An update on noninvasive neuromodulation in the treatment of patients with prolonged disorders of consciousness.

BACKGROUND: With the improvement of emergency techniques, the survival rate of patients with severe brain injury has increased. However, this has also led to an annual increase in the number of patients with prolonged disorders of consciousness (pDoC). Hence, recovery of consciousness is an important part of treatment. With advancing techniques, noninvasive neuromodulation seems a promising intervention. The objective of this review was to summarize the latest techniques and provide the basis for protocols of noninvasive neuromodulations in pDoC. METHODS: This review summarized the advances in noninvasive neuromodulation in the treatment of pDoC in the last 5 years. RESULTS: Variable techniques of neuromodulation are used in pDoC. Transcranial ultrasonic stimulation (TUS) and transcutaneous auricular vagus nerve stimulation (taVNS) are very new techniques, while transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are still the hotspots in pDoC. Median nerve electrical stimulation (MNS) has received little attention in the last 5 years. CONCLUSIONS: Noninvasive neuromodulation is a valuable and promising technique to treat pDoC. Further studies are needed to determine a unified stimulus protocol to achieve optimal effects as well as safety.

National Trends in Neuromodulation for Urinary Incontinence Among Insured Adult Women and Men, 2004-2013: The Urologic Diseases in America Project.

OBJECTIVE: To examine US trends in neuromodulation for urinary incontinence (UI) treatment from 2004 to 2013. METHODS: This study utilized 2 data sources: the Optum© de-identified Clinformatics® Data Mart Database for privately insured adults aged 18-64 years with a UI diagnosis (N≈40,000 women and men annually) and the Medicare 5% Sample for beneficiaries aged ≥65 years with a UI diagnosis (N≈65,000 women and men annually). We created annual cross-sectional cohorts and assessed prevalence of UI-related neuromodulation procedures among men and women separately from 2004 to 2013. Analyses were conducted overall and stratified by age, race/ethnicity, and geographic region. RESULTS: Nearly all neuromodulation procedures occurred in outpatient settings. Sacral neuromodulation (SNM) procedures for UI in both women and men grew steadily from 2004 to 2013, with more procedures performed in women than men. Among women with UI, SNM prevalence grew from 0.1%-0.2% in 2004 to 0.5%-0.6% in 2013. Posterior tibial nerve stimulation (PTNS) experienced growth from 2011 to 2013. Chemodenervation of the bladder with onabotulinumtoxinA (BTX) combined with other injectable procedures (including urethral bulking) remained stable over time. CONCLUSIONS: From 2004 to 2013, SNM procedures remained relatively uncommon but increased consistently. PTNS experienced growth starting in 2011 when PTNS-specific insurance claims became available. BTX trends remain unclear; future studies should assess it separately from other injectable procedures. Neuromodulation has a growing role in UI treatment, and ongoing trends will be important to examine.

Meeting Proceedings for SCI 2020: Launching a Decade of Disruption in Spinal Cord Injury Research.

The spinal cord injury (SCI) research community has experienced great advances in discovery research, technology development, and promising clinical interventions in the past decade. To build upon these advances and maximize the benefit to persons with SCI, the National Institutes of Health (NIH) hosted a conference February 12-13, 2019 titled "SCI 2020: Launching a Decade of Disruption in Spinal Cord Injury Research." The purpose of the conference was to bring together a broad range of stakeholders, including researchers, clinicians and healthcare professionals, persons with SCI, industry partners, regulators, and funding agency representatives to break down existing communication silos. Invited speakers were asked to summarize the state of the science, assess areas of technological and community readiness, and build collaborations that could change the trajectory of research and clinical options for people with SCI. In this report, we summarize the state of the science in each of five key domains and identify the gaps in the scientific literature that need to be addressed to move the field forward.

Outcomes following percutaneous tibial nerve stimulation (PTNS) treatment for neurogenic and idiopathic overactive bladder.

