Rational thresholding of circulating tumor DNA concentration for improved surveillance of metastatic breast cancer.

BACKGROUND: The use of circulating tumor DNA (ctDNA) concentration for metastatic cancer surveillance is promising, but uncertainty remains about cut-offs with clinical validity. MATERIALS AND METHODS: This observational study recruited 136 subjects with advanced metastatic breast cancer (irrespective of ERBB2/hormone receptor status) for sequencing of their primary tumor in search for PIK3CA hotspot variants amenable for monitoring by droplet digital PCR (ddPCR). The study analyzed 341 on-treatment samples from 19 patients with PIK3CA variants H1047R or E545K enrolled for long-term (median 85 weeks, range 13-125 weeks), frequent (every 3-5 weeks, median of 14 time points per subject, range 2-29) blood sampling for ctDNA quantification by ddPCR, orthogonally validated by deep sequencing. The diagnostic accuracy of ctDNA versus cancer antigen 15-3 (CA15-3) concentrations to predict disease progression within 12 weeks was investigated using receiver operating characteristic (ROC) analysis. Likelihood ratios were used for rational selection of ctDNA result intervals. RESULTS: ctDNA [area under the ROC curve (AUC) 0.848, 95% confidence interval (CI) 0.791-0.895] showed superior diagnostic performance than CA15-3 (AUC 0.670, 95% CI 0.601-0.735, P < 0.001) to predict clinical progression within 12 weeks. ctDNA levels below 10 mutant allele copies/ml had high negative predictive value (88%), while levels above 100 copies/ml detected 64% of progressions 10 weeks earlier versus standard of care. Logistic regression analysis indicated complementary value of ctDNA and the presence of two consecutive CA15-3 rises, resulting in a model with 86% (95% CI 74% to 93%) positive predictive value and a clinically meaningful result in 89% of blood draws. CONCLUSIONS: Intensive ctDNA quantification improves metastatic breast cancer surveillance and enables individualized risk-based scheduling of clinical care.

The effect of oral dexamethasone on duration of analgesia after upper limb surgery under infraclavicular brachial plexus block: a randomised controlled trial.

The effects of oral dexamethasone on peripheral nerve blocks have not been investigated. We randomly allocated adults scheduled for forearm or hand surgery to oral placebo (n = 61), dexamethasone 12 mg (n = 61) or dexamethasone 24 mg (n = 57) about 45 min before lateral infraclavicular block. Mean (SD) time until first pain after block were: 841 (327) min; 1171 (318) min; and 1256 (395) min, respectively. Mean (98.3%CI) differences in time until first postoperative pain for dexamethasone 24 mg vs. placebo and vs. dexamethasone 12 mg were: 412 (248-577) min, p < 0.001; and 85 (-78 to 249) min, p = 0.21, respectively. Mean (98.3%CI) difference in time until first postoperative pain for dexamethasone 12 mg vs. placebo was 330 (186-474) min, p < 0.001. Both 24 mg and 12 mg of oral dexamethasone increased the time until first postoperative pain compared with placebo in patients having upper limb surgery under infraclavicular brachial plexus block.

Automated lung cancer assessment on 18F-PET/CT using Retina U-Net and anatomical region segmentation.

OBJECTIVES: To develop and test a Retina U-Net algorithm for the detection of primary lung tumors and associated metastases of all stages on FDG-PET/CT. METHODS: A data set consisting of 364 FDG-PET/CTs of patients with histologically confirmed lung cancer was used for algorithm development and internal testing. The data set comprised tumors of all stages. All lung tumors (T), lymphatic metastases (N), and distant metastases (M) were manually segmented as 3D volumes using whole-body PET/CT series. The data set was split into a training (n = 216), validation (n = 74), and internal test data set (n = 74). Detection performance for all lesion types at multiple classifier thresholds was evaluated and false-positive-findings-per-case (FP/c) calculated. Next, detected lesions were assigned to categories T, N, or M using an automated anatomical region segmentation. Furthermore, reasons for FPs were visually assessed and analyzed. Finally, performance was tested on 20 PET/CTs from another institution. RESULTS: Sensitivity for T lesions was 86.2% (95% CI: 77.2-92.7) at a FP/c of 2.0 on the internal test set. The anatomical correlate to most FPs was the physiological activity of bone marrow (16.8%). TNM categorization based on the anatomical region approach was correct in 94.3% of lesions. Performance on the external test set confirmed the good performance of the algorithm (overall detection rate = 88.8% (95% CI: 82.5-93.5%) and FP/c = 2.7). CONCLUSIONS: Retina U-Nets are a valuable tool for tumor detection tasks on PET/CT and can form the backbone of reading assistance tools in this field. FPs have anatomical correlates that can lead the way to further algorithm improvements. The code is publicly available. KEY POINTS: • Detection of malignant lesions in PET/CT with Retina U-Net is feasible. • All false-positive findings had anatomical correlates, physiological bone marrow activity being the most prevalent. • Retina U-Nets can build the backbone for tools assisting imaging professionals in lung tumor staging.

