Process Intensification of the Continuous Synthesis of Bio-Derived Monomers for Sustainable Coatings Using a Taylor Vortex Flow Reactor.

We describe the optimization and scale-up of two consecutive reaction steps in the synthesis of bio-derived alkoxybutenolide monomers that have been reported as potential replacements for acrylate-based coatings (Sci. Adv.2020, 6, eabe0026). These monomers are synthesized by (i) oxidation of furfural with photogenerated singlet oxygen followed by (ii) thermal condensation of the desired 5-hydroxyfuranone intermediate product with an alcohol, a step which until now has involved a lengthy batch reaction. The two steps have been successfully telescoped into a single kilogram-scale process without any need to isolate the 5-hydroxyfuranone between the steps. Our process development involved FTIR reaction monitoring, FTIR data analysis via 2D visualization, and two different photoreactors: (i) a semicontinuous photoreactor based on a modified rotary evaporator, where FTIR and 2D correlation spectroscopy (2D-COS) revealed the loss of the methyl formate coproduct, and (ii) our fully continuous Taylor Vortex photoreactor, which enhanced the mass transfer and permitted the use of near-stoichiometric equivalents of O2. The use of in-line FTIR monitoring and modeling greatly accelerated process optimization in the Vortex reactor. This led to scale-up of the photo-oxidation in 85% yield with a projected productivity of 1.3 kg day-1 and a space-time yield of 0.06 mol day-1 mL-1. Higher productivities could be achieved while sacrificing yield (e.g., 4 kg day-1 at 40% yield). The use of superheated methanol at 200 °C in a pressurized thermal flow reactor accelerated the second step, the thermal condensation of 5-hydroxyfuranone, from a 20 h batch reflux reaction (0.5 L, 85 g) to a space time of <1 min in a reactor only 3 mL in volume operating with projected productivities of >700 g day-1. Proof of concept for telescoping the two steps was established with an overall two-step yield of 67%, producing a process with a projected productivity of 1.1 kg day-1 for the methoxybutenolide monomer without any purification of the 5-hydroxyfuranone intermediate.

Neural patterns differentiate traumatic from sad autobiographical memories in PTSD.

For people with post-traumatic stress disorder (PTSD), recall of traumatic memories often displays as intrusions that differ profoundly from processing of 'regular' negative memories. These mnemonic features fueled theories speculating a unique cognitive state linked with traumatic memories. Yet, to date, little empirical evidence supports this view. Here we examined neural activity of patients with PTSD who were listening to narratives depicting their own memories. An intersubject representational similarity analysis of cross-subject semantic content and neural patterns revealed a differentiation in hippocampal representation by narrative type: semantically similar, sad autobiographical memories elicited similar neural representations across participants. By contrast, within the same individuals, semantically similar trauma memories were not represented similarly. Furthermore, we were able to decode memory type from hippocampal multivoxel patterns. Finally, individual symptom severity modulated semantic representation of the traumatic narratives in the posterior cingulate cortex. Taken together, these findings suggest that traumatic memories are an alternative cognitive entity that deviates from memory per se.

Long term structural and functional neural changes following a single infusion of Ketamine in PTSD.

NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (-0.33, sd = 0.13, 95%HDI [-0.56,-0.04]) and hippocampus (-0.3 (sd = 0.19), 95%HDI [-0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (-0.28, sd = 0.11, 95%HDI [-0.46, -0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: -0.01108, 95% HDI [-0.0184,-0.003]; follow-up: -0.0183, 95% HDI [-0.02719,-0.0107]; left: post-treatment: -0.019, 95% HDI [-0.028,-0.011]; follow-up: -0.017, 95% HDI [-0.026,-0.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.

Amygdala downregulation training using fMRI neurofeedback in post-traumatic stress disorder: a randomized, double-blind trial.

Hyperactivation of amygdala is a neural marker for post-traumatic stress disorder (PTSD) and improvement in control over amygdala activity has been associated with treatment success in PTSD. In this randomized, double-blind clinical trial we evaluated the efficacy of a real-time fMRI neurofeedback intervention designed to train control over amygdala activity following trauma recall. Twenty-five patients with PTSD completed three sessions of neurofeedback training in which they attempted to downregulate the feedback signal after exposure to personalized trauma scripts. For subjects in the active experimental group (N = 14), the feedback signal was from a functionally localized region of their amygdala associated with trauma recall. For subjects in the control group (N = 11), yoked-sham feedback was provided. Changes in control over the amygdala and PTSD symptoms served as the primary and secondary outcome measurements, respectively. We found significantly greater improvements in control over amygdala activity in the active group than in the control group 30-days following the intervention. Both groups showed improvements in symptom scores, however the symptom reduction in the active group was not significantly greater than in the control group. Our finding of greater improvement in amygdala control suggests potential clinical application of neurofeedback in PTSD treatment. Thus, further development of amygdala neurofeedback training in PTSD treatment, including evaluation in larger samples, is warranted.

