Search

The presence of aggregates in monoclonal antibody (mAb) drug product (DP) formulations can present product quality challenges. Here we show that use of High Performance Size Exclusion Chromatography (HP-SEC), in conjunction with high-throughput dynamic light scattering (HT-DLS) analyses of mAb DPs can be a useful strategy to determine monomer content and the presence of aggregates under simulated stress conditions. This analytical approach was used to evaluate four commercially available mAb DPs under different conditions i.e.; original formulations, diluted, and thermo-mechanical stressed condition. Due to particle size limitations of HP-SEC columns, resulting in particles accumulating in the column frits prior to reaching the detector for analysis, there is a possibility that large mAb aggregates may not be detected. Both HP-SEC and HT-DLS were able to detect and resolve the mAb monomer (~10–12 nm) of the DPs in their recommended storage conditions. However, the ability to detect large aggregates (>40 nm) by both analytical methods differed, and HT-DLS was able to detect aggregates between 60 nm and 1400 nm under stress conditions. Our data indicates that HP-SEC, in conjunction with HT-DLS, may be beneficial to detect both mAb DP monomer content and multiple aggregate species (1–1000 nm) in the submicron size range.

Objective To perform a pilot study of short-term safety, tolerability, and impact on urinary stone risk parameters of the vasopressin V2-receptor antagonist tolvaptan (which increases urinary excretion of free water) among adolescents and young adults with cystinuria. Materials and Methods We enrolled cystinuria patients age 12-25 years. Subjects were treated for 4 days at low-dose tolvaptan (0.3 mg/kg/day, maximum 30 mg) and 4 days at high dose (0.6 mg/kg/day, maximum 60 mg). Twenty-four-hour urine collections were done at baseline, day 3-4 of the dosing period, day 7-8 of the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L, target capacity > 0). Secondary outcomes included other urinary/serum parameters, tolerability, and thirst response. Results Two females (17, 23 years) and 2 males (13, 24 years) were enrolled. Cystine capacity respectively went from baseline of −312, −82, −353, and −628 mg/L to 97, 111, 75, and −3 mg/L on high dose (Figure 1). Twenty-four-hour volume went from 1.96, 3.0, 2.1, and 0.91 L to 11.74, 6.5, 9.9, and 2.8 L on high dose (Figure 2). There were no abnormalities in serum electrolytes or liver enzymes. Subjects did experience extreme thirst (9/10 on visual scale), but none discontinued treatment or reduced dose. Conclusion Dilutional therapy with tolvaptan increased both cystine capacity and urinary volumes. This treatment approach has the potential to reduce recurrence of stones in this population. Further investigation should study longer term effects and safety, and determine optimal dosing to improve tolerability.

Objective To assess the accuracy of renal ultrasound (RUS) in detecting renal scarring (RS). Methods All initial DMSA scans performed from 2006 to 2009 for history of urinary tract infection (UTI) or vesicoureteral reflux (VUR) in patients under 14 years old were identified, and clinical history obtained via chart review. Patients who had RUS within 4 months of DMSA scan and no documented UTI during that interval were included. Decreased uptake of tracer associated with loss of contours or cortical thinning defined a positive DMSA study. Increased echogenicity/dysplasia, cortical thinning, atrophic kidney and/or abnormal corticomedullary differentiation defined a positive RUS. The sensitivity and specificity of RUS in identifying RS were calculated using DMSA scan as the gold standard. Results A total of 144 patients had initial DMSA scans performed for UTI or VUR, with a RUS within 4 months, and no UTI between the 2 studies. Ninety-five of 144 (66%) had RS on DMSA and 49/144 (34%) did not. Patients with or without RS on DMSA were not different in gender (P = .073), age (P = .432), insurance (P = 1.000) or VUR grade (P = .132). Only 39/144 (27.1%) patients had positive RUS. The sensitivity of RUS for RS was 35.8% and the specificity was 89.8%, leading to an accuracy of 54.2% (95%CI; 45.7-62.5%, P = .999). Conclusion RUS demonstrated poor sensitivity for RS visualized on DMSA scan. This suggests that RUS is a poor screening test for RS or indicators of future renal scar. A normal ultrasound does not rule out RS or risk of future renal scar. Specificity of RUS was excellent.

