etiology of which is largely unknown, although no causal relationships have been established. Objective: The aim of the study was to evaluate the associations of personal risk factors and self-reported environmental and occupational exposures with risk of ALS. Methods: The cases involved ALS patients (n = 66) identified from major neurological centers in Pittsburgh and Philadelphia, Pa., USA, from 2008 to 2010. The age-, race- and sex-matched controls included outpatient hospital and population-based controls (n = 66). A detailed questionnaire obtaining data on occupation, vocational and avocational exposure as well as personal lifestyle factors was administered. Results: Occupational exposure to metals (odds ratio, OR = 3.65; 95% CI: 1.15, 11.60) and pesticides (OR = 6.50; 95% CI: 1.78, 23.77) was related to increased risk of ALS after controlling for smoking and education. No associations were found for occupational exposure to organic or aromatic solvents. Conclusion: Workers exposed to metals and pesticides may be at greater risk of ALS. Future research should involve more accurate exposure assessment through the use of job exposure matrices, confirmation of occupation and biomarkers.

Isaacs' syndrome is a rare disease resulting from hyperexcitability of peripheral nerves causing continuous muscle fiber activity characterized by muscle twitching and stiffness at rest and delayed muscle relaxation after voluntary contraction. Our objective was to discuss the relationship of Isaacs' syndrome to paraneoplastic syndromes as reported in the available literature and in 3 patients evaluated at our academic medical center.We review the literature on Isaacs' syndrome and describe 3 patients in whom Isaacs' syndrome heralded underlying malignancy or benign neoplasm, including their presenting symptoms, electrophysiologic findings, and laboratory and pathology results.In all 3 cases, clinical and electrodiagnostic testing was suggestive of Isaacs' syndrome. Two patients tested positive, and one was negative for voltage-gated potassium channel antibodies. Two of the patients developed malignant tumors, that is, one was diagnosed with metastatic thymoma and one with lymphoplasmacytic lymphoma, ranging from 6 months to 1 year after the diagnosis of Isaacs' syndrome. One patient was diagnosed with a spinal cord hemangioblastoma 5 years after he was diagnosed with Isaacs' syndrome.Our case series highlights the association of Isaacs' syndrome with a variety of neoplasms both malignant and benign. Our report also underscores the fact that Isaacs' syndrome may be diagnosed several years before a neoplasm is discovered. In our cases, Isaacs' syndrome overlapped with other neuromuscular disorders, that is, myasthenia gravis in a patient with thymoma and chronic inflammatory demyelinating polyneuropathy in a patient with lymphoplasmacytic lymphoma with paraproteinemia. To our knowledge, this is the first report of an association between Isaacs' syndrome with lymphoplasmacytic lymphoma and a spinal cord hemangioblastoma.

The pathophysiology of migraine is not well understood. A rimarily “vascular” theory, proposing that migraine auras are ssociated with vasoconstriction and “oligemia” has given way o a theory of complex neurochemical processes leading to ypometabolism and decreased blood flow termed a “spreadng cortical depression” [1]. Localized decreasing flow, as well as ortical hypometabolism, preferentially affecting the posterior cirulation, has been measured using multiple imaging modalities. The neuroimaging of migraine has helped bolster theories of he nature of the underlying physiological processes, which correate with the well-known clinical manifestation of this common, et mysterious disorder. We present a patient with migraine assoiated with hemispheric cerebral hypoperfusion and stroke-like ymptoms in whom noninvasive dynamic perfusion computed omography (CT) imaging helped determine treatment options. The ynamic changes in CT perfusion seen in cases of migraine varints may help us understand the process of this disorder. Although RI easily rules out many stroke mimics, routine CT scans (done ithout perfusion studies) are often the only imaging done prior to iving thrombolytics.

At national level, almost a third of elderly victims are abused in their own home and almost as many are abused in residential care. The most common type of abuse was physical, followed by acts of neglect or omission. Increasing cases of elder abuses are largely an outcome of changing global phenomena where the family bonds are not as strong as in the past and elders are being marginalised. The paper is an attempt to examine the nature and causes of elderly abuse and to record the feelings of the elderly. Five hundred responded above 60 years age were randomly selected from rural and urban areas of district Rohtak. It is found that though there is not any major case of elder abuse, yet oral abuses and neglect are reported. Contrary to the common perception, sons are largely responsible for abuse and neglect. About 27.6 per cent of the respondents admitted that they have met out one or the other type of abuse. The percentage of abused females is larger than their counterparts. The abused feel sad and depressed. Nearly 21 per cent abused respondents reported depression and about 6 per cent thought to commit suicide.