Neural valuation of rewards and punishments in posttraumatic stress disorder: a computational approach.

Posttraumatic stress disorder (PTSD) is associated with changes in fear learning and decision-making, suggesting involvement of the brain's valuation system. Here we investigate the neural mechanisms of subjective valuation of rewards and punishments in combat veterans. In a functional MRI study, male combat veterans with a wide range of posttrauma symptoms (N = 48, Clinician Administered PTSD Scale, CAPS-IV) made a series of choices between sure and uncertain monetary gains and losses. Activity in the ventromedial prefrontal cortex (vmPFC) during valuation of uncertain options was associated with PTSD symptoms, an effect which was consistent for gains and losses, and specifically driven by numbing symptoms. In an exploratory analysis, computational modeling of choice behavior was used to estimate the subjective value of each option. The neural encoding of subjective value varied as a function of symptoms. Most notably, veterans with PTSD exhibited enhanced representations of the saliency of gains and losses in the neural valuation system, especially in ventral striatum. These results suggest a link between the valuation system and the development and maintenance of PTSD, and demonstrate the significance of studying reward and punishment processing within subject.

Rapid titration of VNS therapy reduces time-to-response in epilepsy.

BACKGROUND: Common titration strategies for vagus nerve stimulation (VNS) prioritize monitoring of tolerability during small increases in stimulation intensity over several months. Prioritization of tolerability is partially based on how quickly side effects can be perceived and reported by patients, and the delayed onset of clinical benefits from VNS. However, many practices assess the clinical benefit of VNS at one year after implantation, and excessive caution during the titration phase can significantly delay target dosing or prevent a patient from reaching a therapeutic dose entirely. OBJECTIVE: This study aimed to characterize the relationship between titration speed and the onset of clinical response to VNS. METHODS: To assess differences between more aggressive titration strategies and more conservative ones, we analyzed the relationship between time-to-dose and time-to-response using a weighted Cox regression. The target dose was empirically defined as 1.625 mA output current delivered at 250 microsecond pulse widths at 20 Hz. Patient-level outcomes and dosing data were segregated into fast (<3 months), medium (3-6 months), and slow (>6 months) cohorts based on their titration speed. RESULTS: The statistical model revealed a significant relationship between titration speed and onset of clinical response, defined as a 50% reduction from baseline in seizure frequency. Frequency of adverse events reported between each cohort trended toward higher rates of adverse events in adults who were titrated quickly; however, the pediatric population appeared to be more tolerant of titration at any speed. CONCLUSIONS: This analysis indicates that faster titration yields faster onset of clinical benefit and is especially practical in the pediatric population, though attempts to accelerate adult titration may still be warranted.

VNS parameters for clinical response in Epilepsy.

BACKGROUND: While vagus nerve stimulation (VNS) has been in use for over two decades, little professional guidance exists to describe dosing and titration of therapy which is the consequence of a limited amount of evidence developed during the pre-market phase of therapy development. Post-market surveillance of dosing practice has revealed significant deviations from dosing and titration guidance offered by professional societies as well as the manufacturer. OBJECTIVE: This analysis aims to identify a target dose for VNS Therapy in Epilepsy. METHODS: Herein, VNS clinical outcomes are linked to the patient-specific dosing parameters for each study visit (n = 1178 patients). A generalized linear mixed model was built to ascertain the relationship between key stimulation parameters (i.e., Output Current, Pulse Width, Signal Frequency, and Duty Cycle) and clinical response, defined as a 50% or greater reduction in seizure frequency from baseline. Other demographic parameters of interest, such as duration of epilepsy and age at implant, were also explored. RESULTS: A population level target output current and duty cycle for VNS therapy for epilepsy was identified as 1.61 mA and 17.1% duty cycle. Patients with shorter duration of epilepsy were identified to have a higher likelihood to respond to VNS therapy (p < 0.001). While patients who were on the therapy longer were more likely to respond to the therapy, the effect did not interact with the dosing settings - suggesting that patients who have been chronically underdosed may still benefit from achieving the target dose. CONCLUSION: An opportunity exists to improve upon VNS outcomes by aligning clinical practice around this evidence-based target dose.