PURPOSE: Percutaneous tibial nerve stimulation is a minimally invasive neuromodulation technique for treating overactive bladder symptoms. The aim of this study was to assess safety, efficacy and impact on quality of life of percutaneous tibial nerve stimulation in neurological patients reporting overactive bladder symptoms. METHODS: In this retrospective evaluation over 18 months at a tertiary healthcare centre, patients finding first-line treatments for overactive bladder ineffective or intolerable underwent a standard 12-week course of percutaneous tibial nerve stimulation (Urgent PC, Uroplasty). Symptoms were evaluated using standardised International Consultation on Incontinence Questionnaires and bladder diaries. RESULTS: Of 74 patients (52 women, 22 men, mean age 56 years), 49 (66.2%) patients had neurological disorder [19 (25.7%) multiple sclerosis and 30 (40.5%) other neurological conditions] and 25 (33.8%) idiopathic overactive bladder. Overall for the entire cohort significant improvements were recorded after 12 weeks in the following domains: 24-h frequency on bladder diary - 1.67 (- 3.0, 0.33) (p = 0.002), number of incontinent episodes on bladder diary - 0.0 (- 1, 0) (p = 0.01), incontinence severity on bladder diary 0 (- 0.33, 0) (p = 0.007), OAB symptoms - 3 (- 11.5, 5) (p = 0.01), and quality of life - 16 (- 57, 6.5) (p = 0.004). There were no significant differences in outcomes between patients with idiopathic and neurogenic overactive bladder. CONCLUSIONS: Percutaneous tibial nerve stimulation appears to be a possible promising alternative for patients with neurological disorder reporting overactive bladder symptoms who find first-line treatments either ineffective or intolerable. However, a properly designed study is required to address safety and efficacy.

Tremor Control Devices for Essential Tremor: A Systematic Literature Review.

Background: There is a growing interest in nonpharmacological approaches for essential tremor (ET), including tremor cancelation devices. However, the true efficacy of such devices in ET remains unclear. Methods: A systematic literature review was conducted using standardized criteria regarding efficacy and comfortability. Devices focused on design or experimental testing in which tremor was simulated in a robot were excluded. Results: Out of 324 articles initially identified, 12 articles were included. Orthoses using biomechanical loading and neuromodulation with electrical stimulation, and external tremor cancelation devices, were the main interventions used to suppress tremor. All devices were designed to control tremor of the upper limbs at different anatomical locations. Overall, an average tremor attenuation of 50-98% was reported (level of evidence III). Interference with voluntary movements and portability was described as the main drawback. Discussion: In conclusion, this review highlights the growing interest in emerging tremor control devices and the importance of assessing comfort without affecting voluntary movements. However, the level of evidence regarding the efficacy of these tremor control devices remains low. An integrated multidisciplinary combination approach of engineering, robotics, physiology, physiotherapy, and clinical assessment is needed to improve the quality of non-pharmacological interventions for ET.

Percutaneous peripheral nerve stimulation and other alternatives for perineural catheters for postoperative analgesia.

A perineural catheter with a continuous infusion of local anesthetic is an excellent option for postoperative analgesia; however, its limitations include limited duration of action (i.e., 3-7 days) as well as a risk of infection and dislodgement. Furthermore, these blocks may cause dense sensory and motor blockades that under certain circumstances may not be ideal. There is novel evidence that ultrasound-guided percutaneous peripheral nerve stimulation (pPNS) may serve as an alternative approach free of the limitations associated with peripheral nerve blocks. In this review, we discuss the evidence for pPNS on postoperative acute pain management. Subsequently, we briefly discuss additional alternatives to continuous peripheral nerve blocks, including cryoanalgesia and liposomal bupivacaine.

Existing and emerging applications for the neuromodulation of nerve activity through targeted delivery of electric stimuli.

The effective treatment of many diseases requires the use of multiple treatment strategies among which neuromodulation is playing an increasingly important role. Neuromodulation devices that act to normalize or modulate nerve activity through the targeted delivery of electrical stimuli will be the focus of this review. These devices encompass deep brain stimulators, vagus nerve stimulators, spinal cord simulators and sacral nerve stimulators. Already neuromodulation has proven successful in the treatment of a broad range of conditions from Parkinson's disease to chronic pain and urinary incontinence. Many of these approaches seek to exploit the activities of the autonomic nervous system, which influences organ function through the release of neurotransmitters and associated signalling cascades. This review will outline existing and emerging applications for each of these neuromodulation devices, proposed mechanisms of action and clinical studies evaluating both their safety and therapeutic efficacy.

