H-Wave® Device Stimulation for Chronic Neck Pain: A Patient-Reported Outcome Measures (PROMs) Study.

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.

Comparison of transvaginal ultrasound utilization between radiology and point of care ultrasound in first trimester pregnancy.

BACKGROUND: Transvaginal (TVUS) and transabdominal ultrasound (TAUS) are both utilized in the evaluation of early pregnancy patients. While many practitioners using point of care ultrasound (POCUS) will generally not pursue TVUS in cases where an intrauterine pregnancy (IUP) is visualized on TAUS, this may not be true in Radiology performed ultrasound. OBJECTIVES: To evaluate for differences in transvaginal ultrasound (TVUS) utilization between Radiology performed (RP) ultrasound and point of care ultrasound (POCUS) by Emergency Department (ED) physicians in early pregnancy patients. Secondarily, to assess length of stay (LOS) differences and the impact of specialized emergency ultrasound training on TVUS utilization. METHODS: This was a retrospective study at a single academic ED. Study population was all ED patients who underwent first trimester ultrasound during the one year period of March 1, 2021 to February 28, 2022. Variables evaluated were chief complaint, gestational age, LOS, TAUS and TVUS utilization, ultrasound findings, and ultrasound specialty training of the ED physician. RESULTS: There were 133 cases of POCUS ultrasound and 254 cases of RP ultrasound. All cases had TAUS imaging performed. Median LOS for patients when POCUS was utilized was 207 min (IQR 151-294) and 258 min (IQR 208-328) for those only using RP ultrasound, p ≤ 0.001. In the POCUS cohort, 38% (95% CI 30%-46%) received TVUS, while 94% received TVUS in the RP cohort (95% CI 90%-96%), p ≤ 0.001. Patients seen by ED faculty with ultrasound specialty training had TVUS 53% of the time (95% CI 41%-65%), while those seen by other ED faculty had TVUS 79% (95% CI 74%-83%) of the time, p = 0.035. CONCLUSION: POCUS in early pregnancy is associated with a significant reduction in TVUS usage. We suspect that POCUS users elect not to pursue TVUS after an IUP is identified on TAUS, while technicians perform protocol-based TVUS irrespective of TAUS findings. Patients seen by ultrasound trained ED physicians are less likely to receive TVUS.

Resident Remediation: A National Survey of Urology Program Directors.

OBJECTIVES: To describe formal remediation rates and processes in urology training programs nationally. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study by surveying program directors (PDs) through the Society of Academic Urologists. Formal remediation was defined as the process initiated when resident competency deficiencies were significant enough to necessitate documentation and notification of the Graduate Medical Education (GME) office. The primary outcome was the prevalence of urology programs that initiated formal remediation over the past 5 years. Secondary outcomes included reported competency deficiencies and formal remediation processes. RESULTS: Across 148 institutions, 73 (49%) PDs responded to the survey. The majority of PDs (67%, 49/73) stated that at least 1 resident underwent formal remediation over the last 5 years (median 1). "Professionalism" and "Interpersonal and Communication Skills" were the most common competency deficiencies that prompted formal remediation, whereas "Technical Skill" was the least common. While the majority of respondents notified the GME office of residents undergoing remediation, formal remediation plans varied from faculty coaching and mentorship (80%, 39/49) to simulation training (10%, 5/49). Absence of documented faculty feedback on poor performance was the most commonly cited barrier to formal remediation. The majority of PDs reported documentation in a resident's file (81%, 59/73); however, remediation processes differed with only half of PDs reporting that GME offices were routinely involved in creating and overseeing corrective action plans (56%, 41/73). Over the study period, 15% (11/73) of PDs did not promote a resident to the next year of training, and 23% (17/73) of PDs stated "Yes" to graduating a resident who they would not trust to care for a loved one. CONCLUSIONS: Formal remediation among urology residency programs is common, and processes vary across institutions. The most common competency areas prompting remediation were "Professionalism" and "Interpersonal and Communication Skills." Future research should address developing resources to facilitate resident remediation.

