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Steven M Falowski,1,* Louis J Raso,2 Vipul Mangal,3 Ali Nairizi,4 Denis G Patterson,5 Michael D Danko,6 Rafael Justiz,7 Rainer S Vogel,8 Sebastian Koga,9 Yousseff Josephson,10 Jason E Pope,11,* Oluwatodimu Richard Raji12 1Argires-Marotti Neurosurgical Associates of Lancaster, Lancaster, PA, USA; 2Jupiter Medical Center, Jupiter, FL, USA; 3National Spine and Pain Centers, Oxon Hill, MD, USA; 4Reno Tahoe Pain Associates, Reno, NV, USA; 5Nevada Pain Specialists, Reno, NV, USA; 6Premier Pain Treatment Institute, Loveland, OH, USA; 7Oklahoma Pain Physicians, Oklahoma City, OK, USA; 8Comprehensive and Interventional Pain Management, Henderson, NV, USA; 9Koga Neurosurgery, Covington, LA, USA; 10National Spine and Pain Centers, Voorhees, NJ, USA; 11Evolve Restorative Center, Santa Rosa, CA, USA; 12Medical Device Development, San Francisco, CA, USA*These authors contributed equally to this workCorrespondence: Oluwatodimu Richard Raji, Medical Device Development, 2390 Mission Street, Suite 8, San Francisco, CA, 94110, USA, Tel +15105707741, Email richardraji@mdevdev.comPurpose: Lumbar interlaminar decompression with interspinous fixation is an established safe and effective treatment for spinal stenosis. Early maintenance of improvements in pain intensity and function are critical for durability of symptom relief. The purpose of this study was to investigate the efficacy of minimally invasive treatments for low back pain during the early period after treatment and their utility in setting the course for longer term success.Patients and Methods: This study utilized patient evaluations at 3- and 6-months following treatment and is part of an actively enrolling, institutional review board (IRB) approved, single-arm, multicenter, prospective, open-label 12-month study. Clinical efficacy was assessed primarily using the change from baseline in Oswestry Disability Index (ODI), Visual Analog Scale (VAS) of the back and leg pain during walking and standing, and Zurich Claudication Questionnaire (ZCQ), and secondarily using the Patient Global Impression of Change (PGIC) and Patient-Reported Outcomes Measurement Information System (PROMIS) 29 v2.1. The safety endpoints were the adverse events and reoperations or revisions at the index level(s).Results: At 6-month post-op, 76%, 62%– 64%, and 64% of patients demonstrated clinical meaningful, and statistically significant improvement in their pain as defined by ZCQ, VAS (back and leg), and ODI, respectively. In addition, 78% of patients noted improvement in PGIC. Two procedure-related adverse events were noted which fully resolved without surgical intervention.Conclusion: This 6-month interim analysis at 42% enrollment of patients was conducted to determine prolonged safety and efficacy of the interspinous fusion device. Our analysis showed a sustained improvement in clinical efficacy, and safety endpoints, when compared to the 3-months evaluations, across both interventional pain and neurosurgery specialties.Keywords: interspinous fixation, degenerative disc disease, neurogenic claudication, spinal stenosis

BACKGROUND: Environmental toxicants are allegedly involved in decreasing semen quality in recent decades; however, definitive proof is not yet available. In 1976 an accident exposed residents in Seveso, Italy, to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). OBJECTIVE: The purpose of this study was to investigate reproductive hormones and sperm quality in exposed males. METHODS: We studied 135 males exposed to TCDD at three age groups, infancy/prepuberty (1-9 years), puberty (10-17 years), and adulthood (18-26 years), and 184 healthy male comparisons using 1976 serum TCDD levels and semen quality and reproductive hormones from samples collected 22 years later. RESULTS: Relative to comparisons, 71 men (mean age at exposure, 6.2 years; median serum TCDD, 210 ppt) at 22-31 years of age showed reductions in sperm concentration (53.6 vs. 72.5 million/mL; p = 0.025); percent progressive motility (33.2% vs. 40.8%; p < 0.001); total motile sperm count (44.2 vs. 77.5 x 10(6); p = 0.018); estradiol (76.2 vs. 95.9 pmol/L; p = 0.001); and an increase in follicle-stimulating hormone (FSH; 3.58 vs. 2.98 IU/L; p = 0.055). Forty-four men (mean age at exposure, 13.2 years; median serum TCDD, 164 ppt) at 32-39 years of age showed increased total sperm count (272 vs. 191.9 x 10(6); p = 0.042), total motile sperm count (105 vs. 64.9 x10(6); p = 0.036), FSH (4.1 vs. 3.2 UI/L; p = 0.038), and reduced estradiol (74.4 vs. 92.9 pmol/L; p < 0.001). No effects were observed in 20 men, 40-47 years of age, who were exposed to TCDD (median, 123 ppt) as adults (mean age at exposure, 21.5 years). CONCLUSIONS: Exposure to TCDD in infancy reduces sperm concentration and motility, and an opposite effect is seen with exposure during puberty. Exposure in either period leads to permanent reduction of estradiol and increased FSH. These effects are permanent and occur at TCDD concentrations < 68 ppt, which is within one order of magnitude of those in the industrialized world in the 1970s and 1980s and may be responsible at least in part for the reported decrease in sperm quality, especially in younger men. [ABSTRACT FROM AUTHOR]

Objective: Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents. Design: We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass. Participants: Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976. Results: TCDD half-life in persons < 18 years of age averaged 1.6 years while those >/=18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response. Conclusions: Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens.RelevanceModeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400-700 ppt. [ABSTRACT FROM AUTHOR]

Background: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin), is commonly considered the most toxic man-made substance. We have previously shown that high serum concentrations of TCDD in parents from Seveso, Italy, were linked to their having a relative increase in the number of female births after the parents exposure to a release of dioxin in 1976. We have continued the study to determine whether the parents' sex and/or age at exposure affected the sex ratio of their children. Methods: We measured the TCDD concentrations in serum samples from potentially exposed parents collected in 1976 and 1977, and investigated the sex ratio of their offspring. Findings: Serum samples were collected from 239 men and 296 women. 346 girls and 328 boys were born to potentially exposed parents between 1977 and 1996, showing an increased probability of female births (lower sex ratio) with increasing TCDD concentrations in the serum samples from the fathers (p=0.008). This effect starts at concentrations less than 20 ng per kg bodyweight. Fathers exposed when they were younger than 19 years of age sired significantly more girls than boys (sex ratio 0.38 [95% CI 0.30-0.47]). Interpretation: Exposure of men to TCDD is linked to a lowered male/female sex ratio in their offspring, which may persist for years after exposure. The median concentration of dioxin in fathers in this study is similar to doses that induce epididymal impairments in rats and is about 20 times the estimated average concentration of TCDD currently found in human beings in industrialised countries. These observations could have important public-health implications. [ABSTRACT FROM AUTHOR]

