Intraoperative clonidine in endometriosis and spine surgery: A protocol for two randomised, blinded, placebo-controlled trials.

BACKGROUND: A high proportion of patients who undergo surgery continue to suffer from moderate to severe pain in the early postoperative period despite advances in pain management strategies. Previous studies suggest that clonidine, an alpha2 adrenergic agonist, administered during the perioperative period could reduce acute postoperative pain intensity and opioid consumption. However, these studies have several limitations related to study design and sample size and hence, further studies are needed. AIM: To investigate the effect of a single intravenous (IV) dose of intraoperative clonidine on postoperative opioid consumption, pain intensity, nausea, vomiting and sedation after endometriosis and spine surgery. METHODS: Two separate randomised, blinded, placebo-controlled trials are planned. Patients scheduled for endometriosis (CLONIPAIN) will be randomised to receive either 150 µg intraoperative IV clonidine or placebo (isotonic saline). Patients undergoing spine surgery (CLONISPINE) will receive 3 µg/kg intraoperative IV clonidine or placebo. We aim to include 120 patients in each trial to achieve power of 90% at an alpha level of 0.05. OUTCOMES: The primary outcome is opioid consumption within the first three postoperative hours. Secondary outcomes include pain intensity at rest and during coughing, nausea, vomiting and sedation within the first two postoperative hours and opioid consumption within the first six postoperative hours. Time to discharge from the PACU will be registered. CONCLUSION: This study is expected to provide valuable information on the efficacy of intraoperative clonidine in acute postoperative pain management in patients undergoing endometriosis and spine surgery.

Peak fat oxidation, peak oxygen uptake, and running performance increase during pre-season in sub-elite male football players.

PURPOSE: In Football, the high-intensity running bouts during matches are considered decisive. Interestingly, recent studies showed that peak fat oxidation rates (PFO) are higher in football players than other athletes. This study aimed to investigate whether PFO increases following a pre-season. Secondarily, and due to COVID-19, we investigated whether PFO is related to the physical performance in a subgroup of semi-professional male football players. METHODS: Before and after 8 weeks of pre-season training, 42 sub-elite male football players (18 semi-professionals and 24 non-professionals) had a dual-energy x-ray absorptiometry scan and performed a graded exercise test on a treadmill for the determination of PFO, the exercise intensity eliciting PFO (Fatmax) and peak oxygen uptake (V̇O2peak). Additionally, the semi-professional players performed a Yo-Yo Intermittent Recovery Test level 2 (YYIR2) before and after pre-season training to determine football-specific running performance. RESULTS: PFO increased by 11 ± 10% (mean ± 95% CI), p = 0.031, and V̇O2peak increased by 5 ± 1%, p < 0.001, whereas Fatmax was unchanged (+12 ± 9%, p = 0.057), following pre-season training. PFO increments were not associated with increments in V̇O2peak (Pearson's r2 = 0.00, p = 0.948) or fat-free mass (FFM) (r2 = 0.00, p = 0.969). Concomitantly, YYIR2 performance increased in the semi-professional players by 39 ± 17%, p < 0.001, which was associated with changes in V̇O2peak (r2 = 0.35, p = 0.034) but not PFO (r2 = 0.13, p = 0.244). CONCLUSIONS: PFO, V̇O2peak, and FFM increased following pre-season training in sub-elite football players. However, in a subgroup of semi-professional players, increments in PFO were not associated with improvements in YYIR2 performance nor with increments in V̇O2peak and FFM.

Effect of repeated prolonged exercise on liver fat content and visceral adipose tissue in well-trained older men.

INTRODUCTION: Liver fat (LF) and visceral adipose tissue (VAT) content decreases with training, however, this has mainly been investigated in sedentary obese or healthy participants. The aim of this study was to investigate the effects of repeated prolonged exercise on LF and VAT content in well-trained older men and to compare baseline LF and VAT content to recreationally active older men. METHOD: A group of five well-trained older men were tested before and after cycling a total distance of 2558 km in 16 consecutive days. VAT content and body composition was measured using DXA before a bicycle ergometer test was performed to determine maximal fat oxidation (MFO), maximal oxygen consumption ( VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ ), and the relative intensity at which MFO occurred (Fatmax). LF content was measured on a separate day using MRI. For comparison of baseline values, a control group of eight healthy age- and BMI-matched recreationally active men were recruited. RESULTS: The well-trained older men had lower VAT (p = 0.02), and a tendency toward lower LF content (p = 0.06) compared with the control group. The intervention resulted in decreased LF content (p = 0.02), but VAT, fat mass, and lean mass remained unchanged. VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ , MFO, and Fatmax were not affected by the intervention. CONCLUSION: The study found that repeated prolonged exercise reduced LF content, but VAT and VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ remained unchanged. Aerobic capacity was aligned with lower LF and VAT in older active men.

