Functional and Clinical Outcomes After Plate Osteosynthesis Versus Intramedullary Nailing of a Humeral Shaft Fracture:The Results of the HUMMER Multicenter, Prospective Cohort Study

BACKGROUND: Plate osteosynthesis (referred to throughout as plating) and intramedullary nailing (referred to throughout as nailing) are the most common operative strategies for humeral shaft fractures. However, it is undecided which treatment is more effective. This study aimed to compare functional and clinical outcomes of these treatment strategies. We hypothesized that plating would result in an earlier recovery of shoulder function and fewer complications. METHODS: From October 23, 2012, to October 3, 2018, adults with a humeral shaft fracture, OTA/AO type 12A or 12B, were enrolled in a multicenter, prospective cohort study. Patients were treated with plating or nailing. Outcome measures included the Disabilities of the Arm, Shoulder and Hand (DASH) score, Constant-Murley score, ranges of motion of the shoulder and elbow, radiographic healing, and complications until 1 year. Repeated-measure analysis was done with correction for age, sex, and fracture type. RESULTS: Of the 245 included patients, 76 were treated with plating and 169 were treated with nailing. Patients in the plating group were younger, with a median age of 43 years compared with 57 years for the nailing group (p &lt; 0.001). The mean DASH score after plating improved faster over time, but did not differ significantly from the score after nailing at 12 months (11.7 points [95% confidence interval (CI), 7.6 to 15.7 points]) for plating and 11.2 points [95% CI, 8.3 to 14.0 points] for nailing). The Constant-Murley score and shoulder abduction, flexion, external rotation, and internal rotation displayed a significant treatment effect (p treatment ≤ 0.001), in favor of plating. The plating group had 2 implant-related complications, whereas the nailing group had 24, including 13 nail protrusions and 8 screw protrusions. Plating resulted in more postoperative temporary radial nerve palsy (8 patients [10.5%] compared with 1 patient [0.6%]; p &lt; 0.001) and a trend toward fewer nonunions (3 patients [5.7%] compared with 16 patients [11.9%]; p = 0.285) than nailing. CONCLUSIONS: Plating of a humeral shaft fracture in adults results in faster recovery, especially of shoulder function. Plating was associated with more temporary nerve palsies, but fewer implant-related complications and surgical reinterventions, than nailing. Despite heterogeneity in implants and surgical approach, plating seems to be the preferred treatment option for these fractures. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.</p

Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing

Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3 and KMT2A were detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Functional and clinical outcome after operative versus nonoperative treatment of a humeral shaft fracture (HUMMER): results of a multicenter prospective cohort study

Purpose: The best treatment of humeral shaft fractures in adults is still under debate. This study aimed to compare functional and clinical outcome of operative versus nonoperative treatment in adult patients with a humeral shaft fracture. We hypothesized that operative treatment would result in earlier functional recovery. Methods: From October 23, 2012 to October 03, 2018, adults with a humeral shaft fracture AO type 12A or 12B were enrolled in a prospective cohort study in 29 hospitals. Patients were treated operatively or nonoperatively. Outcome measures were the Disabilities of the Arm, Shoulder, and Hand score (DASH; primary outcome), Constant–Murley score, pain (Visual Analog Score, VAS), health-related quality of life (Short Form-36 (SF-36) and EuroQoL-5D-3L (EQ-5D)), activity resumption (Numeric Rating Scale, NRS), range of motion (ROM) of the shoulder and elbow joint, radiologic healing, and complications. Patients were followed for one year. Repeated measure analysis was done with correction for age, gender, and fracture type. Results: Of the 390 included patients, 245 underwent osteosynthesis and 145 were primarily treated nonoperatively. Patients in the operative group were younger (median 53 versus 62 years; p < 0.001) and less frequently female (54.3% versus 64.8%; p = 0.044). Superior results in favor of the operative group were noted until six months follow-up for the DASH, Constant–Murley, abduction, anteflexion, and external rotation of the shoulder, and flexion and extension of the elbow. The EQ-US, and pronation and supination showed superior results for the operative group until six weeks follow-up. Malalignment occurred only in the nonoperative group (N = 14; 9.7%). In 19 patients with implant-related complications (N = 26; 10.6%) the implant was exchanged or removed. Nonunion occurred more often in the nonoperative group (26.3% versus 10.10% in the operative group; p < 0.001). Conclusion: Primary osteosynthesis of a humeral shaft fracture (AO type 12A and 12B) in adults is safe and superior to nonoperative treatment, and should therefore be the treatment of choice. It is associated with a more than twofold reduced risk of nonunion, earlier functional recovery and a better range of motion of the shoulder and elbow joint than nonoperative treatment. Even after including the implant-related complications, the overall rate of complications as well as secondary surgical interventions was highest in the nonoperative group. Trial registration: NTR3617 (registration date 18-SEP-2012)