FGF2 overrides key pro-fibrotic features of bone marrow stromal cells isolated from Modic type 1 change patients.

Extensive extracellular matrix production and increased cell-matrix adhesion by bone marrow stromal cells (BMSCs) are hallmarks of fibrotic alterations in the vertebral bone marrow known as Modic type 1 changes (MC1). MC1 are associated with non-specific chronic low-back pain. To identify treatment targets for MC1, in vitro studies using patient BMSCs are important to reveal pathological mechanisms. For the culture of BMSCs, fibroblast growth factor 2 (FGF2) is widely used. However, FGF2 has been shown to suppress matrix synthesis in various stromal cell populations. The aim of the present study was to investigate whether FGF2 affected the in vitro study of the fibrotic pathomechanisms of MC1-derived BMSCs. Transcriptomic changes and changes in cell-matrix adhesion of MC1-derived BMSCs were compared to intra-patient control BMSCs in response to FGF2. RNA sequencing and quantitative real-time polymerase chain reaction revealed that pro-fibrotic genes and pathways were not detectable in MC1-derived BMSCs when cultured in the presence of FGF2. In addition, significantly increased cell-matrix adhesion of MC1-derived BMSCs was abolished in the presence of FGF2. In conclusion, the data demonstrated that FGF2 overrides key pro-fibrotic features of MC1 BMSCs in vitro. Usage of FGF2-supplemented media in studies of fibrotic mechanisms should be critically evaluated as it could override normally dominant biological and biophysical cues.

Comparison of the analgesic effect of an adductor canal block using a new suture-method catheter vs. standard perineural catheter vs. single-injection: a randomised, blinded, controlled study.

We performed a randomised, blinded, controlled study with adult patients scheduled for primary total knee arthroplasty under spinal anaesthesia. The aim was to investigate the analgesic effects of adductor canal block using catheter-based repeated boluses, either through a new suture-method catheter or a standard perineural catheter, compared with a single-injection technique. All patients received an adductor canal block after surgery with an initial bolus of 20 ml ropivacaine 0.75%, followed by 20 ml of ropivacaine 0.2% every 8 h in the standard and suture-method catheter groups, and sham boluses for the single-injection group. The primary outcome measure was total opioid consumption (intravenous morphine equivalents) from the end of surgery until 12:00 on postoperative day 2. Secondary outcomes were pain, muscle strength and ambulation. We randomly assigned (1:1:1) and analysed 153 patients. Total opioid consumption was median (IQR [range]) 24 (11-37 [0-148]) mg in the suture-method group, 38 (17-51 [0-123]) mg in the standard catheter group and 37 (14-57 [0-158]) mg in the single-injection group (p = 0.049). Differences were not statistically significant after Bonferroni correction (α = 0.05/3). There were no differences between groups on postoperative day 1. On postoperative day 2, there were no differences between catheter groups, but muscle strength and ambulation were improved compared with the single-injection group. We conclude that providing repeated boluses via a catheter did not decrease opioid consumption or pain compared with a single injection, but improved muscle strength and ambulation on postoperative day 2. The two types of catheters were similar.

Plakophilin-2 Truncation Variants in Patients Clinically Diagnosed With Catecholaminergic Polymorphic Ventricular Tachycardia and Decedents With Exercise-Associated Autopsy Negative Sudden Unexplained Death in the Young.

OBJECTIVES: This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY). BACKGROUND: Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT. METHODS: A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. RESULTS: Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p = 3.1 × 10-13). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death. CONCLUSIONS: Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.

Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series.

