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Abstract Introduction Chronic neck pain (cNP) is one of the leading causes of disability worldwide, often being refractory to conventional forms of treatment. Various forms of electrical stimulation have been proposed to decrease pain and improve function. Patient-reported outcome measures (PROMs) for treatment of cNP have rarely been published. Methods An independent retrospective statistical analysis of PROMs data for users of H-Wave® device stimulation (HWDS), prospectively collected by the device manufacturer over a 4-year period, was conducted. Final surveys for 34,192 pain management patients were filtered for pain chronicity limited to 3–24 months and device use of 22–365 days, resulting in 11,503 patients with “all diagnoses”; this number was further reduced to 1482 patients with cNP, sprain, or strain. Results Neck pain was reduced by 3.13 points (0–10 pain scale), with significant (≥ 20%) relief in 86.6%. Function/activities of daily living (ADL) improved in 96.19%, while improved work performance was reported in 84.76%. Medication use decreased or stopped in 65.42% and sleep improved in 60.39%. Over 95% reported having expectations met or exceeded, service satisfaction, and confidence in device use, while no adverse events were reported. Subgroup analyses found positive benefit associations with longer duration of device use. Conclusion Near-equivalent outcomes were self-reported by cNP HWDS patients as for (previously published) chronic low back pain (cLBP) patients. HWDS provided effective and safe cNP relief, improvements in function and ADL, along with additional benefits including decreased medication use, better sleep, and improved work performance.

Abstract Introduction Chronic low back pain (cLBP) is a problem globally, creating a tremendous economic burden. Since conventional treatments often fail, various forms of electrical stimulation have been proposed to improve function and decrease pain. Patient-reported outcome measures (PROMs) have not been adequately reported in the electrical stimulation literature. Methods A retrospective independent statistical analysis was conducted on PROMs data for users of H-Wave® device stimulation (HWDS) collected by the device manufacturer over a period of 4 years. Final surveys for 34,192 pain management patients were filtered for pain chronicity limited to 3–24 months and device use of 22–365 days, resulting in 11,503 patients with “all diagnoses”; this number was then reduced to 2711 patients with nonspecific cLBP, sprain, or strain. Results Reported pain was reduced by 3.12 points (0–10 pain scale), with significant (≥ 20%) relief in 85.28%. Function/activities of daily living (ADL) improved in 96.36%, while improved work performance was reported in 81.61%. Medication use decreased or stopped in 64.41% and sleep improved in 59.76%. Over 96% reported having expectations met or exceeded, service satisfaction, and confidence in device use, while no adverse events were reported. Subgroup analyses found positive associations with longer duration of device use, home exercise participation, and working, whereas older age and longer pain chronicity resulted in reduced benefit. Similar analysis of the larger all-diagnoses cohort demonstrated near-equivalent positive outcomes. Conclusion Treatment outcomes directly reported by cLBP HWDS patients demonstrated profound positive effects on function and ADL, robust improvement in pain perception, and additional benefits like decreased medication use, better sleep, and improved work performance, representing compelling new evidence of treatment efficacy.

The strength matching and toughness of girth welded joints are very important to the service safety of pipelines. In order to better understand the failure mechanism of girth weld, the microstructure and properties of two types of high-Nb X80 girth welded joints with different strength matching were tested by mechanical performance testing and microstructure analysis. Meanwhile, the strain behavior of the welded joints applied with the tensile load was studied by the digital image correlation (DIC) method. The results show that both of the undermatched and overmatched girth welded joints have good impact toughness and similar average Charpy impact absorption energy. Under the tensile load, strain concentration appears in the root welds and the heat affected zones (HAZ) at first. With the increase of tensile load, the strain concentration of the overmatched girth welded joint shifts to the base metal gradually, and the bearing capacity of the pipeline to the axial load and deformation is greater than that of the undermatched girth welded joint. Additionally, the undermatched girth welded joints are prone to fracture due to the plastic strain accumulation in the weld and HAZ, even if they have good toughness.

Abstract There is a growing need to provide effective adventitious agent mitigation for high risk upstream cell culture raw materials used for the production of biologics. It is also highly important in the growing fields of cell and gene therapies. Glucose is a critical raw material necessary for effective cell growth and productivity; however, glucose is the highest risk animal‐origin‐free raw material for viral contamination, and often the highest risk raw material in the upstream process as more companies move to chemically defined media. This study examines the efficacy of utilizing High Temperature Short Time (HTST) pasteurization for inactivation of physiochemically resistant, worst‐case parvovirus using a bench‐scale HTST system. We demonstrated approximately six log inactivation of Minute Virus of Mice (MVM) in concentrated glucose feeds without impacting the subsequent performance of the glucose in a Chinese Hamster Ovary (CHO) expression system.

