Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.

SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.

Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease.

BACKGROUND: Canavan disease is a devastating neurometabolic disorder caused by accumulation of N acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (ASPA). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective. METHODS: We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample. RESULTS: Measuring N-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6-13.6 µmol/L [n = 45] vs 0.44; 0.24-0.99 µmol/L [n = 59] (p < 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1-9.9 µmol/L [n = 8]) and neonatal controls (0.93; 0.4-1.8 µmol/L [n = 784]) (p < 0.05). CONCLUSIONS: We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.

Major cardiovascular events in patients with cardiovascular monosodium urate deposits in atherosclerotic plaques.

OBJECTIVE: To determine the association of cardiovascular atherosclerotic plaque monosodium urate deposits with the occurrence of major cardiovascular events in gout and hyperuricemia patients. METHODS: This retrospective cohort study included patients with clinically suspicion of gout, who performed a dual energy computed tomography of the affected limb and thorax between June 1st, 2012 and December 5th, 2019. Clinical and laboratory parameters were retrieved from patients charts. Established cardiovascular risk factors were evaluated. Medical history review identified the presence of major adverse cardiac events with a median follow up time of 33 months (range 0-108 months) after the performed computed tomography scan. RESULTS: Full data sets were available for 189 patients: 131 (69.3%) gout patients, 40 (21.2%) hyperuricemia patients, and 18 (9.5%) controls. Patients with cardiovascular monosodium urate deposits (n = 85/189, 45%) revealed increased serum acute phase reactants, uric acid levels and calcium scores in computed tomography compared with patients without cardiovascular monosodium urate deposits. Major adverse cardiac events were observed in 35 patients (18.5%) with a higher prevalence in those patients revealing cardiovascular monosodium urate deposits (n = 22/85, 25.9%) compared with those without cardiovascular monosodium urate deposits (n = 13/104, 12.5%, OR 2.4, p= 0.018). CONCLUSION: This is the first study demonstrating the higher hazard of major adverse cardiac events in patients with dual energy computed tomography-verified cardiovascular monosodium urate deposits. The higher prevalence of cardiac events in patients with cardiovascular monosodium urate deposits may facilitate risk stratification of gout patients, as classical cardiovascular risk scores or laboratory markers fail in their proper identification.

Randomized comparison of HARVesting the Left Internal Thoracic Artery in a skeletonized versus pedicled technique: the HARVITA trial-study protocol.

Latest research has indicated a potential adverse effect on graft patency rates and clinical outcomes with skeletonizing the left internal thoracic artery. We aim to provide a prospective, randomized, multicentre trial to compare skeletonized versus pedicled harvesting technique of left internal thoracic artery concerning graft patency rates and patient survival. A total of 1350 patients will be randomized to either skeletonized or pedicled harvesting technique and undergo surgical revascularization. Follow-up will be performed at 30 days, 1 year, 2 years and 5 years after surgery. The primary outcome will be death or left internal thoracic artery graft occlusion in coronary computed tomography angiography or invasive angiography within 2 years (+/- 3 months) after surgery. The secondary outcome will be major adverse cardiac events (composite outcome of all-cause death, myocardial infarction and repeated revascularization) within 1 year, 2 years and 5 years after surgery. The primary end point will be compared in the modified intention-to-treat population between the two treatment groups using Kaplan-Meier graphs, together with log-rank testing. Hereby, we present the study protocol of the first adequately powered prospective, randomized, multicentre trial which compares skeletonized and pedicled harvesting technique of left internal thoracic artery regarding graft patency rates and patient survival.

Toward Post-Hartree-Fock Accuracy for Protein-Ligand Affinities Using the Molecules-in-Molecules Fragmentation-Based Method.

