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The present work aimed to develop a Field-based 3D-QSAR model with existing JAK-2 inhibitors. The JAK-STAT pathway is known to play a role in the development of autoimmune diseases, including rheumatoid arthritis, ulcerative colitis, and Crohn's disease. Dysregulation of JAK-STAT is also linked to the development of myelofibrosis and other myeloproliferative diseases. JAK antagonists can be used in many areas of medicine. There are many compounds that already show inhibition of Jak-2. We have developed a Field-based 3D QSAR model which showed good correlation values ( r 2 0.884 and q 2 0.67) with an external test set regression pred_ r 2 0.562. Various properties, such as electronegativity, electro positivity, hydrophobicity, and shape features, were studied under the activity atlas to determine the inhibitory potential of ligands. These were also identified as important structural features responsible for biological activity. We performed virtual screening based on the pharmacophore features of the co-crystal ligand (PDB ID: 3KRR) and a dataset of NPS was selected with a RMSD value less than 0.8. The developed 3D QSAR model was used to screen ligands and calculate the predicted JAK-2 inhibition activity (pKi). The results of the virtual screening were validated using molecular docking and molecular dynamics simulations. SNP1 (SN00154718) and SNP2 (SN00213825) showed binding affinity of -11.16 and -11.08 kcal/mol, respectively, which were very close to the crystal ligand of 3KRR, -11.67 kcal/mol. The RMSD plot of the protein-ligand complex of SNP1 and 3KRR showed stable interactions with an average RMSD of 2.89 Å. Thus, a statistically robust 3D QSAR model could reveal more inhibitors and aid in the design of novel JAK-2 inhibitors.

Purpose: Assessment of ocular surface in patients using anti-glaucoma medications (AGM) is rarely a priority for clinicians since glaucoma management targets intraocular pressure and preserves vision. This review summarizes the various adverse effects of topical AGM on the ocular surface and highlights the importance of ocular surface assessment in these patients., Methods: A literature search of articles (English only) on the subject matter was conducted focusing on recent articles published in the past 5 years., Results: The use of multiple anti-glaucoma medications in glaucoma patients increases patients' exposure to the drug and the preservatives present in these medications. Long-term use of these medications has deleterious effects on the conjunctiva, cornea, eyelids, and periocular tissues like trichiasis, entropion, symblepharon, forniceal shortening, punctate keratopathy, non-healing epithelial defects, and pannus. Treatment requires drug withdrawal or substitution by oral or topical non-preserved and less toxic preparations of AGMs. The ocular surface and symptoms can improve if the condition is diagnosed early and after drug withdrawal in over 90% of eyes. However, stopping or changing AGMs can often present with its own unique set of challenges in intra-ocular pressure control which may often need glaucoma surgery in close to 20% of eyes for IOP control., Conclusion: Topical antiglaucoma medications (with their preservatives) can induce severe ocular surface and periorbital changes. Early identification and withdrawal of the offending drug/preservative can help to reverse the changes except in eyes with extensive cicatrization.