H-Wave® Device Stimulation for Chronic Low Back Pain: A Patient-Reported Outcome Measures (PROMs) Study.

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.

A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response.

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

Astrocytic TIMP-1 regulates production of Anastellin, an inhibitor of oligodendrocyte differentiation and FTY720 responses.

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of Timp1 do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global Timp1 knockout (Timp1KO) mice do not efficiently remyelinate following a demyelinating injury. Here, we performed an unbiased proteomic analysis and identified a fibronectin-derived peptide called Anastellin (Ana) that was unique to the Timp1KO astrocyte secretome. Ana was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Ana is known to act upon the sphingosine-1-phosphate receptor 1, and we determined that Ana also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation in vitro. Administration of FTY720 to wild-type C57BL/6 mice during MOG35-55-experimental autoimmune encephalomyelitis ameliorated clinical disability while FTY720 administered to mice lacking expression of Timp1 (Timp1KO) had no effect. Analysis of Timp1 and fibronectin (FN1) transcripts from primary human astrocytes from healthy and multiple sclerosis (MS) donors revealed lower TIMP1 expression was coincident with elevated FN1 in MS astrocytes. Last, analyses of proteomic databases of MS samples identified Ana peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high disease activity. A role for Ana in MS as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and innate remyelination potential in the MS brain.

Comparative Analyses and Ablation Efficiency of Thulium Fiber Laser by Stone Composition.

PURPOSE: There are limited data on ablation effects of thulium fiber laser (TFL) settings with varying stone composition. Similarly, little is known surrounding the photothermal effects of TFL lithotripsy regarding the chemical and structural changes after visible char formation. We aim to understand the TFL's ablative efficiency across various stone types and laser settings, while simultaneously investigating the photothermal effects of TFL lithotripsy. MATERIALS AND METHODS: Human specimens of calcium oxalate monohydrate, calcium oxalate dihydrate, uric acid, struvite, cystine, carbonate apatite, and brushite stones were ablated using 13 prespecified settings with the Coloplast TFL Drive. Pre- and postablation mass, ablation time, and total energy were recorded. Qualitative ablative observations were recorded at 1-minute intervals with photographs and gross description. Samples were analyzed with Fourier-transform infrared spectroscopy pre- and postablation and electron microscopy postablation to assess the photothermal effects of TFL. RESULTS: Across all settings and stone types, 0.05 J × 1000 Hz was the best numerically efficient ablation setting. When selected for more clinically relevant laser settings (ie, 10-20 W), 0.2 J × 100 Hz, short pulse was the most numerically efficient setting for calcium oxalate dihydrate, cystine, and struvite stones. Calcium oxalate monohydrate ablated with the best numerical efficiency at 0.4 J × 40 Hz, short pulse. Uric acid and carbonate apatite stones ablated with the best numerical efficiency at 0.3 J × 60 Hz, short pulse. Brushite stones ablated with the best numerical efficiency at 0.5 J × 30 Hz, short pulse. Pulse duration impacted ablation effectiveness greatly with 6/8 (75%) of inadequate ablations occurring in medium or long pulse settings. The average percent of mass lost during ablation was 57%; cystine stones averaged the highest percent mass lost at 71%. Charring was observed in 36/91 (40%) specimens. Charring was most often seen in uric acid, cystine, and brushite stones across all laser settings. Electron microscopy of char demonstrated a porous melting effect different to that of brittle fracture. Fourier-transform infrared spectroscopy of brushite char demonstrated a chemical composition change to amorphous calcium phosphate. CONCLUSIONS: We describe the optimal ablation settings based on stone composition, which may guide urologists towards more stone-specific care when using thulium laser for treating renal stones (lower energy settings would be safer for ureteral stones). For patients with unknown stone composition, lasers can be preset to target common stone types or adjusted based on visual cues. We recommend using short pulse for all TFL lithotripsy of calculi and altering the settings based on visual cues and efficiency to minimize the charring, an effect which can make the stone refractory to further dusting and fragmentation.

Cross-Referencing Self-Training Network for Sound Event Detection in Audio Mixtures.

