Validity of claims-based diagnoses for infectious diseases common among immunocompromised patients in Japan.

BACKGROUND: To validate Japanese claims-based disease-identifying algorithms for herpes zoster (HZ), Mycobacterium tuberculosis (MTB), nontuberculous mycobacteria infections (NTM), and Pneumocystis jirovecii pneumonia (PJP). METHODS: VALIDATE-J, a multicenter, cross-sectional, retrospective study, reviewed the administrative claims data and medical records from two Japanese hospitals. Claims-based algorithms were developed by experts to identify HZ, MTB, NTM, and PJP cases among patients treated 2012-2016. Diagnosis was confirmed with three gold standard definitions; positive predictive values (PPVs) were calculated for prevalent (regardless of baseline disease-free period) and incident (preceded by a 12-month disease-free period for the target conditions) cases. RESULTS: Of patients identified using claims-based algorithms, a random sample of 377 cases was included: HZ (n = 95 [55 incident cases]); MTB (n = 100 [58]); NTM (n = 82 [50]); and PJP (n = 100 [84]). PPVs ranged from 67.4-70.5% (HZ), 67.0-90.0% (MTB), 18.3-63.4% (NTM), and 20.0-45.0% (PJP) for prevalent cases, and 69.1-70.9% (HZ), 58.6-87.9% (MTB), 10.0-56.0% (NTM), and 22.6-51.2% (PJP) for incident cases, across definitions. Adding treatment to the algorithms increased PPVs for HZ, with a small increase observed for prevalent cases of NTM. CONCLUSIONS: VALIDATE-J demonstrated moderate to high PPVs for disease-identifying algorithms for HZ and MTB using Japanese claims data.

Validation of a claims-based algorithm to identify cases of ulcerative colitis in Japan.

BACKGROUND AND AIM: The prevalence of ulcerative colitis (UC) is increasing in Japan. Validated claims-based definitions are required to investigate the epidemiology of UC and its treatment and disease course in clinical practice. This study aimed to develop a claims-based algorithm for UC in Japan. METHODS: A committee of epidemiologists, gastroenterologists, and internal medicine physicians developed a claims-based definition for UC, based on diagnostic codes and claims for UC treatments, procedures (cytapheresis), or surgery (postoperative claims). Claims data and medical records for a random sample of 200 cases per site at two large tertiary care academic centers in Japan were used to calculate the positive predictive value (PPV) of the algorithm for three gold standards of diagnosis, defined as physician diagnosis in the medical records, adjudicated cases, or registration in the Japanese Intractable Disease Registry (IDR). RESULTS: Overall, 1139 claims-defined UC cases were identified. Among 393 randomly sampled cases (mean age 44; 48% female), 94% had received ≥ 1 systemic treatment (immunosuppressants, tumor necrosis factor inhibitors, corticosteroids, or antidiarrheals), 7% had cytapheresis, and 7% had postoperative claims. When physician diagnosis was used as a gold standard, PPV was 90.6% (95% confidence interval [CI]: 87.7-93.5). PPV with expert adjudication was also 90.6% (95% CI: 87.7-93.5). PPVs with enrollment in the IDR as gold standard were lower at 41.5% (95% CI: 36.6-46.3) due to incomplete case registration. CONCLUSIONS: The claims-based algorithm developed for use in Japan is likely to identify UC cases with high PPV for clinical studies using administrative claims databases.

