Nordihydroguaiaretic acid microparticles are effective in the treatment of osteoarthritis.

Several disease-modifying osteoarthritis (OA) drugs have emerged, but none have been approved for clinical use due to their systemic side effects, short half-life, and rapid clearance from the joints. Nordihydroguaiaretic acid (NDGA), a reactive oxygen species (ROS) scavenger and autophagy inducer, could be a potential treatment for OA. In this report, we show for the first time that sustained delivery of NDGA through polymeric microparticles maintains therapeutic concentrations of drug in the joint and ameliorates post-traumatic OA (PTOA) in a mouse model. In vitro treatment of oxidatively stressed primary chondrocytes from OA patients using NDGA-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles (NDGA-MP) inhibited 15-lipoxygenase, induced autophagy, prevented chondrosenescence, and sustained matrix production. In vivo intra-articular delivery of NDGA-MP was non-toxic and had prolonged retention time (up to 35 days) in murine knee joints. Intra-articular therapy using NDGA-MP effectively reduced cartilage damage and reduced pain in the surgery-induced PTOA mouse model. Our studies open new avenues to modulate the immune environment and treat post-traumatic OA using ROS quenchers and autophagy inducers.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Machine learning approaches for the treatment of textile wastewater using sugarcane bagasse (Saccharum officinarum) biochar.

Most dyes present in wastewater from the textile industry exhibit toxicity and are resistant to biodegradation. Hence, the imperative arises for the environmentally significant elimination of textile dye by utilising agricultural waste. The achievement of this objective can be facilitated through the utilisation of the adsorption mechanism, which entails the passive absorption of pollutants using biochar. In this study, we compare the efficacy of the response surface methodology (RSM), the artificial neural network (ANN), the k-nearest neighbour (kNN), and adaptive neuro-fuzzy inference system (ANFIS) in removing crystal violet (CV) from wastewater. The characterisation of biochar is carried out by scanning electron microscope (SEM) and Fourier transform infrared (FTIR). The impacts of the solution pH, adsorbent dosage, initial dye concentration, and temperature were investigated using a variety of models (RSM, ANN, kNN, and ANFIS). The statistical analysis of errors was conducted, resulting in a maximum removal effectiveness of 97.46% under optimised settings. These conditions included an adsorbent dose of 0.4 mg, a pH of 5, a CV concentration of 40.1 mg/L, and a temperature of 20 °C. The ANN, RSM, kNN, and ANFIS models all achieved R2 0.9685, 0.9618, 0.9421, and 0.8823, respectively. Even though all models showed accuracy in predicting the removal of CV dye, it was observed that the ANN model exhibited greater accuracy compared to the other models.

Integrating artificial neural networks and response surface methodology for predictive modeling and mechanistic insights into the detoxification of hazardous MB and CV dyes using Saccharum officinarum L. biomass.

The presence of dye pollutants in industrial wastewater poses significant environmental and health risks, necessitating effective treatment methods. The optimal adsorption treatment of methylene blue (MB) and crystal violet (CV) dye-simulated wastewater utilising Saccharum officinarum L presents a key challenge in the selection of appropriate modelling approaches. While RSM and ANN models are frequently used, there is a noticeable knowledge gap when it comes to evaluating their relative strengths and weaknesses in this context. The study compared the predictive abilities of response surface methodology (RSM) and artificial neural network (ANN) for the adsorption treatment of MB and CV dye-simulated wastewater using Saccharum officinarum L. The process experimental variables were modelled and predicted using a three-layer artificial neural network trained using the Levenberg-Marquard backpropagation algorithm and 30 central composite designs (CCD). The adsorption study used a specific mechanism, which led to noteworthy maximum removals of 98.3% and 98.2% for dyes (MB and CV), respectively. The RSM model achieved an impressive R2 of 0.9417, while the ANN model achieved 0.9236 in MB. Adsorption is commonly used to remove colour from many different materials. Saccharum officinarum L., a byproduct of sugarcane processing, has shown potential as an efficient and ecological adsorbent in this environment. The purpose of this study is to evaluate sugarcane bagasse's potential as an adsorbent for the removal of dyes MB and CV from industrial wastewater, providing a long-term strategy for reducing dye pollution. Due to its beneficial economic and environmental characteristics, the Saccharum officinarum L. adsorbent has prompted research into sustainable resources with low pollutant indices.