Sound event detection is an important facet of audio tagging that aims to identify sounds of interest and define both the sound category and time boundaries for each sound event in a continuous recording. With advances in deep neural networks, there has been tremendous improvement in the performance of sound event detection systems, although at the expense of costly data collection and labeling efforts. In fact, current state-of-the-art methods employ supervised training methods that leverage large amounts of data samples and corresponding labels in order to facilitate identification of sound category and time stamps of events. As an alternative, the current study proposes a semi-supervised method for generating pseudo-labels from unsupervised data using a student-teacher scheme that balances self-training and cross-training. Additionally, this paper explores post-processing which extracts sound intervals from network prediction, for further improvement in sound event detection performance. The proposed approach is evaluated on sound event detection task for the DCASE2020 challenge. The results of these methods on both "validation" and "public evaluation" sets of DESED database show significant improvement compared to the state-of-the art systems in semi-supervised learning.

Antimicrobial Prophylaxis for Percutaneous Nephrolithotomy: Contemporary Practice Patterns.

Background: Updated in 2019, the American Urological Association's (AUA) Best Practice Statement on Urologic Procedures and Antimicrobial Prophylaxis outlines prophylaxis for percutaneous nephrolithotomy (PCNL). Recent studies have challenged these recommendations. We hypothesized that endourologists do not routinely follow the AUA's statement on antibiotic use during PCNL and assessed their prescribing patterns. Methods: A 24-question survey was distributed to members of the Endourological Society. The primary outcome was adherence to the AUA's recommendations. Two multiple logistic regression analyses were performed with demographics and antibiotic preference as predictors of following the AUA. Results: A total of 51.4% of endourologists follow the AUA Best Practice Statement for antimicrobial prophylaxis of uncomplicated PCNL. No demographic data were predictive of following the AUA. 90.9% and 83.6% reported they have "never" used the first-line recommendation options of metronidazole and aztreonam, respectively. Preferred antibiotics were cephalosporins (uncomplicated 60%, complicated 52.6%), fluoroquinolones (13.3%, 7.2%), aminoglycosides (12.7%, 17.8%), penicillins (7.9%, 11.2%), carbapenems (0.6%, 0.7%), trimethoprim-sulfamethoxazole (2.4%, 5.9%), fosfomycin (0.6%, 0.7%), nitrofurantoin (2.4%, 2.6%), aztreonam (0%, 0.7%), and clindamycin (0%, 0.7%). For uncomplicated PCNL, 63.1% prescribe ≤24 hours of perioperative antibiotics. For complicated PCNL, 16.2% prescribe ≤24 hours of perioperative antibiotics, while 20.4% begin antibiotics 7 or more days prior. Conclusions: Nearly half of respondents do not follow the AUA's recommendations for antibiotic choice for PCNL. Few endourologists prescribe 7 days of preoperative antibiotics for complicated PCNL despite supporting data. Metronidazole and aztreonam are rarely used as a first-line antibiotic choice for PCNL and their roles needs to be further evaluated as first-line prophylaxis recommendations. Updates on antibiotic recommendations for PCNL are needed based on current literature, antimicrobial stewardship, and contemporary practice patterns.

Evaluation of a stabilized RSV pre-fusion F mRNA vaccine: Preclinical studies and Phase 1 clinical testing in healthy adults.