Predicting COVID-19 Incidence Using Wastewater Surveillance Data, Denmark, October 2021-June 2022.

Analysis of wastewater is used in many settings for surveillance of SARS-CoV-2, but it remains unclear how well wastewater testing results reflect incidence. Denmark has had an extensive wastewater analysis system that conducts 3 weekly tests in ≈200 sites and has 85% population coverage; the country also offers free SARS-CoV-2 PCR tests to all residents. Using time series analysis for modeling, we found that wastewater data, combined with information on circulating variants and the number of human tests performed, closely fitted the incidence curve of persons testing positive. The results were consistent at a regional level and among a subpopulation of frequently tested healthcare personnel. We used wastewater analysis data to estimate incidence after testing was reduced to a minimum after March 2022. These results imply that data from a large-scale wastewater surveillance system can serve as a good proxy for COVID-19 incidence and for epidemic control.

Prediction of pseudoprogression in post-treatment glioblastoma using dynamic susceptibility contrast-derived oxygenation and microvascular transit time heterogeneity measures.

OBJECTIVES: To evaluate the added value of MR dynamic susceptibility contrast (DSC)-perfusion-weighted imaging (PWI)-derived tumour microvascular and oxygenation information with cerebral blood volume (CBV) to distinguish pseudoprogression from true progression (TP) in post-treatment glioblastoma. METHODS: This retrospective single-institution study included patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and a newly developed or enlarging measurable contrast-enhancing mass within 12 weeks after concurrent chemoradiotherapy. CBV, capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were obtained from DSC-PWI. Predictors were selected using univariable logistic regression, and performance was measured with adjusted diagnostic odds with tumour volume and area under the curve (AUC) of receiver operating characteristics analysis. RESULTS: A total of 103 patients were included (mean age, 59.6 years; 59 women), with 67 cases of TP and 36 cases of pseudoprogression. Pseudoprogression exhibited higher CTH (4.0 vs. 3.4, p = .019) and higher OEF (12.7 vs. 10.7, p = .014) than TP, but a similar CBV (1.48 vs. 1.53, p = .13) and CMRO2 (7.7 vs. 7.3s, p = .598). Independent of tumour volume, both high CTH (adjusted odds ratio [OR] 1.52; 95% confidence interval [CI]: 1.11-2.09, p = .009) and high OEF (adjusted OR 1.17; 95% CI:1.03-1.33, p = .016) were predictors of pseudoprogression. The combination of CTH, OEF, and CBV yielded higher diagnostic performance (AUC 0.71) than CBV alone (AUC 0.65). CONCLUSION: High intratumoural capillary transit heterogeneity and high oxygen extraction fraction derived from DSC-PWI have enhanced the diagnostic value of CBV in pseudoprogression of post-treatment IDH-wild type glioblastoma. CLINICAL RELEVANCE STATEMENT: In the early post-treatment stage of glioblastoma, pseudoprogression exhibited both high oxygen extraction fraction and high capillary transit heterogeneity and these dynamic susceptibility contrast-perfusion weighted imaging derived parameters have added value in cerebral blood volume-based noninvasive differentiation of pseudoprogression from true progression. KEY POINTS: • Capillary transit time heterogeneity and oxygen extraction fraction can be measured noninvasively through processing of dynamic susceptibility contrast imaging. • Pseudoprogression exhibited higher capillary transit time heterogeneity and higher oxygen extraction fraction than true progression. • A combination of cerebral blood volume, capillary transit time heterogeneity, and oxygen extraction fraction yielded the highest diagnostic performance (area under the curve 0.71).

Accuracy of a Clinical Applicable Method for Prediction of VO2max Using Seismocardiography.