Radiofrequency ablation for Barrett's oesophagus related neoplasia with the 360 Express catheter: initial experience from the United Kingdom and Ireland-preliminary results.

BACKGROUND: Radio-frequency ablation (RFA) for Barrett's oesophagus (BE)-related neoplasia is currently used after endoscopic resection of visible neoplasia. The HALO 360 balloon has been used to ablate long segment BE. The Barrx™ 360 Express RFA self-sizing catheter ('RFA Express') may potentially allow quicker ablation times and improved treatment outcomes. The aim of this paper is to present real world data on the use of the 360 Express Device. METHODS: Centres in the UK and Ireland submitted cases where the RFA Express was used. The primary outcome was regression of BE at 3 months. Secondary outcomes were the rate of symptomatic stricture formation and resolution of intestinal metaplasia (CR-IM) and dysplasia (CR-D) at End of Treatment (EoT). RESULTS: 11 centres submitted 123 consecutive patients. 112 had a follow up endoscopy. The median age was 67 years (IQR 62-75). 3 dosimetries were used. The mean reduction in Circumferential (C) length was 78% ± 36 and mean reduction in Maximal length (M) was 55% ± 36. 17 patients (15%) developed strictures requiring dilation. There was a higher rate of stricture formation when the 12 J energy was used (p < 0.05). 47 patients had EoT biopsies, 40 (85%) had CR-D and 34(76%) had CR-IM. CONCLUSIONS: The RFA 360 Express catheter shows reduction in length of baseline BE at 3 months after index treatment, and eradication of intestinal metaplasia and dysplasia at 12 months similar to other studies with earlier devices. It appears that the symptomatic stricture rate is slightly higher than previous series with the HALO 360 catheter. This study was performed as part of the HALO registry and has been approved by the Research Ethics Committee - MREC Number 08/H0714/27 Local project reference 08/0104 Project ID 15,033 IRAS Number 54678 EudraCT 2009-015980-1. Registered on ISRCTN as below: ISRCTN93069556. https://doi.org/10.1186/ISRCTN93069556.

Endoscopic ultrasound-guided ethanol and radiofrequency ablation of pancreatic insulinomas: a systematic literature review.

BACKGROUND: Insulinoma is the most common neuroendocrine neoplasm of the pancreas, characterised by hypoglycaemic symptoms. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) and ethanol ablation (EUS-EA) are novel methods for treating insulinoma.We aimed to perform a systematic review to assess the efficacy and safety of EUS-guided ablation techniques for pancreatic insulinomas. METHODS: We systematically searched for articles detailing EUS-guided ablations of insulinomas. We performed a qualitative analysis and summarised data on the efficacy and safety of EUS-RFA and EUS-EA techniques. RESULTS: In total, we identified 35 case reports and case series describing 75 patients with insulinomas treatment with EUS-guided ablation. Twenty-seven patients were treated with EUS-RFA, 47 patients with EUS-EA, and 1 patient received EUS-EA and EUS-RFA in the same session. In total, 84 insulinomas were ablated (EUS-RFA: 31, EUS-EA: 53). Most insulinomas were in the head of the pancreas (40%). The clinical success rate for EUS-guided ablation techniques was 98.5%. The median glucose level was 1.95 (Q1-Q3: 1.69-2.13) mmol/L before ablation compared to 6.20 (Q1-Q3: 5.30-7.05) mmol/L after treatment. The median insulin and C-peptide levels before and after RFA/EA were 230 (Q1-Q2: 120-257) pmol/L and 41 (Q1-Q2 35-42) pmol/L; 2077 (Q1-Q2 1644-2459) pmol/L and 819 (Q1-Q2 696-1072) pmol/L, respectively. There were eleven adverse events: seven abdominal pain, two mild acute pancreatitis, one necrotising acute pancreatitis and one local hematoma. All patients recovered, and there were no periprocedural deaths. CONCLUSIONS: EUS-guided ablation of insulinoma seems to be a safe and effective treatment and is an alternative to surgical resection in selected cases.

Inherent maternal type 2 immunity: Consequences for maternal and offspring health.