BACKGROUND: Potentially lethal cardiac channelopathies/cardiomyopathies may underlie a substantial portion of sudden unexplained death in the young (SUDY). The whole-exome molecular autopsy represents the latest approach to postmortem genetic testing for SUDY. However, proper variant adjudication in the setting of SUDY can be challenging. METHODS: From January 2012 through December 2013, 25 consecutive cases of SUDY from 1 to 40 years of age (average age at death 27±5.7 years; 13 white, 12 black) from Cook County, Illinois, were referred after a negative (n=16) or equivocal (n=9) conventional autopsy. A whole-exome molecular autopsy with analysis of 99 sudden death-susceptibility genes was performed. The predicted pathogenicity of ultrarare, nonsynonymous variants was determined using the American College of Medical Genetics guidelines. RESULTS: Overall, 27 ultrarare nonsynonymous variants were seen in 16/25 (64%) victims of SUDY. Among black individuals, 9/12 (75%) had an ultrarare nonsynonymous variant compared with 7/13 (54%) white individuals. Of the 27 variants, 10 were considered pathogenic or likely pathogenic in 7/25 (28%) individuals in accordance with the American College of Medical Genetics guidelines. Pathogenic/likely pathogenic variants were identified in 5/16 (31%) of autopsy-negative cases and in 2/6 (33%) victims of SUDY with equivocal findings of cardiomyopathy. Overall, 6 pathogenic/likely pathogenic variants in 4/25 (16%) cases were congruent with the phenotypic findings at autopsy and therefore considered clinically actionable. CONCLUSIONS: Whole-exome molecular autopsy with gene-specific surveillance is an effective approach for the detection of potential pathogenic variants in SUDY cases. However, systematic variant adjudication is crucial to ensure accurate and proper care for surviving family members.

Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses.

Pregabalin has demonstrated anti-hyperalgesic properties and was introduced into acute pain treatment in 2001. Our aim was to evaluate the beneficial and harmful effects of pregabalin in postoperative pain management. We included randomized clinical trials investigating perioperative pregabalin treatment in adult surgical patients. The review followed Cochrane methodology, including Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and used trial sequential analyses (TSAs). The primary outcomes were 24 h morphine i.v. consumption and the incidence of serious adverse events (SAEs) defined by International Conference of Harmonisation Good Clinical Practice guidelines. Conclusions were based primarily on trials with low risk of bias. Ninety-seven randomized clinical trials with 7201 patients were included. The 24 h morphine i.v. consumption was reported in 11 trials with overall low risk of bias, finding a reduction of 5.8 mg (3.2, 8.5; TSA adjusted confidence interval: 3.2, 8.5). Incidence of SAEs was reported in 21 trials, with 55 SAEs reported in 12 of these trials, and 22 SAEs reported in 10 trials with overall low risk of bias. In trials with overall low risk of bias, Peto's odds ratio was 2.9 (1.2, 6.8; TSA adjusted confidence interval: 0.1, 97.1). Based on trials with low risk of bias, pregabalin may have a minimal opioid-sparing effect, but the risk of SAEs seems increased. However, the GRADE-rated evaluations showed only moderate to very low quality of evidence. Consequently, a routine use of pregabalin for postoperative pain treatment cannot be recommended.

Modified Cone Reconstruction of the Tricuspid Valve for Ebstein Anomaly as Performed in Siberia.

The cone reconstruction technique, first described by da Silva and modified by Dearani and by others, has become the repair method of choice in patients with Ebstein anomaly of the tricuspid valve. This report details the outcome of the modified cone reconstruction technique in 6 children who underwent surgical correction of Ebstein anomaly at the Tomsk Institute of Cardiology in Siberia. From 2012 through 2015, 4 boys and 2 girls (age range, 11 mo-12 yr) underwent surgery to correct Ebstein anomaly. All had presented with cyanosis, exertional dyspnea, fatigue, or new-onset atrial arrhythmia, and none had undergone previous cardiac surgery. All survived the operation. One patient needed tricuspid valve replacement with a bioprosthesis after early breakdown of the cone reconstruction. As of December 2016, all the patients had no symptoms, tricuspid stenosis, or arrhythmia. This series indicates that cone reconstruction-the most anatomic repair technique for the dysmorphic Ebstein tricuspid valve-can be successfully performed in pediatric heart centers with a large experience.

Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy.

Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site. Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS. Additional biochemical assays demonstrated enhanced activation of both RAS/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS. Mutational analysis of MRAS in a cohort of 109 unrelated patients with phenotype-positive/genotype-negative NS and cardiac hypertrophy yielded another patient with a sporadic de novo MRAS variant (p.Thr68Ile, c.203C>T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene.