Can Medical Nutrition Therapy Affect Feto-Maternal Outcomes in Gestational Glucose Intolerance: An Open-Label Pilot Randomized Control Trial in World's Diabetes Capital.

Introduction: Gestational diabetes is defined as the carbohydrate intolerance of variable severity with onset or first recognition during pregnancy. Gestational glucose intolerance (GGI) is used to indicate pregnant women whose 2-h postprandial glucose is > 120 mg/dl and below 140 mg/dl (Diabetes in Pregnancy Study Group of India, DIPSI criteria). Aim: This study was planned to see whether intervention in GGI group helps to improve feto-maternal outcomes. Methodology: This open-label randomized control trial was conducted in Department of Obstetrics and Gynaecology of King George's Medical University, Lucknow. Inclusion criteria were all the antenatal women attending the antenatal clinic and diagnosed as GGI, and exclusion criteria were overt diabetes. Results: Total of 1866 antenatal women were screened, and among them, 220 (11.8%) women were diagnosed as gestational diabetes; 412 (22.1%) women were diagnosed as GGI. The mean fasting blood sugars in the women with GGI who had medical nutrition therapy were much lower than the women with GGI who did not have any intervention. The present study showed the women with GGI had higher complications like polyhydramnios, PPROM, foetal growth restriction, macrosomia, preeclampsia, preterm labour and vaginal candidiasis more in the women with GGI as compared to euglycaemic women. Conclusion: The present study of nutritional intervention in GGI group has shown trend towards lesser complication if we start medical nutrition therapy reflected by delayed development of GDM and less neonatal hypoglycaemia and hyperbilirubinemia.

Introducing machine learning model to response surface methodology for biosorption of methylene blue dye using Triticum aestivum biomass.

A major environmental problem on a global scale is the contamination of water by dyes, particularly from industrial effluents. Consequently, wastewater treatment from various industrial wastes is crucial to restoring environmental quality. Dye is an important class of organic pollutants that are considered harmful to both people and aquatic habitats. The textile industry has become more interested in agricultural-based adsorbents, particularly in adsorption. The biosorption of Methylene blue (MB) dye from aqueous solutions by the wheat straw (T. aestivum) biomass was evaluated in this study. The biosorption process parameters were optimized using the response surface methodology (RSM) approach with a face-centred central composite design (FCCCD). Using a 10 mg/L concentration MB dye, 1.5 mg of biomass, an initial pH of 6, and a contact time of 60 min at 25 °C, the maximum MB dye removal percentages (96%) were obtained. Artificial neural network (ANN) modelling techniques are also employed to stimulate and validate the process, and their efficacy and ability to predict the reaction (removal efficiency) were assessed. The existence of functional groups, which are important binding sites involved in the process of MB biosorption, was demonstrated using Fourier Transform Infrared Spectroscopy (FTIR) spectra. Moreover, a scan electron microscope (SEM) revealed that fresh, shiny particles had been absorbed on the surface of the T. aestivum following the biosorption procedure. The bio-removal of MB from wastewater effluents has been demonstrated to be possible using T. aestivum biomass as a biosorbent. It is also a promising biosorbent that is economical, environmentally friendly, biodegradable, and cost-effective.

The contribution of competing mechanisms in stroke despite anticoagulation in patients with atrial fibrillation.

BACKGROUND: For reasons poorly understood, strokes frequently occur in patients with atrial fibrillation (AF) despite oral anticoagulation. Better data are needed to inform randomised trials (RCTs) of new strategies to prevent recurrence in these patients. We investigate the relative contribution of competing stroke mechanisms in patients with AF who have stroke despite anticoagulation (OAC+) compared with those who are anticoagulant naïve (OAC-) at the time of their event. PATIENTS AND METHODS: We performed a cross-sectional study leveraging data from a prospective stroke registry (2015-2022). Eligible patients had ischemic stroke and AF. Stroke classification was performed by a single stroke-specialist blinded to OAC status using TOAST criteria. The presence of atherosclerotic plaque was determined using duplex ultrasonography, computerised tomography (CT) or magnetic resonance (MR) angiography. Imaging was reviewed by a single reader. Logistic regression was used to identify independent predictors of stroke despite anticoagulation. RESULTS: Of 596 patients included, 198 (33.2%) were in the OAC+ group. A competing cause for stroke was more frequent in patients with OAC+ versus OAC- (69/198 (34.8%)) versus 77/398 (19.3%), p < 0.001). After adjustment, both small vessel occlusion (odds ratio (OR): 2.46, 95% CI: 1.20-5.06) and arterial atheroma (⩾50% stenosis) (OR: 1.78, 95% CI: 1.07-2.94) were independently associated with stroke despite anticoagulation. DISCUSSION AND CONCLUSION: Patients with AF-associated stroke despite OAC are much more likely than patients who are OAC-naïve to have competing stroke mechanisms. Rigorous investigation for alternative stroke causes in stroke despite OAC has a high diagnostic yield. These data should be used to guide patient selection for future RCTs in this population.