We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single‐blind, placebo‐controlled study, following once‐daily multiple ascending dosing to steady‐state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half‐life of ~ 60 hours. A dose/concentration‐effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady‐state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration‐dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction.

Abstract Verinurad is a selective inhibitor of uric acid transporter 1 (URAT1). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of verinurad + allopurinol and verinurad monotherapy in healthy participants. Studies 1 (NCT03836599) and 2 (NCT02608710) were randomized Phase 1 studies. In Study 1, 12 healthy Asian participants received 24 mg verinurad + 300 mg allopurinol or placebo, and 9 healthy Chinese participants received 12 mg verinurad + 300 mg allopurinol. In Study 2, 24 healthy non‐Asian male participants received 12 mg verinurad. Safety analyses included assessment of adverse events (AEs). Pharmacokinetic parameters included maximum concentration (Cmax) and area under plasma concentration‐time curve (AUC) over 24 h (AUCτ). Pharmacodynamic parameters included percentage change from baseline (day –1) in serum uric acid (sUA) and urinary uric acid (uUA). There were no serious AEs or deaths in either study. In Study 1, steady‐state geometric mean (gCV%) Cmax and AUCτ values of verinurad after 7 days’ dosing were 73.6 (29.0) ng/mL and 478 (18.4) ng·h/mL, respectively, in healthy Asian participants, and 42.0 (40.1) ng/mL and 264 (36.1) ng·h/mL, respectively, in healthy Chinese participants; in Study 2, gCV% values were 36.3 (36.5) ng/mL and 271 (31.0) ng·h/mL, respectively. sUA decreased and uUA excretion increased compared with baseline following verinurad + allopurinol (Study 1) or verinurad (Study 2). When accounting for dose, the steady‐state pharmacokinetics of verinurad following multiple dosing were comparable between healthy Asian and Chinese participants and healthy non‐Asian participants. Verinurad treatments were well tolerated, including at higher verinurad exposures than previously evaluated after repeated dosing.

Recent efforts in semantic segmentation using deep learning framework have made notable advances. While achieving high performance, however, they often require heavy computation, making them impractical to be used in real world applications. There are two reasons that produce prohibitive computational cost: 1) heavy backbone CNN to create high resolution of contextual information and 2) complex modules to aggregate multi-level features. To address these issues, we propose the computationally efficient architecture called “Sketch-and-Fill Network (SFNet)” with a three-stage Coarse-to-Fine Aggregation (CFA) module for semantic segmentation. In the proposed network, lower-resolution contextual information is first produced so that the overall computation in the backbone CNN is largely reduced. Then, to alleviate the detail loss of the lower-resolution contextual information, the CFA module forms global structures and fills fine details in a coarse-to-fine manner. To preserve global structures, the contextual information is passed without any reduction to the CFA module. Experimental results show that the proposed SFNet achieves significantly lower computational loads while delivering comparable or improved segmentation performance with state-of-the-art methods. Qualitative results show that our method is superior to state-of-the-art methods in capturing fine detail while keeping global structures on Cityscapes, ADE20K and RUGD benchmarks.

The North American opioid epidemic has resulted in over 800,000 related premature overdose fatalities since 2000, with the United States leading the world in highest opioid deaths per capita. Despite increased federal funding in recent years, intended to address this crisis, opioid overdose mortality has continued to increase. Legally prescribed opioids also chronically induce a problematic reduction in affect. While an ideal analgesic has yet to be developed, some effective multimodal non-opioid pharmacological regimens for acute pain management are being more widely utilized. Some investigators have suggested that a safer and more scientifically sound approach might be to induce “dopamine homeostasis” through non-pharmacological approaches, since opioid use even for acute pain of short duration is now being strongly questioned. There is also increasing evidence suggesting that some more robust forms of electrotherapy could be applied as an effective adjunct to avoid the problems associated with opioids. This 4-patient case-series presents such an approach to treatment of severe pain. All 4 of these chiropractic treatment cases involved a component of knee osteoarthritis, in addition to other reported areas of pain. Each patient engaged in a home recovery strategy using H-Wave® device stimulation (HWDS) to address residual extremity issues following treatment of spinal subluxation and other standard treatments. A simple statistical analysis was conducted to determine the change in pain scores (Visual Analogue Scale) of pre and post electrotherapy treatments, resulting in significant reductions in self-reported pain (p-value = 0.0002). Three of the four patients continued using the home therapy device long-term as determined by a post-analysis questionnaire. This small case-series demonstrated notably positive outcomes, suggesting consideration of home use of HWDS for safe, non-pharmacological and non-addictive treatment of severe pain.

