A comprehensive value-based method for new nuclear medical service pricing: with case study of radium [223Ra] bone metastases treatment.

IMPORTANCE: Innovative nuclear medicine services offer substantial clinical value to patients. However, these advancements often come with high costs. Traditional payment strategies do not incentivize medical institutes to provide new services nor determine the fair price for payers. A shift towards a value-based pricing strategy is imperative to address these challenges. Such a strategy would reconcile the cost of innovation with incentives, foster transparent allocation of healthcare resources, and expedite the accessibility of essential medical services. OBJECTIVE: This study aims to develop and present a comprehensive, value-based pricing model for new nuclear medicine services, illustrated explicitly through a case study of the radium [223Ra] treatment for bone metastases. In constructing the pricing model, we have considered three primary value determinants: the cost of the new service, associated service risk, and the difficulty of the service provision. Our research can help healthcare leaders design an evidence-based Fee-For-Service (FFS) payment reference pricing with nuclear medicine services and price adjustments. DESIGN, SETTING AND PARTICIPANTS: This multi-center study was conducted from March 2021 to February 2022 (including consultation meetings) and employed both qualitative and quantitative methodologies. We organized focus group consultations with physicians from nuclear medicine departments in Beijing, Chongqing, Guangzhou, and Shanghai to standardize the treatment process for radium [223Ra] bone metastases. We used a specially designed 'Radium Nuclide [223Ra] Bone Metastasis Data Collection Form' to gather nationwide resource consumption data to extract information from local databases. Four interviews with groups of experts were conducted to determine the add-up ratio, based on service risk and difficulty. The study organized consultation meeting with key stakeholders, including policymakers, service providers, clinical researchers, and health economists, to finalize the pricing equation and the pricing result of radium [223Ra] bone metastases service. MAIN OUTCOMES AND MEASURES: We developed and detailed a pricing equation tailored for innovative services in the nuclear medicine department, illustrating its application through a step-by-step guide. A standardized service process was established to ensure consistency and accuracy. Adhering to best practice guidelines for health cost data analysis, we emphasized the importance of cross-validation of data, where validated data demonstrated less variation. However, it required a more advanced health information system to manage and analyze the data inputs effectively. RESULTS: The standardized service of radium [223Ra] bone metastases includes: pre-injection assessment, treatment plan, administration, post-administration monitoring, waste disposal and monitoring. The average duration for each stage is 104 min, 39 min, 25 min, 72 min and 56 min. A standardized monetary value for medical consumables is 54.94 yuan ($7.6), and the standardised monetary value (medical consumables cost plus human input) is 763.68 yuan ($109.9). Applying an agreed value add-up ratio of 1.065, the standardized value is 810.19 yuan ($116.9). Feedback from a consultation meeting with policymakers and health economics researchers indicates a consensus that the pricing equation developed was reasonable and well-grounded. CONCLUSION: This research is the first study in the field of nuclear medicine department pricing methodology. We introduce a comprehensive value-based nuclear medical service pricing method and use radium[223Ra] bone metastases treatment pricing in China as a case study. This study establishes a novel pricing framework and provides practical instructions on its implementation in a real-world healthcare setting.

Development and initial validation of the career resilience instrument for CDC emergency responders in China within the context of public health emergencies: based on a survey conducted in Shanghai.