Polymerized porin as a novel delivery platform for coronavirus vaccine.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seriously threatens human life and health. The correct folding and polymerization of the receptor-binding domain (RBD) protein of coronavirus in Escherichia coli may reduce the cost of SARS-CoV-2 vaccines. In this study, we constructed this nanopore by using the principle of ClyA porin polymerization triggered by the cell membrane. We used surfactants to "pick" the ClyA-RBD nanopore from the bacterial outer membrane. More importantly, the polymerized RBD displayed on the ClyA-RBD polymerized porin (RBD-PP) already displays some correct spatial conformational epitopes that can induce neutralizing antibodies. The nanostructures of RBD-PP can target lymph nodes and promote antigen uptake and processing by dendritic cells, thereby effectively eliciting the production of anti-SARS-CoV-2 neutralizing antibodies, systemic cellular immune responses, and memory T cells. We applied this PP-based vaccine platform to fabricate an RBD-based subunit vaccine against SARS-CoV-2, which will provide a foundation for the development of inexpensive coronavirus vaccines. The development of a novel vaccine delivery system is an important part of innovative drug research. This novel PP-based vaccine platform is likely to have additional applications, including other viral vaccines, bacterial vaccines, tumor vaccines, drug delivery, and disease diagnosis.

Effects of low-intensity pulsed ultrasound on knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To systemically review the effects of low-intensity pulsed ultrasound (LIPUS) on pain relief and functional recovery in patients with knee osteoarthritis (KOA). DATA SOURCES: PubMed, Web of Science, Cochrane Library, Physiotherapy Evidence Database (PEDro), and China National Knowledge Infrastructure (CNKI) were used from inception to 18 March 2022. REVIEW METHODS: Meta-analysis was performed to evaluate pain and function recovery between control and LIPUS groups. Standardized mean difference (SMD) or mean difference (MD) and 95% confidence interval (CI) were calculated, and data were combined using the fixed or random-effect model. RESULTS: Thirteen studies involving 807 patients with KOA were included. Patients' outcomes treated by LIPUS were improved significantly, including Visual analog scale (VAS) score (MD = -0.95, 95% CI: -1.43 to -0.48，P < 0.001), Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) score (MD = -4.35, 95% CI: -8.30 to -0.40, P = 0.0309), Lysholm score (SMD = 1.59, 95% CI: 1.29 to 1.90, P < 0.001), Lequesne index (MD = -1.33, 95% CI: -1.69 to -0.96, P < 0.001), Range of motion (ROM) (MD = 2.43, 95% CI: 0.39 to 4.46, P = 0.0197) and 50 meter walking time (SMD = 1.48, 95% CI: 0.46 to 2.49, P = 0.0044). Subgroup analyses showed monotherapy of LIPUS produced a better effect on reducing VAS score (P = 0.0213), and the shorter therapeutic period (≤4 weeks) produced a more significant effect on raising the WOMAC score (P = 0.0083). CONCLUSION: LIPUS was beneficial for pain relief and functional knee recovery and maybe as an alternative therapy in KOA rehabilitation.

Validity of claims-based algorithms for selected cancers in Japan: Results from the VALIDATE-J study.

PURPOSE: Real-world data from large administrative claims databases in Japan have recently become available, but limited evidence exists to support their validity. VALIDATE-J validated claims-based algorithms for selected cancers in Japan. METHODS: VALIDATE-J was a multicenter, cross-sectional, retrospective study. Disease-identifying algorithms were used to identify cancers diagnosed between January or March 2012 and December 2016 using claims data from two hospitals in Japan. Positive predictive values (PPVs), specificity, and sensitivity were calculated for prevalent (regardless of baseline cancer-free period) and incident (12-month cancer-free period; with claims and registry periods in the same month) cases, using hospital cancer registry data as gold standard. RESULTS: 22 108 cancers were identified in the hospital claims databases. PPVs (number of registry cases) for prevalent/incident cases were: any malignancy 79.0% (25 934)/73.1% (18 119); colorectal 84.4% (3519)/65.6% (2340); gastric 87.4% (3534)/76.8% (2279); lung 88.1% (2066)/79.9% (1636); breast 86.4% (4959)/59.9% (3185); pancreatic 87.1% (582)/80.4% (508); melanoma 48.7% (46)/42.9% (36); and lymphoma 83.6% (1457)/77.8% (1035). Specificity ranged from 98.3% to 100% (prevalent)/99.5% to 100% (incident); sensitivity ranged from 39.1% to 67.6% (prevalent)/12.5% to 31.4% (incident). PPVs of claims-based algorithms for several cancers in patients ≥66 years of age were slightly higher than those in a US Medicare population. CONCLUSIONS: VALIDATE-J demonstrated high specificity and modest-to-moderate sensitivity for claims-based algorithms of most malignancies using Japanese claims data. Use of claims-based algorithms will enable identification of patient populations from claims databases, while avoiding direct patient identification. Further research is needed to confirm the generalizability of our results and applicability to specific subgroups of patient populations.