Kinases are promising targets in cancer drug discovery. IKKβ is an important kinase in the canonical NF-κB pathway, which promotes survival of cancer cells and is constitutively active in number of cancers including pancreatic cancer. Inflammatory stimulus such as tumor necrosis factor-α (TNFα) is known to activate the canonical IKKβ-NF-κB pathway. Upon TNFα stimulation, serine residues 177 and 181 in the activation loop of IKKβ undergo phosphorylation resulting in activated IKKβ. Immunohistochemistry (IHC) studies showed the presence of the proinflammatory cytokine TNFα in ∼50% of surgically resected tumor specimens but in only ∼10% of corresponding normal tissues. Consistently, IHC studies by us with patient samples obtained from the UNMC rapid autopsy pancreatic cancer program showed elevated levels of phosphorylated S181 IKKβ in the tumor and liver metastases samples when compared to the stroma and ductal cells for normal pancreas. Several small molecule IKKβ inhibitors were developed by pharmaceutical industry to treat chronic inflammatory diseases. Despite complete preclinical characterization of many candidates, to date none of them has been approved by the FDA for clinical use. Nearly all the small molecule IKKβ inhibitors reported are ATP competitive. These inhibitors completely block IKKβ mediated NF-κB activity as a result chronic administration in mice leads to granulocytosis and increased susceptibility to infection-mediated death. Here we report the discovery a non-ATP competitive IKKβ inhibitor that allows transient activation but blocks the sustained activation of IKKβ mediated NF-κB activity. We present a model that has a novel-binding site, which is accessible upon activation of IKKβ and explains the observed experimental results. Our IKKβ inhibitor does not share the toxicity profile of the ATP competitive IKKβ inhibitors. In an orthotopic pancreatic tumor model mice treated with our inhibitor showed reduced tumor growth and metastasis compared to vehicle controls. We also showed that in a mantle cell lymphoma model the median survival of mice treated with our inhibitor nearly doubled when compared vehicle treated mice. Our results suggest that non-ATP competitive IKKβ inhibitors are viable lead candidates for cancer therapy. Citation Format: Sandeep Rana, Elizabeth Blowers, Amarnath Natarajan. A non-ATP competitive IKKβ inhibitor for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3645. doi:10.1158/1538-7445.AM2015-3645

West Nile Virus (WNV) is an arthropod-borne flavivirus, which causes flu-like illness and is sporadically associated with encephalitis. Transmission to humans occurs following a bite from an infected mosquito, which acquires the virus after feeding on dead birds. WNV meningoencephalitis is a rare infection with a neuroinvasive disease occurring in less than 1% of the cases, with varied presentations including aseptic meningitis, meningoencephalitis, and acute flaccid paralysis. Chorioretinitis is the most common eye finding in this infection, while other ocular manifestations have been rarely reported in the literature. We present the first case report of WNV meningoencephalitis, with rare ocular manifestations of acute hemorrhagic conjunctivitis, bilateral subconjunctival hemorrhages, and nystagmus. The rare ocular findings of acute hemorrhagic conjunctivitis, bilateral subconjunctival hemorrhages, and nystagmus diagnosed in our case can guide clinicians toward early diagnosis of WNV meningoencephalitis, while serologic testing is still pending.

In this retrospective study, we compared the initial presentation of patients who were eventually diagnosed with either benign fasciculations (BF) or amyotrophic lateral sclerosis (ALS). We found a significantly higher number of patients with BF reporting a past history of psychiatric symptoms, life stressors, and concurrent psychosomatic symptoms. There was no difference between the two groups in patient report of current anxiety or depression symptoms. These findings support our hypothesis that BF are a manifestation of psychological distress due to somatization and that reviewing psychosocial history is important when patients are being evaluated for fasciculations. Patients seeking medical attention for fasciculations and who do not report a history of underlying psychiatric or psychosomatic disorders should be followed closely as fasciculations have been reported to be a presenting feature of ALS.