Background: China faces various public health emergencies, and emergency responders at the Centers for Disease Control and Prevention (CDC emergency responders) are a mainstay in responding to public health emergencies. Career resilience can help CDC emergency responders to effectively respond to and recover from public health emergencies, but there is no specific measurement instrument available. In this study, we aimed to develop and conduct an initial validation of the career resilience instrument for CDC emergency responders in China within the context of public health emergencies from a process perspective. Methods: Based on a survey conducted in Shanghai, interpretive phenomenological analysis (IPA), which is a qualitative research approach to describing and analyzing individual experiences, was used to analyze the interview texts to develop the initial career resilience instrument for CDC emergency responders. The initial career resilience instrument was revised through two rounds of expert consultation. Cronbach's α coefficient and exploratory factor analysis were used to test the reliability and validity of the revised career resilience instrument. Results: The initial career resilience instrument for CDC emergency responders contained three first-level measurement dimensions, 9 second-level measurement dimensions, and 52 measurement items. After expert consultation, the first-level and second-level measurement dimensions were not revised, 13 measurement items were deleted or revised, and six measurement items were added, resulting in 48 measurement items. The revised career resilience instrument was tested for good reliability and validity. Conclusion: Career resilience for CDC emergency responders can be regarded as a set of protective factors and dynamic processes that can be cultivated and intervened in cognitive, affective, and behavioral dimensions to improve their ability to respond to and recover from public health emergencies.

Mutant B3GALT6 in a Multiplex Family: A Dominant Variant Co-Segregated With Moderate Malformations.

B3GALT6 is a well-documented disease-related gene. Several B3GALT6-recessive variants have been reported to cause Ehlers-Danlos syndrome (EDS). To the best of our knowledge, no dominant B3GALT6 variant that causes human disease has been reported. In 2012, we reported on a three-generation, autosomal-dominant family with multiple members who suffered from radioulnar joint rotation limitation, scoliosis, thick vermilion of both lips, and others, but the genetic cause was unknown. Here, exome sequencing of the family identified mutant B3GALT6 as the cause of the multiplex affected family. We observed that, in the compound heterozygous pattern (i.e., c.883C>T:p.R295C and c.510_517del:p.L170fs*268), mutant B3GALT6 led to severe consequences, and in the dominant pattern, an elongated B3GALT6 variant co-segregated with moderate phenotypes. The functional experiments were performed in vitro. The R295C variant led to subcellular mislocalization, whereas the L170fs*268 showed normal subcellular localization, but it led to an elongated protein. Given that most of the catalytic galactosyltransferase domain was disrupted for the L170fs*268 (it is unlikely that such a protein has activity), we propose that the L170fs*268 occupies the normal B3GALT6 protein position in the Golgi and exerts a dominant-negative effect.

MECOM-related disorder: Radioulnar synostosis without hematological aberration due to unique variants.

PURPOSE: The etiology for a considerable proportion of patients with congenital radioulnar synostosis (RUS) remains unclear. This study aimed to investigate the genetic cause of RUS without a known cause. METHODS: Patients with RUS were investigated. Exome sequencing and/or Sanger sequencing was performed. Bioinformatics analysis was also performed. Pathogenicity was evaluated for variants of interest. RESULTS: We identified unique missense variants in MECOM (encodes EVI1) associated with RUS in 8 families. Of them, 6 families had variants in residue R781, including 3 families with R781C (c.2341C>T), 2 families with R781H (c.2342G>A), and 1 family with R781L (c.2342G>T). Another 2 variants included I783T (c.2348T>C) in 1 family and Q777E (c.2329C>G) in 1 family. All these variants were clustered within the ninth zinc finger motif of EVI1. Phenotype evaluation identified that most of these patients with RUS harboring mutant MECOM had finger malformations, but none of them had identifiable hematological abnormalities. Functional experiments showed that MECOM R781C led to alterations in TGF-ß-mediated transcriptional responses. CONCLUSION: This study examined MECOM variants by focusing on RUS instead of hematological abnormalities. The R781 residue in EVI1 is a hotspot for human RUS variants. Mutant MECOM is the second most common cause for familial RUS.

Case series of congenital pseudarthrosis of the tibia unfulfilling neurofibromatosis type 1 diagnosis: 21% with somatic NF1 haploinsufficiency in the periosteum.