Role of cord blood IGF-1 and maternal HbA1c levels to predict interventricular septal hypertrophy among infants of diabetic mothers: A case-control study.

BACKGROUND: Infants of diabetic mothers (IDMs) develop interventricular septal hypertrophy (ISH) (> 6 mm) [1]. The proportion of IDMs developing ISH varies from country to country. Maternal HbA1c and cord blood Insulin-like growth factor-1 (IGF-1) levels have been found useful to predict ISH. METHODS: This was a case-control study of term neonates of diabetic mothers (cases) and of non-diabetic mothers (controls) to evaluate echocardiographic (ECHO) differences among cases and controls and to find the correlation of interventricular septal thickness (IVS) thickness with maternal HbA1C and cord blood IGF-1 levels. RESULTS: Of 32 cases and 34 controls (mean gestational age 37.7 ± 0.9 weeks), 15 (46.8 %) cases, no control developed ISH. Septal thickness was more (6 ± 0.15 cm vs 3 ± 0.06 cm; p = 0.027) in cases than controls. Functional ECHO parameters including left ventricle ejection fraction were comparable (p = 0.9) among the two groups. Maternal HbA1C levels were higher (6.5 % ± 1.3 vs 3.6 % ± 0.7; p = 0.001) with a positive correlation with IVS (Pearson's coefficient 0.784, p < 0.001). Cord blood IGF1 levels were too higher in cases (99.1 ± 6.09 ng/ml vs 37.1 ± 2.99 ng/ml; p < 0.001) with moderate correlation with IVS thickness (Pearson's coefficient 0.402; p = 0.00). Receiver operator curve analysis showed, that at a cut-off of 72 ng/ml, cord blood IGF1 predicted ISH with 72 % sensitivity; 88 % specificity and at a cut-off of 7.35 %, maternal HbA1c predicted ISH with sensitivity; specificity of 93.8 % and 72.1 % respectively. CONCLUSION: ISH was present in 46.8 % in cases as compared to none in controls. IVS thickness correlated well with maternal HbA1C and moderately with cord blood IGF-1 levels. Functional parameters on ECHO were unaffected by maternal diabetic control. At the cut-off of maternal HbA1c of 7.35 % and cord blood IGF-1 of 72 ng /ml, babies need to be monitored clinically with ECHO to look for ISH.

Sustained release resolvin D1 liposomes are effective in the treatment of osteoarthritis in obese mice.

Osteoarthritis (OA) is the most common joint disorder and currently affects >500 million patients worldwide, with ~60% of them also suffering from obesity. There is no drug approved for human use that changes the course of OA progression. OA is one of the most common comorbidities of obesity, and obesity-related OA (ObOA) is a serious health concern because it shows heightened severity of tissue damage and also predominantly affects the working population. Unresolved inflammation is a major driver of ObOA, thus, resolving disease-associated inflammation is a viable strategy to treat ObOA. Resolvins are highly potent molecules that play a role in the resolution of inflammation and promote tissue healing. However, small molecules (like Resolvin D1; RvD1) have to be administered frequently or prior to injury because they lose their in vivo activity rapidly either by lymphatic clearance, or oxidation-mediated deactivation. In this study, we have encapsulated RvD1 in liposomes and established its efficacy in the mouse model of ObOA at much lower dosages than freely administered RvD1. Liposomal RvD1 (lipo-RvD1) acted as a source of the RvD1 molecules for ~11 days in vitro in synovial fluid derived from patients. When administered prophylactically or therapeutically, lipo-RvD1 suppressed cartilage damage in male C57BL/6 mice compared to untreated and free RvD1 treatments. This efficacy was achieved by increasing the proportion of the proresolution M2 macrophages over proinflammatory M1 macrophages in the synovial membrane. These results show the potential of lipo-RvD1 as an anti-OA agent.

Intra-articular injection of rapamycin microparticles prevent senescence and effectively treat osteoarthritis.

