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Finding the dominant cause(s) of variation in process improvement projects is an important task. Before trying to reduce variation in the dominant cause or mitigate the effect of variation in the dominant cause to reduce output variation, it is strongly recommended that we verify we have identified the true (dominant) cause. This article is about how best to verify we have correctly identified a dominant cause, as the existing literature does not properly answer this question. Although it may seem that a randomized controlled experiment is sufficient for this purpose, we show that experimental studies alone cannot provide all the required information. An experiment identifies whether a suspect is a cause of variation; however, we also require additional information (i.e., from observational studies) to determine whether it is dominant and not just significant. This article lists some viable composite study designs, assesses their relative merits, and recommends proper sample sizes. We also investigate how to systematically conduct a verification study in the era of smart manufacturing. Moreover, we provide a tangible example to illustrate our proposed procedure. [ABSTRACT FROM AUTHOR]

Background Monitoring the risk of intussusception after the introduction of rotavirus vaccines is recommended by the World Health Organization (WHO). Although the validity of intussusception monitoring using electronic health records (EHRs) has been confirmed previously, no similar studies have been conducted in China. We aimed to verify the diagnosis and determine an algorithm with the best performance for identification of intussusception using Chinese EHR databases. Research design and methods Using the Regional Health Information Platform in Ningbo, patients aged 0–72 months from 2015 to 2021 with any related visits for intussusception were included. The algorithms were based on diagnostic codes or keywords in different clinical scenarios, and their performance was evaluated with positive predictive value (PPV) and sensitivity in line with the Brighton guidelines. Results Brighton level 1 intussusception was confirmed in 2958 patients with 3246 episodes. Fine-tuned algorithms combining the appearance of the relevant ICD-10 codes or the Chinese keyword ‘Chang Tao’ in any diagnostic reports with the results of enema treatments or related surgeries showed the highest sensitivity, while the highest PPV was obtained by further criteria based on typical radiographic appearances. Conclusion Intussusception could be identified and validated internally using EHRs in Ningbo.

This study aimed to assess analytical characteristics and diagnostic accuracy in management of venous thromboembolism (VTE) in the Emergency Department (ED) of the Abbott D-dimer assay applied on the Alinity c clinical chemistry analyzer (Abbott Laboratories, Chicago, IL) compared to the INNOVANCE D-dimer assay (Siemens Healthineers, Marburg, Germany). Precision was determined at three concentration levels following the CLSI EP15-A3 protocol. Method comparison and diagnostic accuracy were assessed using samples obtained from 85 patients who were referred for diagnostic imaging and D-dimer testing due to clinically suspected VTE. Within-run coefficients of variation (CVs) were 3.0%, 0.5% and 0.5% at D-dimer concentrations of 0.54, 1.42 and 2.68 mg/L FEU, while respective between-run CVs were 2.0%, 3.4% and 2.7%, hence fulfilling the desirable biological variation criteria for imprecision (<12.6%). Passing–Bablok regression analysis yielded a small proportional difference between the two compared assays (y = 1.09 (95% confidence interval (CI): 1.01–1.18) x + 0.09 (95%CI: –0.09 to 0.16)), while Bland–Altman analysis showed significant negative absolute (–0.6 mg/L FEU, 95%CI: –0.9 to −0.3) and relative mean bias (–14.1%, 95%CI: –20.3 to −7.9). Spearman's ρ was 0.979 (95%CI: 0.967–0.986). Inter-assay agreement relative to the cut-off was 92% (kappa coefficient = 0.547 (95%CI: 0.255–0.839)). Diagnostic sensitivity, specificity, positive and negative predictive values of the Abbott assay were 100%, 9.2%, 25.3% and 100%, respectively, compared to the following data for the INNOVANCE assay: 95.0%, 15.4%, 25.7% and 90.9%. Abbott D-dimer assay has shown excellent analytical precision, high comparability with the INNOVANCE D-dimer and high NPV at manufacturer's cut-off. [ABSTRACT FROM AUTHOR]

Monitoring the risk of intussusception after the introduction of rotavirus vaccines is recommended by the World Health Organization (WHO). Although the validity of intussusception monitoring using electronic health records (EHRs) has been confirmed previously, no similar studies have been conducted in China. We aimed to verify the diagnosis and determine an algorithm with the best performance for identification of intussusception using Chinese EHR databases. Using the Regional Health Information Platform in Ningbo, patients aged 0–72 months from 2015 to 2021 with any related visits for intussusception were included. The algorithms were based on diagnostic codes or keywords in different clinical scenarios, and their performance was evaluated with positive predictive value (PPV) and sensitivity in line with the Brighton guidelines. Brighton level 1 intussusception was confirmed in 2958 patients with 3246 episodes. Fine-tuned algorithms combining the appearance of the relevant ICD-10 codes or the Chinese keyword 'Chang Tao' in any diagnostic reports with the results of enema treatments or related surgeries showed the highest sensitivity, while the highest PPV was obtained by further criteria based on typical radiographic appearances. Intussusception could be identified and validated internally using EHRs in Ningbo. [ABSTRACT FROM AUTHOR]

