Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial.

Individuals with kidney failure undergoing hemodialysis are at elevated risk for thromboembolic events. Factor (F) XI, which is in the intrinsic pathway of coagulation, is emerging as an attractive target for new anticoagulants that may be safer than existing agents. Osocimab-an inhibitory FXIa antibody-is a potential treatment option for such patients. We conducted a phase 2b, double-blind, placebo-controlled trial, in which 704 participants (448 male, 256 female) with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo. In total, 686 participants (436 male, 250 female) received treatment for ≤18 months (planned minimal treatment period of 6 months). The co-primary outcomes were clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) and a composite of the incidence of moderate, severe or serious adverse events. Clinically relevant bleeding occurred in 16/232 (6.9%) and 11/224 (4.9%) participants who received lower- and higher-dose osocimab, respectively, and in 18/230 participants (7.8%) who received a placebo. For the composite adverse event endpoint, incidences were 51%, 47% and 43% in the lower-dose osocimab, higher-dose osocimab and placebo groups, respectively. These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220 .

Measuring the Electromagnetic Field of the Human Brain at a Distance Using a Shielded Electromagnetic Field Channel.

Introduction The electromagnetic field (EMF) of the human brain generated by the movement of ions in the brain can be measured in a novel manner. The measurement can be completed through the skull, in a non-contact, non-invasive, continuous manner using a lightweight helmet. This investigation was conducted to determine if brain activity from movement and thoughts of movement can be measured at a distance and if that measurement can be readily evaluated at a distance using shielding with a shielded helmet and a shielded EMF channel surrounding a sensor. Methods Non-clinical human subject volunteers donned a lightweight sensor helmet and performed a variety of specific tasks synchronized with an audible tone generated by a metronome. Constructs were created to determine if the human subjects' brain EMF can be recorded at a distance using sensors surrounded by shielding acting similar to a waveguide in an EMF channel connected to a shielded helmet. Results The EMF sensors appeared to record brain electromagnetic activity as it is funneled into a shielded channel acting as a waveguide at a considerable distance including distances as far as 63 cm away. Conclusion Specific brain EMFs from movement, thoughts of movement, and emotional thought can be continuously measured in a non-contact fashion at a distance using an EMF waveguide approach with an EMF channel and shielded helmet.

Measuring the Electromagnetic Field of Human Subjects Using Induction Sensors and a Shielded Helmet Without the Need for a Shielded Room.

Introduction Neurologic activity is mediated by electrochemical signaling pathways that generate an electric charge. These electrical signals generate electromagnetic fields (EMF) that have been found to be measurable through magnetoencephalography and induction sensors. These technologies typically rely on expensive shielding via shielded rooms to remove influence from the external environment. We aimed to investigate the effects of a lightweight shielded helmet constructed of Mu-metal and interlaced copper mesh and Mu-metal EMF "channels" on shielding externally mediated EMF when measuring cortically generated EMF during human activity. Methods Non-contact, non-invasive, proprietary induction sensors were utilized with a combination of a dual-layer Mu-metal and interlaced copper mesh helmet with sensors placed within EMF channels connected to the helmet. Five human volunteers participated in motor activities, verbalization activities, and visual object naming to evaluate the effectiveness of shielding solely via the helmet and EMF channel construct on generated EMF without placement of individuals within a shielded room. Background data without a subject were obtained. Results Differences in fast Fourier transformed data were noted in the background compared to rest and various activities throughout all trials. There were differences in rest phases and activity phases in each individual identifying active measurement of differences in cortically generated EMF during each activity. Conclusion It appears that eliminating a Mu-metal shielded room is possible when shielding is isolated to the helmet and EMF channels with induction sensors. The external EMF was appropriately excluded with differences in background data in all trials. During the activity, differences were noted between rest phases and activity phases in all activities noting the discernibility of these induction sensors in measuring cortically generated EMF. Measured activity through motor tapping with changes between 4 and 6 Hz appeared to correlate with previously documented changes during motor activity using these sensors in conjunction with shielded rooms.

Evaluating the Intrinsic Electromagnetic Field Generated by Neurons From Repetitive Motor Activities in Humans With a Non-contact Non-invasive Electromagnetic Helmet.

