Where the rubber meets the road: Emerging environmental impacts of tire wear particles and their chemical cocktails.

About 3 billion new tires are produced each year and about 800 million tires become waste annually. Global dependence upon tires produced from natural rubber and petroleum-based compounds represents a persistent and complex environmental problem with only partial and often-times, ineffective solutions. Tire emissions may be in the form of whole tires, tire particles, and chemical compounds, each of which is transported through various atmospheric, terrestrial, and aquatic routes in the natural and built environments. Production and use of tires generates multiple heavy metals, plastics, PAH's, and other compounds that can be toxic alone or as chemical cocktails. Used tires require storage space, are energy intensive to recycle, and generally have few post-wear uses that are not also potential sources of pollutants (e.g., crumb rubber, pavements, burning). Tire particles emitted during use are a major component of microplastics in urban runoff and a source of unique and highly potent toxic substances. Thus, tires represent a ubiquitous and complex pollutant that requires a comprehensive examination to develop effective management and remediation. We approach the issue of tire pollution holistically by examining the life cycle of tires across production, emissions, recycling, and disposal. In this paper, we synthesize recent research and data about the environmental and human health risks associated with the production, use, and disposal of tires and discuss gaps in our knowledge about fate and transport, as well as the toxicology of tire particles and chemical leachates. We examine potential management and remediation approaches for addressing exposure risks across the life cycle of tires. We consider tires as pollutants across three levels: tires in their whole state, as particulates, and as a mixture of chemical cocktails. Finally, we discuss information gaps in our understanding of tires as a pollutant and outline key questions to improve our knowledge and ability to manage and remediate tire pollution.

Impact of bariatric surgery on oral anticancer drugs: an analysis of real-world data.

PURPOSE: The number of patients with bariatric surgery who receive oral anticancer drugs is rising. Bariatric surgery may affect the absorption of oral anticancer drugs. Strikingly, no specific drug dosing recommendations are available. We aim to provide practical recommendations on the application of oral anticancer drugs in patients who underwent bariatric surgery. METHODS: Patients with any kind of bariatric surgery were extracted retrospectively in a comprehensive cancer center. In addition, a flowchart was proposed to assess the risk of inadequate exposure to oral anticancer drugs in patients who underwent bariatric surgery. Subsequently, the flowchart was evaluated retrospectively using routine Therapeutic drug monitoring (TDM) samples. RESULTS: In our analysis, 571 cancer patients (0.4% of 140.000 treated or referred patients) had previous bariatric surgery. Of these patients, 78 unique patients received 152 oral anticancer drugs equaling an overall number of 30 unique drugs. The 30 different prescribed oral anticancer drugs were categorized as low risk (13%), medium risk (67%), and high risk (20%) of underdosing. TDM plasma samples of 25 patients (82 samples) were available, of which 21 samples post-bariatric surgery (25%) were below the target value. CONCLUSIONS: The proposed flowchart can support optimizing the treatment with orally administered anticancer drugs in patients who underwent bariatric surgery. We recommend performing TDM in drugs that belong to BCS classes II, III, or IV. If more risk factors are present in BCS classes II or IV, a priori switches to other drugs may be advised. In specific cases, higher dosages can be provided from the start (e.g., tamoxifen).

Rat hair-follicle-associated pluripotent (HAP) stem cells can differentiate into atrial or ventricular cardiomyocytes in culture controlled by specific supplementation.

There has been only limited success to differentiate adult stem cells into cardiomyocyte subtypes. In the present study, we have successfully induced beating atrial and ventricular cardiomyocytes from rat hair-follicle-associated pluripotent (HAP) stem cells, which are adult stem cells located in the bulge area. HAP stem cells differentiated into atrial cardiomyocytes in culture with the combination of isoproterenol, activin A, bone morphogenetic protein 4 (BMP4), basic fibroblast growth factor (bFGF), and cyclosporine A (CSA). HAP stem cells differentiated into ventricular cardiomyocytes in culture with the combination of activin A, BMP4, bFGF, inhibitor of Wnt production-4 (IWP4), and vascular endothelial growth factor (VEGF). Differentiated atrial cardiomyocytes were specifically stained for anti-myosin light chain 2a (MLC2a) antibody. Ventricular cardiomyocytes were specially stained for anti-myosin light chain 2v (MLC2v) antibody. Quantitative Polymerase Chain Reaction (qPCR) showed significant expression of MLC2a in atrial cardiomyocytes and MLC2v in ventricular cardiomyocytes. Both differentiated atrial and ventricular cardiomyocytes showed characteristic waveforms in Ca2+ imaging. Differentiated atrial and ventricular cardiomyocytes formed long myocardial fibers and beat as a functional syncytium, having a structure similar to adult cardiomyocytes. The present results demonstrated that it is possible to induce cardiomyocyte subtypes, atrial and ventricular cardiomyocytes, from HAP stem cells.