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Rapamycin-loaded in poly(lactic-co-glycolic acid) microparticles (RMPs) induced autophagy, prevented senescence, and sustained sulphated glycosaminoglycans production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, the study demonstrates the feasibility of using RMPs as a potential clinically translatable therapy to prevent the progression of post-traumatic OA.

Use of artificial intelligence for optimizing biosorption of textile wastewater using agricultural waste.

Most of the dyes are toxic and non-biodegradable in textile industry wastewaters. Therefore, removal of textile dye using agriculture waste becomes crucial for the environment. This can be accomplished by the biosorption process which is the passive uptake of pollutants by agricultural waste. In this study, Response Surface Methodology (RSM), Artificial Neural Network (ANN) and Adaptive Neuro-Fuzzy Inference System (ANFIS) were used to obtain optimum conditions for Methylene Blue (MB) removal using sugarcane bagasse and peanut hulls as low-cost agricultural waste. The experimental design was carried out to study the effect of temperature, pH, biosorbent amount and dye concentration. The maximum MB dye removal considering the effect of total dissolved solids from aqueous solutions of 74.49% and 67.99% by sugarcane bagasse and peanut hulls, respectively. The models specify that they could predict biosorption with high accuracy having R2-value above 0.9. Statistical studies for RSM, ANFIS and ANN models were compared. Further, the models were optimized for maximum dye removal was at 1.21 g of biosorbent, pH 5.24, 31.24 mg/L MB concentration, 22.29°C of dye solution using sugarcane bagasse and at 1.37 g of biosorbent, pH 5.77, 36.7 mg/L MB concentration, 26.8°C of dye solution using peanut hulls. Additionally, Fourier Transform Infra-Red (FTIR) spectral analysis was also carried out to confirm the biosorption.

Phenomenology, disability and sexual functioning in female Dhat syndrome: a study of tertiary care gynaecology outpatients.

Background: Dhat syndrome, a clinical condition related to semen loss in urine often found among males in India, has rarely been described as a separate clinical condition in females. Women with the syndrome complain of passing vaginal discharge and can be excessively concerned and preoccupied with it, often attributing various physical symptoms to the loss of vaginal fluids. Aims: This study aimed to assess the sociodemographic and clinical profiles of female patients with Dhat syndrome and their perceived stress, disability and sexual functioning. Methods: Sociodemographic details of 70 females with non-pathological vaginal discharge were evaluated with a semistructured sociodemographic assessment. The phenomenology of the vaginal discharge was assessed with the Scale for Assessment of Female Dhat Syndrome Questionnaire. Anxiety and depressive symptoms were measured with the Hospital Anxiety and Depression Scale. Perceived stress in the past month and disability caused by the illness were assessed with the Perceived Stress Scale and the World Health Organization Disability Assessment Scale. In addition, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Level 2 Somatic Symptoms Scale was administered to rate the severity of somatic symptoms, and sexual functioning was evaluated using the Female Sexual Function Index (FSFI) scale for women who had had sexual intercourse in the past month. Results: The mean age of onset vaginal discharge was 23.0 (6.6) years. Biological factors, such as urinary tract infection, were the commonly attributed cause of the loss of vaginal fluids. Psychiatric comorbidity and perceived moderate stress in the past month were found in 38.6% and 68.6% of female patients with Dhat syndrome, respectively. Disability scores tended to be low. Among the females having had sexual intercourse in the past month, 48.3% had FSFI scores indicative of a female sexual disorder. Conclusions: The clinical presentation of women with non-pathological vaginal discharge is similar to that of males with Dhat syndrome. It requires comprehensive assessment and management that targets the biological, social and psychological factors and cultural issues.

A systematic approach towards optimization of brackish groundwater treatment using nanofiltration (NF) and reverse osmosis (RO) hybrid membrane filtration system.