Up to 84% of patients with congenital pseudarthrosis of the tibia (CPT) present with neurofibromatosis type 1 (NF1) (NF1-CPT). However, the etiology of CPT not fulfilling the NIH diagnostic criteria for NF1 (non-NF1-CPT) is not well understood. Here, we collected the periosteum tissue from the pseudarthrosis (PA) site of 43 non-NF1-CPT patients and six patients with NF1-CPT, together with the blood or oral specimen of trios (probands and unaffected parents). Whole-exome plus copy number variation sequencing, multiplex ligation-dependent probe amplification (MLPA), ultra-high amplicon sequencing, and Sanger sequencing were employed to identify pathogenic variants. The result showed that nine tissues of 43 non-NF1-CPT patients (21%) had somatic mono-allelic NF1 inactivation, and five of six NF1-CPT patients (83.3%) had bi-allelic NF1 inactivation in tissues. However, previous literature involving genetic testing did not reveal somatic mosaicism in non-NF1-CPT patients so far. In NF1-CPT patients, when the results from earlier reports and the present study were combined, 66.7% of them showed somatic NF1 inactivation in PA tissues other than germline inactivation. Furthermore, no diagnostic variants from other known genes (GNAS, AKT1, PDGFRB, and NOTCH3) related to skeletal dysplasia were identified in the nine NF1 positive non-NF1-CPT patients and six NF1-CPT patients. In conclusion, we detected evident somatic mono-allelic NF1 inactivation in the non-NF1-CPT. Thus, for pediatric patients without NF1 diagnosis, somatic mutations in NF1 are important.

Survival Outcomes of Hemoperfusion and Hemodialysis versus Hemodialysis in Patients with End-Stage Renal Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: The maintenance treatment of ESRD puts a great burden on individual patients, society, and the country of China as a whole. Hemoperfusion plus hemodialysis (HP + HD) in ESRD patients can yield modified outcomes such as prolonged life expectancy and improved dialysis quality and quality of life. This study aimed to systematically analyze the effect of HP + HD on the overall survival (OS) rates of ESRD patients and to provide support for clinical decision-making. METHODS: A computerized search was performed in the PubMed, Embase, Cochrane Library, CNKI, WanFang Data and SinoMed databases for relevant original research articles. Studies were included or excluded based on their compliance with predefined selection criteria. RESULTS: Twelve studies were included in the qualitative synthesis and quantitative synthesis (meta-analysis). The meta-analysis showed that the 1-year OS rate (odds ratio [OR]: 3.35, 95% CI: 1.89, 5.91, p < 0.05), 2-year OS rate (OR: 2.88, 95% CI: 1.84, 4.53, p < 0.05), and 5-year OS rate (χ2 = 4.3092, p < 0.05) of patients with ESRD treated with HP + HD were better than those treated with HD, but there was no significant difference in 3-year OS rate (OR: 1.97, 95% CI: 0.76, 5.06, p > 0.05). Subgroup analysis showed the same outcomes in different study designs (1-year OS rate: randomized controlled trials [RCTs]: OR: 4.38, 95% CI: 1.61, 11.88, p < 0.05; cohort studies: OR: 2.90, 95% CI: 1.44, 5.85, p < 0.05; 2-year OS rate: RCTs: OR: 2.99, 95% CI: 1.84, 4.84, p < 0.05) and different age-groups (1-year OS rate: 45-50 years: OR: 3.19, 95% CI: 1.55, 6.57, p < 0.05; 55-60 years: OR: 3.37, 95% CI: 1.07, 10.61, p < 0.05; 2-year OS rate: 50-55 years: OR: 2.86, 95% CI: 1.59, 5.16, p < 0.05: 60-65 years: OR: 4.41, 95% CI: 1.19, 16.30, p < 0.05). CONCLUSIONS: This meta-analysis suggests that the OS rates of ESRD patients treated with HP + HD were better than those of patients treated with HD. A speculative hypothesis for why this is the case may be that HP + HD can achieve the complementary elimination of metabolites, effectively preventing and treating complications caused by long-term dialysis and prolonging life expectancy. Therefore, HP + HD should be widely used in ESRD patients.

