Low-Dose Dietary Fish Oil Improves RBC Deformability without Improving Post-Transfusion Recovery in Mice.

Long-chain polyunsaturated fatty acids (LC-PUFAs) are important modulators of red blood cell (RBC) rheology. Dietary LC-PUFAs are readily incorporated into the RBC membrane, improving RBC deformability, fluidity, and hydration. Female C57BL/6J mice consumed diets containing increasing amounts of fish oil (FO) ad libitum for 8 weeks. RBC deformability, filterability, and post-transfusion recovery (PTR) were evaluated before and after cold storage. Lipidomics and lipid peroxidation markers were evaluated in fresh and stored RBCs. High-dose dietary FO (50%, 100%) was associated with a reduction in RBC quality (i.e., in vivo lifespan, deformability, lipid peroxidation) along with a reduced 24 h PTR after cold storage. Low-dose dietary FO (6.25-12.5%) improved the filterability of fresh RBCs and reduced the lipid peroxidation of cold-stored RBCs. Although low doses of FO improved RBC deformability and reduced oxidative stress, no improvement was observed for the PTR of stored RBCs. The improvement in RBC deformability observed with low-dose FO supplementation could potentially benefit endurance athletes and patients with conditions resulting from reduced perfusion, such as peripheral vascular disease.

ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

Reticulocytes in donor blood units enhance red blood cell alloimmunization.

Although red blood cell (RBC) transfusions save lives, some patients develop clinically-significant alloantibodies against donor blood group antigens, which then have adverse effects in multiple clinical settings. Few effective measures exist to prevent RBC alloimmunization and/or eliminate alloantibodies in sensitized patients. Donor-related factors may influence alloimmunization; thus, there is an unmet clinical need to identify which RBC units are immunogenic. Repeat volunteer blood donors and donors on iron supplements have elevated reticulocyte counts compared to healthy non-donors. Early reticulocytes retain mitochondria and other components, which may act as danger signals in immune responses. Herein, we tested whether reticulocytes in donor RBC units could enhance RBC alloimmunization. Using a murine model, we demonstrate that transfusing donor RBC units with increased reticulocyte frequencies dose-dependently increased RBC alloimmunization rates and alloantibody levels. Transfusing reticulocyte-rich RBC units was associated with increased RBC clearance from the circulation and a robust proinflammatory cytokine response. As compared to previously reported post-transfusion RBC consumption patterns, erythrophagocytosis from reticulocyte-rich units was increasingly performed by splenic B cells. These data suggest that reticulocytes in a donated RBC unit impact the quality of blood transfused, are targeted to a distinct compartment, and may be an underappreciated risk factor for RBC alloimmunization.

Reticulocytes in donor RBC units enhance RBC alloimmunization.

Although red blood cell (RBC) transfusions save lives, some patients develop clinically-significant alloantibodies against donor blood group antigens, which then have adverse effects in multiple clinical settings. Few effective measures exist to prevent RBC alloimmunization and/or eliminate alloantibodies in sensitized patients. Donor-related factors may influence alloimmunization; thus, there is an unmet clinical need to identify which RBC units are immunogenic. Repeat volunteer blood donors and donors on iron supplements have elevated reticulocyte counts compared to healthy non-donors. Early reticulocytes retain mitochondria and other components, which may act as danger signals in immune responses. Herein, we tested whether reticulocytes in donor RBC units could enhance RBC alloimmunization. Using a murine model, we demonstrate that transfusing donor RBC units with increased reticulocyte frequencies dose-dependently increase RBC alloimmunization rates and alloantibody levels. Transfusing reticulocyte-rich RBC units was associated with increased RBC clearance from the circulation and a robust proinflammatory cytokine response. As compared to previously reported post-transfusion RBC consumption patterns, erythrophagocytosis from reticulocyte-rich units was increasingly performed by splenic B cells. These data suggest that reticulocytes in a donated RBC unit impact the quality of blood transfused, are targeted to a distinct compartment, and may be an underappreciated risk factor for RBC alloimmunization.

Efficacy and Safety of Honey Bee Venom (Apis mellifera) Dermal Injections to Treat Osteoarthritis Knee Pain and Physical Disability: A Randomized Controlled Trial.