CD8+ T cells differentiate into two subpopulations in response to acute viral infection: memory precursor effector cells (MPECs) and short-lived effector cells (SLECs). MPECs and SLECs are epigenetically distinct; however, the epigenetic regulators required for formation of these subpopulations are mostly unknown. In this study, we performed an in vivo CRISPR screen in murine naive CD8+ T cells to identify the epigenetic regulators required for MPEC and SLEC formation, using the acute lymphocytic choriomeningitis virus Armstrong infection model. We identified the ATP-dependent chromatin remodeler CHD7 (chromodomain-helicase DNA-binding protein 7) as a positive regulator of SLEC formation, as knockout (KO) of Chd7 reduced SLECs numerically. In contrast, KO of Chd7 increased the formation of central memory T cells following pathogen clearance yet attenuated memory cell expansion following a rechallenge. These findings establish CHD7 as a novel positive regulator of SLEC and a negative regulator of central memory T cell formation., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background: The SENZA-PDN study evaluated high-frequency 10-kHz spinal cord stimulation (SCS) for the treatment of painful diabetic neuropathy (PDN). Over 24 months, 10-kHz SCS provided sustained pain relief and improved health-related quality of life. This report presents additional outcomes from the SENZA-PDN study, focusing on diabetes-related pain and quality of life outcomes., Methods: The SENZA-PDN study randomized 216 participants with refractory PDN to receive either conventional medical management (CMM) or 10-kHz SCS plus CMM (10-kHz SCS + CMM), allowing crossover after six months if pain relief was insufficient. Postimplantation assessments at 24 months were completed by 142 participants with a permanent 10-kHz SCS implant, comprising 84 initial and 58 crossover recipients. Measures included the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN), Diabetes-Related Quality of Life (DQOL), Global Assessment of Functioning (GAF), and treatment satisfaction., Results: Over 24 months, 10-kHz SCS treatment significantly reduced pain severity by 66.9% ( P < .001; BPI-DPN) and pain interference with mood and daily activities by 65.8% ( P < .001; BPI-DPN). Significant improvements were also observed in overall DQOL score ( P < .001) and GAF score ( P < .001), and 91.5% of participants reported satisfaction with treatment., Conclusions: High-frequency 10-kHz SCS significantly decreased pain severity and provided additional clinically meaningful improvements in DQOL and overall functioning for patients with PDN. The robust and sustained benefits over 24 months, coupled with high participant satisfaction, highlight that 10-kHz SCS is an efficacious and comprehensive therapy for patients with PDN., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EAP has received consulting fees from Abbott Laboratories, Biotronik, Boston Scientific, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, Presidio Medical, Saluda, and Vertos Medical; research support from Mainstay, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, ReNeuron, Saluda, and SPR; and stock options from neuro42 and SynerFuse. TGS has received research support from Nevro Corp. JAS has received research support from Boston Scientific, Nevro Corp, Saluda Medical, and Vertiflex. MJJ is an employee of Nevro Corp. DRE received a fee from Nevro Corp for the preparation of this manuscript in her capacity as an independent medical writer. JLW has received consulting fees from California Institute for Biomedical Research and Eli Lilly and research support from Nevro Corp. SMS has received research support from Nevro Corp. KA has received consulting fees from Biotronik, Medtronic, Nalu Medical, Nevro Corp, and Saluda Medical, as well as research support from Biotronik, IPM Medical Group, Nevro Corp, Saluda Medical, SPR Therapeutics, and Vivex Biologics. MNG has received consulting fees from Abbott Laboratories, Avanos Medical, Avertis Pharmacy, Boston Scientific, Nevro Corp, and Saluda Medical, as well as research support from Abbott Laboratories, Avanos Medical, Boston Scientific, Nalu Medical, Neuros Medical, Nevro Corp, and Saluda Medical. JX has received research support from the Cleveland Clinic Velosano Program, the National Institutes of Health, the Steve and Melody Golding Foundation, and Nevro Corp. CY has received research support from Nevro Corp. AN has received consulting fees from Aurora Spine, Flowonix, and Nevro Corp, as well as research support from Nevro Corp. DGP has received consulting fees from Abbott Laboratories, AIS Healthcare, Allergan, Amgen, Aurora Spine, CornerLoc, Flowonix, Lundbeck, Pajunk Medical, Saluda Medical, Spark Biomedical, and Vertos Medical; research support from Abbott Laboratories, Aurora Spine, Flowonix, Nevro Corp, and Saluda Medical; speakers’ bureau or honoraria from Abbott Laboratories, Allergan, Amgen, CornerLoc, Lundbeck, Saluda Medical, and Vertos Medical; and stock options from CornerLoc. MJC has received research support from Nevro Corp. VG has received research support from Biotronik, Medtronic, Nevro Corp, PainTEQ, SPR Therapeutics, and St. Jude. RHB has received research support from Nevro Corp. NDM has received consulting fees from Averitas, Nevro Corp, and Salix Pharmaceuticals, as well as research support from Boston Scientific and Nevro Corp. DS has received consulting fees from Abbott Laboratories, Boston Scientific, Flowonix, Medtronic, Nevro Corp, Vertiflex, and Vertos Medical, as well as research support from Abbott Laboratories, Biotronik, Nevro Corp, Vertiflex, and Vertos Medical. SPL has received consulting fees from Nevro Corp and research support from Nevro Corp. DJD has received research support from Nevro Corp, as well as funding for serving as principal investigator of a study supported by SPR Therapeutics paid to his institution. KAS has received research support from Nevro Corp. JHG has received consulting fees from Abbott Laboratories, Saluda Medical, and Stratus Medical. PWW has received research support from Nevro Corp. CEA has received consulting fees from AbbVie, Amgen, Biohaven, Clexio Biosciences, Collegium, Eli Lilly, Elsevier, Flowonix, Gene Pharma, Lundbeck, Nevro Corp, Novartis, Pfizer, SK Life Science, Teva Pharmaceutical, and Vertex, as well as research support from AbbVie, Allergan, Amgen, Daiichi Sankyo, Eli Lilly, Novartis, Teva Pharmaceutical, and Vertex Pharmaceuticals. CEN has received consulting fees from Exelixis, Neurogastrx, and Nevro Corp, as well as research support from Nevro Corp. RST has received consulting fees from Nevro Corp, Medtronic, and Saluda Medical. DLC is an employee of Nevro Corp. NAM has received consulting fees from Nevro Corp, Relievant Medsystems, Saluda Medical, Sollis Therapeutics, and Vertos Medical, as well as research support from Avanos Medical, Mesoblast, Neuros Medical, and Nevro Corp.