A genotype and phenotype analysis of SMAD6 mutant patients with radioulnar synostosis.

BACKGROUND: SMAD6 variants have been reported in patients with radioulnar synostosis (RUS). This study aimed to investigate the genotypes and phenotypes for a large cohort of patients with RUS having mutant SMAD6. METHODS: Genomic DNA samples were isolated from 251 RUS sporadic patients (with their parents) and 27 RUS pedigrees. Sanger sequencing was performed for the SMAD6 coding regions. For positive probands, co-segregation and parental-origin analysis of SMAD6 variants and phenotypic re-evaluation were performed for their family members. RESULTS: We identified 50 RUS probands with SMAD6 variants (13 co-segregated with RUS in pedigrees and 37 in RUS-sporadic patients). Based on the new and previous data, we identified SMAD6 mutated in 16/38 RUS pedigrees and 61/393 RUS sporadic patients, respectively. Overall, 93 SMAD6 mutant patients with RUS were identified, among which 29 patients had unilateral RUS, where the left side was more involved than the right side (left:right = 20:9). Female protective effects and non-full penetrance were observed, in which only 6.90% mothers (vs. ~50% fathers) of SMAD6 mutant RUS probands had RUS. Pleiotropy was observed as a re-evaluation of SMAD6 mutant families identified: (a) three families had axial skeletal malformations; (b) two families had polydactyly; and (c) eight families had other known malformations. CONCLUSION: SMAD6 was mutated in 42.11% RUS pedigrees and 15.52% RUS sporadic patients. The RUS patients with SMAD6 variants exhibit both non-full-penetrance, variable expressivity, pleiotropy, female protective effects, and the left side is more susceptible than the right side.

Cost-effectiveness analysis of hemodialysis plus hemoperfusion versus hemodialysis alone in adult patients with end-stage renal disease in China.

BACKGROUND: This study evaluates the cost-effectiveness of hemodialysis (HD) plus hemoperfusion (HP) with HD alone in adult patients with end-stage renal disease (ESRD) in China. METHODS: A Markov model was constructed to assess the cost-effectiveness of interventions over a lifetime horizon. Model parameters were informed by the HD/HP trial, the first randomized, open-label multicenter trial comparing survival outcomes and incidence of cardiovascular disease (CVD) for HD + HP versus HD alone, and supplemented by published literature and expert opinion. The primary outcome was the incremental cost-effectiveness ratio (ICER) with respect to quality adjusted life-years (QALY). The robustness of the results was examined in extensive sensitivity analyses. Analyses were conducted from a healthcare perspective. Costs were reported in both Chinese Renminbi (RMB) and US Dollars (USD) in 2019 values. RESULTS: The base case ICER of HD + HP is RMB 174,486 (USD 25,251) per QALY, which is lower than the RMB 212,676 (USD 30,778) willingness-to-pay threshold of three times Gross Domestic Product. This conclusion is sensitive to the mortality for patients with no severe CVD events, the incidence of CVD events, and the cost of HP and HD. At a willingness-to-pay threshold of RMB 212,676 (USD 30,778) per QALY gained, the probability that HD + HP is cost-effective is 58%. CONCLUSIONS: Our results indicate a potential for HD + HP to be cost-effective for patients with ESRD. Further evidence on the longer-term impact of HD + HP on CVD event rates and mortality unrelated to CVD is needed to robustly demonstrate the cost-effectiveness of HD + HP. TRIAL REGISTRATION: The HD/HP trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-16009332).

Network Meta-analysis of the Therapeutic Effects of Hypoglycemic Drugs and Intensive Lifestyle Modification on Impaired Glucose Tolerance.