Medical Methods Patents in Neuromodulation.

There is a rapidly growing number of patents on methods of modulating brain regions. Despite this trend, and the massive potential of neuromodulation for treating patients, researchers and physicians who use neuromodulation techniques and technologies often have little idea of the significant ways these patents could affect their work. This article describes medical method patents, including a brief history of their development, and analyzes their potential direct and indirect effects on neuromodulation treatment and research efforts. As neuromodulation rapidly matures into a commercial and medical reality it is important to consider these effects in a forward thinking and value driven manner. The paper concludes with recommendations concerning how neuromodulation method patents may be used, or not, depending on the values of the inventor.

Surgical Neuromodulation of Tinnitus: A Review of Current Therapies and Future Applications.

INTRODUCTION: Tinnitus is the conscious perception of an auditory sensation in the absence of external stimulus. Proposed theories are based on neuroplastic changes that occur due to sensory deprivation. The authors review the relevant literature on functional imaging and neuromodulation of tinnitus and describe potential targets for deep brain stimulation (DBS). MATERIALS AND METHODS: A MEDLINE keyword and Medical Subject Heading term literature search was performed using PubMed for tinnitus, neuromodulation, DBS, transcranial magnetic stimulation, epidural electrode stimulation, intradural electrode stimulation, functional imaging, and connectivity. Data from these reports were extracted and reviewed. RESULTS: Multiple imaging studies are employed to understand the pathophysiology of tinnitus. Abnormal regions and altered connectivity implicated in tinnitus include auditory pathway and limbic structures. Neuromodulation attempts to correct this hyperexcitable state by disrupting these aberrant oscillations and returning activity to baseline. Applied treatment modalities include transcranial magnetic stimulation, epidural/intradural electrode stimulation, and DBS. More recently, modulation of autonomic pathways through vagus nerve stimulation and paired auditory sounds has demonstrated tinnitus improvement via plasticity changes. CONCLUSIONS: DBS shows much promise as a therapeutic option for tinnitus. Stimulation of the auditory pathway, particularly the medial geniculate body, could counteract thalamocortical dysrhythmias and reduce gamma activity implicated in the tinnitus percept. Stimulation of the limbic pathway could decrease attention to and perception of tinnitus. Additional studies, focusing on the involvement of thalamic and limbic structures in the pathophysiology of tinnitus, are needed to support the use of DBS.

Needleless Transcutaneous Neuromodulation Accelerates Postoperative Recovery Mediated via Autonomic and Immuno-Cytokine Mechanisms in Patients With Cholecystolithiasis.

BACKGROUND: Postsurgical gastrointestinal disturbance is clinically characterized by the delayed passage of flatus and stool, delayed resumption of oral feeding, dyspepsia symptoms, and postsurgical pain. This study was designed 1) to evaluate the effects of needleless transcutaneous neuromodulation (TN) on postoperative recovery; 2) to investigate mechanisms of the TN involving autonomic functions in postoperative patients after removal of the gallbladder. METHODS: Sixty patients scheduled for laparoscopic cholecystectomy (LC) were randomized to TN (n = 30) and sham-TN (n = 30). TN was performed via acupoints ST36 and PC6 for 30 min twice daily from 24 hours before surgery to 72 hours after surgery. Sham-TN was performed using the same parameters at nonacupoints. RESULTS: 1) Compared to sham-TN, TN shortened time to first flatulence (38.9 ± 4.0 vs. 24.9 ± 2.4 hour, p = 0.004) and time to defecation (63.1 ± 4.5 vs. 42.5 ± 3.1 hour, p < 0.001). 2) Compared to sham-TN, TN increased the percentage of normal pace-making activity (66.2 ± 2.2 vs. 73.8 ± 2.3%, p = 0.018). 3) TN enhanced vagal activity. Compared to that 24 hours before surgery, surgery decreased vagal activity (HF) (0.41 ± 0.02 vs. 0.34 ± 0.02, p = 0.043) 3 hours after the operation. Compared to sham-TN, TN increased HF (0.45 ± 0.02 vs. 0.52 ± 0.02, p = 0.045) 72 hours after the operation. Further, HF was negatively correlated with time to defecation and serum norepinephrine. 4) Surgery increased serum IL-6 (1.1 ± 0.1 before surgery vs. 2.9 ± 0.7 pg/mL, p = 0.041) 72 hours after the operation, which was reduced to baseline by TN (0.9 ± 0.1). CONCLUSIONS: In conclusion, the proposed needleless TN accelerates postoperative recovery after LC, possibly mediated via the autonomic and immune-cytokine mechanisms. Needleless and self-administrable TN may be an easy-to-implement and low-cost complementary therapy for postoperative recovery.