Human respiratory syncytial virus (RSV) causes a substantial proportion of respiratory tract infections worldwide. Although RSV reinfections occur throughout life, older adults, particularly those with underlying comorbidities, are at risk for severe complications from RSV. There is no RSV vaccine available to date, and treatment of RSV in adults is largely supportive. A correlate of protection for RSV has not yet been established, but antibodies targeting the pre-fusion conformation of the RSV F glycoprotein play an important role in RSV neutralization. We previously reported a Phase 1 study of an mRNA-based vaccine (V171) expressing a pre-fusion-stabilized RSV F protein (mDS-Cav1) in healthy adults. Here, we evaluated an mRNA-based vaccine (V172) expressing a further stabilized RSV pre-fusion F protein (mVRC1). mVRC1 is a single chain version of RSV F with interprotomer disulfides in addition to the stabilizing mutations present in the mDS-Cav1 antigen. The immunogenicity of the two mRNA-based vaccines encoding mVRC1 (V172) or a sequence-optimized version of mDS-Cav1 to improve transcriptional fidelity (V171.2) were compared in RSV-naïve and RSV-experienced African green monkeys (AGMs). V172 induced higher neutralizing antibody titers than V171.2 and demonstrated protection in the AGM challenge model. We conducted a Phase 1, randomized, placebo-controlled, clinical trial of 25 µg, 100 µg, 200 µg, or 300 µg of V172 in healthy older adults (60-79 years old; N = 112) and 100 µg, 200 µg, or 300 µg of V172 in healthy younger adults (18-49 years old; N = 48). The primary clinical objectives were to evaluate the safety and tolerability of V172, and the secondary objective was to evaluate RSV serum neutralization titers. The most commonly reported solicited adverse events were injection-site pain, injection-site swelling, headache, and tiredness. V172 was generally well tolerated in older and younger adults and increased serum neutralizing antibody titers, pre-fusion F-specific competing antibody titers, and RSV F-specific T-cell responses.

The State of Urotrauma Education Among Residency Programs in the United States: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Management of urotrauma is a crucial part of a urologist's knowledge and training. We therefore sought to understand the state of urotrauma education in the United States. RECENT FINDINGS: Using themes of "Urotrauma" and "Education," we performed a systematic review and meta-analysis by searching for studies in MEDLINE, all Cochrane libraries, EMBASE, BIOSIS, Scopus, and Web of Science through May 2023. The primary outcome was the pooled rate of urology trainee and program director attitudes toward urotrauma education. Secondary outcomes involved a descriptive summary of existing urotrauma curricula and an assessment of factors affecting urotrauma exposure. Of 12,230 unique records, 11 studies met the final eligibility criteria, and we included 2 in the meta-analysis. The majority of trainees and program directors reported having level 1 trauma center rotations (range 88-89%) and considered urotrauma exposure as an important aspect of residency education (83%, 95% CI 76-88%). Despite possible increases in trainee exposure to Society of Genitourinary Reconstructive Surgeons (GURS) faculty over the preceding decade, nearly a third of trainees and program directors currently felt there remained inadequate exposure to urotrauma during training (32%, 95% CI 19-46%). Factors affecting urotrauma education include the limited exposure to GURS-trained faculty and clinical factors such as case infrequency and non-operative trauma management. Urology resident exposure to urotrauma is inadequate in many training programs, underscoring the potential value of developing a standardized curriculum to improve urotrauma education for trainees. Further investigation is needed to characterize this issue and to understand how it impacts trainee practice readiness.

Focused Ultrasonography in Cardiac Arrest.

Rapid diagnostic tools available to the emergency physician caring for cardiac arrest patients are limited. Focused ultrasound (US), and in particular, focused echocardiography, is a useful tool in the evaluation of patients in cardiac arrest. It can help identify possible causes of cardiac arrest like tamponade and pulmonary embolism, which can guide therapy. US can also yield prognostic information, with lack of cardiac activity being highly specific for failure to achieve return of spontaneous circulation. US may also be used to aid in procedural guidance. Recently, focused transesophageal echocardiography has been used in the emergency department setting.

POINT-OF-CARE ULTRASOUND FOR GUIDANCE OF CLOSED REDUCTION OF FIFTH METACARPAL NECK (BOXER'S) FRACTURE.

BACKGROUND: Ultrasound has been used previously in fracture identification, analgesia delivery, and fracture reduction for patients in the emergency department. It has not been previously described as a tool for the guidance of closed fracture reduction in fifth metacarpal neck fractures ("boxer's fractures"). CASE REPORT: A 28-year-old man presented with hand pain and swelling after punching a wall. Point-of-care ultrasound revealed a significantly angulated fifth metacarpal fracture, which was confirmed with a subsequent hand x-ray study. After an ultrasound-guided ulnar nerve block, closed reduction was performed. Ultrasound was used to assess reduction and ensure improvement in bony angulation during the closed reduction attempts. Post-reduction x-ray study confirmed improved angulation and adequate alignment. Why Should an Emergency Physician Be Aware of This? Point-of-care ultrasound has previously had efficacy in fracture diagnosis and anesthesia delivery for fifth metacarpal fractures. Ultrasound can also be used at the bedside to assist in the determination of adequate fracture reduction when performing closed reduction of a boxer's fracture.