PD-1 is a key negative regulator of CD8 + T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8 + T cells in chronic infection, creating a 'sweet spot' of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8 + T cell dysfunction while avoiding excess immunopathology., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: Mental health disorders are increasing among health profession students. Compounding this, students from underrepresented backgrounds may face additional stressors and challenges. The aims of this study were to: (1) assess the extent to which burnout, exhaustion, experiences of discrimination, and stress exist among students in dentistry, nursing, occupational therapy, pharmacy, and physical therapist professional education programs; (2) determine if there are significant differences by key demographic characteristics (those who are first-generation college students [FGCSs], a member of an underrepresented minority [URM] group, or both); and (3) highlight strategies and solutions to alleviate these challenges identified by students., Methods: Cross-sectional survey using a mix of question types of a sample of graduate students from dentistry, nursing, occupational therapy, pharmacy, and physical therapy programs from February to June 2020. Utilizing the Maslach Burnout Inventory Student Survey and campus climate and stress survey, mean subscale scores were calculated for the following outcomes of interest: MBI-SS burnout, dimensions of stress, and observed racism. Logistic regressions examined student factors that may help explain these outcomes. Content analysis examined participants' responses to open-ended questions., Results: There were 611 individuals who completed all survey questions. FGCSs were significantly more likely than non-FGCSs to report exhaustion (adjusted odds ratio [aOR]: 1.50; 95% CI = 1.04-2.16), family stress (aOR: 3.11; 95% CI = 2.13-4.55), and financial stress (aOR: 1.74; 95% CI = 1.21-2.50). URM students reported not feeling supported in their program and mentioned needing additional support, particularly for well-being, from staff and faculty., Conclusion: Findings from this study are consistent with literature that FGCSs experience additional stressors that may lead to burnout and exhaustion. URM students reported not feeling supported in their programs. This study's findings point to the need for leadership and faculty of health professional schools to implement or strengthen current policies, practices, and strategies that support URM students and FGCSs., Impact: Research demonstrates that a diverse student body and faculty enhances the educational experience for health professional students, and that diversity strengthens the learning environment and improves learning outcomes, preparing students to care for an increasingly diverse population. However, this study finds that students from underrepresented backgrounds may still experience more burnout, exhaustion, discrimination, and stress than their peers. Programs and policies to support URM students and FGCSs throughout their academic careers can help improve graduation and retention rates, leading to improved workforce diversity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background To address rural physician workforce shortages, the Health Resources and Services Administration funded multiple Rural Residency Planning and Development (RRPD) awards, beginning in 2019, to develop rural residency programs in needed specialties. Objective To describe early resident recruitment outcomes of the RRPD grants program. Methods A cross-sectional survey of program directors or administrators of these 25 new rural residency training programs across the United States was administered at RRPD award conclusion in 2022. We performed descriptive analyses of applicant and Match data, including applications and interviews per resident position, positions filled in the main Match vs the Supplemental Offer and Acceptance Program (SOAP), and recruitment of residents from the program's state. Results The 25 Cohort 1 RRPD programs ranged from 2 to 8 residents per year. Most programs (16 of 25, 64.0%) were rural expansion tracks of an urban program. Most programs were sufficiently developed to participate in the 2022 (N=17) or 2023 (N=20) Match; we report on 13 of 17 (76.5%) programs for 2022 and 14 of 20 (70.0%) programs for 2023. Programs completed a median of 14.8 interviews per position. Most positions were filled in the Match (43 of 58, 74.1% in 2022; 45 of 58, 77.6% in 2023); most others were filled in the SOAP. On average, 34.4% of enrolled residents were from the same state as the program (range 0-78.6%). Conclusions The early resident recruitment outcomes of the RRPD model for developing new physician training in rural communities had sufficient recruitment success to support program continuation.

Purpose: The Rural Communities Opioid Response Program (RCORP) was funded to help rural communities improve prevention, treatment, and recovery services for Opioid Use Disorder (OUD), including increasing the supply of clinicians with a Drug Enforcement Administration (DEA) waiver to prescribe buprenorphine, which was required before 2023. This research investigates the impact of RCORP funding on the supply of DEA-waivered clinicians in rural communities., Methods: We used 2017-2022 DEA lists of waivered clinicians to assign clinicians to US counties. Using RCORP service area data, we classified rural counties as either being served by an RCORP grantee or not. We calculated the number of counties in each category with a waivered clinician, clinician-to-population ratios, and treatment slot-to-population ratios., Findings: In 2017, 3.7% more of RCORP funded counties had a waivered clinician than non-RCORP counties. RCORP counties also had 1.2 more waivered clinicians per 100,000 population and 57.5 more treatment slots per 100,000 population compared to non-RCORP counties. From 2017 to 2022, these differences more than doubled. The supply of waivered clinicians varied across Census Divisions. In most Census Divisions, a greater percentage of RCORP counties had a waivered clinician as well as more waivered clinicians and treatment slots per population, except for the Pacific Census Division, which had more clinicians and treatment slots per population in non-RCORP counties., Conclusions: Study findings suggest that federal investments to expand rural OUD patients' access to care may have been successful, but only if increases in clinician supply translate into greater provision of OUD treatment., (© 2024 The Author(s). The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

In this study, we examined and compared the beliefs of undergraduate nursing students at a healthcare-focused university in central Japan regarding their abilities to learn English and nursing and sustain effort in their studies. Specifically, the purposes of this research were to learn how Japanese nursing students' mindsets and effort regulation differed across the domains of English and nursing and to determine the extent to which mindsets can predict students' effort regulation in these domains. Data were collected through an online questionnaire ( N = 132). We found that students' mindsets and effort regulation differed across the domains of English and nursing with no significant differences by year of study. Growth mindsets and effort regulation were significantly higher and fixed mindsets were significantly lower in nursing than in English. Mindsets in nursing were found to predict effort regulation in both nursing and English, but mindsets in English were found only to predict effort regulation in English. The findings offer valuable insights into the learning beliefs of Japanese nursing students and may provide ideas about how to better motivate nursing students in their studies. Furthermore, the study contributes to the understanding of how mindsets vary across domains and cultural contexts., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To determine the distinct influences of rural background and rural residency training on rural practice choice among family physicians., Data Sources and Study Setting: We used a subset of The RTT Collaborative rural residency list and longitudinal data on family physicians from the American Board of Family Medicine National Graduate Survey (NGS; three cohorts, 2016-2018) and American Medical College Application Service (AMCAS)., Study Design: We conducted a logistic regression, computing predictive marginals to assess associations of background and residency location with physician practice location 3 years post-residency., Data Collection/extraction Methods: We merged NGS data with residency type-rural or urban-and practice location with AMCAS data on rural background., Principal Findings: Family physicians from a rural background were more likely to choose rural practice (39.2%, 95% CI = 35.8, 42.5) than those from an urban background (13.8%, 95% CI = 12.5, 15.0); 50.9% (95% CI = 43.0, 58.8) of trainees in rural residencies chose rural practice, compared with 18.0% (95% CI = 16.8, 19.2) of urban trainees., Conclusions: Increasing rural programs for training residents from both rural and urban backgrounds, as well as recruiting more rural students to medical education, could increase the number of rural family physicians., (© 2023 Health Research and Educational Trust.)