Percutaneous Peripheral Nerve Stimulation (PNS) for the Treatment of Chronic Low Back Pain Provides Sustained Relief.

OBJECTIVES: The objective of this study was to evaluate the use of percutaneous peripheral nerve stimulation (PNS) for the treatment of chronic low back pain (LBP). Percutaneous PNS offers the potential to provide an effective neuromodulation therapy using a system and fine-wire leads designed specifically for percutaneous use with history of an excellent safety profile. MATERIALS AND METHODS: Subjects with chronic axial LBP received percutaneous PNS leads targeting the medial branch of the dorsal ramus in the region of LBP. Lead placement was guided using ultrasound and confirmed by selective activation of the lumbar multifidus and patient-reported sensations. The percutaneous fine-wire leads remained in place for the 30-day therapy. RESULTS: A majority of subjects reported statistically and clinically significant reductions in both average pain intensity (BPI-5) and worst pain intensity (BPI-3) scores with PNS treatment, which continued long term at the four-month follow-up visit. Subject-reported reductions in pain intensity were substantiated by concomitant and sustained reductions in analgesic medication usage. Subjects also reported clinically significant reductions in patient-centric outcomes of disability (Oswestry Disability Index), pain interference (BPI-9), and patient global impression of change (PGIC). CONCLUSIONS: This work demonstrates the potential value of percutaneous PNS for the treatment of chronic LBP. Improvements in pain, medication, and patient-centric outcomes, which were sustained long term after the removal of PNS leads, demonstrate the significance of this innovative approach to treat chronic LBP.

The Use of Spinal Cord Stimulation/Neuromodulation in the Management of Chronic Pain.

Chronic pain causes a tremendous burden on the society in terms of economic factors and social costs. Rates of spinal surgery, especially spinal fusion, have increased exponentially over the past decade. The opioid epidemic in the United States has been one response to the management of pain, but it has been fraught with numerous catastrophic-related adverse effects. Clinically, spinal cord stimulation (SCS)/neuromodulation has been used in the management of chronic pain (especially spine-related pain) for more than two decades. More recent advances in this field have led to new theories and approaches in which SCS can be used in the management of chronic spine-related pain with precision and efficacy while minimizing adverse effects commonly seen with other forms of chronic pain treatment (eg, narcotics, injections, ablations). Narcotic medications have adverse effects of habituation, nausea, constipation, and the like. Injections sometimes lack efficacy and can have only limited duration of efficacy. Also, they can have adverse effects of cerebrospinal fluid leak, infection, and so on. Ablations can be associated with burning discomfort, lack of efficacy, recurrent symptoms, and infection. High-frequency stimulation, burst stimulation, tonic stimulation with broader paddles, and new stimulation targets such as the dorsal root ganglion hold promise for improved pain management via neuromodulation moving forward. Although a significant rate of complications with SCS technology are well described, this can be a useful tool in the management of chronic spine-related pain.

A Review of Spinal and Peripheral Neuromodulation and Neuroinflammation: Lessons Learned Thus Far and Future Prospects of Biotype Development.

