ClinicalGAN: powering patient monitoring in clinical trials with patient digital twins.

Conducting clinical trials is becoming increasingly challenging lately due to spiraling costs, increased time to market, and high failure rates. Patient recruitment and retention is one of the key challenges that impact 90% of the trials directly. While a lot of attention has been given to optimizing patient recruitment, limited progress has been made towards developing comprehensive clinical trial monitoring systems to determine patients at risk and potentially improve patient retention through the right intervention at the right time. Earlier research in patient retention primarily focused on using deterministic frameworks to model the inherently stochastic patient journey process. Existing generative approaches to model temporal data such as TimeGAN or CRBM , face challenges and fail to address key requirements such as personalized generation, variable patient journey, and multi-variate time-series needed to model patient digital twin. In response to these challenges, current research proposes ClinicalGAN to enable patient level generation, effectively creating a patient's digital twin. ClinicalGAN provides capabilities for: (a) patient-level personalized generation by utilizing patient meta-data for conditional generation; (b) dynamic termination prediction to enable pro-active patient monitoring for improved patient retention; (c) multi-variate time-series training to incorporate relationship and dependencies among different tests measures captured during patient journey. The proposed solution is validated on two Alzheimer's clinical trial datasets and the results are benchmarked across multiple dimensions of generation quality. Empirical results demonstrate that the proposed ClinicalGAN outperforms the SOTA approach by 3-4 × on average across all the generation quality metrics. Furthermore, the proposed architecture is shown to outperform predictive methods at the task of drop-off prediction significantly (5-10% MAPE scores).

A prospective pilot study of repetitive transcranial magnetic stimulation for gait dysfunction in vascular parkinsonism.

OBJECTIVE: Vascular Parkinsonism (VP) causes significant gait dysfunction in patients who otherwise have good lower limb strength. Its pathophysiology is not clearly understood, and current treatment with physical therapy remains unsatisfactory. The study explores repetitive transcranial magnetic stimulation (rTMS) as a potential new and safe therapy for VP. MATERIALS AND METHODS: We prospectively applied 5 Hz rTMS treatment to 5 patients who satisfied all the criteria for VP. Repetitive TMS was performed on 5 consecutive days and patients were assessed on (1) timed 10 m walk (T10MW), (2) Unified Parkinson's Disease Rating Scale (UPDRS) motor subsection, (3) Clinician's Global Impression of Change (CGIC), and (4) Patient's Global Impression of Change (PGIC), for up to 6 weeks post-rTMS. RESULTS: All the outcome measures were found to have improved ratings post-rTMS when compared with baseline, and were statistically significant. The T10MW showed significant improvement at 4 weeks post-rTMS with a trend towards improvement at 2 weeks post-rTMS. The UPDRS motor subscores was significantly reduced at 2 weeks, 4 weeks and 6 weeks post-rTMS. The PGIC and CGIC scores were significantly better post-rTMS. The treatment was well-tolerated and all patients completed the study. CONCLUSION: This study demonstrated for the first time that 5 sessions of rTMS could improve gait in a measurable way for up to 6 weeks without any significant side-effects. Repetitive TMS could be a potentially useful adjunct in rehabilitation of VP patients and further research is warranted.

Rapid screening of doping agents in human urine by vacuum MALDI-linear ion trap mass spectrometry.

Detection of doping agents in urine frequently requires extensive separation prior to chemical analyses. Gas or liquid chromatography coupled to mass spectrometry has produced accurate and sensitive assays, but chromatographic separations require time and, sometimes, chemical derivatization. To avoid such tedious and lengthy procedures, vacuum matrix-assisted laser desorption ionization (vMALDI) coupled with the linear ion trap mass spectrometry (LIT/MS) technique is tested for its applicability as a rapid screening technique. Commonly used doping agents like nandrolone, boldenone, trenbolone, testosterone, and betamethasone were chosen as study compounds. Different MALDI matrixes like alpha-cyano-4-hydroxycinnamic acid (CHCA), dihyroxy benzoic acid (DHB) with and without cetyl trimethyl ammonium bromide (CTAB), a surfactant, and meso-tetrakis(pentafluorophenyl) porphyrin (F20TPP) were tested. Among them, F20TPP (MW 974.57 Da) was selected as the preferred matrix owing to the lack of interfering matrix peaks at the lower mass range (m/z 100-700). Urine samples spiked with study compounds were processed by solid-phase extraction (SPE) and consistently detected through a linear range of 0.1-100 ng/mL. The limit of detection and lower limit of quantification for all five analytes have been determined to be 0.03 and 0.1 ng/mL, respectively, in urine samples. Testosterone-d3 was used as an internal standard, and the quantitative measurements were achieved by the selective reaction monitoring (SRM) mode. The method was validated and showed consistency in the results. Hence, vMALDI-LIT/MS can be used as a rapid screening method to complement the traditional GC/MS and LC/MS techniques for simultaneous identification, confirmation, and quantification of doping agents in urine.

