Developing Consensus Standard Operating Procedures (SOPs) to Evaluate New Types of Insecticide-Treated Nets

In response to growing concerns over the sustained effectiveness of pyrethroid-only based control tools, new products are being developed and evaluated. Some examples of these are dual-active ingredient (AI) insecticide-treated nets (ITNs) which contain secondary insecticides, or synergist ITNs which contain insecticide synergist, both in combination with a pyrethroid. These net types are often termed ‘next-generation’ insecticide-treated nets. Several of these new types of ITNs are being evaluated in large-scale randomized control trials (RCTs) and pilot deployment schemes at a country level. However, no methods for measuring the biological durability of the AIs or synergists on these products are currently recommended. In this publication, we describe a pipeline used to collate and interrogate several different methods to produce a singular ‘consensus standard operating procedure (SOP)’, for monitoring the biological durability of three new types of ITNs: pyrethroid + piperonyl butoxide (PBO), pyrethroid + pyriproxyfen (PPF), and pyrethroid + chlorfenapyr (CFP). This process, convened under the auspices of the Innovation to Impact programme, sought to align methodologies used for conducting durability monitoring activities of next-generation ITNs.

Automated left ventricular dimension assessment using artificial intelligence

Background and purpose Artificial intelligence (AI) has the potential to greatly improve efficiency and reproducibility of quantification in echocardiography, but to gain widespread use it must both meet expert standards of excellence and have a transparent methodology. We developed an online platform to enable multiple collaborators to annotate medical images for training and validating neural networks. Methods Using our online collaborative platform 9 expert echocardiographers labelled 2056 images that comprised the training dataset. They labelled the four points from where the standard parasternal long axis (PLAX) measurements (interventricular septum, posterior wall, left ventricular dimension) would be made. Using these labelled images we trained a 2d convolutional neural network to replicate these labels. Separately, we curated an external validation dataset of the systolic and diastolic frames of 100 PLAX acquisitions. Each of these images were labelled twice by 13 different experts, and the average of the 26 measurements was taken as the consensus standard. We then compared the individual experts and the AI measurements on the external validation dataset to the consensus standard, and calculated the precision standard deviation (SD) of the signed differences from the consensus standard. Results For diastolic septum thickness, the AI had a precision SD of 1.8 mm (ICC 0.81; 95% CI 0.73 to 0.97), compared with 2.0 mm for the individual experts (ICC 0.64; 95% CI 0.57 to 0.72). For diastolic posterior wall thickness, the AI had a precision SD 1.4 mm (ICC 0.54; 95% CI 0.38 to 0.66), and the individual experts 2.2 mm (ICC 0.37; 95% CI 0.29 to 0.46). The AI's precision SD for left ventricular internal dimension was 3.5 mm (ICC 0.93, 95% CI 0.90 to 0.94), and for individual experts was 4.4mm (ICC 0.82, 95% CI 0.78 to 0.95). Both the experts and AI performed better in diastole than systole (precision SD AI 2.5mm vs 4.3mm, p<0.0001; experts 3.3mm vs 5.3mm, p<0.0001). Conclusions AI trained by a group of echocardiography experts was able to perform PLAX measurements which matched the reference standard more closely than any individual expert's own measurements. This open, collaborative approach may be a model for the development of AI that is explainable to, and trusted by clinicians. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIHR Imperil BRC ITMATDr Howard was additionally funded by Wellcome. Online collaborative platform Results of AI and experts

Evaluation of Self-Collected Mid-Turbinate Nasal Swabs and Saliva for Detection of SARS-CoV-2 RNA

Rapid and accurate diagnostic testing is essential to bring the ongoing COVID-19 pandemic to an end. As the demand for SARS-CoV-2 testing continues to increase amid supply shortages, many laboratories have investigated the use of sources other than nasopharyngeal (NP) swabs. Saliva and mid-turbinate nasal swabs are attractive alternatives as they allow for self-collection and are well-accepted by patients. Saliva also requires limited consumables. We compared the performance of health care provider-collected NP swabs, patient-collected mid-turbinate (MT) swabs, and patient-collected saliva specimens for SARS-CoV-2 detection using a laboratory developed PCR assay that had received Emergency Use Authorization by the FDA. Of 281 total evaluable samples, 33 (11.7%) NP swabs, 33 (11.7%) MT swabs, and 32 (11.4%) saliva specimens were positive for SARS-CoV-2 following resolution of discordant results. When compared to NP swabs, saliva exhibited a sensitivity of 90.9% (30/33) and specificity of 99.2% (246/248), while patient-collected MT swabs exhibited a sensitivity of 93.9% (31/33) and specificity of 99.2% (246/248). When comparing to the consensus standard, the sensitivity was 100% (31/31) for both NP and MT swabs and 96.8% (30/31) for saliva specimens, while specificity was the same in both NP swabs and saliva specimens (98.8% [247/250]) and 99.2% (248/250) for MT swabs. Pre-treatment of saliva with proteinase K and heating for 15 minutes prior to extraction reduced the invalid rate from 26.7% (52/195) to 0% (0/195). These data show that patient-collected mid-turbinate nasal swabs and saliva are suitable sources for self-collection in individuals who require routine monitoring for SARS-CoV-2 infection.