Introduction The actions of neurons are dependent on electrochemical signal pathways mediated by neurotransmitters and create measurable electrical charges. These charges have been found to be measurable through neuroimaging technologies and now through a novel non-contact non-invasive sensor without supercooling. Identifying whether this technology can be appropriately interpreted with synchronized motor well-defined activities in vivo may allow for further clinical applications. Methods A non-contact, non-invasive helmet constructed and modified using shielding technology with proprietary magnetic field sensors was utilized to measure the brain's electromagnetic field (EMF). Human volunteers donned helmets and were asked to perform repetitive tapping exercises in order to identify waves consistent with tapping from the left and right hemispheres. A gyroscope was utilized to ensure that measured waves were not from micro-movement but were from neuronal firing. Multiple individuals were tested to evaluate the reproducibility of tapping and commonalities between individuals Results Right and left-sided tapping generated discernible wave changes from baseline measurements obtained by the helmet without a subject as well as differed from when the subject was at rest. Wave patterns varied from person to person but were overall similar in each subject individually. Shielding was necessary to identify signals but EMF was identified when shielding was transitioned from around the helmet to within the helmet design. Conclusion It is possible to measure in-vivo electromagnetic fields generated by the human brain generated by stereotyped tasks in a non-contact non-invasive manner. These waves were reliably obtained within each individual with some variability in morphology from subject to subject however were similar in each subject. Signals varied based on activity and stereotyped motor activities were identified. A helmet using shielding technology within the helmet itself was able to effectively identify EMF signals. Future analysis may focus on translating these waves into functional mapping for clinical applications.

Measuring Electromagnetic Field Activity Generated by Neurons In Vivo by Humans With Thoughts of Repetitive Motor Activities and Emotional Thoughts.

Background In this study, a novel method of electromagnetic field (EMF) measurements of the human brain has been performed to evaluate neuronal activity. This measurement in a non-contact, non-invasive, continuous manner through the human skull and scalp in the standard environment is completed through a lightweight inexpensive helmet. We sought to further delineate whether specific activities of complex thought can be identified using this non-invasive technique. Methodology Non-clinical human subject volunteers donned a lightweight helmet with attached sensors and performed activities of motor movement, specific motor imagery, and specific emotional imagery synchronized to an audible tone for consistency. The human subjects' brain EMF was recorded and analyzed. Results The novel method of continuously recording real-time human brain EMF was able to determine differing brain activity between individuals performing motor movement, motor imagery, and emotional imagery in a non-contact manner at different distances from the scalp. Conclusions It may be possible to measure specific human brain activity using EMF in a non-invasive fashion. Emotional imagery, motor imagery, and motor movement generate different EMFs that have different discernible forms compared to baseline activity.

Novel Method of Electromagnetic Field Measurements of the Human Brain.

Introduction Advancements in neuroimaging have changed the field of medicine. Computed tomography (CT) and magnetic resonance imaging (MRI) typically produce a static image of the brain, while continuous electroencephalogram (EEG) data is limited to the cortical surface. The brain's chemical reactions produce an electric circuit that generates a magnetic field. We seek to test the ability of a non-contact sensor to measure the human brain's electromagnetic field (EMF). Methods A lightweight, inexpensive construct was designed to hold EMF sensors to non-invasively measure the human brain's dynamic EMF. Measurements were conducted on non-clinical human volunteers. Background data without the human subjects was obtained, followed by introducing human subjects. Motionless human subject data was obtained, followed by a subject performing a task. Finally, a subject received auditory stimulation, and data was obtained. Results Our non-contact sensor was able to detect a difference between background activity without a human subject and the electromagnetic field of a human brain within the scalp and skull. Detectable differences in magnetic field potential were also obtained when the subject performed a task and received auditory stimulation. Conclusion It is possible to continuously measure living human brain dynamic electromagnetic fields throughout the entire brain in a non-contact, non-invasive, continuous manner through the human scalp and skull in the standard environment. The signals are unique to the individual human and can be differentiated from background activity.

Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized, phase Ib, VISOR study.

Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long-acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co-administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double-blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co-administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty-five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline- and placebo-adjusted vital signs showed reductions of 1.4-5.1 mmHg (systolic blood pressure) and 0.4-2.9 mmHg (diastolic blood pressure) and increases of 0.0-1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose-dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well-tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.

Improving fretting corrosion resistance of CoCrMo alloy with TiSiN and ZrN coatings for orthopedic applications.

Total hip replacement is the most effective treatment for late stage osteoarthritis. However, adverse local tissue reactions (ALTRs) have been observed in patients with modular total hip implants. Although the detailed mechanisms of ALTRs are still unknown, fretting corrosion and the associated metal ion release from the CoCrMo femoral head at the modular junction has been reported to be a major factor. The purpose of this study is to increase the fretting corrosion resistance of the CoCrMo alloy and the associated metal ion release by applying hard coatings to the surface. Cathodic arc evaporation technique (arc-PVD) was used to deposit TiSiN and ZrN hard coatings on CoCrMo substrates. The morphology, chemical composition, crystal structures and residual stress of the coatings were characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffractometry. Hardness, elastic modulus, and adhesion of the coatings were measured by nano-indentation, nano-scratch test, and the Rockwell C test. Fretting corrosion resistance tests of coated and uncoated CoCrMo discs against Ti6Al4V spheres were conducted on a four-station fretting testing machine in simulated body fluid at 1Hz for 1 million cycles. Post-fretting samples were analyzed for morphological changes, volume loss and metal ion release. Our analyses showed better surface finish and lower residual stress for ZrN coating, but higher hardness and better scratch resistance for TiSiN coating. Fretting results demonstrated substantial improvement in fretting corrosion resistance of CoCrMo with both coatings. ZrN and TiSiN decreased fretting volume loss by more than 10 times and 1000 times, respectively. Both coatings showed close to 90% decrease of Co ion release during fretting corrosion tests. Our results suggest that hard coating deposition on CoCrMo alloy can significantly improve its fretting corrosion resistance and could thus potentially alleviate ALTRs in metal hip implants.

Evaluation of Intermittent Hemodialysis in Critically Ill Cancer Patients with Acute Kidney Injury Using Single-Pass Batch Equipment.

BACKGROUND: Data on renal replacement therapy (RRT) in cancer patients with acute kidney injury (AKI) in the intensive care unit (ICU) is scarce. The aim of this study was to assess the safety and the adequacy of intermittent hemodialysis (IHD) in critically ill cancer patients with AKI. METHODS AND FINDINGS: In this observational prospective cohort study, 149 ICU cancer patients with AKI were treated with 448 single-pass batch IHD procedures and evaluated from June 2010 to June 2012. Primary outcomes were IHD complications (hypotension and clotting) and adequacy. A multiple logistic regression was performed in order to identify factors associated with IHD complications (hypotension and clotting). Patients were 62.2 ± 14.3 years old, 86.6% had a solid cancer, sepsis was the main AKI cause (51%) and in-hospital mortality was 59.7%. RRT session time was 240 (180-300) min, blood/dialysate flow was 250 (200-300) mL/min and UF was 1000 (0-2000) ml. Hypotension occurred in 25% of the sessions. Independent risk factors (RF) for hypotension were dialysate conductivity (each ms/cm, OR 0.81, CI 0.69-0.95), initial mean arterial pressure (each 10 mmHg, OR 0.49, CI 0.40-0.61) and SOFA score (OR 1.16, CI 1.03-1.30). Clotting and malfunctioning catheters (MC) occurred in 23.8% and 29.2% of the procedures, respectively. Independent RF for clotting were heparin use (OR 0.57, CI 0.33-0.99), MC (OR 3.59, CI 2.24-5.77) and RRT system pressure increase over 25% (OR 2.15, CI 1.61-4.17). Post RRT blood tests were urea 71 (49-104) mg/dL, creatinine 2.71 (2.10-3.8) mg/dL, bicarbonate 24.1 (22.5-25.5) mEq/L and K 3.8 (3.5-4.1) mEq/L. CONCLUSION: IHD for critically ill patients with cancer and AKI offered acceptable hemodynamic stability and provided adequate metabolic control.

