Efficacy, Safety and Immunogenicity of Sun's Ranibizumab Biosimilar in Neovascular Age-Related Macular Degeneration: A Phase 3, Double-Blind Comparative Study.

INTRODUCTION: The study aimed to evaluate comparability in terms of efficacy, safety and immunogenicity of Sun's ranibizumab biosimilar with reference ranibizumab in patients with neovascular age-related macular degeneration (nAMD). METHODS: This prospective, randomised, double-blind, two-group, parallel-arm, multicentre, phase 3 comparative study included patients with nAMD ≥ 50 years, randomised (in a 2:1 ratio) in a double-blind manner to receive 0.5 mg (0.05 mL) intravitreal injection of either Sun's ranibizumab or reference ranibizumab in the study eye every 4 weeks until week 16 (total of four doses). RESULTS: Primary endpoint results demonstrated equivalence in the proportion of patients who lost fewer than 15 letters from baseline best-corrected visual acuity (BCVA) to the end of week 16 (99% of patients in Sun's ranibizumab and 100% in reference ranibizumab; p > 0.9999), with the proportional difference (90% confidence interval) at -1% (-2.51, +0.61) lying within a pre-specified equivalence margin. Visual acuity improved by 15 or more letters in 43% of Sun's ranibizumab group and 37% of the reference ranibizumab group (p = 0.4267). The mean increase in BCVA was 15.7 letters in Sun's ranibizumab group and 14.6 letters in the reference ranibizumab group (p < 0.001 within both groups and p = 0.5275 between groups). The mean change in central macular thickness was comparable between groups (p = 0.7946). Anti-ranibizumab antibodies were found in one patient of the reference ranibizumab group, while neutralising antibodies were not found in any patients. Both products were well tolerated. CONCLUSION: Sun's ranibizumab biosimilar is found to be therapeutically equivalent to reference ranibizumab in patients with nAMD. There were no additional safety or immunogenicity concerns. TRIAL REGISTRATION: CTRI/2020/09/027629, registered on 07 September 2020.

Nonketotic hyperglycemia hemichorea and hemiballismus: a case report.

BACKGROUND: Diabetic striatopathy, also known as hyperglycemic hemichorea-hemiballismus, is a rare movement disorder associated with nonketotic hyperglycemia in patients with poorly controlled diabetes mellitus. The pathophysiology is not fully elucidated but may involve hyperviscosity, ischemia, and alterations in basal ganglia neurotransmitters. CASE PRESENTATION: We present a case of a 64-year-old Asian female patient with longstanding poorly controlled type 2 diabetes mellitus who developed abrupt-onset right-sided hemichorea-hemiballismus. Laboratory results showed hyperglycemia without ketoacidosis. Neuroimaging revealed left putaminal hyperdensity on computed tomography and T1 hyperintensity on magnetic resonance imaging. With insulin therapy and tetrabenazine, her movements improved but persisted at 1-month follow-up. DISCUSSION: This case illustrates the typical features of diabetic striatopathy, including acute choreiform movements contralateral to neuroimaging abnormalities in the setting of nonketotic hyperglycemia. While neuroleptics may provide symptomatic relief, prompt glycemic control is critical given the risk of recurrence despite imaging normalization. CONCLUSION: Diabetic striatopathy should be recognized as a rare disorder that can occur with poorly controlled diabetes. Further study of its pathophysiological mechanisms is needed to better guide management. Maintaining tight glycemic control is essential to prevent recurrence of this debilitating movement disorder.

Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.

Chitosan as excellent bio-macromolecule with myriad of anti-activities in biomedical applications - A review.