Micronutrient inadequacy and urinary stone disease: an analysis of the National Health and Nutrition Examination Survey 2007-2018.

Urinary stone disease is common and affects approximately 10% of the American adults. The role of diet in stone formation is well-recognized; however, the literature focus has been on dietary excess rather than micronutrient inadequacy. As patients with stones may be at risk for nutrient inadequacies, we investigated the role of micronutrient inadequacy in stone formation by performing a cross-sectional analysis of the National Health and Nutrition Examination Survey on adults who were not taking dietary supplements. Micronutrient intake was obtained from 24-h dietary recalls, and usual intake was calculated. Survey-weighted, adjusted logistic regression was used for an incident analysis on having any history of stones. An additional analysis on recurrent stone-formers was performed with the outcome being 2 or more stones passed. Finally, a sensitivity analysis using quasi-Poisson regression was performed with the outcome being number of stones passed. There were 9777 respondents representing 81,087,345 adults, of which 9.36% had a stone history. Our incident analysis revealed inadequate vitamin A intake to be associated with stone formation (OR 1.33, 95% CI: 1.03-1.71). Recurrent analysis did not find any significant associations, while our sensitivity analysis revealed inadequate vitamin A (IRR 1.96, 95% CI: 1.28-3.00) and pyridoxine (IRR 1.99, 95% CI: 1.11-3.55) to be associated with a higher number of recurrent stones. Hence, inadequate dietary intake of vitamin A and pyridoxine was associated with nephrolithiasis. Further research is needed to identify the roles of these micronutrients in stone-formers and the potential for evaluation and treatment.

Single- and Multiple-dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP1128, a Novel Peroxisome Proliferator-activated Receptor δ Modulator, in Healthy Participants.

Peroxisome proliferator-activated receptor δ (PPARδ) plays a central role in modulating mitochondrial function in ischemia-reperfusion injury. ASP1128, a potent and selective modulator of PPARδ, is currently under investigation for treating acute kidney injury. This randomized, first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP1128 administered intravenously in healthy participants. Forty-nine participants received a single dose of ASP1128 0.3-10 mg (n = 37) or placebo (n = 12) and 53 received daily (7 days) doses of ASP1128 3-100 mg (n = 39) or placebo (n = 14), including a cohort aged ≥65 years (ASP1128 100 mg, n = 3; placebo, n = 2). Treatment-emergent adverse events occurred in 37.8%, 59.0%, and 33.3%-35.7% of participants in the single ASP1128, multiple ASP1128, and placebo groups, respectively. All were mild in severity, and the frequency of adverse events did not appear to be dose-related. One participant (multiple ASP1128 3 mg group) withdrew with an infusion site erythema, possibly related to study drug. Exposure was roughly dose-proportional, and elimination was generally consistent across doses (mean t½ 14.6-17.4 hours in the 10, 30, and 100 mg groups on day 7). There was little accumulation in plasma following multiple dosing; steady state was reached after ∼4 days. ASP1128 treatment led to rapid and dose-related upregulation of six fatty acid oxidation-related PPARδ target genes at ≥10 mg, which lasted >24 hours postdose. In conclusion, single and multiple intravenous doses of ASP1128 were generally well tolerated, with dose-dependent pharmacokinetics and target gene engagement in healthy participants.

Positive Clinical Outcomes for Severe Reported Pain Using Robust Non-Addictive Home Electrotherapy-A Case-Series.

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.

Clinical and Quality of Life Benefits for End-Stage Workers' Compensation Chronic Pain Claimants following H-Wave® Device Stimulation: A Retrospective Observational Study with Mean 2-Year Follow-Up.