The complexity and size of large molecular systems, such as protein-ligand complexes, pose computational challenges for accurate post-Hartree-Fock calculations. This study delivers a thorough benchmarking of the Molecules-in-Molecules (MIM) method, presenting a clear and accessible strategy for layer/theory selections in post-Hartree-Fock computations on substantial molecular systems, notably protein-ligand complexes. An approach is articulated, enabling augmented computational efficiency by strategically canceling out common subsystem energy terms between complexes and proteins within the supermolecular equation. Employing DLPNO-based post-Hartree-Fock methods in conjunction with the three-layer MIM method (MIM3), this study demonstrates the achievement of protein-ligand binding energies with remarkable accuracy (errors <1 kcal mol-1), while significantly reducing computational costs. Furthermore, noteworthy correlations between theoretically computed interaction energies and their experimental equivalents were observed, with R2 values of approximately 0.90 and 0.78 for CDK2 and BZT-ITK sets, respectively, thus validating the efficacy of the MIM method in calculating binding energies. By highlighting the crucial role of diffuse or small Pople-style basis sets in the middle layer for reducing energy errors, this work provides valuable insights and practical methodologies for interaction energy computations in large molecular complexes and opens avenues for their application across a diverse range of molecular systems.

Leveraging DFT and Molecular Fragmentation for Chemically Accurate pKa Prediction Using Machine Learning.

We present a quantum mechanical/machine learning (ML) framework based on random forest to accurately predict the pKas of complex organic molecules using inexpensive density functional theory (DFT) calculations. By including physics-based features from low-level DFT calculations and structural features from our connectivity-based hierarchy (CBH) fragmentation protocol, we can correct the systematic error associated with DFT. The generalizability and performance of our model are evaluated on two benchmark sets (SAMPL6 and Novartis). We believe the carefully curated input of physics-based features lessens the model's data dependence and need for complex deep learning architectures, without compromising the accuracy of the test sets. As a point of novelty, our work extends the applicability of CBH, employing it for the generation of viable molecular descriptors for ML.

Retrospective cohort study comparing success of medical management of early pregnancy loss in pregnancies conceived with and without medical assistance.

OBJECTIVE: To compare the success rates of medical management using a combined mifepristone and misoprostol protocol in cases of early pregnancy loss (EPL) between women who conceived without medical assistance and those who conceived through in vitro fertilization (IVF), after fresh or frozen embryo transfer, and evaluate for the predictive factors of success, time to first passage of tissue, and time to complete resolution of pregnancy. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): Women who presented with EPL below 13 weeks of gestation between June 2013 and July 2021 who were managed medically with mifepristone 200 mg orally and misoprostol 800 mcg vaginally were included in the study. INTERVENTION(S): Medical management with mifepristone and misoprostol; conception without medical assistance vs. post-IVF, after fresh or frozen embryo transfer. MAIN OUTCOME MEASURE(S): We evaluated overall success and performed subgroup analysis according to the mode of conception and compared fresh vs. frozen-thawed embryo transfers for IVF pregnancies. In all groups, we also calculated success according to gestational age and compared the time to first passage of tissue. The potential predictive factors of treatment success were analyzed. The side effects and complications of treatment were recorded. RESULT(S): A total of 930 women were included in the study, 99 (11%) of whom achieved pregnancy after IVF. The overall success of medical treatment was 89% with no statistically significant difference according to the mode of conception (89% vs. 89%) or type of transfer (fresh 89% vs. frozen 89%). Only lower gestational age by sonography was independently predictive of treatment success, showing a negative regression coefficient of ß = -0.333 and an odds ratio of 0.717. The mean time to first passage of tissue was 5.0 ± 2.1 hours. Altogether, 666 women (72%) showed pregnancy resolution on the day of medication administration, an additional 110 women at 1-week follow-up, and a further 74 women after ≥4 weeks on ultrasound. CONCLUSION(S): Medical management of EPL with mifepristone and misoprostol is a highly successful treatment option that results in completed abortion in a timely fashion in both pregnancies conceived without medical assistance and those conceived after IVF.

Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study.