Background: The currently ongoing outbreak of monkeypox virus in many non‐endemic countries around the world has also raised concerns about the safety of plasma‐derived medicinal products. Based on what is known about the poxviridae, that is, that members are exceedingly large and carry a lipid envelope, effective removal and inactivation by plasma product manufacturing processes is expected. For the widely used solvent‐detergent (S/D) treatments, however, poxviruses have been reported as potentially being a bit more resistant. Study Design and Methods: Using a S/D mixture comprising tri‐n‐butyl‐phosphate, polysorbate 80 and Triton X‐100 (TX‐100), inactivation of vaccinia virus (a model closely resembling monkeypox virus, both within the same genus, i.e., Orthopoxvirus) in a plasma‐derived process intermediate was analyzed over 60 min. As use of Triton X‐100 will, based on environmental concerns, be restricted, similar experiments were conducted with a physicochemically virtually identical alternative, Nereid. Results: Fast inactivation of vaccinia virus to the assay detection limit, that is, reduction of infectivity by greater than 4 log10 within 10–20 min, was measured for the TX‐100 S/D mixture. The alternative S/D mixture (Nereid instead of TX‐100) was found fully equivalent. Conclusion: As for other lipid‐enveloped viruses, treatment of process intermediates with S/D mixtures containing TX‐100 or the closely related detergent Nereid are highly effective in inactivating poxviruses. Thus, the current spread of monkeypox virus does not compromise the viral safety margins of plasma‐derived medicines. [ABSTRACT FROM AUTHOR]

Topically applied drug products have experienced an extraordinary price increase in the United States, mostly due to a lack of generic products. Generic drug development is hindered by high costs and risks associated with clinical endpoint studies required to show bioequivalence (BE) of prospective generic products relative to their reference products. There is a continued need for cost- and time-efficient alternatives to clinical endpoint studies to determine BE of topically applied dermal drug products. Cutaneous PK-based BE studies present such an alternative and dOFM (dermal open flow microperfusion) has already been successfully used in several verifications studies to show an accurate and sensitive assessment of the rate and extent at which drugs become available in the skin. dOFM technology is discussed as well as the dOFM setup of clinical pilot and main studies to achieve BE assessment with a minimum number of participants and an outlook is given on the use of dOFM technology for other drug products. [ABSTRACT FROM AUTHOR]

Topically applied drug products have experienced an extraordinary price increase in the United States, mostly due to a lack of generic products. Generic drug development is hindered by high costs and risks associated with clinical endpoint studies required to show bioequivalence (BE) of prospective generic products relative to their reference products. There is a continued need for cost- and time-efficient alternatives to clinical endpoint studies to determine BE of topically applied dermal drug products. Cutaneous PK-based BE studies present such an alternative and dOFM (dermal open flow microperfusion) has already been successfully used in several verifications studies to show an accurate and sensitive assessment of the rate and extent at which drugs become available in the skin. dOFM technology is discussed as well as the dOFM setup of clinical pilot and main studies to achieve BE assessment with a minimum number of participants and an outlook is given on the use of dOFM technology for other drug products.

We verified the lactate dehydrogenase (LDH) reference interval (RI) provided by the Nordic Reference Interval Project (NORIP). The serum LDH concentration was analysed on the Dimension Vista 1500 system with an IFCC method with a bias of +2.1 % and +2.7 % against NFKK Reference Serum X and ERM-AD453/IFCC, respectively, showing verification of transference of the NORIP RI. Selective data mining in clinical laboratory information systems for retrospective serum LDH test results was used to calculate an indirect RI. For the adult age group (18 to <70 years) the limits of the interval was 127 U/L (90 % CI: 123-132 U/L) and 240 U/L (90 % CI: 234-243 U/L). However, the NORIP upper limit for the adult age group is 205 U/L (90 % CI: 198-210 U/L). Accordingly, 25.1 % of LDH test results were above the NORIPs upper limit of 205 U/L. If LDH analysis was requested by the hospital's medical departments, outpatient clinics or general practitioners 29.2 %, 26.2 % and 20.9 %, respectively, were above the 205 U/L limit. Differences in transport time before centrifugation of blood, and different transport principles could not explain the relative high percent of test results above the NORIP 205 U/L limit. The indirect finding of an upper limit of 240 U/L (90 % CI: 234-243 U/L), and the relative high number of test result >205 U/L, suggests that the NORIP upper limit should be adjusted. [ABSTRACT FROM AUTHOR]