BACKGROUND: There is increasing literature evidence both clinically and experimentally on the existence of potent, adaptive interactions between the central and peripheral aspects of the neuroimmune system in the genesis and maintenance of chronic neuropathic extremity pain and nociceptive back pain. The neuroinflammatory pathways are modulated by the interaction of pro- and anti-inflammatory cytokines and chemokines, which are released by peripheral immune system-derived cell species (macrophages and leukocytes). This review examines the possible impact of spinal and peripheral neurostimulation on the inflammatory response in the context of acute and chronic pain pathologies of different origin. STUDY DESIGN: A narrative review of preclinical and clinical studies addressed to the spinal cord and peripheral nerve stimulation and neuroinflammation. METHODS: Available literature was reviewed on neurostimulation technologies and both acute and chronic low-grade inflammation to identify primary outcome measures and to provide an overview of postulated mechanisms of action of neurostimulation on host inflammatory responses. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles. RESULTS: A comprehensive review of the literature indicates an alternate or synergistic mechanism of action of neurostimulation, beyond modulating somatosensory pain pathways, in modifying inflammatory response associated with chronic pain, by promoting a systemic anti-inflammatory state with upregulation of anti-inflammatory mediators. CONCLUSIONS: These preliminary findings may have important implications on the potential applications of neurostimulation as an anti-inflammatory therapy and the role of molecular profiling as a preimplant screening modality and post-implant outcome validation. Thus, future targeted clinical and experimental research is highly warranted in this particular novel field of neuromodulation.

A Feasibility Study of Percutaneous Peripheral Nerve Stimulation for the Treatment of Postoperative Pain Following Total Knee Arthroplasty.

INTRODUCTION: The objective of the present feasibility study was to investigate the use of a new treatment modality-percutaneous peripheral nerve stimulation (PNS)-in controlling the often severe and long-lasting pain following total knee arthroplasty (TKA). METHODS: For patients undergoing a primary, unilateral TKA, both femoral and sciatic open-coil percutaneous leads (SPR Therapeutics, Cleveland, OH) were placed up to seven days prior to surgery using ultrasound guidance. The leads were connected to external stimulators and used both at home and in the hospital for up to six weeks total. RESULTS: In six of seven subjects (86%), the average of daily pain scores across the first two weeks was <4 on the 0-10 Numeric Rating Scale for pain. A majority of subjects (four out of seven; 57%) had ceased opioid use within the first week (median time to opioid cessation for all subjects was six days). Gross sensory/motor function was maintained during stimulation, enabling stimulation during physical therapy and activities of daily living. At 12 weeks following surgery, six of seven subjects had improved by >10% on the Six-Minute Walk Test compared to preoperative levels, and WOMAC scores improved by an average of 85% compared to before surgery. No falls, motor block, or lead infections were reported. CONCLUSIONS: This feasibility study suggests that for TKA, ultrasound-guided percutaneous PNS is feasible in the immediate perioperative period and may provide analgesia without the undesirable systemic effects of opioids or quadriceps weakness induced by local anesthetics-based peripheral nerve blocks.

Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation: Neuromodulation of the Femoral Nerve for Postoperative Analgesia Following Ambulatory Anterior Cruciate Ligament Reconstruction: A Proof of Concept Study.

OBJECTIVES: The purpose of this prospective proof of concept study was to investigate the feasibility of using percutaneous peripheral nerve stimulation of the femoral nerve to treat pain in the immediate postoperative period following ambulatory anterior cruciate ligament reconstruction with a patellar autograft. MATERIALS AND METHODS: Preoperatively, an electrical lead (SPRINT, SPR Therapeutics, Inc., Cleveland, OH, USA) was percutaneously implanted with ultrasound guidance anterior to the femoral nerve caudad to the inguinal crease. Within the recovery room, subjects received 5 min of either stimulation or sham in a randomized, double-masked fashion followed by a 5-min crossover period, and then continuous active stimulation until lead removal postoperative Day 14-28. Statistics were not applied to the data due to the small sample size of this feasibility study. RESULTS: During the initial 5-min treatment period, subjects randomized to stimulation (n = 5) experienced a slight downward trajectory (decrease of 7%) in their pain over the 5 min of treatment, while those receiving sham (n = 5) reported a slight upward trajectory (increase of 4%) until their subsequent 5-min stimulation crossover, during which time they also experienced a slight downward trajectory (decrease of 11% from baseline). A majority of subjects (80%) used a continuous adductor canal nerve block for rescue analgesia (in addition to stimulation) during postoperative Days 1-3, after which the median resting and dynamic pain scores remained equal or less than 1.5 on the numeric rating scale, respectively, and the median daily opioid consumption was less than 1.0 tablet. CONCLUSIONS: This proof of concept study demonstrates that percutaneous femoral nerve stimulation is feasible for ambulatory knee surgery; and suggests that this modality may be effective in providing analgesia and decreasing opioid requirements following anterior cruciate ligament reconstruction. clinicaltrials.gov: NCT02898103.