BACKGROUND: Friedreich's ataxia (FA) is a rare multisystemic disorder which can cause premature death. OBJECTIVES: To investigate predictors of survival in FA. METHODS: Within a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.gov identifier NCT02069509) we enrolled genetically confirmed FA patients at 11 tertiary centers and followed them in yearly intervals. We investigated overall survival applying the Kaplan-Meier method, life tables, and log-rank test. We explored prognostic factors applying Cox proportional hazards regression and subsequently built a risk score which was assessed for discrimination and calibration performance. RESULTS: Between September 2010 and March 2017, we enrolled 631 FA patients. Median age at inclusion was 31 (range, 6-76) years. Until December 2022, 44 patients died and 119 terminated the study for other reasons. The 10-year cumulative survival rate was 87%. In a multivariable analysis, the disability stage (hazard ratio [HR] 1.51, 95% CI 1.08-2.12, P = 0.02), history of arrhythmic disorder (HR 2.93, 95% CI 1.34-6.39, P = 0.007), and diabetes mellitus (HR 2.31, 95% CI 1.05-5.10, P = 0.04) were independent predictors of survival. GAA repeat lengths did not improve the survival model. A risk score built on the previously described factors plus the presence of left ventricular systolic dysfunction at echocardiography enabled identification of four trajectories to prognosticate up to 10-year survival (log-rank test P < 0.001). CONCLUSIONS: Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Postoperative cardiac biomarker release is not associated with myocardial mass in computer tomography scans.

OBJECTIVES: Myocardial hypertrophy results in increased levels of cardiac biomarkers in healthy individuals and in patients suffering from acute myocardial infarction. The influence of cardiac mass on postoperative cardiac biomarkers release remains unclear. This study investigated the correlation between myocardial mass and the release of high-sensitivity cardiac Troponin T (hs-cTnT) and creatine kinase-myocardial band (CK-MB) after isolated aortic valve replacement (AVR) or bypass surgery. METHODS: Myocardial mass of a consecutive retrospective series of patients was measured automatically using preoperative computer tomography scans (636 patients, AVR = 251; bypass surgery = 385). Levels of cardiac biomarkers were measured before and serially after surgery. Spearman and Pearson correlation and a multivariate regression model was performed to measure the degree of association between myocardial mass and the release of hs-cTnT and CK-MB. RESULTS: Patients were divided into 3 tertiles according to their myocardial mass index. Higher biomarker levels were measured preoperatively in the upper tertile of patients undergoing AVR (P = 0.004) or bypass surgery (P < 0.001). Patients with different heart sizes showed no differences in postoperative biomarker release neither after AVR nor bypass surgery. No statistical significant correlation was observed between myocardial mass index and postoperative release of hs-cTnT or CK-MB in any subgroup (ρ maximum 0.106). CONCLUSIONS: Postoperative biomarker release is not correlated with myocardial mass. Patient factors leading to increased postoperative biomarker levels need to be elucidated in future studies.

Ravidomycin Analogs from Streptomyces sp. Exhibit Altered Antimicrobial and Cytotoxic Selectivity.

Six new ravidomycin analogs (1-4, 6, and 7) were isolated from Streptomyces sp. Am59 using UV- and LCMS-guided separation based on Global Natural Products Social (GNPS) molecular networking analysis. Furthermore, we isolated fucomycin V (9), which possesses the same chromophore as ravidomycin but features a d-fucopyranose instead of d-ravidosamine. This is the first report of 9 as a natural product. Four new analogs (10-13) of 9 were also isolated. The structures were elucidated by combined spectroscopic and computational methods. We also found an inconsistency with the published [α]D25 of deacetylravidomycin, which is reported to have a (-) sign. Instead, we observed a (+) specific rotation for the reported absolute configuration of deacetylravidomycin (containing d-ravidosamine). We confirmed the positive sign by reisolating deacetylravidomycin from S. ravidus and by deacetylating ravidomycin. Finally, antibacterial, antifungal, and cytotoxicity activities were determined for the compounds. Compared to deacetylravidomycin, the compounds 4-6, 9, 11, and 12 exhibited greater antibacterial selectivity.