Does dexamethasone have a perineural mechanism of action? A paired, blinded, randomized, controlled study in healthy volunteers.

BACKGROUND: Dexamethasone prolongs block duration. Whether this is achieved via a peripheral or a central mechanism of action is unknown. We hypothesized that perineural dexamethasone added as an adjuvant to ropivacaine prolongs block duration compared with ropivacaine alone, by a locally mediated effect when controlled for a systemic action. METHODS: We performed a paired, blinded, randomized trial, including healthy men. All subjects received bilateral blocks of the saphenous nerve with ropivacaine 0.5%, 20 ml mixed with dexamethasone 2 mg in one leg and saline in the other, according to randomization. The primary outcome was the duration of sensory block assessed by temperature discrimination in the saphenous nerve distribution. Secondary outcomes were sensory block assessed by mechanical discrimination, pain response to tonic heat stimulation, and warmth and heat pain detection thresholds. RESULTS: We included 20 subjects; one had a failed block and was excluded from the paired analysis. Block duration was not statistically significantly longer in the leg receiving dexamethasone when assessed by temperature discrimination (primary outcome, estimated median difference 1.5 h, 95% confidence interval -3.5 to 0, P=0.050). For all other outcomes, the duration was statistically significantly longer in the leg receiving dexamethasone, but the median differences were <2.0 h. Individual subject analysis revealed that only eight subjects had a block prolongation of at least 2 h in the leg receiving dexamethasone perineurally. CONCLUSION: Perineural administration of dexamethasone 2 mg showed a modest and inconsistent effect of questionable clinical relevance on block duration. CLINICAL TRIAL REGISTRATION: NCT01981746.

The Promise and Peril of Precision Medicine: Phenotyping Still Matters Most.

We illustrate the work necessary to reverse course after identification of a KCNQ1 variant interpreted erroneously as causing long QT syndrome (LQTS) and to identify the true cause of a case of sudden death in the young. Surrogate genetic testing of a decedent's living brother identified a rare KCNQ1-V133I variant, which prompted an implantable cardioverter defibrillator and subsequent diagnosis of LQTS in other family members. Subsequently, this presumed LQT1 family came to our institution for further clinical evaluation and research-based investigations, including KCNQ1-V133I variant-specific analysis of the decedent, heterologous expression studies of KCNQ1-V133I, and a whole-exome molecular autopsy along with genomic triangulation using his unaffected parents' DNA. After evaluating several V133I-positive family members, clinical doubt was cast on the veracity of the previously levied diagnosis of LQT1, resulting in a re-opening of the case and an intense pursuit of the lethal substrate. Furthermore, the decedent tested negative for V133I, and heterologous expression studies demonstrated a normal cellular phenotype for V133I-containing Kv7.1 channels. Instead, after whole-exome molecular autopsy, a de novo pathogenic variant (p.R454W) in DES-encoded desmin was identified. As detailed herein, the forensic evaluation of sudden death in the young requires meticulous focus on the decedent followed by a careful and deliberate assessment of the decedent's relatives. Surrogate genetic testing can have disastrous consequences and should be avoided. Genetic test results require careful scrutiny to avoid unintended and potentially devastating repercussions. Although the root cause of the decedent's tragic death would have remained a mystery, the unintended consequences for the living relatives described herein might have been avoided based on clinical grounds alone. All family members had electrocardiograms with normal QT intervals, making the diagnosis of familial LQTS unlikely. As such, if the clinicians caring for these patients had focused solely on clinical data from the survivors, there might have been no reason to embark on a path of inappropriate treatment based on genetic testing.

Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome.

OBJECTIVE: To use whole exome sequencing (WES) of a family trio to identify a genetic cause for polyvalvular syndrome. METHODS AND RESULTS: A male child was born with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus that were closed surgically. Subsequently, the phenotype of polyvalvular syndrome with involvement of both semilunar and both atrioventricular valves emerged. His family history was negative for congenital heart disease. Because of hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism, either Noonan syndrome- or William syndrome-spectrum disorders were suspected clinically. However, chromosomal analysis was normal and commercially available Noonan syndrome and William syndrome genetic tests were negative. Whole exome sequencing of the patient and both parents was performed. Variants were analyzed by sporadic and autosomal recessive inheritance models. A sporadic mutation, annotated as c.1491 T > A, in TAB2, resulting in a nonsense mutation, p.Y497X, in the TAB2-encoded TGF-beta activated kinase 1 (TAK1) was identified as the most likely disease-susceptibility gene. This mutation results in elimination of the terminal 197 amino acids, including the C-terminal binding motif critical for interactions with TRAF6 and TAK1. CONCLUSIONS: The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome.