Cardiorespiratory fitness measured as ˙VO2max is considered an important variable in the risk prediction of cardiovascular disease and all-cause mortality. Non-exercise ˙VO2max prediction models are applicable, but lack accuracy. Here a model for the prediction of ˙VO2max using seismocardiography (SCG) was investigated. 97 healthy participants (18-65 yrs., 51 females) underwent measurement of SCG at rest in the supine position combined with demographic data to predict ˙VO2max before performing a graded exercise test (GET) on a cycle ergometer for determination of ˙VO2max using pulmonary gas exchange measurements for comparison. Accuracy assessment revealed no significant difference between SCG and GET ˙VO2max (mean±95% CI; 38.3±1.6 and 39.3±1.6 ml·min-1·kg-1, respectively. P=0.075). Further, a Pearson correlation of r=0.73, a standard error of estimate (SEE) of 5.9 ml·min-1·kg-1, and a coefficient of variation (CV) of 8±1% were found. The SCG ˙VO2max showed higher accuracy, than the non-exercise model based on the FRIENDS study, when this was applied to the present population (bias=-3.7±1.3 ml·min-1·kg-1, p<0.0001. r=0.70. SEE=7.4 ml·min-1·kg-1, and CV=12±2%). The SCG ˙VO2max prediction model is an accurate method for the determination of ˙VO2max in a healthy adult population. However, further investigation on the validity and reliability of the SCG ˙VO2max prediction model in different populations is needed for consideration of clinical applicability.

Ticket to perform: an explorative study of trainees' engagement in and transfer of surgical training.

BACKGROUND: Research suggests that simulation-based surgical skills training translates into improved operating room performance. Previous studies have predominantly focused on training methods and design and subsequent assessable performances and outcomes in the operating room, which only covers some aspects of training engagement and transfer of training. The purpose of this qualitative study was to contribute to the existing body of literature by exploring characteristics of first-year trainees' engagement in and perceptions of transfer of surgical skills training. METHODS: We conducted an explorative study based on individual interviews with first-year trainees in General Surgery, Urology, and Gynaecology and Obstetrics who participated in a laparoscopic skills training program. Informants were interviewed during and two months after the training program. A thematic cross-case analysis was conducted using systematic text condensation. RESULTS: We interviewed 12 informants, which produced 24 transcripts for analysis. We identified four main themes: (1) sportification of training, (2) modes of orientation, (3) transferrable skills, and (4) transfer opportunities. Informants described their surgical training using sports analogies of competition, timing, and step-by-step approaches. Visual orientations, kinaesthetic experiences, and elicited dialogues characterised training processes and engagement. These characteristics were identified in both the simulated and the clinical environment. Experiences of specific skills transfer included ambidexterity, coordination, instrument handling, and visuospatial ability. General transfer experiences were salient in informants' altered training approaches. Informants considered the simulation-based training an entry ticket to perform in the operating room and mentioned supervisor-trainee relationships and opportunities in the workplace as critical conditions of transfer. CONCLUSIONS: Our findings elucidate characteristics of surgical training engagement that can be interpreted as self-regulated learning processes that transcend surgical training environments. Despite appreciating the immediate skills improvements resulting from training, trainees' narratives reflected a struggle to transfer their training to the clinical setting. Tensions existed between perceptions of transferable skills and experiences of transfer within the clinical work environments. These results resonate with research emphasising the importance of the work environment in the transfer process. Our findings provide insights that may inform the development of training programs that support self-regulated learning and transfer of training from the simulated to the clinical environment.

QbTest for Monitoring Medication Treatment Response in ADHD: A Systematic Review.

Introduction: Attention deficit hyperactivity disorder (ADHD) is considered one of the most common neurodevelopmental disorders in childhood and adolescence. Pharmacological treatment plays an important part in the therapy of the disorder and verifying the effectiveness of ADHD medication is essential throughout the course of treatment. QbTest is a computerized test, for which intended use is to provide healthcare professionals with objective measurements of hyperactivity, impulsivity, and inattention to aid in the clinical assessment of ADHD and the evaluation of treatment interventions. Methods: A systematic review of relevant articles was conducted for which QbTest was used for monitoring medication treatment response in ADHD. Literature published between 2004 and 2023 was appraised. Results: A total of 15 studies were included in the review. Thirteen articles involved subjects diagnosed with ADHD and two studies that were related to the disorder, which evaluated QbTest in medication treatment response. Changes in QbTest data such as Q-scores, effect size, or improvement/deterioration of QbTest variables were evaluated. A clinically relevant decrease in QbTest Q-scores was found in the majority of the studies when treated with any type of ADHD medication in therapeutic doses, both in comparison to placebo and when compared from baseline to endpoint treatment. Conclusion: QbTest can distinguish pharmacological treatment effects within hours of pharmacological titration and can be used for monitoring of long-term treatment of ADHD. A need for optimization and individualization of medication treatment response could be addressed with access to objective measures in ADHD management.