In an attempt to develop therapeutic agents to treat Alzheimer's disease, a series of flavonoid analogues were collected, which already had established acetylcholinesterase (AChE) enzyme inhibition activity. For each molecule we also collected biological activity data (Ki). Then, 3D-QSAR (quantitative structure-activity relationship model) was developed which showed acceptable predictive and descriptive capability as represented by standard statistical parameters r2 and q2. This SAR data can explain the key descriptors which can be related to AChE inhibitory activity. Using the QSAR model, pharmacophores were developed based on which, virtual screening was done and a dataset was obtained which loaded as a prediction set to fit the developed QSAR model. Top 10 compounds fitting the QSAR model were subjected to molecular docking. CHEMBL1718051 was found to be the lead compound. This study is offering an example of a computationally-driven tool for prioritisation and discovery of probable AChE inhibitors. Further, in vivo and in vitro testing will show its therapeutic potential., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: To determine whether robot-assisted training is cost-effective compared with an enhanced upper limb therapy (EULT) programme or usual care., Design: Economic evaluation within a randomised controlled trial., Setting: Four National Health Service (NHS) centres in the UK: Queen's Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust; Northwick Park Hospital, London Northwest Healthcare NHS Trust; Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde; and North Tyneside General Hospital, Northumbria Healthcare NHS Foundation Trust., Participants: 770 participants aged 18 years or older with moderate or severe upper limb functional limitation from first-ever stroke., Interventions: Participants randomised to one of three programmes provided over a 12-week period: robot-assisted training plus usual care; the EULT programme plus usual care or usual care., Main Economic Outcome Measures: Mean healthcare resource use; costs to the NHS and personal social services in 2018 pounds; utility scores based on EQ-5D-5L responses and quality-adjusted life years (QALYs). Cost-effectiveness reported as incremental cost per QALY and cost-effectiveness acceptability curves., Results: At 6 months, on average usual care was the least costly option (£3785) followed by EULT (£4451) with robot-assisted training being the most costly (£5387). The mean difference in total costs between the usual care and robot-assisted training groups (£1601) was statistically significant (p<0.001). Mean QALYs were highest for the EULT group (0.23) but no evidence of a difference (p=0.995) was observed between the robot-assisted training (0.21) and usual care groups (0.21). The incremental cost per QALY at 6 months for participants randomised to EULT compared with usual care was £74 100. Cost-effectiveness acceptability curves showed that robot-assisted training was unlikely to be cost-effective and that EULT had a 19% chance of being cost-effective at the £20 000 willingness to pay (WTP) threshold. Usual care was most likely to be cost-effective at all the WTP values considered in the analysis., Conclusions: The cost-effectiveness analysis suggested that neither robot-assisted training nor EULT, as delivered in this trial, were likely to be cost-effective at any of the cost per QALY thresholds considered., Trial Registration Number: ISRCTN69371850., Competing Interests: Competing interests: HR reports grants from NIHR, during the conduct of the study; personal fees from Bayer, outside the submitted work; and Member of NIHR HTA CET panel 2010–2014. GF reports grants from National Institute for Health Research, during the conduct of the study; personal fees from Amgen, personal fees from Daiichi Sankyo, grants and personal fees from Medtronic, personal fees from Stryker, personal fees from Pfizer, personal fees from Bayer, outside the submitted work. CP and LS report grants from National Institute for Health Research, during the conduct of the study. HIK reports other from Interactive Motion Technologies, other from 4Motion Robotics, outside the submitted work; in addition, HIK has a patent Interactive Robotic Therapist; US Patent 5466213; 1995; Massachusetts Institute of Technology issued, and a patent Wrist And Upper Extremity Motion; US Patent No. 7618381; 2009; Massachusetts Institute of Technology licensed to Bionik Laboratories., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objective: To report the fidelity of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after stroke (RATULS) randomized controlled trial, the types of goals selected and the proportion of goals achieved., Design: Descriptive analysis of data on fidelity, goal selection and achievement from an intervention group within a randomized controlled trial., Setting: Out-patient stroke rehabilitation within four UK NHS centres., Subjects: 259 participants with moderate-severe upper limb activity limitation (Action Research Arm Test 0-39) between one week and five years post first stroke., Intervention: The enhanced upper limb therapy programme aimed to provide 36 one-hour sessions, including 45 minutes of face-to-face therapy focusing on personal goals, over 12 weeks., Results: 7877/9324 (84%) sessions were attended; a median of 34 [IQR 29-36] per participant. A median of 127 [IQR 70-190] repetitions were achieved per participant per session attended. Based upon the Canadian Occupational Performance Measure, goal categories were: self-care 1449/2664 (54%); productivity 374/2664 (14%); leisure 180/2664 (7%) and 'other' 661/2664 (25%). For the 2051/2664 goals for which data were available, 1287 (51%) were achieved, ranging between 27% by participants more than 12 months post stroke with baseline Action Research Arm Test scores 0-7, and 88% by those less than three months after stroke with scores 8-19., Conclusions: Intervention fidelity was high. Goals relating to self-care were most commonly selected. The proportion of goals achieved varied, depending on time post stroke and baseline arm activity limitation.

