Clinical outcomes of non-COVID-19 orthopaedic patients admitted during the COVID-19 pandemic: a multi-centre interrupted time series analysis across hospitals in six different countries.

OBJECTIVES: To assess across seven hospitals from six different countries the extent to which the COVID-19 pandemic affected the volumes of orthopaedic hospital admissions and patient outcomes for non-COVID-19 patients admitted for orthopaedic care. DESIGN: A multi-centre interrupted time series (ITS) analysis. SETTING: Seven hospitals from six countries who collaborated within the Global Health Data@Work collaborative. PARTICIPANTS: Non-COVID-19 patients admitted for orthopaedic care during the pre-pandemic (January/2018-February/2020) and COVID-19 pandemic (March/2020-June/2021) period. Admissions were categorised as: (1) acute admissions (lower limb fractures/neck of femur fractures/pathological fractures/joint dislocations/upper limb fractures); (2) subacute admissions (bone cancer); (3) elective admissions (osteoarthritis). OUTCOME MEASURES: Monthly observed versus expected ratios (O/E) were calculated for in-hospital mortality, long (upper-decile) length-of-stay and hospital readmissions, with expected rates calculated based on case-mix. An ITS design was used to estimate the change in level and/or trend of the monthly O/E ratio by comparing the COVID-19 pandemic with the pre-pandemic period. RESULTS: 69 221 (pre-pandemic) and 22 940 (COVID-19 pandemic) non-COVID-19 orthopaedic patient admissions were included. Admission volumes were reduced during the COVID-19 pandemic for all admission categories (range: 33%-45%), with more complex patients treated as shown by higher percentages of patients admitted with ≥1 comorbidity (53.8% versus 49.8%, p<0.001). The COVID-19 pandemic was not associated with significant changes in patient outcomes for most diagnostic groups. Only for patients diagnosed with pathological fractures (pre-pandemic n=1671 and pandemic n=749), the COVID-19 pandemic was significantly associated with an immediate mortality reduction (level change of -77.7%, 95% CI -127.9% to -25.7%) and for lower limb fracture patients (pre-pandemic n=9898 and pandemic n=3307) with a significantly reduced trend in readmissions (trend change of -6.3% per month, 95% CI -11.0% to -1.6%). CONCLUSIONS: Acute, subacute, as well as elective orthopaedic hospital admissions volumes were reduced in all global participating hospitals during the COVID-19 pandemic, while overall patient outcomes for most admitted non-COVID-19 patients remained the same despite the strain caused by the surge of COVID-19 patients.

Convergent Validity of 2 Widely Used Methodologies for Calculating the Hospital Standardized Mortality Ratio in Flanders, Belgium.

OBJECTIVES: To assess their construct validity, we compared results from 2 models used for estimating hospital standardized mortality ratios (HSMRs) in Belgium. The method of the Flemish Hospital Network (FHN) is based on a logistic regression for each of the 64 All Patient Refined Diagnosis-Related Groups that explain 80% of mortality and uses the Elixhauser score to correct for comorbidities. (H)SMRs published on the 3M-Benchmark-Portal are calculated by a simpler indirect standardization for All Patient Refined Diagnosis-Related Groups and risk of mortality (ROM) at discharge. METHODS: We used administrative data from all eligible hospital admissions in 22 Flemish hospitals between 2016 and 2019 (FHN, n = 682,935; 3M, n = 2,122,305). We evaluated model discrimination and accuracy and assessed agreement in estimated HSMRs between methods. RESULTS: The Spearman correlation between HSMRs generated by the FHN model and the standard 3M model was 0.79. Although 2 of 22 hospitals showed opposite classification results, that is, an HSMR significantly <1 according to the FHN method but significantly >1 according to the 3M model, classification agreement between methods was significant (agreement for 59.1% of hospitals, κ = 0.45). The 3M model ( c statistic = 0.96, adjusted Brier score = 26%) outperformed the FHN model (0.87, 17%). However, using ROM at admission instead of at discharge in the 3M model significantly reduced model performance ( c statistic = 0.94, adjusted Brier score = 21%), but yielded similar HSMR estimates and eliminated part of the discrepancy with FHN results. CONCLUSIONS: Results of both models agreed relatively well, supporting convergent validity. Whereas the FHN method only adjusts for disease severity at admission, the ROM indicator of the 3M model includes diagnoses not present on admission. Although diagnosis codes generated by complications during hospitalization have the tendency to increase the predictive performance of a model, these should not be included in risk adjustment procedures.