Remote training in laparoscopy: a randomized trial comparing home-based self-regulated training to centralized instructor-regulated training.

BACKGROUND: Simulation-based surgical training (SBST) is key to securing future surgical expertise. Proficiency-based training (PBT) in laparoscopy has shown promising results on skills transfer. However, time constraints and limited possibilities for distributed training constitute barriers to effective PBT. Home-based training may provide a solution to these barriers and may be a feasible alternative to centralized training in times of assembly constraints. METHODS: We randomly assigned first-year trainees in abdominal surgery, gynecology, and urology to either centralized instructor-regulated training (CIRT) or home-based self-regulated training (HSRT) in laparoscopy. All participants trained on portable box trainers providing feedback on metrics and possibility for video reviewing. Training in both groups was structured as PBT with graded proficiency exercises adopted from the Fundamentals of Laparoscopic Surgery (FLS). The HSRT group trained at home guided by online learning materials, while the CIRT group attended two training sessions in the simulation center with feedback from experienced instructors. Performance tests consisted of hand-eye and bimanual coordination, suture and knot-tying, and FLS exercises. We analyzed passing rates, training time and distribution, and test performances. RESULTS: Passing rates were 87% and 96% in the CIRT and HSRT group, respectively. HSRT facilitated distributed training and resulted in greater variation in training times. Task times for hand-eye and bimanual coordination were significantly reduced between pretest and posttest in both groups. Trainees maintained their posttest performances at the 6-month retention test. Our analyses revealed no significant inter-group differences in performances at pretest, posttest, or retention test. Performance improvements in the two groups followed similar patterns. CONCLUSION: CIRT and HSRT in laparoscopy result in comparable performance improvements. HSRT in laparoscopy is a feasible and effective alternative to CIRT when offered inside a supportive instructional design. Further research is needed to clarify trainees' preferences and explore facilitators and barriers to HSRT.

CRISPR-Cas12a based internal negative control for nonspecific products of exponential rolling circle amplification.

False-positive results cause a major problem in nucleic acid amplification, and require external blank/negative controls for every test. However, external controls usually have a simpler and lower background compared to the test sample, resulting in underestimation of false-positive risks. Internal negative controls, performed simultaneously with amplification to monitor the background level in real-time, are therefore appealing in both research and clinic. Herein, we describe a nonspecific product-activated single-stranded DNA-cutting approach based on CRISPR (clustered regularly interspaced short palindromic repeats) Cas12a (Cpf1) nuclease. The proposed approach, termed Cas12a-based internal referential indicator (CIRI), can indicate the onset of nonspecific amplification in an exponential rolling circle amplification strategy here combined with an optomagnetic readout. The capability of CIRI as an internal negative control can potentially be extended to other amplification strategies and sensors, improving the performance of nucleic acid amplification-based methodologies.

Effective electrical resistivity in a square array of oriented square inclusions.