Impact of apitherapy on canine, equine, and chicken lymphocytes, in vitro.

Apitherapy is a form of alternative medicine that utilizes products from the western honeybee (Apis mellifera), including honey, propolis, and honeybee venom, to improve the health status of human patients by altering host immunity. An added benefit of these products is that they are nutraceuticals and relatively inexpensive to aquire. Currently, little is known about the use of honeybee products in veterinary species, as well as their impact on host immunity. In the present in vitro study, honey, propolis, and honeybee venom were co-cultured with enriched canine, equine, and chicken peripheral blood lymphocytes (PBLs) with cell proliferation, cell viability/apoptosis, and cellular morphology evaluated. Concanavalin A (Con A) and dexamethasone were used as stimulatory and suppressive controls, respectively. Honeybee products' effects on the three veterinary species varied by product and the species. Honey stimulated the PBLs proliferation in all three species but also displayed some increased cytotoxicity. Propolis stimulated proliferation in canine and equine PBLs, however, it suppressed proliferation in the chicken PBLs. Honeybee venom was the strongest PBL stimulant for all three species and in the equine, surpassed the stimulant response of Con A and yet, enhanced PBL cell viability post culture. In summary, the results of this preliminary in vitro study show that these three honeybee products do impact lymphocyte proliferation and viability in dogs, horses, and chickens, and that more research both in vitro and in vivo will be necessary to draw conclusions regarding their future use as immune stimulants or inhibitors.

Durable multimodal and holistic response for physiologic closed-loop spinal cord stimulation supported by objective evidence from the EVOKE double-blind randomized controlled trial.

INTRODUCTION: Chronic pain patients may experience impairments in multiple health-related domains. The design and interpretation of clinical trials of chronic pain interventions, however, remains primarily focused on treatment effects on pain intensity. This study investigates a novel, multidimensional holistic treatment response to evoked compound action potential-controlled closed-loop versus open-loop spinal cord stimulation as well as the degree of neural activation that produced that treatment response. METHODS: Outcome data for pain intensity, physical function, health-related quality of life, sleep quality and emotional function were derived from individual patient level data from the EVOKE multicenter, participant, investigator, and outcome assessor-blinded, parallel-arm randomized controlled trial with 24 month follow-up. Evaluation of holistic treatment response considered whether the baseline score was worse than normative values and whether minimal clinical important differences were reached in each of the domains that were impaired at baseline. A cumulative responder score was calculated to reflect the total minimal clinical important differences accumulated across all domains. Objective neurophysiological data, including spinal cord activation were measured. RESULTS: Patients were randomized to closed-loop (n=67) or open-loop (n=67). A greater proportion of patients with closed-loop spinal cord stimulation (49.3% vs 26.9%) were holistic responders at 24-month follow-up, with at least one minimal clinical important difference in all impaired domains (absolute risk difference: 22.4%, 95% CI 6.4% to 38.4%, p=0.012). The cumulative responder score was significantly greater for closed-loop patients at all time points and resulted in the achievement of more than three additional minimal clinical important differences at 24-month follow-up (mean difference 3.4, 95% CI 1.3 to 5.5, p=0.002). Neural activation was three times more accurate in closed-loop spinal cord stimulation (p<0.001 at all time points). CONCLUSION: The results of this study suggest that closed-loop spinal cord stimulation can provide sustained clinically meaningful improvements in multiple domains and provide holistic improvement in the long-term for patients with chronic refractory pain. TRIAL REGISTRATION NUMBER: NCT02924129.

Dolutegravir-induced neural tube defects in mice are folate responsive.