PURPOSE: In the Guidelines for the Prevention and Control of Type 2 Diabetes in China (2017 edition), intensive lifestyle interventions are recommended for preventing the progression of impaired glucose tolerance (IGT) to type 2 diabetes mellitus. Acarbose and metformin can also be considered if intensive lifestyle modification has been ineffective for 6 months. But the effects of intensive lifestyle modification and glucose-lowering drug interventions that work best in the population with IGT are unclear. This network meta-analysis assessed the effectiveness of intensive lifestyle modification, acarbose, and metformin in treating populations with IGT. METHODS: We systematically searched both Chinese- and English-language databases, including China Knowledge, the Cochrane Library, Embase, PubMed, VIP, and Wanfang, for articles published between database inception and September 2019. Randomized, controlled clinical trials in patients with IGT treated with acarbose, metformin, and intensive lifestyle modification were assessed for eligibility. The data from all included studies were evaluated by 2 reviewers independently in accordance with the Cochrane Handbook for Systematic Reviews of Intervention version 6.0. A network meta-analysis was performed by using R software version 3.6.1. FINDINGS: The data from 53 randomized controlled trials were included in the review, with a sample size of 21,208 patients. Compared with the control group, the use of acarbose, metformin, and/or intensive lifestyle modification was associated with reduced rates of progression to diabetes (relative risks [RRs] [95% credible intervals]: acarbose, 0.37 [0.29-0.47]; metformin, 0.39 [0.30-0.50]; intensive lifestyle modification, 0.61 [0.50-0.73]). The surface under the cumulative ranking (SUCRA) value of acarbose was 88.35%, supporting that acarbose was more effective in reducing the rate of progression to diabetes compared with controls. With acarbose, metformin, and intensive lifestyle modification, the rates of achieving a normal glucose level were increased by RR = 2.1, 1.7, and 1.2, respectively when compared with control group. The SUCRA value of acarbose was 99.69%, supporting the optimal effect of acarbose in achieving a normal blood glucose level. IMPLICATIONS: In this meta-analysis in patients with IGT, compared with controls, acarbose and metformin were associated with decreased rates of progression to diabetes and increased rates of achieving a normal glucose level. Acarbose use was associated with an increased rate of achieving a normal glucose level, while intensive lifestyle modification was not.

Disorder of Sexual Development Males With XYY in Blood Have Exactly X/XY/XYY Mosaicism in Gonad Tissues.

Y chromosome represents masculinization. The extra Y chromosome of XYY patients usually leads to over-masculinization phenotypes. The occurrence of several DSD cases with XYY in blood is controversial. Is XYY associated with disorder of sex development (DSD)? What is the mechanism behind DSD in males with XYY in blood? To this end, this study retrospectively analyzed blood-karyotype data of 4,437 DSD male children and karyotypes data of 6,259 newborn males as the control. Exome sequencing (ES) was performed to test whether the patients with DSD and with XYY in blood had other variants on known DSD-genes. Testicular biopsy was performed. Fluorescence in situ hybridization (FISH) was used to test whether a sex chromosome mosaicism was present in the oral epithelial cells or gonad tissue of patients with DSD and with XYY in blood. Among 4,437 DSD males who received cytogenetic evaluation, 14 patients with 47,XYY were identified. By contrast, five individuals among the 6,259 controls had 47,XYY. XYY in blood is more frequent among males with DSD than in other males (p = 0.004). The XYY karyotypes were confirmed again by GTG-banding in blood samples and by FISH performed on oral epithelial cells. ES on seven XYY DSD patients was successfully performed, but results did not identify any pathogenic variant on 55 known DSD genes. Gonad biopsy (n = 3) revealed testicular dysplasia and true hermaphroditism. FISH of gonad tissues (n = 3) showed that all of the samples had mosaic for X/XY/XYY. This study is the first to investigate the relationship between XYY in blood and DSD. The knowledge that XYY is in the blood and in oral cells have X/XY/XYY mosaicism in gonadal tissue is new for both researchers and clinicians who seek to understand the genetic basis of DSD males.