The continuing miniaturization of optoelectronic devices, alongside the rise of electromagnetic metamaterials, poses an ongoing challenge to nanofabrication. With the increasing impracticality of quality control at a single-feature (-device) resolution, there is an increasing demand for array-based metrologies, where compliance to specifications can be monitored via signals arising from a multitude of features (devices). To this end, a square grid with quadratic sub-features is amongst the more common designs in nanotechnology (e.g. nanofishnets, nanoholes, nanopyramids, µLED arrays etc). The electrical resistivity of such a quadratic grid may be essential to its functionality; it can also be used to characterize the critical dimensions of the periodic features. While the problem of the effective electrical resistivity ρ eff of a thin sheet with resistivity ρ 1, hosting a doubly-periodic array of oriented square inclusions with resistivity ρ 2, has been treated before (Obnosov 1999 SIAM J. Appl. Math. 59 1267-87), a closed-form solution has been found for only one case, where the inclusion occupies c = 1/4 of the unit cell. Here we combine first-principle approximations, numerical modeling, and mathematical analysis to generalize ρ eff for an arbitrary inclusion size (0 < c < 1). We find that in the range 0.01 ≤ c ≤ 0.99, ρ eff may be approximated (to within <0.3% error with respect to finite element simulations) by: [Formula: see text] [Formula: see text] whereby at the limiting cases of c â†’ 0 and c â†’ 1, α approaches asymptotic values of α = 2.039 and α = 1/c - 1, respectively. The applicability of the approximation to considerably more complex structures, such as recursively-nested inclusions and/or nonplanar topologies, is demonstrated and discussed. While certainly not limited to, the theory is examined from within the scope of micro four-point probe (M4PP) metrology, which currently lacks data reduction schemes for periodic materials whose cell is smaller than the typical µm-scale M4PP footprint.

Evaluation of functional outcomes after disc excision of deep endometriosis involving low and mid rectum using standardized questionnaires: a series of 80 patients.

AIM: The aim was to assess the functional outcome and quality of life in patients with low and mid rectal endometriosis who have undergone disc excision using a semicircular transanal staple device, a procedure we have named the Rouen technique. METHODS: This was a retrospective study of patients undergoing the Rouen technique between October 2009 and November 2018. Preoperative and postoperative demographic and operative data were recorded prospectively (mean ± SEM). Postoperative complications were recorded using the Clavien-Dindo classification. Rectal function and quality of life were assessed by the low anterior resection syndrome (LARS) and Bowel Endometriosis Syndrome (BENS) scores respectively at ≥6 months. RESULTS: The Rouen procedure was performed on 80 patients (29.7 ± 4.3). The mean diameter of resected specimens was 57 ± 10 mm, and the height of the rectal suture from the anal verge was 4.6 ± 1.2 cm. The Clavien-Dindo complications were Clavien-Dindo 1 (leg compression), Clavien-Dindo 2 (urinary tract infection, bladder self-catheterization) and Clavien-Dindo 3b (bowel obstruction, rectovaginal fistula, pyelic dilation, colorectal stenosis after resection). A rectovaginal fistula (Clavien-Dindo 3b) developed in nine (11.3%) patients and their stoma could be reversed after 99-162 days. The majority of patients (n = 50, 62.5%) had normal postoperative rectal function with LARS score ≤20. However, minor (LARS ≥ 21-29) and major rectal dysfunction (LARS ≥ 30) was seen in 18 (22.5%) and 12 (15%) patients respectively. Quality of life as measured using the BENS score was normal (BENS score 0-8) in 51 (63.8%) patients, slightly reduced (BENS score 9-16) in 24 (30%) patients and in only five (6.3%) was this a major issue (BENS score > 17). The development of a rectovaginal fistula was independently related to risk of major rectal dysfunction (adjusted OR 6.3, 95% CI 1.3-30.6). CONCLUSIONS: In our series of 80 patients with transmural low and mid rectal endometriosis disc excision using a semicircular staple device can result in good functional outcomes and quality of life and avoid the complexity and potential complications of a low anterior resection.

Excision of Deep Endometriosis Nodules of the Sciatic Nerve in 10 Steps.