Correction of metabolic acidosis in hemodialysis: consequences on serum leptin and mineral metabolism.

PURPOSE: Hyperleptinemia and metabolic acidosis (MA) are frequently observed in patients on hemodialysis (HD). While the role of leptin in patients on HD is not completely understood, HD only partially corrects MA. Both leptin and acidosis have effect on bone disease. The goal of the present study was to evaluate the effects of MA correction on chronic kidney disease-mineral and bone disorder laboratory parameters and leptin levels. METHODS: Forty-eight patients on HD, aged 43±19 years, were prospectively studied. Individual adjustments in the bicarbonate dialysate concentration were made to maintain pre-dialysis concentration≥22 mEq/l. Blood gas analysis was done monthly for 4 months (M1-M4). RESULTS: From M0 to M4, serum albumin increased (from 3.5 ±0.3 to 4.0±0.3 g/l, p<0.0001) while ß2 microglobulin decreased (from 27.6±8.3 to 25.8±6.8 µg/ml, p=0.025). Serum leptin decreased in all but three patients, as well as leptin/adiponectin ratio (p<0.0001). There was a decrease in ionized serum calcium (from 5.0±0.5 to 4.7±0.5 mg/dl, p =0.002) and an increase in parathyroid hormone (PTH) [from 191 (85, 459) to 446 pg/ml (212, 983), p<0.0001] and in serum phosphate (from 5.4±1.4 to 5.8±1.1 mg/dl, p=0.048). CONCLUSION: MA correction in HD patients can decrease leptin, an atherogenic marker. The impact of such treatment extends to uremic bone disease, as decrease in serum calcium and increase in PTH. However, this could be an undesirable effect because it may aggravate a secondary hyperparathyroidism. Whether the reduction in leptin levels has impact on outcomes in patients on hemodialysis deserves further investigation.

Prostatic surgery associated acute kidney injury.

Acute kidney injury (AKI) is associated with extended hospital stays, high risks of in-hospital and long-term mortality, and increased risk of incident and progressive chronic kidney disease. Patients with urological diseases are a high-risk group for AKI owing to the coexistence of obstructive uropathy, older age, and preexistent chronic kidney disease. Nonetheless, precise data on the incidence and outcomes of postoperative AKI in urological procedures are lacking. Benign prostatic hyperplasia and prostate cancer are common diagnoses in older men and are frequently treated with surgical procedures. Whereas severe AKI after prostate surgery in general appears to be unusual, AKI associated with transurethral resection of the prostate (TURP) syndrome and with rhabdomyolysis (RM) after radical prostatectomy have been frequently described. The purpose of this review is to discuss the current knowledge regarding the epidemiology, risk factors, outcomes, prevention, and treatment of AKI associated with prostatic surgery. The mechanisms of TURP syndrome and RM following prostatic surgeries will be emphasized.

Is randomization to placebo safe? Risk in placebo-controlled angina trials: angina risk meta-analysis.

OBJECTIVE: It was the aim of this study to document the risks of symptomatic patients with angina in placebo-controlled, anti-anginal drug development trials in which symptom-limited exercise testing was used as the primary endpoint. PATIENTS AND METHODS: The original case report forms submitted to the United States Food and Drug Administration in support of approval of new or supplemental new drug applications between 1973 and 2001 were identified and subjected to a by-patient meta-analysis, utilizing both a maximum likelihood analysis and classical Mantel-Haenszel methods. RESULTS: There were 63 placebo-controlled, clinical trials that randomized 10,865 patients, with 1,047 patient-years of observation time. The trials involved 21 different chemical entities from 4 different drug classes. The relative risk (RR) for withdrawal (placebo compared to drug-treated patients) was not increased [RR = 0.92, 95% confidence interval (CI) 0.78-1.08; p = 0.28]. Of interest, a RR of 0.54 (95% CI 0.26-1.04; p < 0.068) for irreversible harm (a combination of cerebrovascular accidents, myocardial infarction and death) and a RR of 0.89 (95% CI 0.61-1.30; p = 0.56) for serious cardiovascular events (myocardial infarction, congestive heart failure, cerebrovascular accidents) both non-statistically significantly favored being randomized to placebo. CONCLUSIONS: For the development of current or future drugs for the treatment of angina, there is no obvious contraindication to the use of placebo controls and exercise tolerance testing.