CD28 and CD3 have complementary roles in T-cell traction forces.

Mechanical forces have key roles in regulating activation of T cells and coordination of the adaptive immune response. A recent example is the ability of T cells to sense the rigidity of an underlying substrate through the T-cell receptor (TCR) coreceptor CD3 and CD28, a costimulation signal essential for cell activation. In this report, we show that these two receptor systems provide complementary functions in regulating the cellular forces needed to test the mechanical properties of the extracellular environment. Traction force microscopy was carried out on primary human cells interacting with micrometer-scale elastomer pillar arrays presenting activation antibodies to CD3 and/or CD28. T cells generated traction forces of 100 pN on arrays with both antibodies. By providing one antibody or the other in solution instead of on the pillars, we show that force generation is associated with CD3 and the TCR complex. Engagement of CD28 increases traction forces associated with CD3 through the signaling pathway involving PI3K, rather than providing additional coupling between the cell and surface. Force generation is concentrated to the cell periphery and associated with molecular complexes containing phosphorylated Pyk2, suggesting that T cells use processes that share features with integrin signaling in force generation. Finally, the ability of T cells to apply forces through the TCR itself, rather than the CD3 coreceptor, was tested. Mouse cells expressing the 5C.C7 TCR exerted traction forces on pillars presenting peptide-loaded MHCs that were similar to those with α-CD3, suggesting that forces are applied to antigen-presenting cells during activation.

Bmi1 regulates mitochondrial function and the DNA damage response pathway.

Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1(-/-) phenotype. Here we demonstrate that cells derived from Bmi1(-/-) mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1(-/-) mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

Effects of robot-assisted percutaneous kyphoplasty on osteoporotic vertebral compression fractures: a systematic review and meta-analysis.

This study systemically reviewed the effects of robot-assisted percutaneous kyphoplasty (R-PKP) on the clinical outcomes and complications of patients with osteoporotic vertebral compression fracture (OVCF). The articles published from the establishment of the database to 19 April 2024 were searched in PubMed, The Cochrane Library, Web of Science, Embase, Scopus, China National Knowledge Infrastructure (CNKI), and Chinese biomedical literature service system (SinoMed). Meta-analysis was employed to evaluate the status of pain relief and complications between the control and R-PKP groups. Standardized mean difference (SMD) or mean difference (MD), risk ratios (RR), and 95% confidence interval (CI) were selected for analysis, and a common or random effect model was adopted to merge the data. Eight studies involving 773 patients with OCVFs were included. R-PKP could effectively Cobb's angles (MD = -1.00, 95% CI -1.68 to -0.33, P = 0.0034), and decrease the occurrence of cement leakage (RR = 0.36, 95% CI 0.21 to 0.60, P < 0.0001). However, there was no significant effect on the results of visual analog scale (MD = -0.09, 95% CI -0.20 to 0.02, P = 0.1145), fluoroscopic frequency (SMD = 5.31, 95% CI -7.24 to 17.86, P = 0.4072), and operation time (MD = -0.72, 95% CI -7.47 to 6.03, P = 0.8342). R-PKP could significantly correct vertebral angle and reduce cement leakage. Thus, R-PKP maybe an effective choice for correction vertebral Angle and reducing postoperative complications, while its impact on relieving pain, decreasing fluoroscopic frequency, and shortening operation time need further exploration.

Validation of claims-based algorithms for rheumatoid arthritis in Japan: Results from the VALIDATE-J study.