STUDY OBJECTIVE: To present 10 standardized and reproducible surgical steps allowing for complete excision of deep endometriosis nodules involving the sciatic nerve. DESIGN: Surgical education video. The local institutional review board confirmed that the video met the ethical criteria required for publication. Patient consent was obtained. SETTING: Tertiary referral center. INTERVENTIONS: The excision of deep endometriosis involving the sciatic nerve may be performed following 10 steps: (1) Longitudinal incision of the peritoneum covering the external iliac artery, from the hypogastric vessels to the round ligament and the identification of the genitofemoral nerve. (2) Dissection of the iliolumbar space identified laterally by the psoas muscle and medially by the external iliac artery and vein [1-5]. (3) Identification of the obturator nerve. The dissection is performed on contact with the psoas muscle; when the nerve is surrounded by the nodule, its releasing is progressively carried out. (4) Identification of the obturator vessels, which cross the obturator nerve beneath and follow a lateral direction. (5) Opening of the lumbosacral space, below the level of the obturator nerve, and the identification of the sciatic nerve, resulting from the confluence of L4 to S3 roots. During this step, the deep endometriosis nodule is identified on contact with the greater sciatic foramen. (6) Opening of the broad ligament, between the external iliac vessels and the umbilical artery, and identification of the obturator nerve, as it is usually performed in pelvic lymphadenectomy. The surgeon may either perform a separate incision of the posterior leaf of the broad ligament and medial to the infundibulo-pelvic ligament or prolong medially the incision made at step 1. (7) Identification of the sciatic nerve, which is seen below and medially from the obturator nerve and obturator vessels. During this step, the posterior limit of the nodule is identified. (8) Identification of sacral roots S1, S2, and S3 [6]. The pudendal nerve and the posterior femoral cutaneous nerve may be identified below the S3 and medially from the sciatic nerve and before their exit through the greater sciatic foramen. The posterior and medial limit of the nodule is progressively released [7]. (9) The dissection is continued laterally, on contact with the ischium, down to the ischial spine and the coccygeus muscle. The lateral limit of the nodule is identified and released. (10) The anterior limit of the nodule is identified and, when required, is separated from the bladder. The latter 3 steps are less standardized, and the surgeon may alternate lateral, medial, posterior, and anterior dissection of the nodule, depending on the intraoperative circumstances. In most cases, the nerves are compressed but not infiltrated inside the epineurium, and their complete releasing is followed by significant or complete relief of pain and motor problems [6]. When the nodule infiltrates the nerves inside the epineurium, the excision may be performed into the nerve. CONCLUSION: Laparoscopic excision of deep endometriosis nodules involving the sciatic nerve is a challenging procedure, requiring good anatomic knowledge, surgical skills, preliminary specific training, and multidisciplinary postoperative care. Teaching such a complex procedure is a mandatory but delicate task. By following 10 sequential steps, the surgeon may reduce the risk of hemorrhage originating from the external iliac, obturator, and pudendal vessels; preserve somatic nerves; and successfully excise deep endometriosis nodules. Although the 10 steps attempt to standardize the surgical approach in a challenging localization of deep endometriosis, they are not mandatory and should be adapted to the patient.

Postoperative Outcomes after Surgery for Deep Endometriosis of the Sacral Plexus and Sciatic Nerve: A 52-patient Consecutive Series.

STUDY OBJECTIVE: To assess 1-year postoperative outcomes of surgery for deep endometriosis involving the sacral roots and sciatic nerve. DESIGN: Retrospective case series. SETTING: Three referral centers. PATIENTS: Fifty-two women. INTERVENTIONS: Surgery for deep endometriosis involving the sacral roots and sciatic nerve. MEASUREMENTS AND MAIN RESULTS: Deep endometriosis involved the sacral roots in 49 women (94.2%) and the sciatic nerve in 3 cases (5.8%). Sciatic pain (buttock or leg) was recorded in 43 women (82.7%), pudendal neuralgia in 11 women (21.2%), and leg motor weakness in 14 cases (27%). The surgical procedures carried out on the pelvic nerves included complete release and decompression (92.3%), excision of the epineurium by shaving (5.8%), and intraneural excision (1.9%). Additional major surgical procedures involved the digestive tract in 82.7% of the cases and the urinary tract in 46.2%. Rectovaginal fistula occurred in 13.5% of the cases. Self-catheterization was required in 14 cases (27%) at 3 weeks after surgery and in 3 women (5.8%) 12 months later. One-year follow-up showed significant improvement in quality of life measured using the Short-Form 36 questionnaire and standardized gastrointestinal scores. De novo hypoesthesia, hyperesthesia, or allodynia were recorded in 9 women (17.2%). The cumulative pregnancy rate was 77.2%% after natural conception in 47%. CONCLUSION: Laparoscopic management of deep endometriosis involving the sacral roots and sciatic nerve improves patients' symptoms and overall quality of life. Although pain reduction may be rapid after surgery, other sensory or motor complaints, including bladder dysfunction, may be recorded over months or years.

Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Noninvasive Characterization of Tumor Angiogenesis and Oxygenation in Bevacizumab-treated Recurrent Glioblastoma by Using Dynamic Susceptibility MRI: Secondary Analysis of the European Organization for Research and Treatment of Cancer 26101 Trial.