The aim of the study is to explore the myriad of anti-activities of chitosan - deacylated derivative of chitin in biomedical applications. Chitosan consists of reactive residual amino groups, which can be modified chemically to obtain wide range of derivatives. These derivatives exhibit the controlled physicochemical characteristics, which in turn improve its functional properties. Such derivatives find numerous applications in the field of biomedical science, agriculture, tissue engineering, bone regeneration and environmental science. This study presents a comprehensive overview of the multifarious anti-activities of chitosan and its derivatives in the field of biomedical science including anti-microbial, antioxidant, anti-tumor, anti-HIV, anti-fungal, anti- inflammatory, anti-Alzheimer's, anti-hypertensive and anti-diabetic activity. It briefly details these anti-activities with respect to its mode of action, pharmacological effects and potential applications. It also presents the overview of current research exploring novel derivatives of chitosan and its anti- activities in the recent past. Finally, the review projects the prospective potential of chitosan and its derivatives and expects to encourage the readers to develop new drug delivery systems based on such chitosan derivatives and explore its applications in biomedical science for benefit of mankind.

Estimation of air pollution tolerance and anticipated performance index of roadside plants along the national highway in a tropical urban city.

One of the most serious environmental issues is air pollution. Unlike other environmental concerns, this form of pollution is extremely challenging to regulate. The greenery of roadside trees plays a significant role in air purification and pollutant absorption, therefore helping to mitigate environmental pollution. Several plants can absorb and store toxins in their leaves from the atmosphere. Green plants have the potential to work as sinks and filters for air pollutants. Green belt development along national highways is a cost-effective and environmentally sustainable method of reducing air pollution. Sensitive and tolerant plants against air pollution can be identified by evaluating their air pollution tolerance index (APTI) and anticipated performance index (API) values. In this study, the susceptibility level of plant species to air pollution was assessed using APTI and API. The four parameters on which APTI depends are ascorbic acid content, total chlorophyll content, relative water content, and leaf extract pH. For the estimation of API, the plant's biological and socioeconomic factors like tree habit, canopy structure, type, size, texture, and hardness of the plant are also assessed. These parameters were determined and incorporated into a formula that represents the APTI and API of plants. Moreover, multilinear regression modeling was performed using a Statistical Package for the Social Sciences (SPSS, V25) and found that pH and ascorbic acid content in plant leaves have a significant role in the calculation of APTI and tolerance potential of plants. Therefore, APTI was assessed with seventeen plant species that are abundant in the area along the national highway in Kanpur, Uttar Pradesh, from Jan to Mar 2020. The APTI showed that Saraca asoca was the most resistant to air pollution, whereas Vachellia nilotica was the most sensitive. In addition, plants with higher APTI can also be used to reduce air pollution, while plants with lower APTI can be utilized to monitor air pollution. Based on the calculated API score, it is found that Ficus elastica (% score > 90) is the best option for green belt development. Urban local body (ULB) can also adopt Ficus religiosa, Saraca asoca, and Aucuba japonica (having % a grade score of 80-90) for mitigation of air pollution. The study indicates that plantations of tolerant species are useful for biomonitoring and developing green belts on and along national highways.

Quantification of Digital Body Maps for Pain: Development and Application of an Algorithm for Generating Pain Frequency Maps.

BACKGROUND: Pain is an unpleasant sensation that signals potential or actual bodily injury. The locations of bodily pain can be communicated and recorded by freehand drawing on 2D or 3D (manikin) surface maps. Freehand pain drawings are often part of validated pain questionnaires (eg, the Brief Pain Inventory) and use 2D templates with undemarcated body outlines. The simultaneous analysis of drawings allows the generation of pain frequency maps that are clinically useful for identifying areas of common pain in a disease. The grid-based approach (dividing a template into cells) allows easy generation of pain frequency maps, but the grid's granularity influences data capture accuracy and end-user usability. The grid-free templates circumvent the problem related to grid creation and selection and provide an unbiased basis for drawings that most resemble paper drawings. However, the precise capture of drawn areas poses considerable challenges in producing pain frequency maps. While web-based applications and mobile-based apps for freehand digital drawings are widely available, tools for generating pain frequency maps from grid-free drawings are lacking. OBJECTIVE: We sought to provide an algorithm that can process any number of freehand drawings on any grid-free 2D body template to generate a pain frequency map. We envisage the use of the algorithm in clinical or research settings to facilitate fine-grain comparisons of human pain anatomy between disease diagnosis or disorders or as an outcome metric to guide monitoring or discovery of treatments. METHODS: We designed a web-based tool to capture freehand pain drawings using a grid-free 2D body template. Each drawing consisted of overlapping rectangles (Scalable Vector Graphics elements) created by scribbling in the same area of the body template. An algorithm was developed and implemented in Python to compute the overlap of rectangles and generate a pain frequency map. The utility of the algorithm was demonstrated on drawings obtained from 2 clinical data sets, one of which was a clinical drug trial (ISRCTN68734605). We also used simulated data sets of overlapping rectangles to evaluate the performance of the algorithm. RESULTS: The algorithm produced nonoverlapping rectangles representing unique locations on the body template. Each rectangle carries an overlap frequency that denotes the number of participants with pain at that location. When transformed into an HTML file, the output is feasibly rendered as a pain frequency map on web browsers. The layout (vertical-horizontal) of the output rectangles can be specified based on the dimensions of the body regions. The output can also be exported to a CSV file for further analysis. CONCLUSIONS: Although further validation in much larger clinical data sets is required, the algorithm in its current form allows for the generation of pain frequency maps from any number of freehand drawings on any 2D body template.