Internationally educated immigrant healthcare workers face skill underutilization working in lower-skilled healthcare jobs or outside healthcare. This study explored barriers to and solutions for integrating immigrant health professionals. Content analysis identifying key themes from semi-structured qualitative interviews with representatives from Welcome Back Centers (WBCs) and partner organizations. 18 participants completed interviews. Barriers facing immigrant health professionals included lack of access to resources, financial constraints, language difficulties, credentialing challenges, prejudice, and investment in current occupations. Barriers facing programs that assist immigrant health professionals included eligibility restrictions, funding challenges, program workforce instability, recruitment difficulties, difficulty maintaining connection, and pandemic challenges. Long-term program success depended on partner networks, advocacy, addressing prejudice, a client-centered approach, diverse resources and services, and conducting research. Initiatives to integrate immigrant health professionals require multi-level responses to diverse needs and collaborations among organizations that support immigrant health professionals, healthcare systems, labor, and other stakeholders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Immune-related adverse events (irAEs) are a notable complication of PD-1 cancer immunotherapy. A better understanding of how these iatrogenic diseases compare with naturally arising autoimmune diseases is needed for treatment and monitoring of irAEs. We identified differences in anti-PD-1-induced type 1 diabetes (T1D) and spontaneous T1D in non-obese diabetic (NOD) mice by performing single-cell RNA-seq and TCR-seq on T cells from the pancreas, pancreas-draining lymph node (pLN), and blood of mice with PD-1-induced T1D or spontaneous T1D. In the pancreas, anti-PD-1 resulted in expansion of terminally exhausted/effector-like CD8+ T cells, an increase in T-bethi CD4+FoxP3- T cells, and a decrease in memory CD4+FoxP3- and CD8+ T cells in contrast to spontaneous T1D. Notably, anti-PD-1 caused increased TCR sharing between the pancreas and the periphery. Moreover, T cells in the blood of anti-PD-1-treated mice expressed markers that differed from spontaneous T1D, suggesting that the blood may provide a window to monitor irAEs rather than relying exclusively on the autoimmune target organ., (© 2023 Collier et al.)

Objective: This study aimed to assess the safety and effectiveness of a new charge-distributed multiphase stimulation paradigm during an extended spinal cord stimulation (SCS) trial., Materials and Methods: This prospective, multicenter, randomized, single-blind, feasibility study included participants with chronic low back and/or leg pain and baseline numerical rating scale (NRS) for overall pain intensity ≥6. After a successful commercial SCS trial, participants were randomized to multiphase SCS therapy A (approximately 600-1500 Hz) or B (approximately 300-600 Hz), delivered via an investigational external pulse generator and existing leads during an 11-to-12-day testing period. Primary end points were mean NRS change from baseline to final in-office visit for each multiphase therapy and between therapies. Secondary end points included mean NRS change from end of commercial trial to final study visit and incidence of device-related adverse events (AEs). Additional measures included patient-reported outcomes collected at home through electronic watches and written diaries. Power usage was compared between multiphase and commercial therapies., Results: A total of 122 participants initiated a commercial trial; 77 were randomized to a multiphase arm, and 65 completed the study. Reductions in mean NRS scores from baseline to final study visit were significant for multiphase therapy A and B (-4.3 and -4.7, respectively; both p < 0.0001). There was no statistically significant difference in mean NRS reduction or percent pain relief between multiphase therapies. In an additional analysis, 63.9% of participants reported greater pain relief with multiphase than with commercial SCS therapy in the at-home setting. On average, multiphase required less power than did commercial devices. One non-serious device-related AE was reported, and no infections occurred during the extended trial., Conclusions: Multiphase SCS effectively reduced pain in participants with chronic low back and/or leg pain during a trial, with no unanticipated device-related AEs reported. Future studies should evaluate long-term effectiveness of multiphase stimulation., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03594266., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to describe practices and experiences of rurally oriented physician assistant (PA) training programs in providing rural clinical training to PA students., Methods: A survey of PA program directors (PDs) included questions about program characteristics, student and clinical preceptor (CP) recruitment in rural areas, and barriers to, and facilitators of, rural clinical training. Programs that considered rural training "very important" to their goals were identified. We interviewed PDs from rurally oriented programs about their rural clinical training and rural CPs about their experiences training PA students for rural practice. We identified key themes through content analysis., Results: Of 178 programs surveyed, 113 (63.5%) responded, 61 (54.0%) of which were rurally oriented and more likely than other programs to recruit rural students or those with rural practice interests and to address rural issues in didactic curriculum. The 13 PDs interviewed linked successful rural training to finding and supporting rural preceptors who enjoy teaching and helping students understand rural communities. The 13 rural CPs identified enthusiastic and rurally interested students as key elements to successful rural training. Interviewees identified systemic barriers to rural training, including student housing, decreased productivity, competition for training slots, and administrative burden., Conclusions: Physician assistant students can be coached to capitalize on their rural clinical experiences. Knowing how to "jump in" to rotations and having genuine interest in the community are particularly important. Student housing, competition for training slots, and lack of financial incentives are major system-level challenges for sustaining and increasing the availability of PA rural clinical training., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Physician Assistant Education Association.)