OBJECTIVES: In 2018, the Botswana Tsepamo Study reported a nine-fold increased risk of neural tube defects in infants whose mothers were treated with dolutegravir (DTG) from the time of conception. As maternal folate supplementation and status is a well known modifier of neural tube defect (NTD) risk, we sought to evaluate birth outcomes in mice fed normal and low folic acid diets treated with DTG during pregnancy. DESIGN: DTG was evaluated for developmental toxicity using pregnant mice fed normal or low folic acid diet. METHODS: CD-1 mice were provided diet with normal (3 mg/kg) or low (0.3 mg/kg) folic acid. They were treated with water, a human therapeutic-equivalent dose, or supratherapeutic dose of DTG from mouse embryonic day E6.5 to E12.5. Pregnant dams were sacrificed at term (E18.5) and fetuses were inspected for gross, internal, and skeletal defects. RESULTS: Fetuses with exencephaly, an NTD, were present in both therapeutic human equivalent and supratherapeutic exposures in dams fed low folic acid diet. Cleft palates were also found under both folate conditions. CONCLUSIONS: Recommended dietary folic acid levels during mouse pregnancy ameliorate developmental defects that arise from DTG exposure. Since low folate status in mice exposed to DTG increases the risk for NTDs, it is possible that DTG exposures in people living with HIV with low folate status during pregnancy may explain, at least in part, the elevated NTD risk signal observed in Botswana. Based on these results, future studies should consider folate status as a modifier for DTG-associated NTD risk.

Guidelines for reporting action simulation studies (GRASS): Proposals to improve reporting of research in motor imagery and action observation.

Researchers from multiple disciplines have studied the simulation of actions through motor imagery, action observation, or their combination. Procedures used in these studies vary considerably between research groups, and no standardized approach to reporting experimental protocols has been proposed. This has led to under-reporting of critical details, impairing the assessment, replication, synthesis, and potential clinical translation of effects. We provide an overview of issues related to the reporting of information in action simulation studies, and discuss the benefits of standardized reporting. We propose a series of checklists that identify key details of research protocols to include when reporting action simulation studies. Each checklist comprises A) essential methodological details, B) essential details that are relevant to a specific mode of action simulation, and C) further points that may be useful on a case-by-case basis. We anticipate that the use of these guidelines will improve the understanding, reproduction, and synthesis of studies using action simulation, and enhance the translation of research using motor imagery and action observation to applied and clinical settings.

Music and Medicine: Promoting Harmony for Health.

A multitude of clinical trials measuring hemodynamic and psychological parameters have shown the beneficial effects of music on health. However, there are no clear instructions on how to utilize the potential benefits of music to improve health outcomes. Moreover, whether the effect of music is transient or enduring has yet to be determined. To address the effect of music on vital parameters and emotional well-being of patients we provide an overview of methods and findings of some studies that have evaluated the physiological or psychological impacts of music. This review puts forward a proposed model for fostering an individualized approach that can examine the therapeutic effects of music.

A Definition of Neuromodulation and Classification of Implantable Electrical Modulation for Chronic Pain.

OBJECTIVES: Neuromodulation therapies use a variety of treatment modalities (eg, electrical stimulation) to treat chronic pain. These therapies have experienced rapid growth that has coincided with escalating confusion regarding the nomenclature surrounding these neuromodulation technologies. Furthermore, studies are often published without a complete description of the effective stimulation dose, making it impossible to replicate the findings. To improve clinical care and facilitate dissemination among the public, payors, research groups, and regulatory bodies, there is a clear need for a standardization of terms. APPROACH: We formed an international group of authors comprising basic scientists, anesthesiologists, neurosurgeons, and engineers with expertise in neuromodulation. Because the field of neuromodulation is extensive, we chose to focus on creating a taxonomy and standardized definitions for implantable electrical modulation of chronic pain. RESULTS: We first present a consensus definition of neuromodulation. We then describe a classification scheme based on the 1) intended use (the site of modulation and its indications) and 2) physical properties (waveforms and dose) of a neuromodulation therapy. CONCLUSIONS: This framework will help guide future high-quality studies of implantable neuromodulatory treatments and improve reporting of their findings. Standardization with this classification scheme and clear definitions will help physicians, researchers, payors, and patients better understand the applications of implantable electrical modulation for pain and guide informed treatment decisions.

Endocrine-disrupting chemicals: Mainstream recognition of health effects and implications for the practicing internist.