Cerebrovascular disease is rarely reported in neurosarcoidosis and constitutes one of its least well-described forms, though recognition for it has grown in the last decade with recent studies estimating a higher frequency of occurrence than previously known.Patients with ischemic stroke were included if the mechanism was directly attributable to sarcoidosis of the CNS. Patients were excluded if an alternative stroke etiology was of equal or higher likelihood than CNS sarcoidosis.Neurologic disease was the initial presenting manifestation of sarcoidosis in 8/11 (72.7%), and ischemic stroke was an inaugural manifestation of sarcoidosis in 4/11 (36.4%). Small vessel disease was the predominant ischemia subtype (10/11, 90.9%) with pontine perforating vessels (6/11, 54.5%) and lenticulostriate arteries (3/11, 27.3%) being the vasculature most often affected. Vessels with a more rostral supratentorial distribution were uncommonly affected. Common neuroinflammatory accompaniments included leptomeningitis (10/11, 90.9%) and cranial nerve disease (3/11, 27.3%). Recurrent strokes occurred in 8/11 (72.7%), and recurrent neuroinflammation occurred in 7/11 (63.6%). Antiplatelet drugs were used in 6/11 (54.5%) patients. Most (10/11, 90.9%) required at least two lines of immunosuppression to achieve inflammatory disease remission in this context; infliximab was the most successfully employed immunosuppressant (7/8 treatment courses, 87.5%). Recurrent strokes occurred in 8/11 (72.7%) patients, and a second inflammatory attack occurred in 7/11 (63.6%) patients. The presenting median modified Rankin Scale score of 4.0 improved to 2.0 over a median period of follow-up of 52.0 months.Ischemic strokes in neurosarcoidosis occur in a caudal-to-rostral distribution, tend to affect small caliber blood vessels that lack collateral blood flow, and typically associate with inflammatory leptomeningeal disease. The risk for relapse in the forms of stroke or neuroinflammation are high in this neurosarcoidosis phenotype.

Nanoporous silica membranes exhibit excellent H2/CO2 separation properties for sustainable H2 production and CO2 capture but are prepared via complicated thermal processes above 400 oC, which prevent their scalable production at low cost. Here, we demonstrate the rapid fabrication (within 6 minutes) of ultrathin silica membranes (≈6 nm) via oxygen plasma treatment of polydimethylsiloxane based thin-film composite membranes at 20 oC. The resulting organosilica membranes exhibit H2 permeance of 280 - 930 GPU (1 GPU = 3.347×10-10 mol m-2 s-1 Pa-1) and H2/CO2 selectivity of 93 - 32 at 200 °C, far surpassing state-of-the-art membranes and Robeson’s upper bound for H2/CO2 separation. When challenged with a 3-day simulated syngas test containing water vapor and a 340-day stability test at 200 °C, the membrane shows stable separation performance. The robust H2/CO2 separation properties coupled with excellent scalability demonstrate the great potential of these organosilica membranes for economic H2 production with minimal carbon emissions.