Previously promising short-term H-Wave® device stimulation (HWDS) outcomes prompted this retrospective cohort study of the longer-term effects on legacy workers’ compensation chronic pain claimants. A detailed chart-review of 157 consecutive claimants undergoing a 30-day HWDS trial (single pain management practice) from February 2018 to November 2019 compiled data on pain, restoration of function, quality of life (QoL), and polypharmacy reduction into a summary spreadsheet for an independent statistical analysis. Non-beneficial trials in 64 (40.8%) ended HWDS use, while 19 (12.1%) trial success charts lacked adequate data for assessing critical outcomes. Of the 74 final treatment study group charts, missing data points were removed for a statistical analysis. Pain chronicity was 7.8 years with 21.6 ± 12.2 months mean follow-up. Mean pain reduction was 35%, with 89% reporting functional improvement. Opioid consumption decreased in 48.8% of users and 41.5% completely stopped; polypharmacy decreased in 36.8% and 24.4% stopped. Zero adverse events were reported and those who still worked usually continued working. An overall positive experience occurred in 66.2% (p < 0.0001), while longer chronicity portended the risk of trial or treatment failure. Positive outcomes in reducing pain, opioid/polypharmacy, and anxiety/depression, while improving function/QoL, occurred in these challenging chronic pain injury claimants. Level of evidence: III

Abstract Background Tooth hypersensitivity and pain are undesirable side effects of bleaching agents in humans. The aim of this study is to implement strategies to counter such side effects, and to demonstrate the efficacy and mechanisms of action of N-acetyl cysteine (NAC) in countering the side effects of clinically used bleaching agents. Methods In a series of in vitro experiments, animal model studies, and human clinical trials, we demonstrate that NAC protects oral mucosa and teeth from damage induced by bleaching agents. Results The addition of NAC along with clinically used bleaching agents to dental pulp stromal/stem cells (DPSCs), stem-cells of apical papillae (SCAP) and oral epithelial cells, inhibited cell death mediated by bleaching agents in several in vitro assays. In addition, rat teeth, when treated with chair-side or over-the-counter bleaching agents, exerted adverse side effects to pulpal and gingival tissues as evidenced by the white lesions of gingivae as well as decreased survival and function of DPSCs. These side effects of bleaching agents were greatly mitigated by the application of NAC to the surfaces of the teeth and to the oral mucosa. NAC protected the surface topography and the appearance of the tissues after bleaching using scanning electron microscopic (SEM) analysis. Finally, application of NAC prior to the bleaching demonstrated significant translational benefit for the patients since it ameliorated pain and hypersensitivity and protected gingivae from bleaching induced white lesions and improved inflammatory index in the oral mucosa in human clinical trials. Conclusions Therefore, application of NAC to the surfaces of the teeth and oral mucosa prior to the use of bleaching materials is beneficial for countering adverse side effects of bleaching in patients and decreases pain, sensitivity, and potential damage to the dentition and oral mucosa associated with bleaching. Trial registration NCT03534115 (NAC Prevents Side-Effects of Teeth Bleaching). Registration 4 December 2014.

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including genome-wide association studies (GWAS). To develop an accurate test to help identify those at risk for at least alcohol use disorder (AUD), a subset of reward deficiency syndrome (RDS), Blum’s group developed the genetic addiction risk severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions, including pain and even bariatric surgery, as a predictor of severe vulnerability to unwanted addictive behaviors, published since 1990 until now. This analysis calculated the Hardy–Weinberg Equilibrium of each polymorphism in cases and controls. Pearson’s χ2 test or Fisher’s exact test was applied to compare the gender, genotype, and allele distribution if available. The statistical analyses found the OR, 95% CI for OR, and the post risk for 8% estimation of the population’s alcoholism prevalence revealed a significant detection. Prior to these results, the United States and European patents on a ten gene panel and eleven risk alleles have been issued. In the face of the new construct of the “preaddiction” model, similar to “prediabetes”, the genetic addiction risk analysis might provide one solution missing in the treatment and prevention of the neurological disorder known as RDS.