An inherent elevation in type 2 immunity is a feature of maternal and offspring immune systems. This has diverse implications for maternal and offspring biology including influencing success of pregnancy, offspring immune development and maternal and offspring ability to control infection and diseases such as allergies. In this review we provide a broad insight into how this immunological feature of pregnancy and early life impacts both maternal and offspring biology. We also suggest how understanding of this axis of immune influence is and may be utilised to improve maternal and offspring health.

Quality indicators for Barrett's endotherapy (QBET): UK consensus statements for patients undergoing endoscopic therapy for Barrett's neoplasia.

INTRODUCTION: Endoscopic therapy for the management of patients with Barrett's oesophagus (BE) neoplasia has significantly developed in the past decade; however, significant variation in clinical practice exists. The aim of this project was to develop expert physician-lead quality indicators (QIs) for Barrett's endoscopic therapy. METHODS: The RAND/UCLA Appropriateness Method was used to combine the best available scientific evidence with the collective judgement of experts to develop quality indicators for Barrett's endotherapy in four subgroups: pre-endoscopy, intraprocedure (resection and ablation) and postendoscopy. International experts, including gastroenterologists, surgeons, BE pathologist, clinical nurse specialist and patient representative, participated in a three-round process to develop 15 QIs that fulfilled the RAND/UCLA definition of appropriateness. RESULTS: 17 experts participated in round 1 and 20 in round 2. Of the 24 proposed QIs in round 1, 20 were ranked as appropriate (put through to round 2) and 4 as uncertain (discarded). At the end of round 2, a final list of 15 QIs were scored as appropriate. CONCLUSIONS: This UK national consensus project has successfully developed QIs for patients undergoing Barrett's endotherapy. These QIs can be used by service providers to ensure that all patients with BE neoplasia receive uniform and high-quality care.

A Comparison of Clinical Outcomes between Early Cervical Spine Stabilizer Training and Usual Care in Individuals following Anterior Cervical Discectomy and Fusion.

OBJECTIVES: Early physical therapy (PT) with specific stabilization training has been shown to benefit individuals after lumbar spinal surgery but has not been studied in patients after cervical spine surgery. The primary purpose of this study was to compare clinical outcomes between early cervical spine stabilizer (ECS) training and usual care (UC) in patients after anterior cervical discectomy and fusion (ACDF) surgery. The secondary purpose was to determine test-retest reliability of strength and endurance tests of cervical spinal stabilizers in this patient population. METHODS: Forty participants who were scheduled for ACDF surgery were randomized into either the ECS group or the UC group. After surgery, participants received their assigned group intervention during their hospital stay and continued their assigned intervention for 12 weeks. All participants had phone follow-ups twice during the first 6 weeks to address questions or problems. Clinical outcome measures including pain level using the Numeric Pain Rating Scale (NPRS), disability level using the Neck Disability Index (NDI), Craniocervical Flexor Strength (CCF-S), and Craniocervical Flexor Endurance (CCF-E) were collected three times: before surgery and 6 and 12 weeks after surgery. Test-retest reliability was assessed in the first 10 participants. RESULTS: There was no significant interaction between the groups over time for any of the outcome measures. However, all participants made significant improvements in all four outcome measures at 6 and 12 weeks post surgery. The results showed good-to-excellent test-retest reliability for the CCF-S and CCF-E tests. CONCLUSIONS: Both ECS training and UC resulted in the same amount of improvement at 6 and 12 weeks; therefore, both therapy approaches appear to have similar and positive effects on patients in their first 3 months of recovery after ACDF. Both the CCF-S and CCF-E tests can be used reliably to assess the strength and endurance of the cervical spinal stabilizers for patients after ACDF surgery. The study was registered with the ClinicalTrials.gov (NIH, U.S. National Library of Medicine, identifier # NCT01519115) Protocol Registration system.

Radiofrequency ablation for patients with refractory symptomatic anaemia secondary to gastric antral vascular ectasia.