The relationship between publication of high-quality evidence and changes in the volume and trend of subacromial decompression surgery for patients with subacromial pain syndrome in hospitals across Australia, Europe and the United States: a controlled interrupted time series analysis.

AIMS: To evaluate the extent to which publication of high-quality randomised controlled trials(RCTs) in 2018 was associated with a change in volume or trend of subacromial decompression(SAD) surgery in patients with subacromial pain syndrome(SAPS) treated in hospitals across various countries. METHODS: Routinely collected administrative data of the Global Health Data@work collaborative were used to identify SAPS patients who underwent SAD surgery in six hospitals from five countries (Australia, Belgium, Netherlands, United Kingdom, United States) between 01/2016 and 02/2020. Following a controlled interrupted time series design, segmented Poisson regression was used to compare trends in monthly SAD surgeries before(01/2016-01/2018) and after(02/2018-02/2020) publication of the RCTs. The control group consisted of musculoskeletal patients undergoing other procedures. RESULTS: A total of 3.046 SAD surgeries were performed among SAPS patients treated in five hospitals; one hospital did not perform any SAD surgeries. Overall, publication of trial results was associated with a significant reduction in the trend to use SAD surgery of 2% per month (Incidence rate ratio (IRR) 0.984[0.971-0.998]; P = 0.021), but with large variation between hospitals. No changes in the control group were observed. However, publication of trial results was also associated with a 2% monthly increased trend (IRR 1.019[1.004-1.034]; P = 0.014) towards other procedures performed in SAPS patients. CONCLUSION: Publication of RCT results was associated with a significantly decreased trend in SAD surgery for SAPS patients, although large variation between participating hospitals existed and a possible shift in coding practices cannot be ruled out. This highlights the complexities of implementing recommendations to change routine clinical practice even if based on high-quality evidence.

Unwarranted Between-hospital Variation in Mortality, Readmission, and Length of Stay of Urological Admissions: An Important Trigger for Prioritising Quality Targets.

BACKGROUND: Unwarranted between-hospital variation is a persistent health care quality issue. It is unknown whether urology patients are prone to this variation. OBJECTIVE: To examine between-hospital variation in mortality, readmission, and length of stay for all 22 urological All Patient Refined Diagnosis Related Groups (APR-DRGs). DESIGN, SETTING, AND PARTICIPANTS: This study included administrative data from 320640 urological admissions in 99 (98%) Belgian acute-care hospitals between 2016 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used hierarchical mixed-effect logistic regression models to estimate hospital-specific and APR-DRG-specific risk-standardised rates for in-hospital mortality, 30-d readmission, and length of stay above the APR-DRG-specific 90th percentile. Between-hospital variation was assessed based on the estimated variance components. Associations of outcomes with patient and hospital characteristics and time trends were examined. RESULTS AND LIMITATIONS: Our analysis revealed important between-hospital variation in mortality, readmission, and length of stay for urological pathologies, particularly for medical diagnoses. Significant variation was shown in all three outcomes for kidney and urinary tract infections; other kidney and urinary tract diagnoses, signs, and symptoms; urinary stones and acquired upper urinary tract obstruction; and kidney and urinary tract procedures for nonmalignancy. Lowering of mortality rates in upper-quartile hospitals to the median could potentially save 41.5% of deaths in these hospitals, with the largest absolute gain for kidney and urinary tract infections and kidney and urinary tract malignancy. Limitations included a likely underestimation of readmission rates. CONCLUSIONS: Urological patient outcomes are characterised by unwarranted between-hospital variation. We recommend improvement initiatives to prioritise kidney and urinary tract infections because of significant variation across the three outcomes and the largest potential gain in lives saved. PATIENT SUMMARY: We found notable between-hospital variation in mortality, readmission, and length of stay for urological hospital admissions in Belgium. As much as 41.5% of deaths could potentially be avoided if underperforming hospitals improved. Targeting kidney and urinary tract infections could help reduce variation.

A multicenter propensity score matched analysis in 73,843 patients of an association of nutritional risk with mortality, length of stay and readmission rates.