AIM: Validity of Algorithms in Large Databases: Infectious Diseases, Rheumatoid Arthritis, and Tumor Evaluation in Japan (VALIDATE-J) study examined algorithms for identifying rheumatoid arthritis (RA) in Japanese claims data. METHODS: VALIDATE-J was a multicenter, cross-sectional retrospective study. Disease-identifying algorithms were used to detect RA diagnosed between January 2012 and December 2016 using claims data from two Japanese hospitals. An RA diagnosis was confirmed using one of four gold standard definitions. Positive predictive values (PPVs) were calculated for prevalent (regardless of baseline RA-free period) and incident (preceded by a 12-month RA-free period) cases. RESULTS: Of patients identified using claims-based algorithms, a random sample of 389 prevalent and 134 incident cases of RA were included. Cases identified by an RA diagnosis, no diagnosis of psoriasis, and treatment with any disease-modifying antirheumatic drugs (DMARDs) resulted in the highest PPVs versus other claims-based treatment categories (29.0%-88.3% [prevalent] and 41.0%-78.2% [incident]); cases identified by an RA diagnosis, no diagnosis of psoriasis, and glucocorticoid-only treatment had the lowest PPVs. Across claims-based algorithms, PPVs were highest when a physician diagnosis or decision by adjudicators (confirmed and probable cases) was used as the gold standard and were lowest when American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 criteria were applied. PPVs of claims-based algorithms for RA in patients aged ≥66 years were slightly higher versus a USA Medicare population (maximum PPVs of 95.0% and 88.9%, respectively). CONCLUSION: VALIDATE-J demonstrated high PPVs for most claims-based algorithms for diagnosis of prevalent and incident RA using Japanese claims data. These findings will help inform appropriate RA definitions for future claims database research in Japan.

Effects of robot-assisted minimally invasive surgery on osteoporotic vertebral compression fracture: a systematic review, meta-analysis, and meta-regression of retrospective study.

OBJECTIVE: To conduct a systematic review on the effect of robot-assisted minimally invasive surgery (R-MIS) on the clinical outcomes and complications of patients with osteoporotic vertebral compression fractures (OVCFs). METHODS: The researchers searched the papers published on PubMed, The Cochrane Library, Web of Science, Embase, Scopus, Ovid MEDLINE, Wiley Online Library, China National Knowledge Infrastructure (CNKI), Chinese biomedical literature service system (SinoMed), and China Medical Association Data. The standardized mean difference (SMD) or mean difference (MD), relative risk (RR), and 95% confidence interval (CI) were calculated. Besides, the data was merged through the random-effect model or common-effect model. A meta-regression mixed-effects single-factor model was utilized to analyze the sources of heterogeneity. RESULTS: Twelve studies were included, involving 1042 OVCFs cases. The prognosis of patients treated with R-MIS was significantly improved, such as Oswestry disability index (ODI) score (MD = -0.65, P = 0.0171), Cobb's angles (MD = -1.03, P = 0.0027), X-ray fluoroscopy frequency (SMD = -2.41, P < 0.0001), Length of hospital stay (MD = -0.33, P = 0.0002), and Cement leakage (RR = 0.37, P < 0.0001). However, no obvious improvement was found in the results of Visual analog scale (VAS) score (MD = -0.16, P = 0.1555), Volume of bone cement (MD = 0.22, P = 0.8339), and Operation time (MD = -3.20, P = 0.3411) after being treated by R-MIS. The meta-regression analysis demonstrated that R-MIS presented no significant impact on the covariates of VAS and Operation time. CONCLUSION: R-MIS can significantly reduce the patients' ODI, Cobb's angles, X-ray fluoroscopy frequency, and Cement leakage ratio, and shorten the Length of hospital stay. Therefore, R-MIS may be an effective method to promote the patients' functional recovery, correct spinal deformity, reduce the X-ray fluoroscopy frequency, shorten the Length of hospital stay, and reduce the complications of OVCFs bone Cement leakage.

Peptide-Based Therapeutic HPV Cancer Vaccine Synthesized via Bacterial Outer Membrane Vesicles.