Background: Gastric antral vascular ectasia (GAVE) is a rare cause of gastrointestinal bleeding, often causing iron deficiency anaemia. Previous studies have looked at the management of this with argon plasma coagulation, laser therapy and endoscopic band ligation. Methods: This was a single-centre prospective study to evaluate the efficacy and safety of radiofrequency ablation (RFA) in patients with GAVE with persistent anaemia refractory to at least one session of first-line endoscopic therapy. Patients were treated with a through-the-scope (TTS) radiofrequency catheter at two endoscopic sessions six weeks apart. The primary outcome was change in haemoglobin at six months posttreatment. The secondary outcomes were reduction in blood or iron requirements, endoscopic surface area regression and complications. Results: Twenty patients were treated. The mean change in haemoglobin at six months was +12.6 g/l (95% confidence interval 11.7-24.3 g/l), paired t test p < 0.001. At six months, three of 14 individuals who had required blood transfusions had ongoing blood transfusions and five of 17 who had required iron had ongoing iron needs. Surface area regression was scored as 74% ± 25% but no correlation was seen between this and other outcomes. Three of 20 patients experienced pain which was managed with oral analgesia. Of the 14 patients who had reached 12-month follow-up, three required retreatment (21%). Discussion: This small study suggests that RFA is a safe and effective treatment for GAVE. Our study uses the TTS catheter compared to other studies, and demonstrates prolonged improvement in haemoglobin and reduction in blood and iron requirements with a novel assessment of surface area regression.

Author Correction: Neural computations of threat in the aftermath of combat trauma.

The original and corrected figures are shown in the accompanying Author Correction.

Neural computations of threat in the aftermath of combat trauma.

By combining computational, morphological, and functional analyses, this study relates latent markers of associative threat learning to overt post-traumatic stress disorder (PTSD) symptoms in combat veterans. Using reversal learning, we found that symptomatic veterans showed greater physiological adjustment to cues that did not predict what they had expected, indicating greater sensitivity to prediction errors for negative outcomes. This exaggerated weighting of prediction errors shapes the dynamic learning rate (associability) and value of threat predictive cues. The degree to which the striatum tracked the associability partially mediated the positive correlation between prediction-error weights and PTSD symptoms, suggesting that both increased prediction-error weights and decreased striatal tracking of associability independently contribute to PTSD symptoms. Furthermore, decreased neural tracking of value in the amygdala, in addition to smaller amygdala volume, independently corresponded to higher PTSD symptom severity. These results provide evidence for distinct neurocomputational contributions to PTSD symptoms.

Hookworm exposure decreases human papillomavirus uptake and cervical cancer cell migration through systemic regulation of epithelial-mesenchymal transition marker expression.

Persistent infection with human papillomavirus (HPV) is responsible for nearly all new cervical cancer cases worldwide. In low- and middle-income countries (LMIC), infection with helminths has been linked to increased HPV prevalence. As the incidence of cervical cancer rises in helminth endemic regions, it is critical to understand the interaction between exposure to helminths and the progression of cervical cancer. Here we make use of several cervical cancer cell lines to demonstrate that exposure to antigens from the hookworm N. brasiliensis significantly reduces cervical cancer cell migration and global expression of vimentin and N-cadherin. Importantly, N. brasiliensis antigen significantly reduced expression of cell-surface vimentin, while decreasing HPV type 16 (HPV16) pseudovirion internalization. In vivo infection with N. brasiliensis significantly reduced vimentin expression within the female genital tract, confirming the relevance of these in vitro findings. Together, these findings demonstrate that infection with the hookworm-like parasite N. brasiliensis can systemically alter genital tract mesenchymal markers in a way that may impair cervical cancer cell progression. These findings reveal a possible late-stage treatment for reducing cervical cancer progression using helminth antigens.

Locus of control in US combat veterans: Unique associations with posttraumatic stress disorder 5-factor model symptom clusters.

Given elevated rates of posttraumatic stress disorder (PTSD) among US military veterans, identifying correlates of PTSD and specific PTSD symptom clusters that best represent PTSD in veterans (i.e., the five-factor Dysphoric Arousal model) is critical to prevention and intervention efforts. One potential correlate is locus of control (i.e., the extent to which individuals believe they have control over events in their lives). The aim of this study was to examine the relations between locus of control and five-factor model PTSD symptom clusters (i.e., re-experiencing, avoidance, numbing, dysphoric arousal, anxious arousal) among combat veterans. Eighty-nine combat exposed veterans completed self-report measures of demographics, locus of control, PTSD symptoms, and combat exposure. Bivariate correlations indicated relations between locus of control and overall PTSD symptoms, avoidance symptoms, and numbing symptoms. When controlling for sex and combat exposure in regression analyses, only avoidance remained a significant correlate of locus of control. Among veterans with the most extreme scores (n = 26), external locus of control predicted overall PTSD symptoms and avoidance symptoms. External locus of control is uniquely associated with avoidance symptoms, and represents a potentially modifiable factor to address in trauma-focused treatments.

Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy.

OBJECTIVE: Limited data are available regarding the evolution over time of the rate of sudden unexpected death in epilepsy patients (SUDEP) in drug-resistant epilepsy. The objective is to analyze a database of 40 443 patients with epilepsy implanted with vagus nerve stimulation (VNS) therapy in the United States (from 1988 to 2012) and assess whether SUDEP rates decrease during the postimplantation follow-up period. METHODS: Patient vital status was ascertained using the Centers for Disease Control and Prevention's National Death Index (NDI). An expert panel adjudicated classification of cause of deaths as SUDEP based on NDI data and available narrative descriptions of deaths. We tested the hypothesis that SUDEP rates decrease with time using the Mann-Kendall nonparametric trend test and by comparing SUDEP rates of the first 2 years of follow-up (years 1-2) to longer follow-up (years 3-10). RESULTS: Our cohort included 277 661 person-years of follow-up and 3689 deaths, including 632 SUDEP. Primary analysis demonstrated a significant decrease in age-adjusted SUDEP rate during follow-up (S = -27 P = .008), with rates of 2.47/1000 for years 1-2 and 1.68/1000 for years 3-10 (rate ratio 0.68; 95% confidence interval [CI] 0.53-0.87; P = .002). Sensitivity analyses confirm these findings. SIGNIFICANCE: Our data suggest that SUDEP risk significantly decreases during long-term follow-up of patients with refractory epilepsy receiving VNS Therapy. This finding might reflect several factors, including the natural long-term dynamic of SUDEP rate, attrition, and the impact of VNS Therapy. The role of each of these factors cannot be confirmed due to the limitations of the study.

Prospective, randomized multicenter study of cervical arthroplasty versus anterior cervical discectomy and fusion: 5-year results with a metal-on-metal artificial disc.

OBJECTIVE Seven cervical total disc replacement (TDR) devices have received FDA approval since 2006. These devices represent a heterogeneous assortment of implants made from various biomaterials with different biomechanical properties. The majority of these devices are composed of metallic endplates with a polymer core. In this prospective, randomized multicenter study, the authors evaluate the safety and efficacy of a metal-on-metal (MoM) TDR (Kineflex|C) versus anterior cervical discectomy and fusion (ACDF) in the treatment of single-level spondylosis with radiculopathy through a long-term (5-year) follow-up. METHODS An FDA-regulated investigational device exemption (IDE) pivotal trial was conducted at 21 centers across the United States. Standard validated outcome measures including the Neck Disability Index (NDI) and visual analog scale (VAS) for assessing pain were used. Patients were randomized to undergo TDR using the Kineflex|C cervical artificial disc or anterior cervical fusion using structural allograft and an anterior plate. Patients were evaluated preoperatively and at 6 weeks and 3, 6, 12, 24, 36, 48, and 60 months after surgery. Serum ion analysis was performed on a subset of patients randomized to receive the MoM TDR. RESULTS A total of 269 patients were enrolled and randomly assigned to undergo either TDR (136 patients) or ACDF (133 patients). There were no significant differences between the TDR and ACDF groups in terms of operative time, blood loss, or length of hospital stay. In both groups, the mean NDI scores improved significantly by 6 weeks after surgery and remained significantly improved throughout the 60-month follow-up (both p < 0.01). Similarly, VAS pain scores improved significantly by 6 weeks and remained significantly improved through the 60-month follow-up (both p < 0.01). There were no significant changes in outcomes between the 24- and 60-month follow-ups in either group. Range of motion in the TDR group decreased at 3 months but was significantly greater than the preoperative mean value at the 12- and 24-month follow-ups and remained significantly improved through the 60-month period. There were no significant differences between the 2 groups in terms of reoperation/revision surgery or device-/surgery-related adverse events. The serum ion analysis revealed cobalt and chromium levels significantly lower than the levels that merit monitoring. CONCLUSIONS Cervical TDR with an MoM device is safe and efficacious at the 5-year follow-up. These results from a prospective randomized study support that Kineflex|C TDR as a viable alternative to ACDF in appropriately selected patients with cervical radiculopathy. Clinical trial registration no.: NCT00374413 (clinicaltrials.gov).