Aims: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN)., Methods: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding., Results: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection., Conclusions: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN., Trial Registration: ClincalTrials.gov Identifier, NCT03228420., Competing Interests: Declaration of competing interest Author Erika A. Petersen has received consulting fees from Abbott Laboratories, Biotronik, Boston Scientific, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, Presidio Medical, Saluda, and Vertos Medical, research support from Mainstay, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, ReNeuron, Saluda, and SPR, and stock options from neuro42 and SynerFuse. Author Thomas G. Stauss has received research support from Nevro Corp. Author James A. Scowcroft has received research support from Boston Scientific, Nevro Corp, Saluda Medical, and Vertiflex. Author Michael J. Jaasma is an employee of Nevro Corp. Author Elizabeth S. Brooks was an employee of Nevro Corp during her contributions to the work associated with this manuscript. Author Deborah R. Edgar received consulting fees from Nevro in her capacity as an independent medical writer. Author Judith L. White has received consulting fees from California Institute for Biomedical Research and Eli Lilly and research support from Nevro Corp. Author Shawn M. Sills has received research support from Nevro Corp. Author Kasra Amirdelfan has received consulting fees from Biotronik, Medtronic, Nalu Medical, Nevro Corp, and Saluda Medical, as well as research support from Biotronik, IPM Medical Group, Nevro Corp, Saluda Medical, SPR Therapeutics, and Vivex Biologics. Author Maged N. Guirguis has received consulting fees from Abbott Laboratories, Avanos Medical, Avertis Pharmacy, Boston Scientific, Nevro Corp, and Saluda Medical, as well as research support from Abbott Laboratories, Avanos Medical, Boston Scientific, Nalu Medical, Neuros Medical, Nevro Corp, and Saluda Medical. Author Jijun Xu has received research support from the Cleveland Clinic Velosano Program, the National Institutes of Health, the Steve and Melody Golding Foundation, and Nevro Corp. Author Cong Yu has received research support from Nevro Corp. Author Ali Nairizi has received consulting fees from Aurora Spine, Flowonix, and Nevro Corp as well as research support from Nevro Corp. Author Denis G. Patterson has received consulting fees from Abbott Laboratories, AIS Healthcare, Allergan, Amgen, Aurora Spine, CornerLoc, Flowonix, Lundbeck, Pajunk Medical, Saluda Medical, Spark Biomedical, and Vertos Medical, research support from Abbott Laboratories, Aurora Spine, Flowonix, Nevro Corp, and Saluda Medical, speakers’ bureau or honoraria from Abbott Laboratories, Allergan, Amgen, CornerLoc, Lundbeck, Saluda Medical, and Vertos Medical, and stock options from CornerLoc. Author Michael J. Creamer has received research support from Nevro Corp. Author Vincent Galan has received research support from Biotronik, Medtronic, Nevro Corp, PainTEQ, SPR Therapeutics, and St. Jude. Author Richard H. Bundschu has received research support from Nevro Corp. Author Neel D. Mehta has received consulting fees from Averitas, Nevro Corp, and Salix Pharmaceuticals, as well as research support from Boston Scientific and Nevro Corp. Author Dawood Sayed has received consulting fees from Abbott Laboratories, Boston Scientific, Flowonix, Medtronic, Nevro Corp, Vertiflex, and Vertos Medical, as well as research support from Abbott Laboratories, Biotronic, Nevro Corp, Vertiflex, and Vertos Medical. Author Shivanand P. Lad has received consulting fees from Nevro Corp and research support from Nevro Corp. Author David J. DiBenedetto has received research support from Nevro Corp, as well as funding for serving as principal investigator of a study supported by SPR Therapeutics paid to his institution. Author Khalid A. Sethi has received research support from Nevro Corp. Author Johnathan H. Goree has received consulting fees from Abbott Laboratories and Stratus Medical. Author Paul W. Wu has received research support from Nevro Corp. Author Charles E. Argoff has received consulting fees from AbbVie, Amgen, Biohaven, Clexio Biosciences, Collegium, Eli Lilly, Elsevier, Flowonix, Gene Pharma, Lundbeck, Nevro Corp, Novartis, Pfizer, SK Life Science, Teva Pharmaceutical, and Vertex as well as research support from AbbVie, Allergan, Amgen, Daiichi Sankyo, Eli Lilly, Novartis, Teva Pharmaceutical, and Vertex Pharmaceuticals. Author Christian E. Nasr has received consulting fees from Exelixis, Neurogastrx, and Nevro Corp as well as research support from Nevro Corp. Author Rod S. Taylor has received consulting fees from Nevro Corp, Medtronic, and Saluda Medical. Author David L. Caraway is an employee of Nevro Corp. Author Nagy A. Mekhail has received consulting fees from Nevro Corp, Relievant Medsystems, Saluda Medical, Sollis Therapeutics, and Vertos Medical, as well as research support from Avanos Medical, Mesoblast, Neuros Medical, and Nevro Corp., (Copyright © 2023. Published by Elsevier B.V.)

Spinal Cord Stimulation (SCS) is a well-established therapy for treating chronic pain. However, perceived treatment response to SCS therapy may vary among people with chronic pain due to diverse needs and backgrounds. Patient Reported Outcomes (PROs) from standard survey questions do not provide the full picture of what has happened to a patient since their last visit, and digital PROs require patients to visit an app or otherwise regularly engage with software. This study aims to assess the feasibility of using digital biomarkers collected from wearables during SCS treatment to predict pain and PRO outcomes. Twenty participants with chronic pain were recruited and implanted with SCS. During the six months of the study, activity and physiological metrics were collected and data from 15 participants was used to develop a machine learning pipeline to objectively predict pain levels and categories of PRO measures. The model reached an accuracy of 0.768 ± 0.012 in predicting the pain intensity of mild, moderate, and severe. Feature importance analysis showed that digital biomarkers from the smartwatch such as heart rate, heart rate variability, step count, and stand time can contribute to modeling different aspects of pain. The results of the study suggest that wearable biomarkers can be used to predict therapy outcomes in people with chronic pain, enabling continuous, real-time monitoring of patients during the use of implanted therapies., (© 2023. Springer Nature Limited.)

Background: Neurostimulation is a highly effective therapy for the treatment of chronic Intractable pain, however, due to the complexity of pain, measuring a subject's long-term response to the therapy remains difficult. Frequent measurement of patient-reported outcomes (PROs) to reflect multiple aspects of subjects' pain is a crucial step in determining therapy outcomes. However, collecting full-length PROs is burdensome for both patients and clinicians. The objective of this work is to identify the reduced set of questions from multiple validated PROs that can accurately characterize chronic pain patients' responses to neurostimulation therapies., Methods: Validated PROs were used to capture pain, physical function and disability, as well as psychometric, satisfaction, and global health metrics. PROs were collected from 509 patients implanted with Spinal Cord Stimulation (SCS) or Dorsal Root Ganglia (DRG) neurostimulators enrolled in the prospective, international, post-market REALITY study (NCT03876054, Registration Date: March 15, 2019). A combination of linear regression, Pearson's correlation, and factor analysis were used to eliminate highly correlated questions and find the minimal meaningful set of questions within the predefined domains of each scale., Results: The shortened versions of the questionnaires presented almost identical accuracy for classifying the therapy outcomes as compared to the validated full-length versions. In addition, principal component analysis was performed on all the PROs and showed a robust clustering of pain intensity, psychological factors, physical function, and sleep across multiple PROs. A selected set of questions captured from multiple PROs can provide adequate information for measuring neurostimulation therapy outcomes., Conclusions: PROs are important subjective measures to evaluate the physiological and psychological aspects of pain. However, these measures are cumbersome to collect. These shorter and more targeted PROs could result in better patient engagement, and enhanced and more frequent data collection processes for digital health platforms that minimize patient burden while increasing therapeutic benefits for chronic pain patients., (© 2023. The Author(s).)