Stability study of fluoxetine in formalin-fixed liver tissue.

In the present work, we report conversion of fluoxetine (Prozac), a novel anti depressant to N-methyl fluoxetine in formalin fixed liver tissue. Earlier studies indicate that drugs containing secondary amino group will react with formalin to form corresponding N-methyl derivatives. Even though embalming cadavers is common, it may create problems for forensic toxicologists if a case was not previously suspected. In formalin solutions, fluoxetine is methylated producing N-methyl fluoxetine. N-Methyl fluoxetine standard was synthesized by treating fluoxetine in formaldehyde solution. The structure confirmed by (1)HNMR and gas chromatography-mass spectrometry in electron impact ionization mode. Randomly chosen rat liver pieces (200-250 mg) were injected with 100 microg of Fluoxetine. The liver pieces were covered with three different concentrations of formalin, 5%, 10%, and 20%, and at three different pHs, 3.0, 7.0, and 9.5. The reaction was studied for a total period of 30 days, and the reaction products were monitored on days 0, 4, 14, and 30 days. The study indicates that the rate of conversion of fluoxetine to its N-methyl derivative increased with increase in the concentration of formalin and pH of the solution. The conversion is rapid at higher pH values. Fluoxetine was totally converted to its N-methyl derivatives after 30 days in 20% formalin at pH 9.5. Therefore, analysis for parent drug or its N-methyl derivative in embalmed tissues may provide data that will reduce the likelihood of false negatives.

Stability study of propoxur (Baygon) in whole blood and urine stored at varying temperature conditions.

A stability study has been initiated for propoxur (Baygon) in whole blood and urine samples stored over a period of 60 days at four different temperature conditions (room temperature, 4 degrees C, -20 degrees C, and -80 degrees C). Stability data was established on day 0, 1, 7, 14, 28, 42, and 60. Sample purification was done by solid-phase extraction using a weak cation exchange cartridge (Isolute CBA), and quantitation was carried out by a validated high-performance liquid chromatographic method with a photodiode-array UV detector. Propoxur was spiked at two different concentration levels in both blood and urine samples [low concentration (10 microg/L) and high concentration (100 microg/L)]. Isopropoxy phenol was observed as the major degradation product in blood and urine samples and confirmed by liquid chromatography-electrospray ionization-mass spectrometry. At room temperature, a substantial decrease in concentration of about 95% was observed at the end of the stability study in both blood and urine samples. However, at 4 degrees C, the concentration of propoxur observed after 60 days was around 60% in both samples. A decrease in temperature reduced the degradation, and finally propoxur was found to be stable at -80 degrees C and -20 degrees C for the whole observation period (60 days). The data collected suggests that knowledge about time-dependent decrease of propoxur in urine and blood samples is of considerable significance in forensic toxicology, and, therefore, forensic cases should be interpreted with caution.

Conversion of sertraline to N-methyl sertraline in embalming fluid: a forensic implication.

Zoloft (sertraline hydrochloride) is one of the antidepressant medications used to treat depression, obsessive-compulsive disorder, and social anxiety disorder. The practice of embalming a cadaver is common, yet it may create problems for forensic toxicologists if the case was not previously suspected to involve drug overdose. According to the Eschweiler-Clarke reaction, drugs containing a secondary amine group react with formaldehyde to give N-methyl derivatives. Sertraline has a secondary amine group; therefore, we predicted that it may react with formalin to give N-methyl derivatives. The stability of sertraline in formalin solution was studied at three different concentrations (5%, 10%, and 20%) and at three different pHs (3.0, 7.0, and 9.5) for a period of 30 days. Setraline and its degraded products were extracted by liquid-liquid extraction using chloroform, and the concentrated extracts were analyzed by gas chromatography-mass spectrometry using electron impact ionization mode. The rate of conversion is rapid at higher pH. Sertraline was totally converted to the N-methyl derivative after 30 days in 10% and 20% formalin solutions at neutral and basic conditions. Therefore, forensic toxicologists should be cautious when performing a death investigation if formalin solution is the only sample available for analysis. This work shows that analysis for parent drug or its N-methyl derivative may provide data that will reduce the likelihood of false negatives.