Current chronic pain treatments primarily target symptoms and are often associated with harmful side-effects and complications, while safer non-invasive electrotherapies like H-Wave® device stimulation (HWDS) have been less explored. The goal of this study is to evaluate first responder-reported effects of HWDS on job-related and quality-of-life measures. This is a retrospective cohort study where first responders were surveyed following voluntary use of HWDS regarding participant experience, frequency of use, job-related performance, and quality-of-life. Responses were analyzed using means comparison tests, while bivariate analysis assessed responses associated with HWDS usage. Overall, 92.9% of first responder HWDS users (26/28) reported a positive experience (p < 0.0001), with 82.1% citing pain reduction (p = 0.0013), while 78.6% indicated it would be beneficial to have future device access (p = 0.0046). Participants using H-Wave® were at least six times more likely to report higher rates of benefit (100% vs. 0%, p = 0.022), including pain reduction (91.3% vs. 8.7%, p = 0.021) and improved range-of-motion (93.3% vs. 69.2%, p = 0.044). Spending more time with family was associated with better job performance following frequent HWDS use (50% vs. 8.3%, p = 0.032). Repetitive first responder H-Wave® use, with minimal side effects and easy utilization, resulted in significant pain reduction, improvements in job performance and range-of-motion, and increased time spent with family, resulting in overall positive experiences and health benefits. Level of Evidence: III.

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including GWAS. To develop an accurate test to help identify those at risk for at least Alcohol Use Disorder (AUD), Blum’s group developed the Genetic Addiction Risk Severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions published from 1990 until 2021. This analysis calculated the Hardy–Weinberg Equilibrium of each polymorphism in cases and controls. If available, the Pearson’s χ2 test or Fisher’s exact test was applied to comparisons of the gender, genotype, and allele distribution. The statistical analyses found the OR, 95% CI for OR, and a post-risk for 8% estimation of the population’s alcoholism prevalence revealed a significant detection. The OR results showed significance for DRD2, DRD3, DRD4, DAT1, COMT, OPRM1, and 5HTT at 5%. While most of the research related to GARS is derived from our laboratory, we are encouraging more independent research to confirm our findings.

Up to 10% of cytosolic proteins are dependent on the mammalian heat shock protein 90 (HSP90) for folding. However, the interactors of its endoplasmic reticulum (ER) paralogue (gp96, Grp94 and HSP90b1) has not been systematically identified. By combining genetic and biochemical approaches, we have comprehensively mapped the interactome of gp96 in macrophages and B cells. A total of 511 proteins were reduced in gp96 knockdown cells, compared to levels observed in wild type cells. By immunoprecipitation, we found that 201 proteins associated with gp96. Gene Ontology analysis indicated that these proteins are involved in metabolism, transport, translation, protein folding, development, localization, response to stress and cellular component biogenesis. While known gp96 clients such as integrins, Toll-like receptors (TLRs) and Wnt co-receptor LRP6, were confirmed, cell surface HSP receptor CD91, TLR4 pathway protein CD180, WDR1, GANAB and CAPZB were identified as potentially novel substrates of gp96. Taken together, our study establishes gp96 as a critical chaperone to integrate innate immunity, Wnt signaling and organ development.

To our knowledge, this is the largest study evaluating relationships between 3T Magnetic Resonance Imaging (MRI) and P300 and memory/cognitive tests in the literature. The 3T MRI using NeuroQuant has an increased resolution 15 times that of 1.5T MRI. Utilizing NeuroQuant 3T MRI as a diagnostic tool in primary care, subjects (N=169; 19-90 years) displayed increased areas of anatomical atrophy: 34.62% hippocampal atrophy (N=54), 57.14% central atrophy (N=88), and 44.52% temporal atrophy (N=69). A majority of these patients exhibited overlap in measured areas of atrophy and were cognitively impaired. These results positively correlated with decreased P300 values and WMS-III (WMS-III) scores differentially across various brain loci. Delayed latency (p=0.0740) was marginally associated with temporal atrophy; reduced fractional anisotropy (FA) in frontal lobes correlated with aging, delayed P300 latency, and decreased visual and working memory (p=0.0115). Aging and delayed P300 latency correlated with lower FA. The correlation between working memory and reduced FA in frontal lobes is marginally significant (p=0.0787). In the centrum semiovale (CS), reduced FA correlated with visual memory (p=0.0622). Lower demyelination correlated with higher P300 amplitude (p=0.0002). Compared to males, females have higher demyelination (p=0.0064). Along these lines, the higher the P300 amplitude, the lower the bilateral atrophy (p=0.0165). Hippocampal atrophy correlated with increased auditory memory and gender, especially in males (p=0.0087). In considering temporal lobe atrophy correlations: delayed P300 latency and high temporal atrophy (p=0.0740); high auditory memory and low temporal atrophy (p=0.0417); and high working memory and low temporal atrophy (p=0.0166). Central atrophy correlated with aging and immediate memory (p=0.0294): the higher the immediate memory, the lower the central atrophy. Generally, the validation of brain atrophy by P300 and WMS-III could lead to cost-effective methods utilizable in primary care medicine following further confirmation.