Background Relevance of antiangiogenic treatment with bevacizumab in patients with glioblastoma is controversial because progression-free survival benefit did not translate into an overall survival (OS) benefit in randomized phase III trials. Purpose To perform longitudinal characterization of intratumoral angiogenesis and oxygenation by using dynamic susceptibility contrast agent-enhanced (DSC) MRI and evaluate its potential for predicting outcome from administration of bevacizumab. Materials and Methods In this secondary analysis of the prospective randomized phase II/III European Organization for Research and Treatment of Cancer 26101 trial conducted between October 2011 and December 2015 in 596 patients with first recurrence of glioblastoma, the subset of patients with availability of anatomic MRI and DSC MRI at baseline and first follow-up was analyzed. Patients were allocated into those administered bevacizumab (hereafter, the BEV group; either bevacizumab monotherapy or bevacizumab with lomustine) and those not administered bevacizumab (hereafter, the non-BEV group with lomustine monotherapy). Contrast-enhanced tumor volume, noncontrast-enhanced T2 fluid-attenuated inversion recovery (FLAIR) signal abnormality volume, Gaussian-normalized relative cerebral blood volume (nrCBV), Gaussian-normalized relative blood flow (nrCBF), and tumor metabolic rate of oxygen (nTMRO2) was quantified. The predictive ability of these imaging parameters was assessed with multivariable Cox regression and formal interaction testing. Results A total of 254 of 596 patients were evaluated (mean age, 57 years ± 11; 155 men; 161 in the BEV group and 93 in non-BEV group). Progression-free survival was longer in the BEV group (3.7 months; 95% confidence interval [CI]: 3.0, 4.2) compared with the non-BEV group (2.5 months; 95% CI: 1.5, 2.9; P = .01), whereas OS was not different (P = .15). The nrCBV decreased for the BEV group (-16.3%; interquartile range [IQR], -39.5% to 12.0%; P = .01), but not for the non-BEV group (1.2%; IQR, -17.9% to 23.3%; P = .19) between baseline and first follow-up. An identical pattern was observed for both nrCBF and nTMRO2 values. Contrast-enhanced tumor and noncontrast-enhanced T2 FLAIR signal abnormality volumes decreased for the BEV group (-66% [IQR, -83% to -35%] and -33% [IQR, -71% to -5%], respectively; P < .001 for both), whereas they increased for the non-BEV group (30% [IQR, -17% to 98%], P = .001; and 10% [IQR, -13% to 82%], P = .02, respectively) between baseline and first follow-up. None of the assessed MRI parameters were predictive for OS in the BEV group. Conclusion Bevacizumab treatment decreased tumor volumes, angiogenesis, and oxygenation, thereby reflecting its effectiveness for extending progression-free survival; however, these parameters were not predictive of overall survival (OS), which highlighted the challenges of identifying patients that derive an OS benefit from bevacizumab. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Dillon in this issue.

Automated on-chip analysis of tuberculosis drug-resistance mutation with integrated DNA ligation and amplification.

Detection of a single base mutation in Mycobacterium tuberculosis DNA can provide fast and highly specific diagnosis of antibiotic-resistant tuberculosis. Mutation-specific ligation of padlock probes (PLPs) on the target followed by rolling circle amplification (RCA) is highly specific, but challenging to integrate in a simple microfluidic device due to the low temperature stability of the phi29 polymerase and the interference of phi29 with the PLP annealing and ligation. Here, we utilized the higher operation temperature and temperature stability of Equiphi29 polymerase to simplify the integration of the PLP ligation and RCA steps of an RCA assay in two different strategies performed at uniform temperature. In strategy I, PLP annealing took place off-chip and the PLP ligation and RCA were performed in one pot and the two reactions were clocked by a change of the temperature. For a total assay time of about 1.5 h, we obtained a limit of detection of 2 pM. In strategy II, the DNA ligation mixture and the RCA mixture were separated into two chambers on a microfluidic disc. After on-disc PLP annealing and ligation, the disc was spun to mix reagents and initiate RCA. For a total assay time of about 2 h, we obtained a limit of detection of 5 pM. Graphical abstract.

The relationship between peak fat oxidation and prolonged double-poling endurance exercise performance.

