Development and external validation of a prediction model for digit replantation failure after traumatic amputations based on a prospective multicenter cohort.

BACKGROUND: Failure of digit replantation after traumatic amputation is difficult to predict. The authors aimed to develop a prognostic model to better identify factors that better predict replantation failure following traumatic digit amputation. MATERIALS AND METHODS: In this multicenter prospective cohort, the authors identified patients who had received digit replantation between 1 January 2015 and 1 January 2019. Univariable and multivariable analyses were performed successively to identify independently predictive factors for failure of replanted digit. To reduce overfitting, the Bayesian information criterion was used to reduce variables in the original model. Nomograms were created with the reduced model after model selection. This model was then internally validated with bootstrap resampling and further externally validated in validation cohort. RESULTS: Digit replantation was failed in 101 of 1062 (9.5%) digits and 146 of 1156 digits (12.6%) in the training and validation cohorts, respectively. The authors found that six independent prognostic variables were associated with digit replantation failure: age, mechanism of injury, ischemia duration, smoking status, amputation pattern (complete or incomplete), and surgeon's experience. The prediction model achieved good discrimination, with concordance indexes of 0.81 (95% CI: 0.76-0.85) and 0.70 (95% CI: 0.65-0.74) in predicting digit failure in the training and validation cohorts, respectively. Calibration curves were well-fitted for both training and validation cohorts. CONCLUSIONS: The proposed prediction model effectively predicted the failure rate of digit replantation for individual digits of all patients. It could assist in selecting the most suitable surgical plan for the patient.

Contribution of revision amputation vs replantation for certain digits to functional outcomes after traumatic digit amputations: A comparative study based on multicenter prospective cohort.

BACKGROUND: Traumatic digit amputations can result in significant impairment. Optimal surgical treatment is unclear for certain digits in various amputation patterns. Our aim was to compare the contribution of revision amputation vs replantation for each particular digit to functional outcomes. MATERIALS AND METHODS: Prospective cohort study at three tertiary hospitals was conducted in China. Eligible participants were 3192 patients with traumatic digit amputations enrolled from January 1, 2014, to January 1, 2018. The primary outcome was Michigan Hand Outcomes Questionnaire (MHQ) scores 2 years after initial surgery. Secondary outcome was score on the Disabilities of the Arm, Shoulder, and Hand (DASH). RESULTS: Of 3192 enrolled patients, 2890 completed the study. Main-effect linear regression showed that participants with replantation of thumb, index, long, and ring (proximal to the proximal interphalangeal [PIP] joint) fingers had significantly better MHQ scores compared to participants with the corresponding finger revision amputation. DASH results were comparable. Finger-finger interaction analyses conducted with multifactor dimensionality reduction (MDR) revealed that the small finger and ring finger had the smallest and greatest interactions with other fingers, respectively. After stratification by amputation level of thumb, index finger, or long finger, linear regression showed that replantation of the ring finger distal to the PIP joint resulted in better MHQ and DASH when the thumb or long finger was also traumatically amputated proximal to the IP/PIP joint. CONCLUSIONS: Replantation of the thumb, index, long, and ring (proximal to PIP joint) fingers is preferable to revision amputation, regardless of amputation pattern. Replantation of the ring finger amputated distal to PIP was beneficial only when the thumb or long finger was amputated proximal to IP/PIP joint. Replantation or revision amputation of the small finger was indistinguishable in terms of functional outcome. Future investigations and clinical decisions should take into account the role of finger-finger interactions.

A cell-based high-throughput screening method based on a ubiquitin-reference technique for identifying modulators of E3 ligases.

Accumulating evidence indicates that a wide range of E3 ubiquitin ligases are involved in the development of many human diseases. Searching for small-molecule modulators of these E3 ubiquitin ligases is emerging as a promising drug discovery strategy. Here, we report the development of a cell-based high-throughput screening method to identify modulators of E3 ubiquitin ligases by integrating the ubiquitin-reference technique (URT), based on a fusion protein of ubiquitin located between a protein of interest and a reference protein moiety, with a Dual-Luciferase system. Using this method, we screened for small-molecule modulators of SMAD ubiquitin regulatory factor 1 (SMURF1), which belongs to the NEDD4 family of E3 ubiquitin ligases and is an attractive therapeutic target because of its roles in tumorigenesis. Using RAS homolog family member B (RHOB) as a SMURF1 substrate in this screen, we identified a potent SMURF1 inhibitor and confirmed that it also blocks SMURF1-dependent degradation of SMAD family member 1 (SMAD1) and RHOA. An in vitro auto-ubiquitination assay indicated that this compound inhibits both SMURF1 and SMURF2 activities, indicating that it may be an antagonist of the catalytic activity of the HECT domain in SMURF1/2. Moreover, cell functional assays revealed that this compound effectively inhibits protrusive activity in HEK293T cells and blocks transforming growth factor ß (TGFß)-induced epithelial-mesenchymal transition (EMT) in MDCK cells, similar to the effects on these processes caused by SMURF1 loss. In summary, the screening approach presented here may have great practical potential for identifying modulators of E3 ubiquitin ligases.