C4d-positive chronic rejection: a frequent entity with a poor outcome.

BACKGROUND: Chronic rejection (CR) is an important cause of kidney graft loss. Some studies have suggested the role of antibodies mediating chronic graft dysfunction. In this context, C4d identification is an important tool to evaluate antibody-mediated rejection. METHOD: This is a retrospective study that analyzed 80 patients with histological diagnosis of chronic allograft nephropathy (CAN) according Banff 97 and no evidence of transplant glomerulopathy. These patients had renal biopsies available for C4d immunoperoxidase staining at the time of diagnosis. Cases were reclassified by the presence of C4d in peritubular capillaries. RESULTS: C4d was negative in 30 cases (37.5%) and positive in 50 (62.5%). C4d+ group had more female and highly sensitized patients (PRA) at transplant. All variables were similar between C4d- and C4d+ cases at diagnosis time, but more C4d+ patients presented proteinuria (>0.3 g/L). Patients were submitted to various immunosuppression regimens after the CAN diagnosis. Four years after the diagnosis, death-censored graft survival was 87% for C4d- and 50% for C4d+ (P=0.002). In the multivariate Cox regression analysis, C4d+, PRA>10%, and vascular intimal proliferation were the variables that present higher relative risk for graft loss. CONCLUSION: These data indicate that C4d positive chronic rejection is very common, associated with proteinuria, and has a poor outcome. A larger study is warranted to identify which immunosuppressive regimen may modify the poor course of this entity.

Three and five year changes in intraocular pressures after clear corneal phacoemulsification in open angle glaucoma patients, glaucoma suspects, and normal patients.

PURPOSE: This study evaluates the change in intraocular pressure (IOP) and glaucoma medication requirements after clear corneal phacoemulsification in open angle glaucoma patients, glaucoma suspects, and normal patients at 3 years and last follow-up (mean 5 y). PATIENTS AND METHODS: This study represents a retrospective analysis of patients who had clear corneal phacoemulsification and at least 3 years of follow-up. The patients were classified into 3 groups: glaucoma (G), glaucoma suspects (GS), and no glaucoma (NG). No patient had a history of previous intraocular surgery. Single factor analysis of variance, Fisher exact tests, 2-tailed paired Student t tests and Kaplan-Meier analysis were applied. RESULTS: Forty-eight patients (55 eyes) in the glaucoma group, 41 patients (44 eyes) in the GS group, and 59 patients (59 eyes) in the NG group met the above criteria. At 3 years follow-up IOP was significantly decreased in all groups; (G) group decreased 1.4+/-3.3 mm Hg (P = 0.0025), GS 1.4+/-4.2 mm Hg (P = 0.004), and NG 1.7+/-3.1 mm Hg (P = 0.0005). At the final follow-up visit (mean near 5 y for all groups) the IOP was significantly decreased in all groups, (G) group 1.8+/-3.5 mm Hg (P = 0.005), GS 1.3+/-3.7 mm Hg (P = 0.025), and NG 1.5+/-2.5 mm Hg (P < 0.0001). The number of preoperative and postoperative glaucoma medications in the (G) group did not show any significant change at 3 and 5 years (P = 0.36, P = 0.87). Kaplan-Meier analysis shows that at 3 years, 85% of the (G) group, 81% of GS, and 90% of the NG had IOPs less than or equal to their preoperative IOP, with the same number of glaucoma medications or less. At 5 years the percentages were 76%, 79%, and 85%, respectively. CONCLUSIONS: This study demonstrates that cataract removal by clear cornea phacoemulsification in glaucoma patients, glaucoma suspects, and normal patients results in a small but significant decrease in IOP that is sustained at 3 years and a mean of 5 years in all groups. This study does not imply that cataract removal by phacoemulsification is a substitute for a combined procedure but may be an appropriate procedure for certain patients based on medication requirements and extent of optic nerve damage.