This research compares the performance efficiencies of Nanofiltration (NF), Reverse osmosis (RO), and Nanofiltration-Reverse Osmosis (NF-RO) hybrid membrane filtration systems, for treatment of brackish groundwater in Delhi-NCR region. Central composite design (CCD) of response surface methodology (RSM) were applied to formulate predictive models for the optimization and simulation of various responses, viz. Water flux, salt rejection, permeate recovery and specific energy consumption (SEC). Three different input factors (feed concentration, pH and pressure) were evaluated. Significance of RSM model was tested and validated with use of an analysis of variance (ANOVA). The models were also compared graphically for their prediction ability. The optimum conditions were determined by numerical optimization of the NF and RO membrane pilot plants. Finally, hybrid configurations of NF and RO were investigated utilising the optimum conditions to identify the technology suitable for the remediation of brackish groundwater. Despite, RO membrane eliminating over 99% of TDS from groundwater, the lower recovery rate renders it environmentally unfavourable. Result indicates that recovery of the hybrid system (40.35%) was greater than that of RO alone (18.796%) and SEC also decreases (5.090-3.8 kW H/m3). Hence, combining a hybrid membrane arrangement with NF-RO to treat brackish groundwater for improved recovery and lower SEC is a viable alternative.

Resolvin D1-loaded nanoliposomes promote M2 macrophage polarization and are effective in the treatment of osteoarthritis.

Current treatments for osteoarthritis (OA) offer symptomatic relief but do not prevent or halt the disease progression. Chronic low-grade inflammation is considered a significant driver of OA. Specialized proresolution mediators are powerful agents of resolution but have a short in vivo half-life. In this study, we have engineered a Resolvin D1 (RvD1)-loaded nanoliposomal formulation (Lipo-RvD1) that targets and resolves the OA-associated inflammation. This formulation creates a depot of the RvD1 molecules that allows the controlled release of the molecule for up to 11 days in vitro. In surgically induced mice model of OA, only controlled-release formulation of Lipo-RvD1 was able to treat the progressing cartilage damage when administered a month after the surgery, while the free drug was unable to prevent cartilage damage. We found that Lipo-RvD1 functions by damping the proinflammatory activity of synovial macrophages and recruiting a higher number of M2 macrophages at the site of inflammation. Our Lipo-RvD1 formulation was able to target and suppress the formation of the osteophytes and showed analgesic effect, thus emphasizing its ability to treat clinical symptoms of OA. Such controlled-release formulation of RvD1 could represent a patient-compliant treatment for OA.

Hyperacute stroke thrombolysis via telemedicine: a multicentre study of performance, safety and clinical efficacy.

OBJECTIVES: Timely thrombolysis of ischaemic stroke improves functional recovery, yet its delivery nationally is challenging due to shortages in the stroke specialist workforce and large geographical areas. One solution is remote stroke specialist input to regional centres via telemedicine. This study evaluates the usage and key metrics of performance of the East of England Stroke Telemedicine Partnership-the largest telestroke service in the UK-in providing hyperacute stroke care. DESIGN: Prospective observational study. SETTING: The East of England Stroke Telemedicine Partnership provides a horizontal 'hubless' model of out-of-hours hyperacute stroke care to a population of 6.2 million across a 7500 square mile semirural region. PARTICIPANTS: All (2709) telestroke consultations between 1 January 2014 and 31 December 2019. MAIN OUTCOME MEASURES: Thrombolysis decision, pre-thrombolysis and post-thrombolysis stroke severity (National Institutes of Health Stroke Scale, NIHSS), haemorrhagic complications, and hyperacute pathway timings. RESULTS: Over the period, 1149 (42.4%) individuals were thrombolysed. Thrombolysis rates increased from 147/379 (38.8%) in 2014 to 225/490 (45.9%) in 2019. Median (IQR) pre-thrombolysis NIHSS was 10 (6-17), reducing to 6 (2-14) 24-hour post-thrombolysis (p<0.001). Post-thrombolysis haemorrhage occurred in 27 cases (2.3%). Over the period, median (IQR) door-to-needle time reduced from 85 (65-108) min to 68 (55-97.5) min (p<0.01), driven by improved imaging-to-needle times from 52.5 (38-72.25) min to 42 (30.5-62.5) min (p<0.01). However, the same period saw an increase in median onset-to-hospital arrival time from 77.5 (60-109.25) min to 95 (70-135) min (p<0.001). CONCLUSIONS: The results from this large hyperacute telestroke cohort indicate two important points for clinical practice. First, telemedicine via a hubless horizontal model provides a clinically effective and safe method for delivering hyperacute stroke thrombolysis. Second, improved door-to-needle times were offset by a concerning rise in prehospital timings. These findings indicate that although telemedicine may benefit in-hospital hyperacute stroke care, improvements across the whole stroke pathway are essential.

Bioengineering Strategies for Developing Vaccines against Respiratory Viral Diseases.