Background: Peptide-based vaccines have broad application prospects because of their safety, simple preparation, and effectiveness, especially in the development of personalized cancer vaccines, which have shown great advantages. However, the current peptide-based vaccines often require artificial synthesis and intricate delivery technology, which increases the cost and complexity of preparation. Methods: Here, we developed a simple technique for combining a peptide and a delivery system using the natural secretion system of bacteria. Specifically, we biosynthesized an antigenic peptide in bacteria, which was then extracellularly released through the bacterial secretory vesicles, thus simultaneously achieving the biosynthesis and delivery of the peptide. Results: The system utilizes the natural properties of bacterial vesicles to promote antigen uptake and dendritic cell (DC) maturation. Therefore, tumor-specific CD4+ Th1 and CD8+ cytotoxic T lymphocyte (CTL) responses were induced in TC-1 tumor-bearing mice, thereby efficiently suppressing tumor growth. Conclusion: This research promotes innovation and extends the application of peptide-based vaccine biosynthesis technology. Importantly, it provides a new method for personalized cancer immunotherapy that uses screened peptides as antigens in the future.

Cross-Regional Data Initiative for the Assessment and Development of Treatment for Neurological and Mental Disorders.

Purpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN). Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives. Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK. Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.

A new personalized vaccine strategy based on inducing the pyroptosis of tumor cells in vivo by transgenic expression of a truncated GSDMD N-terminus.

The variability and heterogeneity of tumor antigens and the tumor-driven development of immunosuppressive mechanisms leading to tumor escape from established immunological surveillance. Here, the tumor cells were genetically modified to achieve an inducible overexpression of the N-terminal domain of gasdermin D (GSDMD-NT) and effectively cause pyroptosis under a strict control. Pyroptotic tumor cells release damage-associated molecular patterns (DAMPs) and inflammatory cytokines to promote the maturation and migration of bone marrow-derived dendritic cells (BMDCs). Furthermore, local tumor delivery, and preventive or therapeutic subcutaneous immunization of the modified cells, followed by the induction of GSDMD-NT expression, significantly stimulated both the systemic and local responses of antitumor immunity, and reprogrammed the tumor microenvironment, leading to the dramatic suppression of tumor growth in mice. This study has explored the application potency of inducing the pyroptosis of tumor cells in the field of tumor immunotherapy, especially for developing a new and promising personalized tumor vaccine.

AMD3100 is a potent antagonist at CXCR4(R334X) , a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome.

WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal dominant mutations truncating the C-terminus of the chemokine receptor CXC chemokine receptor 4 (CXCR4). WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)-approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing Chinese hamster ovary (CHO) and K562 cell lines matched for expression of recombinant wild-type CXCR4 (CXCR4(WT)) and the most common WHIM variant of CXCR4 (CXCR4(R334X)), as well as leucocytes from a WHIM patient with the CXCR4(R334X) mutation versus healthy controls. We found that CXCR4(R334X) mediated modestly increased signalling (~2-fold) in all functional assays tested, but strongly resisted ligand-dependent down-regulation. AMD3100 was equipotent and equieffective as an antagonist at CXCR4(R334X) and CXCR4(WT) . Together, our data provide further evidence that CXCR4(R334X) is a gain-of-function mutation, and support clinical evaluation of AMD3100 as mechanism-based treatment in patients with WHIM syndrome.

Comparing different methods of gait speed estimation using wearable sensors in individuals with varying levels of mobility impairments.

Wearable sensors, such as inertial measurement units (IMU), provide the ability to quantify gait parameters outside of traditional gait laboratory settings. Walking speed has been shown to be associated with morbidity and mortality. Therefore, the ability of a clinician to easily and inexpensively measure gait speed within their clinic or patients' home setting can improve patient management and care. This study highlights multiple methods used to estimate patient walking speeds based only on IMU data and minimal anthropometric data, and identifies the algorithm appearing to be the most robust; one relying on identifying swing phases of gait first.Clinical relevance- Providing a clinician with a simple, inexpensive and reliable protocol for measuring patients' gait speed and other parameters could offer prevention and individualized care.