Rapidly advancing evidence documents that a broad array of synthetic chemicals found ubiquitously in the environment contribute to disease and disability across the lifespan. Although the early literature focused on early life exposures, endocrine-disrupting chemicals (EDCs) are now understood to contribute substantially to chronic disease in adulthood, especially metabolic, cardiovascular, and reproductive consequences as well as endocrine cancers. The contribution to mortality is substantial, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the United States (US) due to exposure to certain phthalates that are used as plasticizers in food packaging. Importantly, exposures are disproportionately high in low-income and minoritized populations, driving disparities in these conditions. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. Many of these exposures can be modified through safe and simple behavioral changes supported by proactive government action to both limit known hazardous exposures and to proactively screen new industrial chemicals prior to their use. Routine healthcare maintenance should include guidance to reduce EDC exposures, and a recent report by the Institute of Medicine suggests that testing be conducted, particularly in populations heavily exposed to perfluoroalkyl substances-chemicals used in nonstick coatings as well as oil- and water-resistant clothing.

Folate regulation of planar cell polarity pathway and F-actin through folate receptor alpha.

Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, folic acid (FA), and 5-methyltetrahydrofolate (5mTHF), at concentrations of 5 µM, 500 nM, 50 nM, and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages, and cell proliferation and F-actin were monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and F-actin formation. We also found that FOLR1 protein level was positively regulated by folate concentration and the non-canonical Wnt/planar cell polarity (PCP) pathway signaling was significantly enriched among different folate conditions in RNA-sequencing analyses. We demonstrated for the first time that FOLR1 could promote the transcription of Vangl2, one of PCP core genes. The transcription of Vangl2 was down-regulated under folate-deficient condition, which resulted in a decrease in PCP activity and F-actin formation. In summary, we identified a distinct advantage of FA in cell proliferation and F-actin formation over 5mTHF, as well as demonstrating that FOLR1 could promote transcription of Vangl2 and provide a new mechanism by which folate deficiency can contribute to the etiology of NTDs.

Team Approach: Bone Health Optimization in Orthopaedic Surgery.

¼ Bone health optimization (BHO) has become an increasingly important consideration in orthopaedic surgery because deterioration of bone tissue and low bone density are associated with poor outcomes after orthopaedic surgeries.¼ Management of patients with compromised bone health requires numerous healthcare professionals including orthopaedic surgeons, primary care physicians, nutritionists, and metabolic bone specialists in endocrinology, rheumatology, or obstetrics and gynecology. Therefore, achieving optimal bone health before orthopaedic surgery necessitates a collaborative and synchronized effort among healthcare professionals.¼ Patients with poor bone health are often asymptomatic and may present to the orthopaedic surgeon for reasons other than poor bone health. Therefore, it is imperative to recognize risk factors such as old age, female sex, and low body mass index, which predispose to decreased bone density.¼ Workup of suspected poor bone health entails bone density evaluation. For patients without dual-energy x-ray absorptiometry (DXA) scan results within the past 2 years, perform DXA scan in all women aged 65 years and older, all men aged 70 years and older, and women younger than 65 years or men younger than 70 years with concurrent risk factors for poor bone health. All women and men presenting with a fracture secondary to low-energy trauma should receive DXA scan and bone health workup; for fractures secondary to high-energy trauma, perform DXA scan and further workup in women aged 65 years and older and men aged 70 years and older.¼ Failure to recognize and treat poor bone health can result in poor surgical outcomes including implant failure, periprosthetic infection, and nonunion after fracture fixation. However, collaborative healthcare teams can create personalized care plans involving nutritional supplements, antiresorptive or anabolic treatment, and weight-bearing exercise programs, resulting in BHO before surgery. Ultimately, this coordinated approach can enhance the success rate of surgical interventions, minimize complications, and improve patients' overall quality of life.

Mechanisms and Treatment Options for Hyperthyroid-Induced Osteoporosis: A Narrative Review.