BACKGROUND: The reported prevalences and effects of nutritional risk vary widely in the literature because of both methodological differences (e.g., screening tools and statistical analyses) and different patient populations. OBJECTIVE: In this study the authors analyzed in-hospital mortality, 30-d mortality, readmission within 4 mo, and justified length of stay (jLoS) (determined by governmental assessment to justify financial compensation) in hospitalized patients nutritionally at risk compared with hospitalized patients not at risk. DESIGN: This was a multicenter retrospective cohort study in 6 Belgian hospitals among inpatients in 2018. Propensity score matching was applied, including comorbidity score and exact matching for hospital, age group, sex, type of admission, living situation, and medical specialty. RESULTS: In total, 73,843 of 85,677 patients were screened at admission, with 16,141 found to have nutritional risk (prevalence of 21.9%). Oncology patients had the highest risk prevalence of 38.3%, whereas patients receiving plastic or reconstructive surgery had a prevalence of 5.2%. Patients nutritionally at risk had higher odds of dying in the hospital (5.1% compared with 3.3%; OR: 1.56; 95% CI: 1.37, 1.76), dying within 30 d of admission (6.8% compared with 4.3%; OR: 1.62; 95% CI: 1.45, 1.81) and being readmitted within 4 mo after discharge (35.5% compared with 32.9%; OR: 1.12; 95% CI: 1.07, 1.18). These differences were consistent across hospitals. The association between being nutritionally at risk and jLoS was ambiguous. CONCLUSIONS: One out of 5 patients included in this study was nutritionally at risk. Using propensity score matching, higher odds of in-hospital mortality, readmission, and 30-d mortality were observed. In contrast to oft-reported increased length of stay with poor nutrition, propensity matched data for jLoS suggested that this association was less pronounced in this cohort.

Standardised mortality ratios as a user-friendly performance metric and trigger for quality improvement in a Flemish hospital network: multicentre retrospective study.

OBJECTIVE: To illustrate the development and use of standardised mortality rates (SMRs) as a trigger for quality improvement in a network of 27 hospitals. DESIGN: This research was a retrospective observational study. The primary outcome was in-hospital mortality. SMRs were calculated for All Patient Refined-Diagnosis-Related Groups (APR-DRGs) that reflect 80% of the Flemish hospital network mortality. Hospital mortality was modelled using logistic regression. The metrics were communicated to the member hospitals using a custom-made R-Shiny web application showing results at the level of the hospital, patient groups and individual patients. Experiences with the metric and strategies for improvement were shared in chief medical officer meetings organised by the Flemish hospital network. SETTING: 27 Belgian hospitals. PARTICIPANTS: 1 198 717 hospital admissions for registration years 2009-2016. RESULTS: Patient gender, age, comorbidity as well as admission source and type were important predictors of mortality. Altogether the SMR models had a C-statistic of 88%, indicating good discriminatory capability. Seven out of ten APR-DRGs with the highest percentage of hospitals statistically significantly deviating from the benchmark involved malignancy. The custom-built web application and the trusted environment of the Flemish hospital network created an interoperable strategy to get to work with SMR findings. Use of the web application increased over time, with peaks before and after key discussion meetings within the Flemish hospital network. A concomitant reduction in crude mortality for the selected APR-DRGs from 6.7% in 2009 to 5.9% in 2016 was observed. CONCLUSIONS: This study reported on the phased approach for introducing SMR reporting to trigger quality improvement. Prerequisites for the successful use of quality metrics in hospital benchmarks are a collaborative approach based on trust among the participants and a reporting platform that allows stakeholders to interpret and analyse the results at multiple levels.

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

Nuclear Localization of the Autism Candidate Gene Neurobeachin and Functional Interaction with the NOTCH1 Intracellular Domain Indicate a Role in Regulating Transcription.

BACKGROUND: Neurobeachin (NBEA) is an autism spectrum disorders (ASD) candidate gene. NBEA deficiency affects regulated secretion, receptor trafficking, synaptic architecture and protein kinase A (PKA)-mediated phosphorylation. NBEA is a large multidomain scaffolding protein. From N- to C-terminus, NBEA has a concanavalin A-like lectin domain flanked by armadillo repeats (ACA), an A-kinase anchoring protein domain that can bind to PKA, a domain of unknown function (DUF1088) and a BEACH domain, preceded by a pleckstrin homology-like domain and followed by WD40 repeats (PBW). Although most of these domains mediate protein-protein interactions, no interaction screen has yet been performed. METHODS: Yeast two-hybrid screens with the ACA and PBW domain modules of NBEA gave a list of interaction partners, which were analyzed for Gene Ontology (GO) enrichment. Neuro-2a cells were used for confocal microscopy and nuclear extraction analysis. NOTCH-mediated transcription was studied with luciferase reporter assays and qRT-PCR, combined with NBEA knockdown or overexpression. RESULTS: Both domain modules showed a GO enrichment for the nucleus. PBW almost exclusively interacted with transcription regulators, while ACA interacted with a number of PKA substrates. NBEA was partially localized in the nucleus of Neuro-2a cells, albeit much less than in the cytoplasm. A nuclear localization signal was found in the DUF1088 domain, which was shown to contribute to the nuclear localization of an EGFP-DPBW fusion protein. Yeast two-hybrid identified the Notch1 intracellular domain as a physical interactor of the PBW domain and a role for NBEA as a negative regulator in Notch-mediated transcription was demonstrated. CONCLUSION: Defining novel interaction partners of conserved NBEA domain modules identified a role for NBEA as transcriptional regulator in the nucleus. The physical interaction of NBEA with NOTCH1 is most relevant for ASD pathogenesis because NOTCH signaling is essential for neural development.

