Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Production of Stable Electrically Conductive PVDF Membranes Based on Polydopamine-Polyethyleneimine-Assisted Deposition of Carbon Nanotubes.

Electrically conductive membranes (ECMs) have emerged as a multifunctional separation technology that integrates membrane filtration with electrochemical reactions. Physical stability remains a critical challenge for ECMs synthesized by coating polymer membranes with conductive materials. In this article, polydopamine (PDA) and polyethyleneimine (PEI) were used to facilitate the synthesis of significantly more stable ECMs using poly(vinylidene fluoride) (PVDF) ultrafiltration membranes and carbon nanotubes (CNTs). Four different synthesis methods were compared in terms of the final surface stability and separation properties: (1) CNTs deposited on PEI-crosslinked PDA-coated PVDF membranes, (2) PEI-crosslinked CNTs deposited on PDA-coated PVDF, (3) PDA, PEI and CNTs sequentially deposited layer-by-layer on PVDF, and (4) PEI-crosslinked PDA deposited on CNT-coated PVDF. The results revealed that method 1 generated ECMs with the greatest physical stability, highest electrical conductivity (18,518 S/m), and sufficient permeability (395.2 L/(m2·h·bar). In comparison, method 2 resulted in membranes with the highest permeability (2128.5 L/(m2·h·bar), but with low surface conductivity (502 S/m) and poor physical stability (i.e., 53-75% lower peel-off forces compared to other methods). Overall, methods 1, 3, and 4 can be used to make highly conductive membranes with a 97-99% removal of methyl orange by electrochemical degradation at -3 V.

Liver tissues oxidative status, epigenetic and molecular characteristics in rats administered magnetic and microwave treated water.

Physical and chemical changes in the natural of water may affect biological organisms. In this study, we highlight the effect of magnetized-water and microwave-water on rats' liver tissues. Three groups of albino rats were separated. The first, rats were administered tap-water. The second, rats were administered magnetized-water. The third, rats were administered microwave-water. After two months, the results revealed a significant increase in liver functioning enzymes' levels and bilirubin in rats administered microwave-water, compared to tap- and magnetic-water. In relation to oxidative stress, there was a significant increase and decrease in oxidative and antioxidant parameters respectively in liver tissues of rat's administrated microwave-water. At the molecular level, there was a significant down-regulation in Metallothionein, CYP genes in magnetic-water compared to tap-water. Rats administered microwave-water have shown a significant down-regulation in GST, Metallothionein and CYP genes' expression, however, Amylase and HDAC3 genes were significantly up-regulated, compared to the other groups. The intake of microwave-water resulted in notable histopathological changes in liver tissues. Rats administered magnetic-water showed no clear changes in their liver tissues. In summary, microwave-water induced stress and epigenetic effects compared with magnetic-water and tap-water. Also, magnetic-water produced from the higher magnetic power had no side effect on liver tissues.

Effect of Preoperative Antianxiety Medications on Blood Pressure and Blood Loss in Total Knee Arthroplasty: A Case-Control Study.

Background: The increasing number of canceled operations in patients undergoing total knee arthroplasty (TKA) due to high blood pressure readings has put a considerable burden on surgeons. In this study, we aim to assess the effect of giving antianxiety drugs preoperatively on maintaining blood pressure (BP) and blood loss for patients undergoing TKA surgery. Methods: This retrospective case-control study included patients who underwent total knee arthroplasty and divided them into two main groups: those who had taken a 3 mg bromazepam oral tablet at the night preoperatively and the control group. The blood pressure of patients was then measured preoperatively (baseline), in the morning of surgery, in the operating room before anesthesia, and during the surgery. The percentage of measured BP was calculated by dividing the measured BP by the baseline, then multiplying by 100. Results: 301 patients were included in our study: 137 received bromazepam and 164 as a control group. The ratio of systolic BP (SBP) in the morning of surgery to the baseline (percentage of morning SBP) decreased significantly in the bromazepam group compared with the controls. The ratio of SBP, in the operating room before anesthesia (percentage of preanesthesia SBP) also decreased significantly in the bromazepam group. However, the percentage of SBP in the middle of surgery did not change significantly. In addition, there was a significant difference change from the baseline in diastolic BP and mean arterial BP between the two groups in the morning of surgery, inside the theatre, and in the middle of the operation. The bromazepam group also showed a significant decrease in blood loss. Conclusion: Preoperative oral antianxiety drugs (bromazepam) helps in controlling hemodynamic changes associated with anxiety, including maintaining BP in well-controlled hypertensive and healthy patients undergoing TKA, and it plays a role in decreasing the total blood loss.

Novel Algorithm for Automated Optic Nerve Sheath Diameter Measurement Using a Clustering Approach.