Understanding the effect of an educational intervention to optimize HIV testing strategies in primary care in Amsterdam – results of a mixed-methods study

Abstract Background In the Netherlands, general practitioners (GPs) play a key role in provider-initiated HIV testing, but opportunities for timely diagnosis are regularly missed. We implemented an educational intervention to improve HIV testing by GPs from 2015 to 2020, and observed a 7% increase in testing in an evaluation using laboratory data. The objective for the current study was to gain a deeper understanding of whether and how practices and perceptions of GPs’ HIV/sexually transmitted infection (STI) testing behaviour changed following the intervention. Methods We performed a mixed-methods study using questionnaires and semi-structured interviews to assess self-reported changes in HIV/STI testing by participating GPs. Questionnaires were completed by participants at the end of the final educational sessions from 2017 through 2020, and participating GPs were interviewed from January through March 2020. Questionnaire data were analysed descriptively, and open question responses were categorised thematically. Interview data were analysed following thematic analysis methods. Results In total, 101/103 participants completed questionnaires. Of 65 participants that were included in analyses on the self-reported effect of the programme, forty-seven (72%) reported it had changed their HIV/STI testing, including improved STI consultations, adherence to the STI consultation guideline, more proactive HIV testing, and more extragenital STI testing. Patients’ risk factors, patients’ requests and costs were most important in selecting STI tests ordered. Eight participants were interviewed and 15 themes on improved testing were identified, including improved HIV risk-assessment, more proactive testing for HIV/STI, more focus on HIV indicator conditions and extragenital STI testing, and tools to address HIV during consultations. However, several persistent barriers for optimal HIV/STI testing by GPs were identified, including HIV-related stigma and low perceived risk. Conclusions Most GPs reported improved HIV/STI knowledge, attitude and testing, but there was a discrepancy between reported changes in HIV testing and observed increases using laboratory data. Our findings highlight challenges in implementation of effective interventions, and in their evaluation. Lessons learned from this intervention may inform follow-up initiatives to keep GPs actively engaged in HIV testing and care, on our way to zero new HIV infections

Economic evaluation of operative versus nonoperative treatment of a humeral shaft fracture: economic analyses alongside a multicenter prospective cohort study (HUMMER)

Purpose: Operative treatment of a humeral shaft fracture results in faster recovery than nonoperative treatment. The cost-effectiveness, in terms of costs per Quality-Adjusted Life Year (QALY) gained (Dutch threshold €20,000-€80,000) or minimal important change (MIC) in disability reduced (DASH 6.7), is unknown. The aim of this study was to determine cost-utility and cost-effectiveness of operative versus nonoperative treatment in adults with a humeral shaft fracture type 12A or 12B. Methods: This study was performed alongside a multicenter prospective cohort study. Costs for health care and lost productivity until one year after trauma were calculated. The incremental cost-utility ratio (ICUR) was reported in costs per QALY (based on the EuroQoL-5D-3L (EQ-5D)) gained. The incremental cost-effectiveness ratio (ICER) was reported in costs per MIC (based on the DASH score at three months) reduced. Results: Overall, 245 patients were treated operatively and 145 nonoperatively. In the operative group, the mean total costs per patient (€11,925 versus €8793; p < 0.001) and QALYs (0.806 versus 0.778; p < 0.001) were higher. The ICUR of operative treatment was €111,860 per QALY gained (i.e., €3132/0.028). The DASH was 7.3 points (p < 0.001) lower in the operative group. The ICER of operative treatment was €2880 per MIC in disability reduced (i.e., €3132/7.3*6.7). Conclusion: Due to the limited effect of treatment on quality of life measured with the EQ-5D, the ICUR of operative treatment (€111,860 per QALY gained) exceeds the threshold. However, the incremental costs of €2880 per clinically meaningful difference in DASH are much lower and suggest that operative treatment for a humeral shaft fracture is cost-effective

Inherited missense variants that affect GFI1B function do not necessarily cause bleeding diatheses

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