Subclinical hypothyroidism: an audit of management.

BACKGROUND: Subclinical hypothyroidism (SH) is a marker for overt hypothyroidism and vascular disease. Treatment guidelines are not universally followed. Thyroxine is recommended if serum thyroid-stimulating hormone (TSH) concentration is 10 mU/L or more, or if serum TSH is 5-9.9 mU/L (mild SH) with other risk factors, such as thyroid peroxidase antibodies (TPOAb). METHODS: We examined the management of mild SH in a retrospective case note audit of 150 consecutive subjects. Twenty-seven subjects with a serum TSH concentration above 10 mU/L were excluded from analysis. Of the group with mild SH, 27 were also excluded because of previous thyroid disease or amiodarone therapy. RESULTS: The prevalence of previous thyroid disease was similar in subjects with TSH 10 mU/L or more, compared to those with mild SH. Overall, both TPOAb and goitre status were determined in only 39% of subjects with mild SH, but in more by endocrinologists compared with general physicians (63% versus 22% for TPOAb; 47% versus 17% for goitre) (P = 0.001). Endocrinologists treated a greater number of subjects with mild SH who were eligible for thyroxine therapy compared to nonendocrine colleagues (96% versus 67%) (P = 0.024). Both groups treated subjects in whom TPOAb status was not determined (endocrinologists 21% versus general physicians 40%) (P = 0.21). CONCLUSION: In subjects with mild SH, evaluation is incomplete, a large percentage who were TPOAb positive were on appropriate therapy, thyroxine was prescribed when TPOAb status was unknown and, on the whole, endocrinologists performed better than general physicians.

Pneumococcal necrotizing fasciitis in a patient with Type 2 diabetes.

Necrotizing fasciitis (NF) is a rare and often fatal soft-tissue infection involving the superficial fascial layers of the extremities, abdomen or perineum. Progression to septic shock can occur very rapidly with its associated high morbidity and mortality. NF is usually caused by beta haemolytic streptococci; less often a poly-microbial isolate is the cause. It typically occurs in patients with some degree of immune dysfunction. We present a case of severe pneumococcal necrotizing fasciitis in an obese patient with Type 2 diabetes. There was no history of trauma or evidence of diabetes-related complications. The initial presentation was with features of septic arthritis of the left knee, which subsequently progressed to NF. Differentiation from cellulitis is often difficult in the early stages. Invasive pneumococcal infections are extremely rare, with only a few reported in the literature. Moreover, our case highlights the need to consider other differential diagnoses (and to look out for complications) in patients with diabetes, especially if there is little clinical response to the initial treatment.

Life-threatening thrombotic complications of relative polycythaemia.

Relative polycythaemia refers to raised haematocrit with normal red cell mass. Plasma volume may be reduced. This condition is associated with acute hypoxia, smoking, alcohol and diuretics. We describe two life-threatening thrombotic events in two patients with relative polycythaemia under age 40 years. The first had myocardial infarction and on admission haemoglobin was 21.6 g dL-1. The second developed pulmonary embolism and haemoglobin was 19.1 g dL-1. Both patients received antithrombotic measures and isovolumetric venesection. Sixteen patients (age <40 years) who attended our accident and emergency department in 1 year had a haemoglobin level of >18.0 g dL-1. Recognition of relative polycythaemia in at risk-individuals may help reduce thrombotic risk.

Kinetics of hydrolysis of sucrose catalyzed by invertase immobilized on egg shells and on zeolites.

A simple, inexpensive and reliable method for immobilizing yeast invertase on egg shells and on zeolites was developed. The activity of the immobilized preparations when compared with that of native enzyme at varying pH, temperature and substrate concentrations, showed improved stability and sigmoidal kinetic behaviour. The immobilized enzyme could be easily removed from the reaction mixture at any specified time.