A Retrospective Analysis of 25 Cases With Peripheral Nerve Field Stimulation for Chronic Low Back Pain and the Predictive Value of Transcutaneous Electrical Nerve Stimulation for Patient Selection.

OBJECTIVE: Transcutaneous electrical nerve stimulation (TENS) and peripheral nerve field stimulation (PNFS) may be proposed to patients with chronic lumbar pain refractory to conventional treatment. Aim of this study was to assess the importance of preoperatively treatment with TENS as a predictive value for later successful PNFS and impact of PNFS in follow-up of 12 months. METHODS: Between 2012 and 2016, a retrospective analysis of 25 patients with chronic lumbar pain and implantation of a PNFS-system was performed. Pain intensity (NRS), health-related quality of life (EQ-5D-5L), Oswestry disability index (ODI), actual mood state scale (ASTS), and treatment satisfaction (CSQ-8) were assessed pre/postoperatively, after 6 and 12 months. TENS use before surgery was assessed. RESULTS: The cohort consisted of 25 patients with a median age of 56 years (IQR25-75 51-63). In a subgroup analysis, 18 patients used TENS before surgery, 7 did not use TENS and were excluded. No pain relief was observed in 14 patients. Ten of these patients showed later positive effect in PNFS trial stimulation. In four patients, pain relief with TENS was seen. One patient later on had no benefit after PNFS trial, three had sufficient pain relief. In the whole cohort, five patients had no benefit after PNFS trial, in 20 patients a neurostimulator was implanted. NRS, EQ-5D-5L, and ODI measures showed significant improvement in the whole follow-up after PNFS implantation. ASTS scale showed an increase of values for positive mood and a reduction in values for sorrow, fatigue, and anger. In 55%, a sustained reduction in demand for analgesics was seen after 6 months, 50% after 12 months, respectively. CONCLUSION: In this retrospective analysis, TENS has no predictive value in the selection of patients with low back pain for the PFNS treatment. PNFS is effective and safe to relieve significantly symptoms of chronic low back pain.

Pocket Pain and Neuromodulation: Negligible or Neglected?

OBJECTIVES: Pain encountered at the site of the implantable pulse generator (IPG) after invasive neuromodulation is a well-known and important complication. The reported incidence of implant site pain is variable, ranging between 0.4 and 35%. Implant site pain has never been systematically studied and no treatment guidelines are available. MATERIAL AND METHODS: We performed an observational study (study registration number mp05728) on the incidence and the determining factors of implant site pain, the subjective rating of intensity by sending questionnaires (n = 554) to our cohort of neuromodulation patients with IPGs. The number of revision surgeries and explants due to implant site pain were also analyzed. RESULTS: Total response rate was 50% (n = 278). Pain patients suffered significantly (p < 0.05) more often from IPG site pain than other patients undergoing neuromodulation therapies. Up to 64% of patients undergoing spinal cord stimulation reported IPG site discomfort or pain. Severe pocket pain was found in up to 8% of patients. No association was found between other variables (age, BMI, duration of follow-up, gender, smoking, number of pocket surgeries) and implant site pain. CONCLUSION: Pocket pain represents an important problem after invasive neuromodulation and is more prevalent in pain patients. We believe further technological improvements with miniaturized IPGs will impact the incidence of pocket pain and could even obviate the need for an IPG pocket.

Interventional procedures and future drug therapy for hypertension.

Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care.