The peak fat oxidation rate (PFO) and the exercise intensity that elicits PFO (Fatmax ) are associated with endurance performance during exercise primarily involving lower body musculature, but it remains elusive whether these associations are present during predominant upper body exercise. The aim was to investigate the relationship between PFO and Fatmax determined during a graded exercise test on a ski-ergometer using double-poling (GET-DP) and performance in the long-distance cross-country skiing race, Vasaloppet. Forty-three healthy men completed GET-DP and Vasaloppet and were divided into two subgroups: recreational (RS, n = 35) and elite (ES, n = 8) skiers. Additionally, RS completed a cycle-ergometer GET (GET-Cycling) to elucidate whether the potential relationships were specific to exercise modality. PFO (r2  = .10, P = .044) and Fatmax (r2  = .26, P < .001) were correlated with performance; however, V ˙ O 2 peak was the only independent predictor of performance (adj. R2  = .36) across all participants. In ES, Fatmax was the only variable associated with performance (r2  = .54, P = .038). Within RS, DP V ˙ O 2 peak (r2  = .11, P = .047) and ski-specific training background (r2  = .30, P = .001) were associated with performance. Between the two GETs, Fatmax (r2  = .20, P = .006) but not PFO (r2  = .07, P = .135) was correlated. Independent of exercise mode, neither PFO nor Fatmax were associated with performance in RS (P > .05). These findings suggest that prolonged endurance performance is related to PFO and Fatmax but foremost to V ˙ O 2 peak during predominant upper body exercise. Interestingly, Fatmax may be an important determinant of performance among ES. Among RS, DP V ˙ O 2 peak , and skiing experience appeared as performance predictors. Additionally, whole-body fat oxidation seemed specifically coupled to exercise modality.

Cross-Reactive Antibodies With the Capacity to Mediate HIV-1 Envelope Glycoprotein-Targeted Antibody-Dependent Cellular Cytotoxicity Identified in HIV-2-Infected Individuals.

Disease progression of human immunodeficiency virus type 1 (HIV-1) is delayed by HIV type 2 (HIV-2) in individuals with dual HIV-1/HIV-2 infection. The protective mechanisms, however, are still to be revealed. In the current study we examined type-specific and cross-reactive antibody-dependent cellular cytotoxicity (ADCC) in HIV-1 and HIV-2 monoinfection or dual infection. Of note, intertype cross-reactive antibodies that mediated HIV-1 envelope glycoprotein (Env)-targeted ADCC were frequently identified in HIV-2-infected individuals. Furthermore, the magnitude of HIV-1 cross-reactive ADCC activity during HIV-2 infections depended on the HIV-1 Env origin and was associated with the duration of infection. These results suggest that preexisting antibodies against HIV-2, which mediate intertype ADCC, might contribute to control of HIV-1 during dual infection.

Ultrasensitive Real-Time Rolling Circle Amplification Detection Enhanced by Nicking-Induced Tandem-Acting Polymerases.

Padlock probe ligation-based rolling circle amplification (RCA) can distinguish single-nucleotide variants, which is promising for the detection of drug-resistance mutations in, e.g., Mycobacterium tuberculosis (Mtb). However, the clinical application of conventional linear RCA is restricted by its unsatisfactory picomolar-level limit of detection (LOD). Herein, we demonstrate the mechanism of a nicking-enhanced RCA (NickRCA) strategy that allows several polymerases to act simultaneously on the same looped template, generating single-stranded amplicon monomers. Limiting factors of NickRCA are investigated and controlled for higher amplification efficiency. Thereafter, we describe a NickRCA-based magnetic nanoparticle (MNP) dimer formation strategy combined with a real-time optomagnetic sensor monitoring MNP dimers. The proposed methodology is applied for the detection of a common Mtb rifampicin-resistance mutation, rpoB 531 (TCG/TTG). Without additional operation steps, an LOD of 15 fM target DNA is achieved with a total assay time of ca. 100 min. Moreover, the proposed biosensor holds the advantages of single-nucleotide mutation discrimination and the robustness to quantify targets in 10% serum samples. NickRCA produces short single-stranded monomers instead of the DNA coils produced in conventional RCA, which makes it more convenient for downstream operation, immobilization or detection, thus being applicable with different molecular tools and biosensors.