Normal thyroid hormone levels are crucial for the homeostasis of many metabolic cycles and processes throughout the human body. Thyroid dysfunction, such as thyrotoxicosis, can result from many different etiologies, including Graves' disease (GD), toxic multinodular goiter (MNG), and toxic adenoma. These hyperthyroid disease states can cause devastating complications and disease, including the disruption of the bone remodeling cycle and skeletal development, which can result in osteoporosis. Osteoporosis is characterized by a decrease in bone mineral density and a propensity for fragility fractures. In addition to patients with overt hyperthyroidism, studies have provided evidence of other high-risk patient demographics, such as individuals with subclinical hyperthyroidism and postmenopausal women, who may be at an increased risk for the development of secondary osteoporosis. The treatment of patients with hyperthyroid-induced osteoporosis often requires a multifaceted management plan that may be unique to each patient's situation. Antithyroid therapy is often the first step in treating this disease and may include thioamide medications. Radioactive iodine-131 therapy (RAI) and the surgical removal of the thyroid gland may also be reasonable approaches for restoring normal thyroid function. Following thyrotoxicosis mitigation, antiresorptive drugs such as bisphosphonates, calcitonin, and selective estrogen receptor modulators (SERMs) may be used to counteract decreased bone mineral density (BMD). Additionally, the implementation of vitamin D, calcium supplements, and weight-bearing exercise may also reduce bone loss. While the effects of thyroid stimulating hormone (TSH) and triiodothyronine (T3) on bone remodeling have been studied in the past, more research is needed to identify unknown mechanisms and develop future improved treatments for this condition.

Growth of Coal Mining Operations in the Elk River Valley (Canada) Linked to Increasing Solute Transport of Se, NO3-, and SO42- into the Transboundary Koocanusa Reservoir (USA-Canada).

Koocanusa Reservoir (KOC) is a waterbody that spans the United States (U.S.) and Canadian border. Increasing concentrations of total selenium (Se), nitrate + nitrite (NO3-, nitrite is insignificant or not present), and sulfate (SO42-) in KOC and downstream in the Kootenai River (Kootenay River in Canada) are tied to expanding coal mining operations in the Elk River Watershed, Canada. Using a paired watershed approach, trends in flow-normalized concentrations and loads were evaluated for Se, NO3-, and SO42- for the two largest tributaries, the Kootenay and Elk Rivers, Canada. Increases in concentration (SO42- 120%, Se 581%, NO3- 784%) and load (SO42- 129%, Se 443%, NO3- 697%) in the Elk River (1979-2022 for NO3-, 1984-2022 for Se and SO42-) are among the largest documented increases in the primary literature, while only a small magnitude increase in SO42- (7.7% concentration) and decreases in Se (-10%) and NO3- (-8.5%) were observed in the Kootenay River. Between 2009 and 2019, the Elk River contributed, on average, 29% of the combined flow, 95% of the Se, 76% of the NO3-, and 38% of the SO42- entering the reservoir from these two major tributaries. The largest increase in solute concentrations occurred during baseflows, indicating a change in solute transport and delivery dynamics in the Elk River Watershed, which may be attributable to altered landscapes from coal mining operations including altered groundwater flow paths and increased chemical weathering in waste rock dumps. More recently there is evidence of surface water treatment operations providing some reduction in concentrations during low flow times of year; however, these appear to have a limited effect on annual loads entering KOC. These findings imply that current mine water treatment, which is focused on surface waters, may not sufficiently reduce the influence of mine-waste-derived solutes in the Elk River to allow constituent concentrations in KOC to meet U.S. water-quality standards.

The Collagen Synthesis Response to an Acute Bout of Resistance Exercise Is Greater when Ingesting 30 g Hydrolyzed Collagen Compared with 15 g and 0 g in Resistance-Trained Young Men.

BACKGROUND: Resistance exercise (RE) stimulates collagen synthesis in skeletal muscle and tendon but there is limited and equivocal evidence regarding an effect of collagen supplementation and exercise on collagen synthesis. Furthermore, it is not known if a dose-response exists regarding the effect of hydrolyzed collagen (HC) ingestion and RE on collagen synthesis. OBJECTIVE: To determine the HC dose-response effect on collagen synthesis after high-intensity RE in resistance-trained young men. METHODS: Using a double-blind, randomized crossover design, 10 resistance-trained males (age: 26 ± 3 y; height: 1.77 ± 0.04 m; mass: 79.7 ± 7.0 kg) ingested 0 g, 15 g, or 30 g HC with 50 mg vitamin C 1 h before performing 4 sets' barbell back squat RE at 10-repetition maximum load, after which they rested for 6 h. Blood samples were collected throughout each of the 3 interventions to analyze procollagen type Ⅰ N-terminal propeptide (PINP) and ß-isomerized C-terminal telopeptide of type I collagen (ß-CTX) concentration, and the concentration of 18 collagen amino acids. RESULTS: The serum PINP concentration × time area under the curve (AUC) was greater for 30 g (267 ± 79 µg·L-1·h) than for 15 g (235 ± 70 µg·L-1·h, P = 0.013) and 0 g HC (219 ± 88 µg·L-1·h, P = 0.002) but there was no difference between 0 and 15 g HC (P = 0.225). The AUCs of glycine and proline were greater for 30 g than for 15 and 0 g HC (P < 0.05). Plasma ß-CTX concentration decreased from -1 to +6 h (P < 0.05), with no differences between interventions. CONCLUSIONS: Ingesting 30 g HC before high-intensity RE augments whole-body collagen synthesis more than 15 g and 0 g HC in resistance-trained young males.