Repetitive levosimendan infusions for patients with advanced chronic heart failure in the vulnerable post-discharge period: The multinational randomized LeoDOR trial.

AIM: The LeoDOR trial explored the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute heart failure (HF). METHODS AND RESULTS: In this prospective multicentre, double-blind, two-armed trial, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or matching placebo for 12 weeks. All patients had left ventricular ejection fraction (LVEF) ≤30% during index hospitalization. Levosimendan was administered according to centre preference either as 6 h infusion at a rate of 0.2 µg/kg/min every 2 weeks, or as 24 h infusion at a rate of 0.1 µg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank score consisting of three hierarchical groups. Secondary clinical endpoints included the composite risk of tiers 1 and 2 at 14 and 26 weeks, respectively. Due to the COVID-19 pandemic, the planned number of patients could not be recruited. The final modified intention-to-treat analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm), which reduced the statistical power to detect a 20% risk reduction in the primary endpoint to 60%. Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint: the mean rank score was 72.55 for the levosimendan group versus 73.81 for the placebo group (p = 0.863). However, there was a signal towards a higher incidence of the individual clinical components of the primary endpoint in the levosimendan group versus the placebo group both after 14 weeks (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.12-7.68; p = 0.021) and 26 weeks (HR 1.64, 95% CI 0.87-3.11; p = 0.122). CONCLUSIONS: Among patients recently hospitalized with HF and reduced LVEF, intermittent levosimendan therapy did not improve post-hospitalization clinical stability.

Surface immobilized Cu-1,10-phenanthroline complexes with α-aminophosphonate groups in the 5-position as heterogenous catalysts for efficient atom-transfer radical cyclizations.

Many Cu catalyzed ATRC reactions suffer from low catalyst activity and stability. We have synthesized five 1,10-phenanthroline ligands substituted in the 5-position with α-aminophosphonate groups, through which the corresponding Cu complexes can be immobilized on Al2O3. These catalysts show similar activity and higher selectivity than the homogenous catalysts while being recyclable.

Approaching Coupled Cluster Accuracy with Density Functional Theory Using the Generalized Connectivity-Based Hierarchy.

This Perspective reviews connectivity-based hierarchy (CBH), a systematic hierarchy of error-cancellation schemes developed in our group with the goal of achieving chemical accuracy using inexpensive computational techniques ("coupled cluster accuracy with DFT"). The hierarchy is a generalization of Pople's isodesmic bond separation scheme that is based only on the structure and connectivity and is applicable to any organic and biomolecule consisting of covalent bonds. It is formulated as a series of rungs involving increasing levels of error cancellation on progressively larger fragments of the parent molecule. The method and our implementation are discussed briefly. Examples are given for the applications of CBH involving (1) energies of complex organic rearrangement reactions, (2) bond energies of biofuel molecules, (3) redox potentials in solution, (4) pKa predictions in the aqueous medium, and (5) theoretical thermochemistry combining CBH with machine learning. They clearly show that near-chemical accuracy (1-2 kcal/mol) is achieved for a variety of applications with DFT methods irrespective of the underlying density functional used. They demonstrate conclusively that seemingly disparate results, often seen with different density functionals in many chemical applications, are due to an accumulation of systematic errors in the smaller local molecular fragments that can be easily corrected with higher-level calculations on those small units. This enables the method to achieve the accuracy of the high level of theory (e.g., coupled cluster) while the cost remains that of DFT. The advantages and limitations of the method are discussed along with areas of ongoing developments.

Quantitative Prediction of Vertical Ionization Potentials from DFT via a Graph-Network-Based Delta Machine Learning Model Incorporating Electronic Descriptors.