Respiratory viral pathogens like influenza and coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused outbreaks leading to millions of deaths. Vaccinations are, to date, the best and most economical way to control such outbreaks and have been highly successful for several pathogens. Currently used vaccines for respiratory viral pathogens are primarily live attenuated or inactivated and can risk reversion to virulence or confer inadequate immunity. The recent trend of using potent biomolecules like DNA, RNA, and protein antigenic components to synthesize vaccines for diseases has shown promising results. Still, it remains challenging to translate due to their high susceptibility to degradation during storage and after delivery. Advances in bioengineering technology for vaccine design have made it possible to control the physicochemical properties of the vaccines for rapid synthesis, heightened antigen presentation, safer formulations, and more robust immunogenicity. Bioengineering techniques and materials have been used to synthesize several potent vaccines, approved or in trials, against coronavirus disease 2019 (COVID-19) and are being explored for influenza, SARS, and Middle East respiratory syndrome (MERS) vaccines as well. Here, we review bioengineering strategies such as the use of polymeric particles, liposomes, and virus-like particles in vaccine development against influenza and coronaviruses and the feasibility of adopting these technologies for clinical use.

Motor cortical excitability predicts cognitive phenotypes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke's cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p < 0.005), while ALS-Cog (63.3 ± 12.7) and ALS (60.8 ± 13.9, not significant) were similar to controls. Short interval intracortical inhibition (SICI) was reduced across all ALS groups compared to controls, indicating hyperexcitability. On receiver operating characteristic curve analysis, RMT differentiated ALS-FTD from ALS (area under the curve AUC = 0.745, p = 0.011). The present study has identified a distinct pattern of cortical excitability across cognitive phenotypes in ALS. As such, assessment of cortical physiology may provide more precise clinical prognostication in ALS.

Response surface methodology and artificial neural network modelling for the performance evaluation of pilot-scale hybrid nanofiltration (NF) & reverse osmosis (RO) membrane system for the treatment of brackish ground water.

Artificial neural network (ANN) and response surface methodology (RSM) were employed to develop models for process optimisation of pilot scale nanofiltration (NF) and reverse osmosis (RO) membrane filtration system for the treatment of brackish groundwater. The process variables for this study were feed concentration, temperature, pH and pressure. The performance of NF/RO was assessed in terms of permeate flux, water recovery, salt rejection and specific energy consumption, which were considered as responses. The experimental design was employed to develop both RSM and ANN models. RSM model was validated for the whole range of experimental levels, while the ANN model was considered for the whole range of experimental design. RSM and ANN models were statistically analysed using analysis of variance (ANOVA). Further, the models were graphically compared for its predictive capacity. Numerical optimisation of NF and RO pilot plant to determine the optimum conditions were verified. Finally, using the optimum conditions, three hybrid configurations of NF and RO were studied to determine the best mode for the treatment of brackish groundwater. It was found that parallel NF-RO had a recovery of 57.18% and rejection of 44.89%, for RO-concentrate-NF (RO-C-NF) recovery was 49.55% and rejection of 38.64% & for NF-concentrate-RO (NF-C-RO), the recovery of 39.53% and rejection of 49.66% was obtained. Results obtained also suggested that the mode of configurations and the feed concentration affect the performance of the hybrid system.

Interrogating cortical function with transcranial magnetic stimulation: insights from neurodegenerative disease and stroke.

Transcranial magnetic stimulation (TMS) is an accessible, non-invasive technique to study cortical function in vivo. TMS studies have provided important pathophysiological insights across a range of neurodegenerative disorders and enhanced our understanding of brain reorganisation after stroke. In neurodegenerative disease, TMS has provided novel insights into the function of cortical output cells and the related intracortical interneuronal networks. Characterisation of cortical hyperexcitability in amyotrophic lateral sclerosis and altered motor cortical function in frontotemporal dementia, demonstration of cholinergic deficits in Alzheimer's disease and Parkinson's disease are key examples where TMS has led to advances in understanding of disease pathophysiology and potential mechanisms of propagation, with the potential for diagnostic applications. In stroke, TMS methodology has facilitated the understanding of cortical reorganisation that underlie functional recovery. These insights are critical to the development of effective and targeted rehabilitation strategies in stroke. The present review will provide an overview of cortical function measures obtained using TMS and how such measures may provide insight into brain function. Through an improved understanding of cortical function across a range of neurodegenerative disorders, and identification of changes in neural structure and function associated with stroke that underlie clinical recovery, more targeted therapeutic approaches may now be developed in an evolving era of precision medicine.