Rapid Reduction of CEA and Stable Metastasis in an NRAS-mutant Rectal-Cancer Patient Treated With FOLFIRI and Bevacizumab Combined With Oral Recombinant Methioninase and a Low-Methionine Diet Upon Metastatic Recurrence After FOLFIRI and Bevacizumab Treatment Alone.

BACKGROUND/AIM: The choice of chemotherapy agents for RAS-mutant colorectal cancer is limited, and prognosis is poor compared to RAS-wild-type colorectal cancer. The purpose of the present study was to evaluate the effectiveness of methionine restriction combined with chemotherapy in a patient with NRAS-mutant rectal cancer. PATIENTS AND METHODS: A 59-year-old female was diagnosed with lung-metastatic recurrence of NRAS-mutant rectal cancer two and a half years after resection of the primary tumor. She started chemotherapy, which consisted of fluorouracil, irinotecan (FOLFIRI), and bevacizumab, in October 2020. Eight months later, stereotactic body radiation therapy (SBRT) was performed to treat the lung metastases. She stopped chemotherapy at this point and had blood tests and computed tomography (CT) scans regularly. Her CEA level increased to 139.91 ng/ml and her lung metastasis became larger by September 2022. Therefore, she was reintroduced to FOLFIRI and bevacizumab in October 2022, and also started a low-methionine diet and oral recombinant methioninase (o-rMETase) as a supplement. RESULTS: After starting the combination therapy with o-rMETase, a low-methionine diet, FOLFIRI, and bevacizumab, blood CEA levels very rapidly decreased and were almost within the normal limits five months later. CT findings showed the lung metastasis did not grow. CONCLUSION: Methionine restriction comprising o-rMETase and a low-methionine diet combined with first-line chemotherapy was effective in a patient with NRAS-mutant rectal cancer in which metastasis had re-occurred after first-line chemotherapy alone.

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.

Peripheral Nerve Stimulation for Pain Management: A Review.

PURPOSE OF REVIEW: Peripheral nerve stimulation has seen a recent upsurge in utilization for various chronic pain conditions, specifically from a neuropathic etiology, where a single peripheral nerve can be pinpointed as a culprit for pain. RECENT FINDINGS: There is conflicting evidence about the efficacy and long-term outcomes of peripheral nerve stimulation for chronic pain, with most studies being small sized. The focus of this article is to review available evidence for the utilization of peripheral nerve stimulation for chronic pain syndromes as well as upcoming evidence in the immediate postoperative realm. The indications for the use of PNS have expanded from neuropathic pain such as occipital neuralgia and post-amputation pain, to more widespread disease processes such as chronic low back pain. Percutaneous PNS delivered over a 60-day period may provide significant carry-over effects including pain relief, potentially avoiding the need for a permanently implanted system while enabling improved function in patients with chronic pain.

Radiotherapy and Immunotherapy in Lung Cancer.

The emergence of immune checkpoint inhibitors (ICIs) as a pillar of cancer treatment has emphasized the immune system's integral role in tumor control and progression through cancer immune surveillance. ICIs are being investigated and incorporated into the treatment paradigm for lung cancers across stages and histology. To date, definitive concurrent chemoradiotherapy followed by consolidative durvalumab is the only National Comprehensive Cancer Network's recommended treatment paradigm including radiotherapy with ICI in lung cancers, although there are other recommendations for ICI with chemotherapy and/or surgery. This narrative review provides an overall view of the evolving integration and synergistic role of immunotherapy and radiotherapy and outlines the use of immunotherapy with radiotherapy for the management of small cell lung cancer and non-small cell lung cancer. It also reviews selected, practice-changing clinical trials that led to the current standard of care for lung cancers.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.