While accurate wave function theories like CCSD(T) are capable of modeling molecular chemical processes, the associated steep computational scaling renders them intractable for treating large systems or extensive databases. In contrast, density functional theory (DFT) is much more computationally feasible yet often fails to quantitatively describe electronic changes in chemical processes. Herein, we report an efficient delta machine learning (ΔML) model that builds on the Connectivity-Based Hierarchy (CBH) scheme─an error correction approach based on systematic molecular fragmentation protocols─and achieves coupled cluster accuracy on vertical ionization potentials by correcting for deficiencies in DFT. The present study integrates concepts from molecular fragmentation, systematic error cancellation, and machine learning. First, we show that by using an electron population difference map, ionization sites within a molecule may be readily identified, and CBH correction schemes for ionization processes may be automated. As a central feature of our work, we employ a graph-based QM/ML model, which embeds atom-centered features describing CBH fragments into a computational graph to further increase accuracy for the prediction of vertical ionization potentials. In addition, we show that the incorporation of electronic descriptors from DFT, namely electron population difference features, improves model performance well beyond chemical accuracy (1 kcal/mol) to approach benchmark accuracy. While the raw DFT results are strongly dependent on the underlying functional used, for our best models, the performance is robust and much less dependent on the functional.

Optimization of postoperative surveillance protocols in upper tract urothelial cancer: A retrospective cohort study.

Upper tract urothelial carcinoma (UTUC) is an aggressive disease that is managed by radical or organ-sparing surgery. High recurrence rates require early detection and strict follow-up (FU) protocols. Recommendations are assigned to a low level of evidence. Our aim was to identify time-to-tumor recurrence, analyze the temporal relation to recommended FU regimens, and provide a critical proposal for further surveillance. This retrospective study included 54 patients receiving radical nephroureterectomy (RNU) in high-risk UTUC and 14 patients assigned to kidney-sparing surgery (KSS) with low-risk disease. FU surveillance protocols consisted of close intervals irrespective of the received type of surgery. In total, 68 patients were included with a median FU of 23 months. Mean overall survival (OS) was significantly shorter in RNU compared to KSS (P = .027). Recurrence in the bladder and/or upper urinary tract (UUT) was 57.1% in KSS and 38.9% after RNU (P = .241). Mean recurrence-free survival (RFS) was significantly shorter in RNU patients compared to KSS (22.4 vs. 47.9 months, P = .013), and 76.2% of the recurrences in the RNU group occurred in the first postoperative year. UUT recurrence was diagnosed after a median of 3.0 (RNU) and 25.0 (KSS) months. There was a frequent onset of metastases in the RNU group, with 85.7% in the first year compared to the KSS group with 50%. Multivariable regression analysis showed that the tumor stage was the parameter independently related to OS (P = .002), RFS (P = .008), and metastasis-free survival (MFS, P = .002). In conclusion, surveillance of UTUC should be adapted to real-time occurrence patterns. Strict imaging protocols are recommended in the first two years irrespective of the method of surgery. As recurrence is equally distributed over the years after KSS, cystoscopy should be offered regularly for five years and diagnostic URS for three years. After RNU, cystoscopies should be decreased to yearly intervals after year three. Contralateral UUT should also be examined after RNU.

High concentration of first-measured HCG after embryo transfer is associated with subsequent development of pre-eclampsia.

RESEARCH QUESTION: Are outlier high values of first-measured human chorionic gonadotrophin (HCG) following embryo transfer related to pregnancy complications, specifically pre-eclampsia? DESIGN: This retrospective cohort study screened 3448 women aged 18-45 years who underwent IVF between 2014 and 2019 and evaluated 614 women who had an intrauterine pregnancy following single embryo transfer (SET), 423 of whom had a live birth. Pregnancy and birth outcome information was available for final analysis in 280 cases. The setting was a university-based IVF centre. HCG was measured at a standardized time after the embryo transfer and the values correlated with adverse pregnancy outcomes associated with poor placentation. RESULTS: Women with first-measured HCG in the highest quintile had a higher incidence of pre-eclampsia than those with lower HCG concentrations (odds ratio [OR] 4.08, 95% confidence interval [CI] 1.41-11.82) even after controlling for age, body mass index, parity and type of embryo transfer. Additionally controlling for embryo stage at embryo transfer did not change the results (OR 3.97, 95% CI 1.37-11.46). No differences were found in the incidence of fetal growth restriction. CONCLUSIONS: This is the first known report that links high first-measured HCG after SET to an adverse pregnancy outcome. If confirmed by future studies, initiation of preventive interventions at a very early stage of pregnancy merits further evaluation in this cohort of patients.