Functionalization of polycaprolactone/hydroxyapatite scaffolds with Usnea lethariiformis extract by using supercritical CO2.

Investigation of an integrated supercritical fluid extraction and supercritical solvent impregnation process for fabrication of microporous polycaprolactone-hydroxyapatite (PCL-HA) scaffolds with antibacterial activity is presented. The HA content and particle size as well as the operating conditions of the integrated process is optimized regarding the amount of impregnated antibacterial agent (Usnea lethariiformis extract) in the PCL-HA matrix, scaffold morphology and antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA) strains. High pressure differential scanning calorimetry (HP-DSC) assay reveals that an increasing amount of HA results in decreasing melting temperature as well as crystallinity at an operating pressure of 17 MPa. The PCL-HA composites with micrometric sizes of the HA particles are convenient for being processed by the integrated process due to the simple preparation, a good interaction between the PCL matrix and filler and the advantageous impact on sorption. The scaffold obtained from PCL-HA with 20% of the HA shows the highest impregnation yield at 17 MPa and 35 °C (5.9%) and subsequently also the best bactericidal effect on the tested MRSA strains at an initial bacterial inoculum of 2 × 10(-4)CFU/mL.

Optimal volume of local anaesthetic for adductor canal block: using the continual reassessment method to estimate ED95.

BACKGROUND: Theoretically, the ideal volume of local anaesthetic for adductor canal block (ACB) would ensure sufficient filling of the canal and avoid proximal spread to the femoral triangle. In this dose-finding study, we aimed to investigate the minimal effective volume for an ACB needed to fill the adductor canal distally in at least 95% of patients (ED95). METHODS: We performed a blinded trial, enrolling 40 healthy men. All subjects received an ACB with lidocaine 1%. Volumes were assigned sequentially to the subjects using the continual reassessment method followed by Bayesian analysis to determine the ED95. Distal filling of the adductor canal was assessed by magnetic resonance imaging (primary outcome). Secondary outcomes were the effect of volume on proximal spread to the femoral triangle (also assessed by magnetic resonance imaging), quadriceps muscle weakness (decrease by ≥25% from baseline) and sensory block. RESULTS: The ED95 was 20 ml, with an estimated probability of sufficiently filling the canal of 95.1% (95% credibility interval: 0.91-0.98). Proximal spread to the femoral triangle was seen in 0/4 (0%), 7/12 (58%), 4/8 (50%), and 8/16 (50%) subjects with the 5, 10, 15, and 20 ml doses, respectively (P=0.25). Seven subjects had a reduction in muscle strength, but there was no difference between groups (P=0.85). CONCLUSIONS: For an ACB, the dose closest to the ED95 needed to fill the adductor canal distally was 20 ml. There was no significant correlation between volume and proximal spread or muscle strength. CLINICAL TRIAL REGISTRATION: NCT02033356.

Adductor canal blockade for moderate to severe pain after arthroscopic knee surgery: a randomized controlled trial.

BACKGROUND: The analgesic effect of the adductor canal block (ACB) after knee surgery has been evaluated in a number of trials. We hypothesized that the ACB would provide substantial pain relief to patients responding with moderate to severe pain after arthroscopic knee surgery. METHODS: Fifty subjects with moderate to severe pain after arthroscopic knee surgery were enrolled in this placebo-controlled, blinded trial. All subjects received two ACBs; an initial ACB with either 30 ml ropivacaine 7.5 mg/ml (n = 25) (R group) or saline (n = 25) (C group) and after 45 min a second ACB with the opposite study medication, according to randomization. Primary outcome was pain during 45 degrees active flexion of the knee at 45 min after the first block, assessed on a 0-100 mm visual analogue scale. Secondary outcome measures were: pain at rest and during flexion of the knee, worst pain experienced during a 5-m walk, patient's evaluation of muscle strength during walk, and amount of sufentanil administered during the 90-min study period. RESULTS: Regarding primary outcome, mean pain score difference between groups was 34 (95% CI: 25 to 44) mm, P < 0.001, in favour of the R group. At rest, mean pain score difference was 32 (23 to 41) mm, P < 0.001, and during walk: 21 (6 to 36) mm, P = 0.01 in favour of the R group. There were no differences between groups regarding other secondary outcome measures. CONCLUSION: The ACB is a relevant option for patients with moderate to severe pain after arthroscopic knee surgery.