Imputation strategies for missing baseline neurological assessment covariates after traumatic brain injury: A CENTER-TBI study.

Statistical models for outcome prediction are central to traumatic brain injury research and critical to baseline risk adjustment. Glasgow coma score (GCS) and pupil reactivity are crucial covariates in all such models but may be measured at multiple time points between the time of injury and hospital and are subject to a variable degree of unreliability and/or missingness. Imputation of missing data may be undertaken using full multiple imputation or by simple substitution of measurements from other time points. However, it is unknown which strategy is best or which time points are more predictive. We evaluated the pseudo-R2 of logistic regression models (dichotomous survival) and proportional odds models (Glasgow Outcome Score-extended) using different imputation strategies on the The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study dataset. Substitution strategies were easy to implement, achieved low levels of missingness (<< 10%) and could outperform multiple imputation without the need for computationally costly calculations and pooling multiple final models. While model performance was sensitive to imputation strategy, this effect was small in absolute terms and clinical relevance. A strategy of using the emergency department discharge assessments and working back in time when these were missing generally performed well. Full multiple imputation had the advantage of preserving time-dependence in the models: the pre-hospital assessments were found to be relatively unreliable predictors of survival or outcome. The predictive performance of later assessments was model-dependent. In conclusion, simple substitution strategies for imputing baseline GCS and pupil response can perform well and may be a simple alternative to full multiple imputation in many cases.

CoV2-Detect-Net: Design of COVID-19 prediction model based on hybrid DE-PSO with SVM using chest X-ray images.

For Covid-19 suspected cases, it is critical to diagnose them accurately and rapidly so that they can be isolated and provided with required medical care. A self-learning automation model will be helpful to diagnose the COVID-19 suspected individual using chest X-rays. AI based designs, which utilizes chest X-rays, have been recently proposed for the detection of COVID-19. However, these approaches are either using non-public database or having a complex design. In this study we have proposed a novel framework for real time detection of coronavirus patients without manual intervention. In our framework, we have introduced a 3-step process in which initially K-means clustering, and feature extraction is performed as a data pre-processing step. In the second step, the selected features are optimized by a novel feature optimization approach based on hybrid differential evolution algorithm and particle swarm optimization. The optimized features are then feed forwarded to SVM classifier. Empirical results show that our proposed model is able to achieve 99.34% accuracy. This shows that our model is robust and sustainable in diagnosis of COVID-19 infected individual.

Use and impact of high intensity treatments in patients with traumatic brain injury across Europe: a CENTER-TBI analysis.

PURPOSE: To study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European Intensive Care Units (ICUs). METHODS: We studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO2 < 4 kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended (GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP. RESULTS: 313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio = 2.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE ≥ 5). The use of high TIL treatment was not significantly associated with worse outcome (285 matched pairs, OR 1.4, 95% CI [1.0-2.0]). However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome. CONCLUSION: Substantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies. TAKE HOME MESSAGE: Substantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments. TRIAL REGISTRATION: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014, https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582).