Effects of Cannabis on PTSD Recovery: Review of the Literature and Clinical Insights.

Purpose of Review: Individuals with posttraumatic stress disorder (PTSD) may use cannabis to reduce symptoms yet are also at risk for developing problematic use. This review outlines theories, summarizes recent empirical studies, and discusses clinical implications of cannabis use and PTSD recovery. Recent Findings: Although naturalistic studies and open trials find a relationship between cannabinoids and PTSD symptom reduction, methodological limitations preclude definitive conclusions. The only randomized controlled trial to date found cannabis had no greater effect on PTSD symptoms than placebo. Summary: Rigorous studies of the long-term impact of cannabis use on PTSD recovery are needed. Clinicians and researchers must weigh the potential therapeutic effect against the costs and risks associated with long-term cannabis use. Clinicians should consider all available PTSD treatment options, along with client level factors such as the function of cannabis use, motivation to change use, and the potential impact of cannabis on treatment engagement when making clinical recommendations.

Comparative assessment of QM-based and MM-based models for prediction of protein-ligand binding affinity trends.

Methods which accurately predict protein-ligand binding strengths are critical for drug discovery. In the last two decades, advances in chemical modelling have enabled steadily accelerating progress in the discovery and optimization of structure-based drug design. Most computational methods currently used in this context are based on molecular mechanics force fields that often have deficiencies in describing the quantum mechanical (QM) aspects of molecular binding. In this study, we show the competitiveness of our QM-based Molecules-in-Molecules (MIM) fragmentation method for characterizing binding energy trends for seven different datasets of protein-ligand complexes. By using molecular fragmentation, the MIM method allows for accelerated QM calculations. We demonstrate that for classes of structurally similar ligands bound to a common receptor, MIM provides excellent correlation to experiment, surpassing the more popular Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) methods. The MIM method offers a relatively simple, well-defined protocol by which binding trends can be ascertained at the QM level and is suggested as a promising option for lead optimization in structure-based drug design.

Free Flap Outcome in Irradiated Recipient Sites: A Systematic Review and Meta-analysis.

The impact of previous radiotherapy on free flap outcome is still a subject of debate. Clinical investigations have come to divergent conclusions and the true effect of radiotherapy (XRT) on flap survival is not definitely known. Most studies investigating the factor often have their methodological limitations such as lack of statistical power as a consequence of the overall low failure rates together with few irradiated cases. This study will attempt to address the question whether previous radiotherapy is associated with a significantly higher incidence of flap failure or not. Methods: A systematic review and meta-analysis were conducted in concordance with the PRISMA protocol using the PubMed database. Fixed-effect and random-effect models were applied to obtain the odds ratio of total flap failure and partial flap failure between radiation and nonradiation groups. Statistical heterogeneity and publication bias were assessed and forest plots and funnel plots were constructed for graphic illustration. Results: A total of 43 studies were included for qualitative and quantitative analysis involving 18,776 flaps in 17,532 patients. Patients with preoperative XRT were significantly associated with an increased risk for total (odds ratio fixed = 1.675, 95% confidence interval [CI] = 1.405-1.996, P < 0.001) and partial free flap failure (odds ratio fixed = 2.161, 95% CI = 1.472-2.172, P < 0.001). Conclusion: The study suggests that preoperative radiotherapy is associated with an increased risk for total and partial free flap failure. Further studies are needed to investigate the effect of total XRT dose and time after radiation on free flap outcome.