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.

Astrocytic TIMP-1 regulates production of Anastellin, a novel inhibitor of oligodendrocyte differentiation and FTY720 responses.

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. We have previously demonstrated that murine astrocytes that lack expression of Timp1 do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global Timp1 knockout ( Timp1 KO ) mice do not efficiently remyelinate following a demyelinating injury. To better understand the basis of this, we performed unbiased proteomic analyses and identified a fibronectin-derived peptide called anastellin that is unique to the murine Timp1 KO astrocyte secretome. Anastellin was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Anastellin is known to act upon the sphingosine-1-phosphate receptor 1 (S1PR1), and we determined that anastellin also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation in vitro . Further, administration of FTY720 to wild-type C57BL/6 mice during MOG 35-55 -EAE ameliorated clinical disability while FTY720 administered to mice lacking expression of Timp1 in astrocytes ( Timp1 cKO ) had no effect. Analysis of human TIMP1 and fibronectin ( FN1 ) transcripts from healthy and multiple sclerosis (MS) patient brain samples revealed an inverse relationship where lower TIMP1 expression was coincident with elevated FN1 in MS astrocytes. Lastly, we analyzed proteomic databases of MS samples and identified anastellin peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high versus low disease activity. The prospective role for anastellin generation in association with myelin lesions as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and the innate remyelination potential of the the MS brain. Significance Statement: Astrocytic production of TIMP-1 prevents the protein catabolism of fibronectin. In the absence of TIMP-1, fibronectin is further digested leading to a higher abundance of anastellin peptides that can bind to sphingosine-1-phosphate receptor 1. The binding of anastellin with the sphingosine-1-phosphate receptor 1 impairs the differentiation of oligodendrocytes progenitor cells into myelinating oligodendrocytes in vitro , and negates the astrocyte-mediated therapeutic effects of FTY720 in the EAE model of chronic CNS inflammation. These data indicate that TIMP-1 production by astrocytes is important in coordinating astrocytic functions during inflammation. In the absence of astrocyte produced TIMP-1, elevated expression of anastellin may represent a prospective biomarker for FTY720 therapeutic responsiveness.

Automation of Macular Degeneration Classification in the AREDS Dataset, Using a Novel Neural Network Design.

Purpose: To create an ensemble of Convolutional Neural Networks (CNNs), capable of detecting and stratifying the risk of progressive age-related macular degeneration (AMD) from retinal photographs. Design: Retrospective cohort study. Methods: Three individual CNNs are trained to accurately detect 1) advanced AMD, 2) drusen size and 3) the presence or otherwise of pigmentary abnormalities, from macular centered retinal images were developed. The CNNs were then arranged in a "cascading" architecture to calculate the Age-related Eye Disease Study (AREDS) Simplified 5-level risk Severity score (Risk Score 0 - Risk Score 4), for test images. The process was repeated creating a simplified binary "low risk" (Scores 0-2) and "high risk" (Risk Score 3-4) classification. Participants: There were a total of 188,006 images, of which 118,254 images were deemed gradable, representing 4591 patients, from the AREDS1 dataset. The gradable images were split into 50%/25%/25% ratios for training, validation and test purposes. Main Outcome Measures: The ability of the ensemble of CNNs using retinal images to predict an individual's risk of experiencing progression of their AMD based on the AREDS 5-step Simplified Severity Scale. Results: When assessed against the 5-step Simplified Severity Scale, the results generated by the ensemble of CNN's achieved an accuracy of 80.43% (quadratic kappa 0.870). When assessed against a simplified binary (Low Risk/High Risk) classification, an accuracy of 98.08%, sensitivity of ≥85% and specificity of ≥99% was achieved. Conclusion: We have created an ensemble of neural networks, trained on the AREDS 1 dataset, that is able to accurately calculate an individual's score on the AREDS 5-step Simplified Severity Scale for AMD. If the results presented were replicated, then this ensemble of CNNs could be used as a screening tool that has the potential to significantly improve health outcomes by identifying asymptomatic individuals who would benefit from AREDS2 macular supplements.