Background: Loss of arm function is common after stroke. Robot-assisted training may improve arm outcomes., Objective: The objectives were to determine the clinical effectiveness and cost-effectiveness of robot-assisted training, compared with an enhanced upper limb therapy programme and with usual care., Design: This was a pragmatic, observer-blind, multicentre randomised controlled trial with embedded health economic and process evaluations., Setting: The trial was set in four NHS trial centres., Participants: Patients with moderate or severe upper limb functional limitation, between 1 week and 5 years following first stroke, were recruited., Interventions: Robot-assisted training using the Massachusetts Institute of Technology-Manus robotic gym system (InMotion commercial version, Interactive Motion Technologies, Inc., Watertown, MA, USA), an enhanced upper limb therapy programme comprising repetitive functional task practice, and usual care., Main Outcome Measures: The primary outcome was upper limb functional recovery 'success' (assessed using the Action Research Arm Test) at 3 months. Secondary outcomes at 3 and 6 months were the Action Research Arm Test results, upper limb impairment (measured using the Fugl-Meyer Assessment), activities of daily living (measured using the Barthel Activities of Daily Living Index), quality of life (measured using the Stroke Impact Scale), resource use costs and quality-adjusted life-years., Results: A total of 770 participants were randomised (robot-assisted training, n  = 257; enhanced upper limb therapy, n  = 259; usual care, n  = 254). Upper limb functional recovery 'success' was achieved in the robot-assisted training [103/232 (44%)], enhanced upper limb therapy [118/234 (50%)] and usual care groups [85/203 (42%)]. These differences were not statistically significant; the adjusted odds ratios were as follows: robot-assisted training versus usual care, 1.2 (98.33% confidence interval 0.7 to 2.0); enhanced upper limb therapy versus usual care, 1.5 (98.33% confidence interval 0.9 to 2.5); and robot-assisted training versus enhanced upper limb therapy, 0.8 (98.33% confidence interval 0.5 to 1.3). The robot-assisted training group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale) than the usual care group at 3 and 6 months. The enhanced upper limb therapy group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale), better mobility (as measured by the Stroke Impact Scale mobility domain) and better performance in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the usual care group, at 3 months. The robot-assisted training group performed less well in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the enhanced upper limb therapy group at 3 months. No other differences were clinically important and statistically significant. Participants found the robot-assisted training and the enhanced upper limb therapy group programmes acceptable. Neither intervention, as provided in this trial, was cost-effective at current National Institute for Health and Care Excellence willingness-to-pay thresholds for a quality-adjusted life-year., Conclusions: Robot-assisted training did not improve upper limb function compared with usual care. Although robot-assisted training improved upper limb impairment, this did not translate into improvements in other outcomes. Enhanced upper limb therapy resulted in potentially important improvements on upper limb impairment, in performance of activities of daily living, and in mobility. Neither intervention was cost-effective., Future Work: Further research is needed to find ways to translate the improvements in upper limb impairment seen with robot-assisted training into improvements in upper limb function and activities of daily living. Innovations to make rehabilitation programmes more cost-effective are required., Limitations: Pragmatic inclusion criteria led to the recruitment of some participants with little prospect of recovery. The attrition rate was higher in the usual care group than in the robot-assisted training or enhanced upper limb therapy groups, and differential attrition is a potential source of bias. Obtaining accurate information about the usual care that participants were receiving was a challenge., Trial Registration: Current Controlled Trials ISRCTN69371850., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 54. See the NIHR Journals Library website for further project information.