[Renal stone disease: collaborative management between primary care and specialized physicians]. / Approche pratique de la lithiase rénale: duo entre généralistes et spécialistes.

Nephrolithiasis is a highly prevalent pathology with a 10% lifetime risk in the Western population. Although it is often minimized and qualified as "idiopathic" significant comorbidities are frequently observed, e.g. the metabolic syndrome, type 2 diabetes mellitus, hypertension and bone fragility. Therefore nephrolithiasis can be regarded as a systemic disorder. A specialized diagnostic and therapeutic approach should be offered to such patients with active kidney stone disease in order to prevent stone recurrence and favor early diagnosis of said comorbidities.

Prevalence of saphenous nerve injury after adductor-canal-blockade in patients receiving total knee arthroplasty.

BACKGROUND: Adductor-canal-blockade is a new technique for pain relief after knee surgery. This block could cause nerve injury and the aim of this follow-up study was to determine the prevalence of saphenous nerve injury in patients receiving adductor-canal-blockade for pain treatment after total knee arthroplasty. METHODS: All patients included in two former studies of adductor-canal-blockade following total knee arthroplasty were invited to participate in this follow-up study 3-6 months after surgery. We examined the cutaneous area on the medial aspect of the lower leg (medial crural branch of the saphenous nerve), as well as the anterior, posterior, lateral and infrapatellar part of the affected and contralateral lower leg. Sensory function was tested with pinprick (sharp and blunt needle), temperature discrimination (cold disinfectant swabs) and light brush. RESULTS: We included 97 patients. None of the patients [0-5.3% (99% confidence interval)] had sensory changes related to temperature or light brush corresponding to the medial crural branch of the saphenous nerve, but 10 patients could not discriminate between blunt and sharp stimulation with a needle. In the infrapatellar area of the operated knee, 76 patients could not discriminate between blunt and sharp stimulation with a needle, 81 patients could not discriminate between cold and warmth, and 82 patients displayed an altered sensation to light brush. CONCLUSION: We found no indications of saphenous nerve injury caused by the adductor-canal-blockade at the mid-thigh level. However, 84% of the patients had signs of injury to the infrapatellar branch of the saphenous nerve in the operated leg. Such findings are well-known complications to the surgical procedure.

Effect of adductor-canal-blockade on established, severe post-operative pain after total knee arthroplasty: a randomised study.

BACKGROUND: In this proof-of-concept study, we investigated the effect of the predominantly sensory adductor-canal-blockade on established pain in the early post-operative period after total knee arthroplasty (TKA). We hypothesised that the adductor-canal-blockade would reduce pain during flexion of the knee (primary end point) and at rest, as well as reducing morphine consumption and morphine-related side effects (secondary outcomes) compared with placebo. METHODS: We enrolled patients scheduled for elective TKA into this double-blind, placebo-controlled, randomised study. During general anaesthesia, we placed a catheter in the adductor canal, and after obtaining pre-block pain scores 30 min post-operatively, we injected 30 ml of ropivacaine 0.75% (n = 21) or saline (n = 20) according to randomisation. Clinicaltrials.gov Identifier: NCT01261897. RESULTS: Forty-two patients were randomised, and 41 were analysed. Mean (standard deviation) pain scores during flexion of the knee at 1 h post-operatively were 58 (22) mm and 67 (29) mm, ropivacaine and placebo group, respectively (P = 0.23) but was significantly reduced in the ropivacaine group when calculated as area under the curve for the interval 1-6 h (P = 0.02). There were no statistically significant differences regarding pain at rest (P = 0.08), morphine consumption (P = 0.06), nor morphine-related side effects, apart from nausea (P = 0.04). CONCLUSION: This proof-of-concept study shows promising results regarding the analgesic efficacy of adductor-canal-blockade in post-operative pain treatment after TKA, with a significant reduction in pain during flexion of the knee in the early post-operative period compared with placebo. However, the study was not sufficiently powered to permit final conclusions.