Metabolic and Behavioural Phenotypes in Nestin-Cre Mice Are Caused by Hypothalamic Expression of Human Growth Hormone.

The Nestin-Cre driver mouse line has mild hypopituitarism, reduced body weight, a metabolic phenotype and reduced anxiety. Although several causes have been suggested, a comprehensive explanation is still lacking. In this study we examined the molecular mechanisms leading to this compound phenotype. Upon generation of the Nestin-Cre mice, the human growth hormone (hGH) minigene was inserted downstream of the Cre recombinase to ensure efficient transgene expression. As a result, hGH is expressed in the hypothalamus. This results in the auto/paracrine activation of the GH receptor as demonstrated by the increased phosphorylation of signal transducer and activator of transcription 5 (STAT5) and reduced expression of growth hormone releasing hormone (Ghrh). Low Ghrh levels cause hypopituitarism consistent with the observed mouse growth hormone (mGH) deficiency. mGH deficiency caused reduced activation of the GH receptor and hence reduced phosphorylation of STAT5 in the liver. This led to decreased levels of hepatic Igf-1 mRNA and consequently postnatal growth retardation. Furthermore, genes involved in lipid uptake and synthesis, such as CD36 and very low-density lipoprotein receptor were upregulated, resulting in liver steatosis. In conclusion, this study demonstrates the unexpected expression of hGH in the hypothalamus of Nestin-Cre mice which is able to activate both the GH receptor and the prolactin receptor. Increased hypothalamic GH receptor signaling explains the observed hypopituitarism, reduced growth and metabolic phenotype of Nestin-Cre mice. Activation of either receptor is consistent with reduced anxiety.

Liver-Specific Inactivation of the Proprotein Convertase FURIN Leads to Increased Hepatocellular Carcinoma Growth.

Proprotein convertases are subtilisin-like serine endoproteases that cleave and hence activate a variety of proproteins, including growth factors, receptors, metalloproteases, and extracellular matrix proteins. Therefore, it has been suggested that inhibition of the ubiquitously expressed proprotein convertase FURIN might be a good therapeutic strategy for several tumor types. Whether this is also the case for hepatocellular carcinoma (HCC) is currently not clear. In a mouse model for HCC expression of Furin was not altered in the tumors, while those of PC7, PC5/6, and PACE4 significantly decreased, at least at some time points. To investigate the impact of Furin inhibition on the development and progression of HCC in this model, Furin was genetically ablated in the liver. Furin inactivation resulted in an increased tumor mass after 5 weeks. This was not caused by decreased apoptosis, since no differences in the apoptosis index could be observed. However, it could at least partially be explained by increased hepatocyte proliferation at 5 weeks. The tumors of the Furin knockout mice were histologically similar to those in wild type mice. In conclusion, liver-specific Furin inhibition in HCC enhances the tumor formation and will not be a good therapeutic strategy for this tumor type.

The association of common variants in PCSK1 with obesity: a HuGE review and meta-analysis.

Congenital deficiency of the proprotein convertase subtilisine/kexin type 1 gene (PCSK1), which encodes proprotein convertase 1/3, causes a severe multihormonal disorder marked by early-onset obesity. The single nucleotide polymorphisms (SNPs) rs6232 and rs6234-rs6235 in PCSK1 have been associated with obesity. However, case-control studies carried out in populations of different ethnicities have only partly replicated this association. Moreover, these SNPs have only weakly been associated with body mass index (weight (kg)/height (m)(2)) at a genome-wide level of significance. To investigate this discrepancy, we conducted a systematic search for studies published before December 2013 and extracted relevant data. Pooled estimates were calculated for overall and subgroup analyses. This meta-analysis confirmed the association of PCSK1 SNPs with obesity and provides the first evidence that the association between PCSK1 rs6232 and obesity is stronger for childhood obesity than for adult obesity. Moreover, we identified weak associations with body mass index and significantly stronger associations with waist circumference for rs6234-rs6235. No difference was found in the association with different obesity grades, and no association of PCSK1 rs6234-rs6235 with obesity was identified in Asian populations. This systematic Human Genome Epidemiology (HuGE) review showed convincingly that the SNPs rs6232, rs6234, and rs6235 in PCSK1 are associated with obesity in Caucasians.