Economic evaluation of olmesartan/amlodipine fixed-dose combination for hypertension treatment in China.

Objectives: To evaluate the cost-effectiveness of olmesartan/amlodipine fixed-dose combination vs olmesartan and amlodipine free combination, amlodipine single drug, and valsartan/amlodipine fixed-dose combination in the treatment of hypertensive patients from payer perspective in China.Methods: A Markov model was constructed, which included five health states of hypertensive patients who are aged 35-84 years at baseline and free of cardiovascular disease. Clinical data were obtained from a network meta-analysis. Epidemiology data, adverse events (AEs), cost, and utility data were obtained from the literature. The cost associated with AEs was estimated based on the cost of same symptoms of hypertensive patients in an electric medical record database. The model projected quality-adjusted life years (QALYs) gained, total costs per patient in a 20-year time horizon, and incremental cost-effectiveness ratios. Probability sensitivity analyses (PSA) and one-way sensitivity analyses were conducted for the main parameters to test the robustness of the model.Results: Compared to olmesartan and amlodipine free combination, amlodipine, and valsartan/amlodipine fixed-dose combination, treatment with olmesartan/amlodipine fixed-dose combination led to fewer CVD events and deaths; resulted in an incremental cost of ¥-5,439 ($-791.36), ¥6,530 ($950.09), and ¥-1,019 ($-148.26) and gained additional QALYs of 0.052, 0.094, and 0.037 per patient, respectively. Compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, olmesartan/amlodipine fixed-dose combination was dominant. Compared with amlodipine alone, the incremental cost-effectiveness ratios were below the WHO recommended cost-effectiveness threshold, indicating the olmesartan/amlodipine fixed-dose combination was a cost-effective option for hypertensive patients in China. The 10-years' time horizon scenario analysis showed similar results to the 20-years' time horizon. Probabilistic sensitivity analysis and one-way sensitivity analyses showed the robustness of the model results.Conclusions: Olmesartan/amlodipine fixed-dose combination confers better health outcomes and costs less compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, and is cost-effective compared to amlodipine for hypertension treatment in China.

Management of Benign Tracheal Stenosis by Small-diameter Tube-assisted Bronchoscopic Balloon Dilatation.

BACKGROUND: A limitation of bronchoscopic balloon dilatation (BBD) is that airflow must be completely blocked for as long as possible during the operation. However, the patient often cannot hold his or her breath for a long period affecting the efficacy of the procedure. In this study, we used an extra-small-diameter tube to provide assisted ventilation to patients undergoing BBD and assessed the efficacy and safety of this technique. METHODS: Bronchoscopic balloon dilatation was performed in 26 patients with benign tracheal stenosis using an extra-small-diameter tube. The tracheal diameter, dyspnea index, blood gas analysis results, and complications were evaluated before and after BBD. Statistical analyses were performed by SPSS version 16.0 for Windows (SPSS, Inc., Chicago, IL, USA). RESULTS: Sixty-three BBD procedures were performed in 26 patients. Dyspnea immediately improved in all patients after BBD. The tracheal diameter significantly increased from 5.5 ± 1.5 mm to 13.0 ± 1.3 mm (P < 0.001), and the dyspnea index significantly decreased from 3.4 ± 0.8 to 0.5 ± 0.6 (P < 0.001). There was no significant change in the partial pressure of oxygen during the operation (before, 102.5 ± 27.5 mmHg; during, 96.9 ± 30.4 mmHg; and after, 97.2 ± 21.5 mmHg; P = 0.364), but there was slight temporary retention of carbon dioxide during the operation (before, 43.5 ± 4.2 mmHg; during, 49.4 ± 6.8 mmHg; and after, 40.1 ± 3.9 mmHg; P < 0.001). CONCLUSION: Small-diameter tube-assisted BBD is an effective and safe method for the management of benign tracheal stenosis.