Objectives: To evaluate purified honey bee (Apis mellifera) venom (HBV) biotherapy for the treatment of osteoarthritis (OA) knee pain and physical function. Design and Patients: Five hundred and thirty-eight patients with Kellgren/Lawrence grade 1-3 radiographic knee OA and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥2 were randomized 1:2 to either control ("histamine") or HBV in this double-blind study. Interventions: After a dose escalation period, patients received 12 weekly dermal injections of control ("histamine") or HBV. At each of the 12 weekly visits, a set of 15 dermal injections (each containing 2.75 µg histamine or 100 µg HBV) were administered at prespecified acupuncture points (5 on each knee: knee top, eye-1 medial, eye-2 lateral, ST 34, BL 40 and 5 near the spinous processes: BL 19, 21, 23, 25, and 27). Outcome Measures: Assessments included WOMAC pain and physical function subscales, visual analog scale (VAS), patient global assessment (PGA), and physician global assessment (PhGA). Rescue medication use (acetaminophen) and routine safety parameters were monitored. Results: HBV biotherapy demonstrated a highly significant improvement over control in WOMAC pain score after 12 weeks (1.1 U mean difference; confidence interval [95% CI]: 0.3-2.0; analysis of covariance [ANCOVA] p = 0.0010 with baseline as covariate) that was also sustained 4 weeks post-treatment. Furthermore, WOMAC physical function was significantly improved over control with HBV (3.1 U mean difference; 95% CI: 0.3-5.9; ANCOVA p = 0.0046), and sustained 4 weeks post-treatment. VAS scores were significantly improved with HBV versus control, as well as PGA and PhGA evaluations, which showed that patients responded more favorably ("very good/good") to their overall OA condition (82.0% vs. 62.4% [p = 0.0001] and 82.1% vs. 54.9% [p = 0.0015], respectively). Use of rescue acetaminophen was similar between the groups (77%-78% of patients). HBV was associated with higher incidence of injection site reactions (<5%); however, the overall safety profiles were comparable between the treatment groups. Conclusions: This phase 3 trial demonstrated that HBV biotherapy resulted in significant improvements in knee OA pain and physical function.

Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.

Animal and human studies indicate that electrical stimulation of dorsal root ganglion (DRG) neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multicenter, randomized comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (spinal cord stimulation, SCS). The primary end point was a composite of safety and efficacy at 3 months, and subjects were assessed through 12 months for long-term outcomes and adverse events. The predefined primary composite end point of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in visual analog scale score from preimplant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥50% pain relief and treatment success was greater in the DRG arm (81.2%) than in the SCS arm (55.7%, P < 0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. Dorsal root ganglion stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (P < 0.001) and reduced extraneous stimulation in nonpainful areas (P = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. As the largest prospective, randomized comparative effectiveness trial to date, the results show that DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.

Use of Dietary Vitamin Supplements and Risk of Thyroid Cancer: A Population-Based Case-Control Study in Connecticut.

Certain dietary supplements have been reported to increase the risk of some cancers. Over half of the US population regularly uses dietary supplements. Thyroid cancer incidence has increased over the past several decades. However, few studies have investigated the association between dietary supplements and thyroid cancer. Thus, it is essential to clarify any association between dietary supplements and risk of thyroid cancer. MATERIALS AND METHODS: A population-based case-control study in Connecticut was conducted during 2010-2011 among 462 histologically confi rmed incident thyroid cancer cases and 498 population-based controls. Dietary supplement intake was ascertained through in-person interviews and a food frequency questionnaire. Multivariate unconditional logistic regression models were used to estimate the risk of thyroid cancer and dietary supplement use. RESULTS: Overall, no statistically signifi cant associations were observed between dietary supplementation and thyroid cancer risk. Stratifi ed analyses revealed a suggestive protective effect on risk of papillary microcarcinoma among longterm (> 10 years) use of multivitamins (OR = 0.59, 95 % CI: 0.33, 1.04) and calcium supplementation (OR = 0.45, 95 % CI: 0.22, 0.93). An increased risk of large papillary thyroid cancers (tumor size > 1 cm) was observed among short-term (< 5 years) users of calcium supplements (OR = 2.24, 95 % CI: 1.30, 3.88). DISCUSSION: No signifi cant associations were observed between supplementation and overall thyroid cancer risk. The different associations between calcium supplements and risk of papillary thyroid cancer by tumor size warrant further investigation.

The prospective evaluation of safety and success of a new method of introducing percutaneous paddle leads and complex arrays with an epidural access system.