Staging and stratifying cognitive dysfunction in multiple sclerosis

Background: The sequence in which cognitive domains become impaired in multiple sclerosis (MS) is yet to be formally demonstrated. It is unclear whether processing speed dysfunction temporally precedes other cognitive impairments, such as memory and executive function. Objective: Determine the order in which different cognitive domains become impaired in MS and validate these findings using clinical and vocational outcomes. Methods: In a longitudinal sample of 1073 MS patients and 306 healthy controls, we measured performance on multiple, consensus-standard, neurocognitive tests. We used an event-based staging approach to model the sequence in which cognitive domains become impaired. Linear and logistic mixed-effects models were used to explore associations between stages of impairment, neurological disability, and employment status. Results: Our model suggested that the order of impairments was as follows: processing speed, visual learning, verbal learning, working memory/attention, and executive function. Stage of cognitive impairment predicted greater neurological disability, β = 0.16, SE = 0.02, p < 0.001, and probability of unemployment, β = 1.14, SE = 0.001, p < 0.001. Conclusion: This is the first study to introduce a cognitive staging and stratification system for MS. Findings underscore the importance of using the Symbol Digit Modalities Test in routine screening for cognitive impairment and memory testing to assess patients later in disease evolution.

Lessons learned from contemporary glioblastoma randomized clinical trials through systematic review and network meta-analysis: Part 2 Recurrent glioblastoma

Background There exists no consensus standard of treatment for patients with recurrent glioblastoma (GB). Here we used a network meta-analysis on treatments from randomized control trials (RCT) to assess effect on Overall survival (OS) and progression free survival (PFS) to determine if any concensus treatment can be determined for recurrent GB. Methods We included all recurrent GB RCTs with at least 20 patients in each arm, and for whom patients underwent SOC at the time of their GB initial diagnosis. Our primary outcome was overall survival (OS), with secondary outcomes including progression-free survival (PFS) and adverse reactions. Hazard ratio (HR) and its 95% confidence interval (CI) of the comparison of study arms regarding OS and PFS were extracted from each paper. For comparative efficacy analysis, we utilized a frequentist network meta-analysis, an extension of the classic pair-wise meta-analysis. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results Fifteen studies were included representing 29 separate treatment arms, and 2194 patients. In our network meta-analysis, combination treatment with TTF and VEGF inhibitor ranked first in improving OS (P score=0.80). Concomitant Anti-VEGF and Lomustine treatment was superior to Lomustine alone for extending PFS (HR 0.57, 95% CI 0.41-0.79) and ranked first in improving PFS compared to other included treatments (P score=0.86). Conclusions Our analysis highlights the numerous studies performed on recurrent GB, with no proven consensus treatment that is superior to the current SOC. Inter-trial heterogeneity precludes drawing strong conclusions, and confidence analysis was low to very low. Further confirmation by future trials is recommended for our exploratory results..

Optimal tube voltage for abdominal enhanced CT in children: a self-controlled study

Background The use of weight-adapted pediatric computed tomography (CT) tube voltage protocols has been suggested, but a consensus standard has not been established and clinical available studies are not sufficient. Purpose To determine the best tube voltage for low dose abdominal CT imaging in children. Material and Methods Eighty-seven cases who needed three CT exams in a 1–3-month interval between scans were enrolled (mean age = 4.69 ± 3.20 years). The three scans were performed with three different tube voltages at 80 kV, 100 kV, and 120 kV, keeping the same radiation dose and same contrast injection protocol. Patients were divided into five groups for analysis based on their body weight. The subjective image quality of the three exams were evaluated using a 4-point scale (4 being the best) for image noise and image quality. The objective evaluation in terms of CT values and standard deviation in aorta, liver, spleen, pancreas, and kidney were measured to calculate the degree of enhancement and contrast-to-noise ratio (CNR) of organs. One-way ANOVA was used to compare the subjective and objective image quality with respect to different tube voltages and different patient weights. Result The 80-kV tube voltage provided the highest overall enhancement and CNR for the entire patient population and the best objective image quality for the 6.1–28.0 kg subgroup. Conclusion Patient weight-dependent tube voltage selection maximizes image quality for abdominal enhanced CT in children. The optimal tube voltage for children with weight <28 kg is 80 kV; higher voltages should be selected for children weighing 28.1–50.0 kg.