Enantioselective in vitro ADME, absolute oral bioavailability, and pharmacokinetics of (-)-lumefantrine and (+)-lumefantrine in mice.

Lumefantrine (LFN) is a chiral antimalarial drug. Enantioselective in vitro attributes and absolute oral pharmacokinetics for (-)-LFN and (+)-LFN have been characterized in mice. No stereoselectivity was seen with either of the enantiomers when compared with rac-LFN in the executed in vitro studies (solubility, metabolic stability, protein binding, permeability and blood partitioning). Post intravenous or oral administration of rac-LFN, the AUC0-∞ and MRT of (+)-LFN was higher over (-)-LFN, which is reflected in higher clearance value for (-)-LFN. Following (-)-LFN intravenous administration to mice, the key PK parameters were comparable to (-)-LFN from rac-LFN; however, post intravenous administration of (+)-LFN alone to mice, the AUC0-∞ was 1.3-fold higher than (+)-LFN from rac-LFN. Similarly, post oral administration of (-)-LFN to mice, both AUC0-∞ and Cmax were 1.3-fold higher than (-)-LFN from rac-LFN. On other hand, (+)-LFN showed 1.4-fold higher AUC0-∞ and 1.7-fold higher Cmax post oral administration over (+)-LFN from rac-LFN.

Novel methodology to perform incurred sample reanalysis on dried blood spot cards: Experimental data using darolutamide and filgotinib.

Different options on performing incurred sample reanalysis (ISR) on dried blood spot (DBS) cards were investigated using drugs belonging to various therapeutic areas: (a) darolutamide (to treat prostate cancer) and (b) filgotinib (to treat rheumatoid arthritis). The proposed novel methodology included the generation of half-DBS and quarter-DBS discs after initial blood collection using the full-DBS discs. Accordingly, blood collection via DBS was performed in male BALB/c mice following intravenous and oral dosing of darolutamide; in male Sprague Dawley rats following intravenous and oral dosing of filgotinib. The ISR data generated from the full-DBS disc, half-DBS disc and quarter-DBS disc were compared for the assessment of the proposed methodology. Quantification of darolutamide and filgotinib was accomplished using liquid chromatography-electrospray ionization/tandem mass spectrometry methods. Darolutamide and filgotinib ISR samples, which were collected and prepared using full-, half- and quarter-DBS discs, met the acceptance criteria for ISR analysis. In conclusion, this is the first report showing a viable tool for the performance of ISR on DBS cards. The use of quarter- or half-DBS discs would aid in not only ISR but also in long-term storage experiments of analytes because it would avoid the need for additional blood sampling in patients.

Enantioselective LC-ESI-MS/MS method for quantitation of (-)-lumefantrine and (+)-lumefantrine in mice plasma and application to a pharmacokinetic study.

We developed and validated a simple, sensitive, selective, and reliable LC-MS/MS-ESI method for the direct quantitation of lumefantrine (LFN) enantiomers [(-)-LFN and (+)-LFN] in mice plasma as per regulatory guideline. LFN enantiomers and carbamazepine (internal standard) were extracted from mice plasma using Strata X SPE (solid-phase extraction) cartridges. Good resolution between enantiomers was achieved on a Chiralpak IA-3 column using an isocratic mobile phase (0.1% of diethyl amine in methanol), which was delivered at a flow rate of 0.8 mL/min. Detection and quantitation were performed using multiple reaction monitoring mode following the transitions m/z 530.27 → 512.30 and 237.00 → 194.00 for LFN enantiomers and the internal standard, respectively, in the positive-ionization mode. The proposed method provided accurate and reproducible results over the linearity range of 2.39-895 ng/mL for each enantiomer. The intra- and inter-day precisions were in the range of 1.03-6.14 and 6.36-8.70 and 2.03-4.88 and 5.82-11.5 for (-)-LFN and (+)-LFN, respectively. Both (-)-LFN and (+)-LFN were found to be stable under different stability conditions. The method was successfully used to delineate stereoselective pharmacokinetics of LFN enantiomers in mice after an oral administration of rac-LFN (20 mg/kg). The pharmacokinetic results indicated that the disposition of LFN enantiomers was stereoselective in mice.