This is the first quantitative analysis of data from urine drug tests for compliance to treatment medications and abstinence from drug abuse across "levels of care" in six eastern states of America. Comprehensive Analysis of Reported Drugs (CARD) data was used in this post-hoc retrospective observational study from 10,570 patients, filtered to include a total of 2,919 patients prescribed at least one treatment medication during 2010 and 2011. The first and last urine samples (5,838 specimens) were analyzed; compliance to treatment medications and abstinence from drugs of abuse supported treatment effectiveness for many. Compared to non-compliant patients, compliant patients were marginally less likely to abuse opioids, cannabinoids, and ethanol during treatment although more likely to abuse benzodiazepines. Almost 17% of the non-abstinent patients used benzodiazepines, 15% used opiates, and 10% used cocaine during treatment. Compliance was significantly higher in residential than in the non-residential treatment facilities. Independent of level of care, 67.2% of the patients (n = 1963; P

Various studies have demonstrated that increased leptin levels and obesity are inversely related to cognitive decline in menopausal women. It is hypothesized that adiposity is inversely correlated with cognitive decline, as women with increased weight are less vulnerable to diminishing cognition. However, it is increasingly observed that menopausal women, even with increased adiposity, experience significant cognitive decline. Positron emission tomography (PET) has been used to analyze cognitive function and processing in menopausal women. Evoked potentials (P300) and neurophysiologic tests have validated brain metabolism in cognitively impaired patients. Post-hoc analyses of 796 female patients entering PATH Medical Clinic, between January 4, 2009 and February 24, 2013, were performed as part of the "Menopause Analytical Hormonal Correlate Outcome Study" (MAHCOS). Patient age range was 39-76 years (46.7 ± 0.2). P300 latency and amplitude correlated with a number of hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, estrone, estriol, DHEA, pregnenolone, progesterone, free and total testosterone, thyroid stimulating hormone (TSH), Vitamins D 1.25 and D 25OH, leptin, and insulin-like growth factor-binding protein 3 (IGF-BP3). Corrected statistics did not reveal significant associations with P300 latency or amplitude for these hormones except for leptin plasma levels. However, factor analysis showed that FSH and LH clustered together with Vitamin D1.25 and Vitamin D25OH, P300 latency (not amplitude), and log leptin were found to be associated in the same cluster. Utilizing regression analysis, once age adjusted, leptin was the only significant predictor for latency or speed (p = 0.03) with an effect size of 0.23. Higher plasma leptin levels were associated with abnormal P300 speed (OR = 0.98). Our findings show a significant relationship of higher plasma leptin levels, potentially due to leptin resistance, and prolonged P300 latency. This suggests leptin resistance may delay electrophysiological processing of memory and attention, which appears to be the first of such an association.

Addictions to illicit drugs are among the nation's most critical public health and societal problems. The current opioid prescription epidemic and the need for buprenorphine/naloxone (Suboxone®; SUBX) as an opioid maintenance substance, and its growing street diversion provided impetus to determine affective states ("true ground emotionality") in long-term SUBX patients. Toward the goal of effective monitoring, we utilized emotion-detection in speech as a measure of "true" emotionality in 36 SUBX patients compared to 44 individuals from the general population (GP) and 33 members of Alcoholics Anonymous (AA). Other less objective studies have investigated emotional reactivity of heroin, methadone and opioid abstinent patients. These studies indicate that current opioid users have abnormal emotional experience, characterized by heightened response to unpleasant stimuli and blunted response to pleasant stimuli. However, this is the first study to our knowledge to evaluate "true ground" emotionality in long-term buprenorphine/naloxone combination (Suboxone™). We found in long-term SUBX patients a significantly flat affect (p

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