Background: Loss of arm function is a common problem after stroke. Robot-assisted training might improve arm function and activities of daily living. We compared the clinical effectiveness of robot-assisted training using the MIT-Manus robotic gym with an enhanced upper limb therapy (EULT) programme based on repetitive functional task practice and with usual care., Methods: RATULS was a pragmatic, multicentre, randomised controlled trial done at four UK centres. Stroke patients aged at least 18 years with moderate or severe upper limb functional limitation, between 1 week and 5 years after their first stroke, were randomly assigned (1:1:1) to receive robot-assisted training, EULT, or usual care. Robot-assisted training and EULT were provided for 45 min, three times per week for 12 weeks. Randomisation was internet-based using permuted block sequences. Treatment allocation was masked from outcome assessors but not from participants or therapists. The primary outcome was upper limb function success (defined using the Action Research Arm Test [ARAT]) at 3 months. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN69371850., Findings: Between April 14, 2014, and April 30, 2018, 770 participants were enrolled and randomly assigned to either robot-assisted training (n=257), EULT (n=259), or usual care (n=254). The primary outcome of ARAT success was achieved by 103 (44%) of 232 patients in the robot-assisted training group, 118 (50%) of 234 in the EULT group, and 85 (42%) of 203 in the usual care group. Compared with usual care, robot-assisted training (adjusted odds ratio [aOR] 1·17 [98·3% CI 0·70-1·96]) and EULT (aOR 1·51 [0·90-2·51]) did not improve upper limb function; the effects of robot-assisted training did not differ from EULT (aOR 0·78 [0·48-1·27]). More participants in the robot-assisted training group (39 [15%] of 257) and EULT group (33 [13%] of 259) had serious adverse events than in the usual care group (20 [8%] of 254), but none were attributable to the intervention., Interpretation: Robot-assisted training and EULT did not improve upper limb function after stroke compared with usual care for patients with moderate or severe upper limb functional limitation. These results do not support the use of robot-assisted training as provided in this trial in routine clinical practice., Funding: National Institute for Health Research Health Technology Assessment Programme., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Loss of arm function is a common and distressing consequence of stroke. We describe the protocol for a pragmatic, multicentre randomised controlled trial to determine whether robot-assisted training improves upper limb function following stroke., Methods/design: Study design: a pragmatic, three-arm, multicentre randomised controlled trial, economic analysis and process evaluation., Setting: NHS stroke services., Participants: adults with acute or chronic first-ever stroke (1 week to 5 years post stroke) causing moderate to severe upper limb functional limitation. Randomisation groups: 1. Robot-assisted training using the InMotion robotic gym system for 45 min, three times/week for 12 weeks 2. Enhanced upper limb therapy for 45 min, three times/week for 12 weeks 3. Usual NHS care in accordance with local clinical practice Randomisation: individual participant randomisation stratified by centre, time since stroke, and severity of upper limb impairment., Primary Outcome: upper limb function measured by the Action Research Arm Test (ARAT) at 3 months post randomisation., Secondary Outcomes: upper limb impairment (Fugl-Meyer Test), activities of daily living (Barthel ADL Index), quality of life (Stroke Impact Scale, EQ-5D-5L), resource use, cost per quality-adjusted life year and adverse events, at 3 and 6 months. Blinding: outcomes are undertaken by blinded assessors. Economic analysis: micro-costing and economic evaluation of interventions compared to usual NHS care. A within-trial analysis, with an economic model will be used to extrapolate longer-term costs and outcomes. Process evaluation: semi-structured interviews with participants and professionals to seek their views and experiences of the rehabilitation that they have received or provided, and factors affecting the implementation of the trial., Sample Size: allowing for 10% attrition, 720 participants provide 80% power to detect a 15% difference in successful outcome between each of the treatment pairs. Successful outcome definition: baseline ARAT 0-7 must improve by 3 or more points; baseline ARAT 8-13 improve by 4 or more points; baseline ARAT 14-19 improve by 5 or more points; baseline ARAT 20-39 improve by 6 or more points., Discussion: The results from this trial will determine whether robot-assisted training improves upper limb function post stroke., Trial Registration: ISRCTN, identifier: ISRCTN69371850 . Registered 4 October 2013.

An 89-year-old woman was admitted with a fall. She had severe dementia and was on no medication. She was mobile with carers visiting her at home twice daily. While her stay in the hospital, she was diagnosed with atrial fibrillation. Her rate was controlled with bisoprolol and was already given aspirin after risk assessment for stroke and CT scan of head. Several days into admission, she complained of sudden onset of weakness of her right upper limb with pain. On examination, there were absent brachial and radial pulses on the side along with weakness and decreased sensation below right elbow. She underwent urgent CT angiogram which revealed absent flow beyond right subclavian artery. She was treated with heparin infusion and then warfarin with regular vascular team follow-up. Further issues such as duration of warfarin therapy including possible substitution with direct thrombin inhibitor such as dabigatran etexilate is under consideration.

The authors present the case of a 25-year-old individual who presented acutely following a generalised tonic-clonic seizure. Brain MRI of the individual demonstrated the classical appearance of multiple cerebral cavernous haemangiomas (cavernomas). There was an autosomal dominant family history. Genetic testing identified a truncating mutation in the KRIT1 gene in the individual and confirmed the diagnosis of familial cerebral cavernomas as the cause of epilepsy in the family.

A 78-year-old man presented to the accident and emergency department following sudden onset of back pain, with attendant loss of power and sensation in the lower half of his body and urinary retention. Onset occurred while he was seated in a chair and he fell as he tried to get up. Neurological examination revealed symmetrical lower motor weakness (MRC grade 4/5) in both lower limbs with downgoing plantar reflexes. There was a clear sensory boundary at D4 with loss of joint position and sensation to light touch below this level. Rectal examination was unremarkable. While a CT head scan was normal, spinal MRI showed multilevel disc desiccations in the dorsal and lumbar spine. Additionally, in the dorsal spine at D4/5, there was a thin plaque of epidural tissue representing an epidural haematoma. Within 48-72 h the patient gradually and spontaneously regained full power.