OBJECTIVES: Spinal cord stimulation (SCS) has become a mainstay in the continuum of care for patients suffering from chronic neuropathic pain of the trunk and limbs. Options for placing these devices have included a percutaneous method of using an epidural needle to place a cylindrical (percutaneous) lead to stimulate the spinal cord, or an open laminotomy method for placing a paddle lead at the location of the surgical decompression of the laminae. Both of these methods have been successful in a high percentage of patients, but neither have been ideal. Limitations of the percutaneous leads have been inefficiency of power delivery, inability to achieve desired depth of stimulation in the spinal cord, occasional lead migration and difficulty covering complex pain patterns. Limitations of the paddle lead have been the need for surgical laminotomy, inability to steer the lead once placed, limits on placement in the vicinity of the surgical decompression, and a perceived risk of increased bleeding and trauma to the tissue. These factors have led many minimally invasive spine specialists to seek new options for SCS. This paper presents the initial US experience with a newly approved device to place both paddle leads, and multi-lead arrays into the epidural space via a percutaneous Seldinger-guided approach through a single needle placement. We will both describe the technique and review the outcomes of some of the early cases. MATERIALS AND METHODS: After Investigational Review Board clearance, patients consented to data collection in a prospective fashion regarding the use of a new percutaneous epidural introducer (Epiducer, St. Jude Neurological, Minneapolis, MN, USA) to place paddle leads and complex lead arrays. The patients underwent education regarding expectations and risks of the procedure consistent with our normal preoperative period. Patients underwent preoperative anesthesia screening and proper testing as outlined by the Joint Commission on Hospital Accreditation, and were given the opportunity to ask questions concerning the procedure. Once the patient wished to move forward, they were consented using the approved case reporting form and followed during the course of their care. The initial cases were performed in West Virginia with subsequent cases following at the other centers involved in this analysis. The outcomes of this analysis focused on three areas: 1. The technical success in placing the percutaneous sheath. This included the ability to successfully complete: • epidural access with a 14-gauge Tuohy needle • ability to place a styleted guidewire • ability to introduce the introduction system over the wire into the epidural space • ability to remove the guidewire and introduction tip leaving the 10-gauge sheath intact. 2. The ability to place the desired lead or leads into the epidural space via the percutaneous introduction sheath. 3. The presence of any major adverse event which were defined as: • nerve injury • paraplegia • worsening of baseline pain • epidural hematoma • epidural infection • dural tear • dural rent • retained device that could not be removed. This information was carefully recorded for each implant, and summarized in this communication. RESULTS: During the initial 30 days of the evaluation period, 43 epidural introduction systems were attempted in 38 patients. In patients in whom more than one paddle lead was placed, the system required the reinsertion of the guidewire through the Epiducer, removal of the Epiducer, and rewiring over the guidewire. This is necessary because the diameter of a paddle lead does not allow two or three leads to be placed without rewiring the system. The success of placement was 42/43, with inability to access the epidural space in one patient in whom ligamentum flavum hypertrophy was present on the preoperative imaging study. In all patients, the system was placed at the L1-L2 level, or lower, based on the Food and Drug Administration labeling. The total numbers of leads placed were 75, with both paddle and percutaneous arrays implanted successfully. There were no adverse events during this prospective surveillance evaluation. Ten patients complained of soreness at the entry site and post-procedure stiffness. These complaints were treated with ice, rest, and analgesics and resolved without incident. CONCLUSION: This paper describes the initial US cases of the placement of a paddle lead via a minimally invasive percutaneous method, as well as complex cylindrical arrays with a single needle entry to the epidural space. The device functioned successfully and presented a safe option for placing paddle leads and complex arrays.

Spinal cord stimulation as a method of reducing opioids in severe chronic pain: a case report and review of the literature.

Opioid addiction and abuse are growing problems in the United States, particularly in Appalachian areas, which has led to a major social health problem costing millions of dollars in lost wages, medical care and lost productivity. In some patients with chronic moderate to severe pain, opioids are indicated and can be successfully used with proper monitoring. In this report, we present a case where the use of spinal cord stimulation (SCS) led to an elimination of opioids, a return to work, and to productive function. We also review the literature on the use of SCS to reduce opioid use and improve function based on objective criteria.

EXAFS study of mercury(II) sorption to Fe- and Al-(hydr)oxides. I. Effects of pH.

The study of mercury sorption products in model systems using appropriate in situ molecular-scale probes can provide detailed information on the modes of sorption at mineral/water interfaces. Such studies are essential for assessing the influence of sorption processes on the transport of Hg in contaminated natural systems. Macroscopic uptake of Hg(II) on goethite (alpha-FeOOH), gamma-alumina (gamma-Al(2)O(3)), and bayerite (beta-Al(OH)(3)) as a function of pH has been combined with Hg L(III)-edge EXAFS spectroscopy, FTIR spectroscopy, and bond valence analysis of possible sorption products to provide this type of information. Macroscopic uptake measurements show that Hg(II) sorbs strongly to fine-grained powders of synthetic goethite (Hg sorption density Gamma=0.39-0.42 micromol/m(2)) and bayerite (Gamma=0.39-0.44 micromol/m(2)), while sorbing more weakly to gamma-alumina (Gamma=0.04-0.13 micromol/m(2)). EXAFS spectroscopy on the sorption samples shows that the dominant mode of Hg sorption on these phases is as monodentate and bidentate inner-sphere complexes. The mode of Hg(II) sorption to goethite was similar over the pH range 4.3-7.4, as were those of Hg(II) sorption to bayerite over the pH range 5.1-7.9. Conversion of the gamma-Al(2)O(3) sorbent to a bayerite-like phase in addition to the apparent reduction of Hg(II) to Hg(I), possibly by photoreduction during EXAFS data collection, resulted in enhanced Hg uptake from pH 5.2-7.8 and changes in the modes of sorption that correlate with the formation of the bayerite-like phase. Bond valence calculations are consistent with the sorption modes proposed from EXAFS analysis. EXAFS analysis of Hg(II) sorption products on a natural Fe oxyhydroxide precipitate and Al/Si-bearing flocculent material showed sorption products and modes of surface attachment similar to those for the model substrates, indicating that the model substrates are useful surrogates for the natural sediments.