Validated LC-MS/MS method for quantitation of a selective JAK1 inhibitor, filgotinib in rat plasma, and its application to a pharmacokinetic study in rats.

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, filed in Japan for the treatment of rheumatoid arthritis. In this paper, we report a validated liquid chromatography coupled with tandem mass spectrometry for the quantification of filgotinib in rat plasma using tofacitinib as an internal standard (IS) as per the Food and Drug Administration regulatory guidelines. Filgotinib and the IS were extracted from rat plasma using ethyl acetate as an extraction solvent and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 20:80, v/v) at a flow rate of 0.9 mL/min on a Gemini C18 column. Filgotinib and the IS were eluted at ~1.31 and 0.89 min, respectively. The MS/MS ion transitions monitored were m/z 426.3 → 291.3 and m/z 313.2 → 149.2 for filgotinib and the IS, respectively. The calibration range was 0.78-1924 ng/mL. No matrix effect and carryover were observed. Intra- and inter-day accuracies and precisions were within the acceptance range. Filgotinib was stable for three freeze-thaw cycles: on bench-top up to 6 h, in an autosampler up to 21 h, and at -80°C for 1 month. This novel method has been applied to a pharmacokinetic study in rats.

Validated DBS method for filgotinib quantitation in rat dried blood spots and its application to a pharmacokinetic study in rats.

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, showed efficacy in patients suffering from moderate-to-severe rheumatoid arthritis. In this paper, we present the data on the development and validation of a sensitive, selective and high-throughput LC-MS/MS (liquid chromatography with tandem mass spectrometry) method for the quantitation of filgotinib from rat dried blood spot (DBS) cards. To the DBS disc cards, 0.2% formic acid enriched with internal standard (IS) was added and sonicated. Thereafter the extraction of filgotinib and the IS (tofacitinib) was accomplished using ethyl acetate as an extraction solvent. The resolution of filgotinib and the IS was achieved on a Gemini C18 column with an isocratic mobile phase, which is a mixture of 0.2% formic acid:acetonitrile (20:80, v/v) at a flow-rate of 0.9 mL/min. The total run time was 2.90 min and the retention time of filgotinib and the IS was ~1.31 and 0.89 min, respectively. Filgotinib and the IS were analyzed using positive ion scan mode and parent-daughter mass to charge ion (m/z) transition of 426.3→291.3 and m/z 313.2→149.2, respectively, for quantitation. The calibration range was 1.37-1937 ng/mL. No matrix effect and carry over were observed. All the validation parameters met the acceptance criteria. The validated method has been applied to a pharmacokinetic study in rats. A good correlation between DBS and plasma concentrations for filgotinib was observed.

Relationship between the Use of Aluminium Utensils for Cooking Meals and Chronic Aluminum Toxicity in Patients on Maintenance Hemodialysis: A Case Control Study.