Summary Background During the COVID-19 crisis, there has been widespread reporting that non-COVID-19-related medical care has been delayed, even for emergent conditions. Testicular torsion is an emergent condition with higher risk of testicular loss with longer ischemic times. We sought to investigate whether patients with testicular torsion had longer time from symptom onset to initial presentation, longer total ischemic time, and higher rate of orchiectomy during the pandemic. Materials and methods Using billing data, we identified all patients age >1yo seen in our hospital from 1/1/2018 through 5/31/2020 who underwent emergent scrotal exploration for confirmed testicular torsion, comparing the COVID-19 crisis (3/1/2020–5/31/20) to the pre-COVID-19 period (1/1/2018–2/29/20). The primary outcome was time from symptom onset to initial presentation and secondary outcomes were ischemic time (time from symptom onset to entry of the OR) and orchiectomy rate. Parameters were compared with Mann–Whitney U and Fisher's exact tests; Poisson regression compared rates of torsion. Results Of 94 total cases, 77 occurred during the pre-COVID-19 period and 17 during the COVID-19 crisis. Median time from symptom onset to initial presentation was not significantly different (2.4 h [IQR 1.1 h–38.9] during COVID-19 vs. 5.6 h [IQR 1.6–16.9] during pre-COVID-19 period, p = 0.476). Time to presentation was >12 h in 5/17 patients (29%) during COVID-19 and 24/77 patients (31%) during pre-COVID-19 period (p = 1.00). Median ischemic time during COVID-19 was 7.5 h (IQR 4.7 h–45.5 h) compared to 9.4 h (IQR 5.4 h–22.5 h) during pre-COVID-19 period (p = 0.694). Incidence of orchiectomy in our center was 29% (5/17) during COVID-19 and 17% (13/77) during pre-COVID-19 period (p = 0.397). About half of patients were seen initially at outside facilities prior to arrival (47% [8/17] during COVID-19 vs. 49% [38/77] during pre-COVID-19 period, p = 1.00). The number of torsion case presentations per week to our facility increased from 0.7 cases/week in the pre-COVID-19 period to 1.3 cases/week during COVID-19 (p = 0.015); when comparing only the March 1 to May 31 calendar period, there were 0.6 cases/week during the pre-COVID-19 period and 1.3 cases/week during COVID-19 (p = 0.021). Conclusion Time to presentation, ischemic times, and orchiectomy rates for testicular torsion at our center were not significantly different during the COVID-19 period compared to the preceding 2 year period. The number of torsion case per week presenting to our facility increased significantly. Summary Table 1 . Comparison of patients, timing, and testicular outcomes among patients with testicular torsion before and during COVID-19 crisis. Overall Pre-COVID COVID p-value n 94 77 17 Age, years (median [IQR]{range}) 14.38 [12.70, 15.87] {1.3–19.7} 14.22 [12.64, 15.83]{1.3–19.7} 15.24 [14.21, 16.01]{4.2–17.4} 0.2950 Time from symptom onset to presentation, hours (median [IQR]{range}) 5.38 [1.49, 18.38]{0.7, 148.0} 5.58 [1.60, 16.85]{0.7, 81.3} 2.40 [1.12, 38.92]{0.9, 148.0} 0.4760 Time from symptom onset to presentation > 6 h, n (%) 43 (45.7) 35 (45.5) 8 (47.1) 1.0000 Time from symptom onset to presentation > 12 h, n (%) 29 (30.9) 24 (31.2) 5 (29.4) 1.0000 Ischemic time, hours (Time from symptom onset to OR) (median [IQR]{range}) 9.19 [5.32, 26.02]{2.7, 152.2} 9.40 [5.42, 22.52]{2.7, 86.3} 7.52 [4.67, 45.45]{2.7, 152.2} 0.6940 Orchiectomy, n (%) 18 (19.1) 13 (16.9) 5 (29.4) 0.3970 Presentation at OSH, n (%) 46 (48.9) 38 (49.4) 8 (47.1) 1.0000

Stimuli-responsive membranes have been widely explored to mitigate fouling on the membrane surface to achieve the stable performance of water purification. Herein, a facile one-step coating of photo-mobile materials on membrane surface was developed to impart self-cleaning property upon exposure alternatively to ultraviolet (UV) and visible light. Specifically, photo-mobile 4,4′-azodianiline (AZO) and a bio-adhesive polydopamine (PDA) were co-deposited on the surface of ultrafiltration (UF) membranes. The effect of the coating layer on the surface hydrophilicity and pure water permeance was systematically evaluated. The photoresponsive properties of AZO in solutions and thin films with PDA was characterized using UV–Vis absorption spectroscopy. When exposed with UV light, AZO undergoes photoisomerization from trans-AZO to cis-AZO, decreasing the volume, while the exposure to visible light enables the transition from the cis- to trans- configuration, increasing the volume. The resulted self-cleaning behavior of the modified membranes through the reversible volume change is demonstrated in treating 1 g/L bovine serum albumin (BSA) solution. After exposure to the alternative UV/vis light, the AZO-coated UF membranes showed an increased water permeance by ~160%.

Two different highly cross-linked benzimidazole linked polymers (BILPs) displaying high surface area were successfully incorporated into Matrimid polymer to form a series of new mixed matrix membranes (MMMs). The surface functionality of the BILPs, BILP-4 and BILP-101, were exploited to assure the interaction with the Matrimid matrix and produce robust MMMs, which displayed significantly improved CO2 gas permeability. The ideal selectivities for CO2/N2 were calculated with enhancements as high as 34% at 15 wt% BILP loading. While BILP-4 and BILP-101 have similar structures and functionality, the two materials have notably different surface areas and CO2 adsorption capacity. Despite the differences in their gas adsorption properties, MMMs composed of Matrimid/BILP-4 and Matrimid/BILP-101 had very similar gas transport properties. These results suggest that the functional groups of the filler particle and the resulting interaction with the polymer matrix may have had more influence on the gas separation properties of the mixed matrix membrane than the adsorption properties of the fillers.