Evaluation of a Novel Microarray Immunoblot Assay for Detection of IgM- and IgG-Class Antibodies toBorrelia burgdorferi

ABSTRACTDiagnostic testing for Lyme disease (LD) remains dependent on detection of antibodies to LDBorreliausing serologic assays, in adherence to the standard two-tiered testing (STTT) algorithm. We present the first analytic evaluation of the automatedBorreliaB31 ViraChip IgM and IgG microarray immunoblot (MIB) assays (Viramed Biotech AG, Planegg, Germany) in comparison to two different, semiautomated blot assays for LD, including theBorreliaB31 ViraStripe IgM and IgG line immunoassays (LIAs) (Viramed) and the MarDxBorrelia burgdorferiIgM and IgG Western blot (WB) assays (Trinity Biotech, Carlsbad, CA), using prospectively collected sera (n= 411) and archived, clinically characterized samples (n= 91). We show comparable overall agreement (>84%) of the ViraChip MIB assays against the two aforementioned LD blot methods. The ViraChip MIB assays were also compared to a consensus standard, whereby samples were classified as positive or negative for IgM or IgG toB. burgdorferiif the analyte-matched ViraStripe LIA or MarDx WB assay were positive or negative, respectively. The ViraChip IgM and IgG MIB assays showed >93% positive, negative, and overall agreement versus these consensus criteria. The ViraChip MIB assays were associated with a time savings of 28 min to process one full batch of samples compared to the time required for the ViraStripe LIAs. The ViraChip MIB assays can be programmed and performed on an open-system, automated enzyme-linked immunosorbent assay (ELISA) processor, negating the need for assay-specific equipment and enabling laboratories to consolidate LD testing onto a single platform. We conclude that the ViraChip IgM and IgG MIB assays may be added to the repertoire of supplemental, second-tier blot testing systems for diagnosis of LD.

Manned Underwater Vehicles Operations Consensus Standard

The Manned Underwater Vehicles industry has evolved since the launch of DSV ALVIN in 1964 and the establishment of tourist passenger submersibles in the 1980’s and 1990’s. The emergence of the tourist passenger submersible sector in 1993 prompted the US Coast Guard to regulate commercial marine operations in the interest of public safety through NVIC 5-93. The rules were designed specifically for submersibles selling seats to members of the general public. To ensure public safety, the USCG helped define safeguards for those participants. Submersibles owned by the government, research institutions and corporations; or submersibles used for purposes other than selling rides to members of the general public, were not wholly addressed because growth in that sector was unforeseen. Almost 25 years after its release, the industry is regulated across all sectors of MUV operations by definitions established for the operation of a narrow segment of the industry, the tourism submersibles. However, construction over the past 23 years is 18% tourism submersibles, 8% government and 7% research. The remaining 67% of vessels, fall into an “other” category which does not have adequate definition. This white papers proposes that the Marine Technology Society committee on Manned Underwater Vehicles conduct a study for an updated Manned Underwater Vehicle Operations Safety Guideline with broad participation of the MUV stakeholders; International MUV industry members, Marine Technology Society, ASME PVHO, ABS, DNVGL, US Coast Guard and Navy. The challenge is to find the correct balance of regulatory control and commercial freedom to promote commercial growth while having a robust regulatory framework to manage the various concepts. Paper published with permission.

Reference Materials: Critical Importance to the Infant Formula Industry

Infant formula is one of the most regulated foodsin the world. It has advanced in complexity over theyears as a result of numerous research innovations. To ensure product safety and quality, analytical technologies have also had to advance to keep pace. Given the rigorous performance demands expected of these methods and the ever-growing array of complex matrixes, there is the potential for gaps to exist in current Official MethodsSMand other recognized international methods for infant formula and adult nutritionals. Food safety concerns, particularly for infants, drive the need for extensive testing by manufacturers and regulators. The net effect is the potential for an increase in time-and resource-consuming regulatory disputes. In an effort to mitigate such costly activities, AOAC INTERNATIONAL, under the direction of the Infant Formula Council of America—a trade association of manufacturers and marketers of formulated nutritional products—agreed to establish voluntary consensus Standard Method Performance Requirements, and, ultimately, to identify and publish globally recognized, fit-for-purpose standard methods.To accomplish this task, nutritional reference materials (RMs), representing all major commercially available nutritional formulations, were (and continue to be) a critical necessity. In this paper, various types of RMs will be defined, followed by review and discussion of their importance to the infant formulaindustry.