Background and Objectives: Although rural family medicine residency programs are effective in placing trainees into rural practice, many struggle to recruit students. Lacking other public measures, students may use residency match rates as a proxy for program quality and value. This study documents match rate trends and explores the relationship between match rates and program characteristics, including quality measures and recruitment strategies., Methods: Using a published listing of rural programs, 25 years of National Resident Matching Program data, and 11 years of American Osteopathic Association match data, this study (1) documents patterns in initial match rates for rural versus urban residency programs, (2) compares rural residency match rates with program characteristics for match years 2009-2013, (3) examines the association of match rates with program outcomes for graduates in years 2013-2015, and (4) explores recruitment strategies using residency coordinator interviews., Results: Despite increases in positions offered over 25 years, the fill rates for rural programs have improved relative to urban programs. Small rural programs had lower match rates relative to urban programs, but no other program or community characteristics were predictors of match rate. Match rates were not indicative of any of five measures of program quality nor of any single recruiting strategy., Conclusions: Understanding the intricacies of rural residency inputs and outcomes is key to addressing rural workforce gaps. Match rates likely reflect challenges of rural workforce recruitment generally and should not be conflated with program quality.

The transcription factor Interferon regulatory factor 8 (IRF8) is involved in maintaining B cell identity. However, how IRF8 regulates T cell independent B cell responses are not fully characterized. Here, an in vivo CRISPR/Cas9 system was optimized to generate Irf8 -deficient murine B cells and used to determine the role of IRF8 in B cells responding to LPS stimulation. Irf8 -deficient B cells more readily formed CD138 + plasmablasts in response to LPS with the principal dysregulation occurring at the activated B cell stage. Transcriptional profiling revealed an upregulation of plasma cell associated genes prematurely in activated B cells and a failure to repress the gene expression programs of IRF1 and IRF7 in Irf8 -deficient cells. These data expand on the known roles of IRF8 in regulating B cell identity by preventing premature plasma cell formation and highlight how IRF8 helps evolve TLR responses away from the initial activation towards those driving humoral immunity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (© 2023 The Authors.)

Objectives. To compare rural versus urban local public health workforce competencies and training needs, COVID-19 impact, and turnover risk. Methods. Using the 2021 Public Health Workforce Interest and Needs Survey, we examined the association between local public health agency rural versus urban location in the United States (n = 29 751) and individual local public health staff reports of skill proficiencies, training needs, turnover risk, experiences of bullying due to work as a public health professional, and posttraumatic stress disorder symptoms attributable to COVID-19. Results. Rural staff had higher odds than urban staff of reporting proficiencies in community engagement, cross-sectoral partnerships, and systems and strategic thinking as well as training needs in data-based decision-making and in diversity, equity, and inclusion. Rural staff were also more likely than urban staff to report leaving because of stress, experiences of bullying, and avoiding situations that made them think about COVID-19. Conclusions. Our findings demonstrate that rural staff have unique competencies and training needs but also experience significant stress. Public Health Implications. Our findings provide the opportunity to accurately target rural workforce development trainings and illustrate the need to address reported stress and experiences of bullying. ( Am J Public Health. 2023;113(6):689-699. https://doi.org/10.2105/AJPH.2023.307273).

Purpose: Little research has been conducted on the outcomes of postgraduate nurse practitioner (NP) programs (referred to as residencies), particularly those located in rural communities. This study examined the purpose and characteristics of rural NP residencies that aim to promote the successful recruitment, transition, and retention of NPs in rural primary care practice., Methods: We compiled a list of rural NP residencies and verified the location of each clinic as rural if it met any of several federal definitions of rurality. We interviewed grant and project administrators, residency program directors, clinic personnel, and former and current NP residents using semistructured guides., Findings: Of 20 rural NP residencies identified, we interviewed 12 program directors or managers; 8 NPs; and 4 clinic personnel. All but 1 program was 12 months long. Three-quarters had federal funding. Each slowly increased residents' patient load and included didactic content and specialty rotations. We identified 2 different program models and 3 administrative models. Some NPs' intentionally chose rural practice, while others opted for a rural residency when unable to secure employment in an urban location. Most programs were new and not yet able to report on residents' subsequent employment locations., Conclusions: It is premature to conclude definitively that rural NP residencies facilitate and promote NP connectedness to, and investment in, rural communities based on our investigation. Nonetheless, these programs are an option to encourage the recruitment and retention of NPs in rural practice, with further study needed to determine their long-term contribution to rural primary care practice., (© 2022 The Authors. The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Background and Objectives: Family physicians are the most common health professional providing rural obstetric (OB) care, but the number of family physicians practicing OB is declining. To address rural/urban disparities in parental and child health, family medicine must provide robust OB training to prepare family physicians to care for parent-newborn dyads in rural communities. This mixed-methods study aimed to inform policy and practice solutions., Methods: We surveyed 115 rural family medicine residency programs (program directors, coordinators, or faculty) and conducted semistructured interviews with personnel from 10 rural family medicine residencies. We calculated descriptive statistics and frequencies for survey responses. Two authors conducted a directed content analysis of qualitative survey and interview responses., Results: The survey yielded 59 responses (51.3%); responders and nonresponders were not significantly different by geography or program type. Most programs (85.5%) trained residents to provide comprehensive prenatal and postpartum care. Continuity clinic sites were predominantly rural across all years and OB training was largely rural in postgraduate year 2 (PGY2) and PGY3. Almost half of programs listed "competition with other OB providers" (49.1%) and "shortage of family medicine faculty providing OB care" (47.3%) as major challenges. Individual programs tended to report either few challenges or multiple challenges. In qualitative responses, common themes included the importance of faculty interest and skill, community and hospital support, volume, and relationships., Conclusions: To improve rural OB training, our findings support prioritizing relationships between family medicine and other OB clinicians, sustaining family medicine OB faculty, and developing creative solutions to interrupt cascading and interrelated challenges.