BACKGROUND: Chronic aluminum toxicity (CAT) in end stage kidney disease (ESKD) patients is now a rare clinical disorder, unlike in the past, because of improvements in hemodialysis water purification systems and discontinuation of use of aluminum hydroxide as a phosphate binder. The use of aluminum utensils for cooking could be an unrecognised cause of the CAT. OBJECTIVE: To assess the association between aluminum kitchen utensils used for cooking meals and chronic aluminum toxicity (CAT) in patients on maintenance hemodialysis (MHD). MATERIAL AND METHODS: In this case control study, a total of 31 (cases n=10; controls n=21) patients on MHD for more than one year were included. Cases were defined as patients with clinical manifestations (including laboratory parameters) of CAT and high (>200 mcg/L) serum aluminum levels. Control group was chosen from the same hemodialysis facilities. Association between use of aluminum utensils for cooking and occurrence of CAT was assessed. RESULTS: The mean age of patients in the cases and the control group was 52.90 and 52.95 years respectively with on significant difference (p=0.99). There was no difference in mean duration of dialysis (p=0.78), serum calcium level (p=0.06), serum phosphate level (p=0.19), serum albumin level (p=0.06), history of hypertension (p=1.00) and history of diabetes (n=0.12) between two groups. Mean haemoglobin (p<0.05) and mean iPTH (p<0.05) was significantly lower in the cases as compared to control group. Thirteen patients had history of use of aluminum utensils [cases 10 (76.90%) and control 3 (23.10%); p<0.05]. All cases i.e. 10 (100%) had exposure to aluminum utensils whereas three (14.3%) patients in the control group had exposure to aluminum utensils whereas 18 (85.7%) patients had no exposure. The relative risk of having CAT because of use of aluminum utensils compared to not using was 28.46 (1.81 to 445.3) and the odd's ratio estimated was 120 (5.45 to 2642). CONCLUSION: Use of aluminum utensils for cooking meals is associated with CAT. Larger studies are required to confirm these findings.

Determination of Tofacitinib in Mice Whole Blood on Dried Blood Spots Using LC-ESI-MS/MS: Application to Pharmacokinetic Study in Mice.

A simple, sensitive and rapid assay method has been developed and validated as per regulatory guideline for the estimation of tofacitinib on mice dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. The method employs liquid extraction of tofacitinib from DBS disk of mice whole blood followed by chromatographic separation using 5 mM ammonium acetate (pH 6.5):acetonitrile (20:80, v/v) at a flow rate of 0.60 mL/min on an X-Terra Phenyl column with a total run time 2.5 min. The MS/MS ion transitions monitored were m/z 313→149 for tofacitinib and m/z 316→149 for the internal standard (13C3, 15N-tofacitinib). The assay was linear in the range of 0.99-1980 ng/mL. The intra- and inter-day precision was in the range of 1.17-10.3 and 3.37-10.9%, respectively. Stability studies showed that tofacitinib was stable on DBS cards for one month. This novel method has been applied to analyze the DBS samples of tofacitinib obtained from a pharmacokinetic study in mice.

Optimal intensive care outcome prediction over time using machine learning.

BACKGROUND: Prognostication is an essential tool for risk adjustment and decision making in the intensive care unit (ICU). Research into prognostication in ICU has so far been limited to data from admission or the first 24 hours. Most ICU admissions last longer than this, decisions are made throughout an admission, and some admissions are explicitly intended as time-limited prognostic trials. Despite this, temporal changes in prognostic ability during ICU admission has received little attention to date. Current predictive models, in the form of prognostic clinical tools, are typically derived from linear models and do not explicitly handle incremental information from trends. Machine learning (ML) allows predictive models to be developed which use non-linear predictors and complex interactions between variables, thus allowing incorporation of trends in measured variables over time; this has made it possible to investigate prognosis throughout an admission. METHODS AND FINDINGS: This study uses ML to assess the predictability of ICU mortality as a function of time. Logistic regression against physiological data alone outperformed APACHE-II and demonstrated several important interactions including between lactate & noradrenaline dose, between lactate & MAP, and between age & MAP consistent with the current sepsis definitions. ML models consistently outperformed logistic regression with Deep Learning giving the best results. Predictive power was maximal on the second day and was further improved by incorporating trend data. Using a limited range of physiological and demographic variables, the best machine learning model on the first day showed an area under the receiver-operator characteristic curve (AUC) of 0.883 (σ = 0.008), compared to 0.846 (σ = 0.010) for a logistic regression from the same predictors and 0.836 (σ = 0.007) for a logistic regression based on the APACHE-II score. Adding information gathered on the second day of admission improved the maximum AUC to 0.895 (σ = 0.008). Beyond the second day, predictive ability declined. CONCLUSION: This has implications for decision making in intensive care and provides a justification for time-limited trials of ICU therapy; the assessment of prognosis over more than one day may be a valuable strategy as new information on the second day helps to differentiate outcomes. New ML models based on trend data beyond the first day could greatly improve upon current risk stratification tools.