The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.

Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism.

Haploinsufficiency of the autism candidate gene Neurobeachin induces autism-like behaviors and affects cellular and molecular processes of synaptic plasticity in mice.

Neurobeachin (NBEA), a brain-enriched multidomain scaffolding protein involved in neurotransmitter release and synaptic functioning, has been identified as a candidate gene for autism spectrum disorder (ASD) in four unrelated patients haploinsufficient for NBEA. The aim of this study was to map the behavioral phenotype of Nbea(+/-) mice in order to understand its contribution to the pathogenesis of ASD. ASD-like behavioral variables of Nbea(+/-) mice were related to basal neuronal activity in different brain regions by in situ hybridizations and extracellular field recordings of synaptic plasticity in hippocampal cornu ammonis 1 (CA1) region. Levels of BDNF and phosphorylated cAMP response element-binding protein (CREB) were measured in an attempt to investigate putatively underlying changes in these neuromolecules. Nbea(+/-) mice exhibit several ASD-like features, including changes in self-grooming behavior, social behaviors, conditioned fear responses, and spatial learning and memory, which coincided with enhanced long-term potentiation (LTP) in their CA1 region. The observed alterations in learning and memory and hippocampal LTP are concomitant with decreased expression of the immediate early gene zif268 in dorsomedial striatum and hippocampal CA1 region, increased CREB phosphorylation, and increased hippocampal BDNF expression. These findings indicate that Nbea haploinsufficiency leads to various molecular and cellular changes that affect neuroplasticity and behavioral functions in mice, and could thus underlie the ASD symptomatology in NBEA deficient humans.

Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity.

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.

Genetic and functional characterization of PCSK1.

PC1/3 is a neuroendocrine-specific member of the mammalian subtilisin-like proprotein convertase family. This seven-member family is involved in the endoproteolytic cleavage of a large number of precursor proteins including prohormones, proneuropeptides, zymogens, and proreceptors. PC1/3 is synthesized as a zymogen, proPC1/3, and its propeptide is rapidly and autocatalytically cleaved in the endoplasmic reticulum. The mature protein is sorted and stored in dense-core secretory vesicles, together with its substrates. Compound-inactivating mutations in the PCSK1 gene, which encodes PC1/3, cause monogenic obesity. Furthermore, the contribution of two common nonsynonymous variants in PCSK1 to polygenic obesity risk has recently been established. Additional rare variants have been identified in non-consanguineous extremely obese Europeans but functional characterization has not yet been described. Sequencing efforts of larger cohorts of obese patients might reveal more variants conferring risk of obesity.

Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression ultrasonography, and D-dimer test.

PURPOSE: To evaluate a new noninvasive diagnostic strategy for ruling out deep vein thrombosis consisting of either a combination of low clinical probability and normal ultrasonography or a combination of moderate-to-high clinical probability, normal ultrasonography, and a normal D-dimer test. SUBJECTS AND METHODS: We studied 811 patients with clinically suspected deep vein thrombosis using a diagnostic management strategy that combined clinical probability, ultrasonography, and measurement of D-dimers. The primary endpoint was venous thromboembolism occurring during a 3-month follow-up. RESULTS: Of the 280 patients (35%) with a low clinical probability, 30 (11%) had an abnormal initial ultrasonography and were treated. Of the other 250 untreated patients with low clinical probability and a normal ultrasonography, 5 (2%; 95% confidence interval [CI]: 1% to 5%) developed a nonfatal venous thromboembolism during follow-up. Of the 531 patients (65%) with a moderate-to-high clinical probability, 300 (56%) had an abnormal ultrasonography. Of the remaining 231 patients with a normal ultrasonography, 148 had a normal D-dimer test; none of these patients developed deep vein thrombosis during follow-up (0%; 95% CI: 0% to 3%). Of the 83 patients with an abnormal D-dimer test, 77 underwent repeat ultrasonography about 1 week later; none of the 64 patients with a second normal ultrasound developed symptomatic deep vein thrombosis during follow-up (0%; 95% CI: 0% to 6%). CONCLUSIONS: This management strategy, which combines clinical probability, ultrasonography, and D-dimer measurements, is practical and safe in ruling out deep vein thrombosis in patients with clinically suspected thrombosis and reduces the need for repeat ultrasonography.