Purpose of Study: Medical students who identify as Black, Indigenous, and People of Color (BIPOC) regularly experience mistreatment and discrimination. This study sought to understand these student experiences during rotations in rural and urban underserved community teaching sites., Methods: Self-identified BIPOC medical students who completed the University of Washington School of Medicine's Rural Underserved Opportunities Program from 2019 through 2021 were invited to participate in a 60- to 90-minute focus group discussion via Zoom. From August to September 2021, 4 focus groups and 1 individual interview were conducted with a total of 12 participants. A current BIPOC medical student facilitated the sessions utilizing questions developed by the research team. Four study team members coded transcripts for key themes related to experiences of microaggressions., Findings: All participants reported having an overall positive experience, but everyone also witnessed and/or experienced at least 1 microaggression. Unlike those in urban placements, participants placed in rural sites expressed anxiety about being in predominantly White communities and experienced feelings of racial and/or ethnic isolation during the rotation. Participants recommended that rural preceptors identify themselves as trusted advocates and the program should prioritize placing BIPOC students at diverse clinical sites., Conclusions: Medical schools must take action to address the mistreatment of BIPOC medical students in the clinical environment. Schools and rural training sites need to consider how to best support students to create an equitable learning environment and recruit more BIPOC physicians to rural practice., (© 2023 National Rural Health Association.)

Policy Points Although a single definition of the population health workforce does not yet exist, this workforce needs to have the skills and competencies to address the social determinants of health, to understand intersectionality, and to coordinate and work in concert with an array of skilled providers in social and health care to address multiple health drivers. On-the-job training programs and employer support are needed for the current health workforce to gain skills and competencies to address population health. Funding and leadership combined are critical for developing the population health workforce with the goal of supporting a broad set of workers beyond health and social care to include, for example, those in urban planning, law enforcement, or transportation professions to address population health., (© 2023 Milbank Memorial Fund.)

Background and Objectives: The quality of training in rural family medicine (FM) residencies has been questioned. Our objective was to assess differences in academic performance between rural and urban FM residencies., Methods: We used American Board of Family Medicine (ABFM) data from 2016-2018 residency graduates. Medical knowledge was measured by the ABFM in-training examination (ITE) and Family Medicine Certification Examination (FMCE). The milestones included 22 items across six core competencies. We measured whether residents met expectations on each milestone at each assessment. Multilevel regression models determined associations between resident and residency characteristics milestones met at graduation, FMCE score, and failure., Results: Our final sample was 11,790 graduates. First-year ITE scores were similar between rural and urban residents. Rural residents passed their initial FMCE at a lower rate than urban residents (96.2% vs 98.9%) with the gap closing upon later attempts (98.8% vs 99.8%). Being in a rural program was not associated with a difference in FMCE score but was associated with higher odds of failure. Interactions between program type and year were not significant, indicating equal growth in knowledge. The proportions of rural vs urban residents who met all milestones and each of six core competencies were similar early in residency but diverged over time with fewer rural residents meeting all expectations., Conclusions: We found small, but persistent differences in measures of academic performance between rural- and urban-trained FM residents. The implications of these findings in judging the quality of rural programs are much less clear and warrant further study, including their impact on rural patient outcomes and community health.

Background and Objectives: Little is known about how rural and urban family medicine residencies compare in preparing physicians for practice. This study compared the perceptions of preparation for practice and actual postgraduation scope of practice (SOP) between rural and urban residency program graduates., Methods: We analyzed data on 6,483 early-career, board-certified physicians surveyed 2016-2018, 3 years after residency graduation, and 44,325 later-career board-certified physicians surveyed 2014-2018, every 7 to 10 years after initial certification. Bivariate comparisons and multivariate regressions of rural and urban residency graduates examined perceived preparedness and current practice in 30 areas and overall SOP using a validated scale, with separate models for early-career and later-career physicians., Results: In bivariate analyses, rural program graduates were more likely than urban program graduates to report being prepared for hospital-based care, casting, cardiac stress tests, and other skills, but less likely to be prepared in some gynecologic care and pharmacologic HIV/AIDS management. Both early- and later-career rural program graduates reported broader overall SOPs than their urban-program counterparts in bivariate analyses; in adjusted analyses this difference remained significant only for later-career physicians., Conclusions: Compared with urban program graduates, rural graduates more often rated themselves prepared in several hospital care measures and less often in certain women's health measures. Controlling for multiple characteristics, only rurally trained, later-career physicians reported a broader SOP than their urban program counterparts. This study demonstrates the value of rural training and provides a baseline for research exploring longitudinal benefits of this training to rural communities and population health.

Both research and medical education make substantial contributions to rural primary care and health. An inaugural Scholarly Intensive for Rural Programs was conducted in January 2022 to connect rural programs within a community of practice focused on promoting scholarly activity and research in rural primary health care, education, and training. Participant evaluations confirmed that key learning objectives were met, including stimulating scholarly activity in rural health professions education programs, providing a forum for faculty and student professional development, and growing a community of practice that supports education and training in rural communities. This novel strategy brings enduring scholarly resources to rural programs and the communities they serve, teaches skills to health profession trainees and rurally located faculty, empowers clinical practices and educational programs, and supports the discovery of evidence that can improve the health of rural people., Competing Interests: Conflicts of interest: authors report none., (© 2023 Annals of Family Medicine, Inc.)

Immune checkpoint receptors such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and T cell immunoglobulin and ITIM domain (TIGIT) have distinct and overlapping inhibitory functions that regulate Tcell activation, differentiation, and function. These inhibitory receptors also mediate tolerance, and dysregulation of these receptors can result in a breach of tolerance and the development of autoimmune syndromes. Similarly, antibody blockade of immune checkpoint receptors or their ligands for cancer immunotherapy may trigger a spectrum of organ inflammation that resembles autoimmunity, termed immune-related adverse events (irAE). In this review, we discuss recent advances in the regulation of autoimmunity by immune checkpoint receptors. We highlight coordinated gene expression programs linking checkpoint receptors, heterogeneity within autoreactive T-cell populations, parallels between irAE and autoimmunity, and bidirectional functional interactions between immune checkpoint receptors and their ligands., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: We undertook a study to evaluate the current state of pedagogy on antiracism, including barriers to implementation and strengths of existing curricula, in undergraduate medical education (UME) and graduate medical education (GME) programs in US academic health centers., Methods: We conducted a cross-sectional study with an exploratory qualitative approach using semistructured interviews. Participants were leaders of UME and GME programs at 5 institutions participating in the Academic Units for Primary Care Training and Enhancement program and 6 affiliated sites from November 2021 to April 2022., Results: A total of 29 program leaders from the 11 academic health centers participated in this study. Three participants from 2 institutions reported the implementation of robust, intentional, and longitudinal antiracism curricula. Nine participants from 7 institutions described race and antiracism-related topics integrated into health equity curricula. Only 9 participants reported having "adequately trained" faculty. Participants mentioned individual, systemic, and structural barriers to implementing antiracism-related training in medical education such as institutional inertia and insufficient resources. Fear related to introducing an antiracism curriculum and undervaluing of this curriculum relative to other content were identified. Through learners and faculty feedback, antiracism content was evaluated and included in UME and GME curricula. Most participants identified learners as a stronger voice for transformation than faculty; antiracism content was mainly included in health equity curricula., Conclusions: Inclusion of antiracism in medical education requires intentional training, focused institutional policies, enhanced foundational awareness of the impact of racism on patients and communities, and changes at the level of institutions and accreditation bodies., Competing Interests: Conflicts of interest: authors report none., (© 2023 Annals of Family Medicine, Inc.)