INTRODUCTION: Using ultrasound to measure optic nerve sheath diameter (ONSD) has been shown to be a useful modality to detect elevated intracranial pressure. However, manual assessment of ONSD by a human operator is cumbersome and prone to human errors. We aimed to develop and test an automated algorithm for ONSD measurement using ultrasound images and compare it to measurements performed by physicians. MATERIALS AND METHODS: Patients were recruited from the Neurological Intensive Care Unit. Ultrasound images of the optic nerve sheath from both eyes were obtained using an ultrasound unit with an ocular preset. Images were processed by two attending physicians to calculate ONSD manually. The images were processed as well using a novel computerized algorithm that automatically analyzes ultrasound images and calculates ONSD. Algorithm-measured ONSD was compared with manually measured ONSD using multiple statistical measures. RESULTS: Forty-four patients with an average/Standard Deviation (SD) intracranial pressure of 14 (9.7) mmHg were recruited and tested (with a range between 1 and 57 mmHg). A t-test showed no statistical difference between the ONSD from left and right eyes (P > 0.05). Furthermore, a paired t-test showed no significant difference between the manually and algorithm-measured ONSD with a mean difference (SD) of 0.012 (0.046) cm (P > 0.05) and percentage error of difference of 6.43% (P = 0.15). Agreement between the two operators was highly correlated (interclass correlation coefficient = 0.8, P = 0.26). Bland-Altman analysis revealed mean difference (SD) of 0.012 (0.046) (P = 0.303) and limits of agreement between -0.1 and 0.08. Receiver Operator Curve analysis yielded an area under the curve of 0.965 (P < 0.0001) with high sensitivity and specificity. CONCLUSION: The automated image-analysis algorithm calculates ONSD reliably and with high precision when compared to measurements obtained by expert physicians. The algorithm may have a role in computer-aided decision support systems in acute brain injury.

Resonance Raman Spectroscopy Derived Tissue Hemoglobin Oxygen Saturation in Critically Ill and Injured Patients.

BACKGROUND: In this study, we examined the ability of resonance Raman spectroscopy to measure tissue hemoglobin oxygenation (R-StO2) noninvasively in critically ill patients and compared its performance with conventional central venous hemoglobin oxygen saturation (ScvO2). METHODS: Critically ill patients (n = 138) with an indwelling central venous or pulmonary artery catheter in place were consented and recruited. R-StO2 measurements were obtained by placing a sensor inside the mouth on the buccal mucosa. R-StO2 was measured continuously for 5 min. Blood samples were drawn from the distal port of the indwelling central venous catheter or proximal port of the pulmonary artery catheter at the end of the test period to measure ScvO2 using standard co-oximetry analyzer. A regression algorithm was used to calculate the R-StO2 based on the observed spectra. RESULTS: Mean (SD) of pooled R-StO2 and ScvO2 were 64(7.6) % and 65(9.2) % respectively. A paired t test showed no significant difference between R-StO2 and ScvO2 with a mean(SD) difference of -1(7.5) % (95% CI: -2.2, 0.3%) with a Clarke Error Grid demonstrating 84.8% of the data residing within the accurate and acceptable grids. Area under the receiver operator curve for R-StO2's was 0.8(0.029) (95% CI: 0.7, 0.9 P < 0.0001) at different thresholds of ScvO2 (≤60%, ≤65%, and ≤70%). Clinical adjudication by five clinicians to assess the utility of R-StO2 and ScvO2 yielded Fleiss' Kappa agreement of 0.45 (P < 0.00001). CONCLUSIONS: R-StO2 has the potential to predict ScvO2 with high precision and might serve as a faster, safer, and noninvasive surrogate to these measures.

An empirical determination of the whole-life cost of FO-based open-loop wastewater reclamation technologies.

Over the past 5-10 years it has become apparent that the significant energy benefit provided by forward osmosis (FO) for desalination arises only when direct recovery of the permeate product from the solution used to transfer the water through the membrane (the draw solution) is obviated. These circumstances occur specifically when wastewater purification is combined with saline water desalination. It has been suggested that, for such an "open loop" system, the FO technology offers a lower-cost water reclamation option than the conventional process based on reverse osmosis (RO). An analysis is presented of the costs incurred by this combined treatment objective. Three process schemes are considered combining the FO or RO technologies with membrane bioreactors (MBRs): MBR-RO, MBR-FO-RO and osmotic MBR (OMBR)-RO. Calculation of the normalised net present value (NPV/permeate flow) proceeded through developing a series of empirical equations based on available individual capital and operating cost data. Cost curves (cost vs. flow capacity) were generated for each option using literature MBR and RO data, making appropriate assumptions regarding the design and operation of the novel FO and OMBR technologies. Calculations revealed the MBR-FO-RO and OMBR-RO schemes to respectively offer a ∼20% and ∼30% NPV benefit over the classical MBR-RO scheme at a permeate flow of 10,000 m3  d-1, provided the respective schemes are applied to high and low salinity wastewaters. Outcomes are highly sensitive to the FO or OMBR flux sustained: the relative NPV benefit (compared to the classical system) of the OMBR-RO scheme declined from 30% to ∼4% on halving the OMBR flux from a value of 6 L m-2. h-1.