Introduction: Lumbar degenerative disease and the accompanying pain and dysfunction affect a significant number of patients in the USA and around the world. As surgery and innovation are moving towards minimally invasive treatments, this study looks to explore interspinous fixation as a standalone posterior approach to treat lumbar degenerative disc disease in the presence of neurogenic claudication and spinal stenosis., Methods: This study was approved by an institutional review board (IRB) and is actively enrolling in a single-arm, multicenter, prospective, open-label fashion. Patients are followed with reporting at 3 months, and 12 months for primary endpoint analysis of efficacy and safety based on improved composite endpoints relative to baseline, with success defined as greater than 20 mm back pain reduction in Visual Analog Scale 100 mm (VAS) while standing or walking, greater than 20 mm leg pain reduction in VAS while standing or walking, Zurich Claudication Questionnaire (ZCQ) improvement of 0.5 or greater in two or three domains, Oswestry Disability Index (ODI) improvement of a least 10 points and no reoperations or revisions at the index level(s). Secondary endpoints included a multidimensional assessment in the Patient-Reported Outcomes Measurement Information System (PROMIS) 29 v2.1 and Patient Global Impression of Change (PGIC)., Results: In this interim 3-month analysis, 82% of patients reported they were improved from the procedure, while 65% of patients demonstrated clinical meaningful improvement in their pain and function, as defined by the VAS, ODI, and ZCQ. There was only one adverse event and no complications were identified at last clinic research follow-up visit., Conclusions: This interim analysis of the first 20% of the enrolled patients out to 3 months was to determine safety of the procedure and report on adverse events, acknowledging the heterogeneity of surgical specialty. Further follow-up and greater numbers are needed as the study is ongoing., Trial Registration: ClinicalTrials.gov identifier, NCT05504499., (© 2022. The Author(s).)

Problem and Purpose: Healthcare provider implicit bias influences the learning environment and patient care. Bias awareness is one of the key elements to be included in implicit bias education. Research on education enhancing bias awareness is limited. Bias awareness can motivate behavior change. The objective was to evaluate whether exposure to a brief online course, Implicit Bias in the Clinical and Learning Environment , increased bias awareness., Materials and Methods: The course included the history of racism in medicine, social determinants of health, implicit bias in healthcare, and strategies to reduce the impact of implicit bias in clinical care and teaching. A sample of U.S. academic family, internal, and emergency medicine providers were recruited into the study from August to December 2019. Measures of provider implicit and explicit bias, personal and practice characteristics, and pre-post-bias awareness measures were collected., Results: Of 111 participants, 78 (70%) were female, 81 (73%) were White, and 63 (57%) were MDs. Providers held moderate implicit pro-White bias on the Race IAT (Cohen's d = 0.68) and strong implicit stereotypes associating males rather than females with 'career' on the Gender-Career IAT (Cohen's d = 1.15). Overall, providers held no explicit race bias (Cohen's d = 0.05). Providers reported moderate explicit male-career (Cohen's d = 0.68) and strong female-family stereotype (Cohen's d = 0.83). A statistically significant increase in bias awareness was found after exposure to the course ( p = 0.03). Provider implicit and explicit biases and personal and practice characteristics were not associated with an increase in bias awareness., Conclusions: Implicit bias education is effective to increase providers' bias awareness regardless of strength of their implicit and explicit biases and personal and practice characteristics. Increasing bias awareness is one step of many toward creating a positive learning environment and a system of more equitable healthcare.

Objective: To evaluate high-frequency (10-kHz) spinal cord stimulation (SCS) treatment in refractory painful diabetic neuropathy., Patients and Methods: A prospective, multicenter randomized controlled trial was conducted between Aug 28, 2017 and March 16, 2021, comparing conventional medical management (CMM) with 10-kHz SCS+CMM. The participants had hemoglobin A1c level of less than or equal to 10% and pain greater than or equal to 5 of 10 cm on visual analog scale, with painful diabetic neuropathy symptoms 12 months or more refractory to gabapentinoids and at least 1 other analgesic class. Assessments included measures of pain, neurologic function, and health-related quality of life (HRQoL) over 12 months with optional crossover at 6 months., Results: The participants were randomized 1:1 to CMM (n=103) or 10-kHz SCS+CMM (n=113). At 6 months, 77 of 95 (81%) CMM group participants opted for crossover, whereas none of the 10-kHz SCS group participants did so. At 12 months, the mean pain relief from baseline among participants implanted with 10-kHz SCS was 74.3% (95% CI, 70.1-78.5), and 121 of 142 (85%) participants were treatment responders (≥50% pain relief). Treatment with 10-kHz SCS improved HRQoL, including a mean improvement in the EuroQol 5-dimensional questionnaire index score of 0.136 (95% CI, 0.104-0.169). The participants also reported significantly less pain interference with sleep, mood, and daily activities. At 12 months, 131 of 142 (92%) participants were "satisfied" or "very satisfied" with the 10-kHz SCS treatment., Conclusion: The 10-kHz SCS treatment resulted in substantial pain relief and improvement in overall HRQoL 2.5- to 4.5-fold higher than the minimal clinically important difference. The outcomes were durable over 12 months and support 10-kHz SCS treatment in patients with refractory painful diabetic neuropathy., Trial Registration: clincaltrials.gov Identifier: NCT03228420., (© 2022 The Authors.)

B cell differentiation is associated with substantial transcriptional, metabolic, and epigenetic remodeling, including redistribution of histone 3 lysine 27 trimethylation (H3K27me3), which is associated with a repressive chromatin state and gene silencing. Although the role of the methyltransferase EZH2 (Enhancer of zeste homolog 2) in B cell fate decisions has been well established, it is not known whether H3K27me3 demethylation is equally important. In this study, we showed that simultaneous genetic deletion of the two H3K27 demethylases UTX and JMJD3 (double-knockout [ Utx fl/fl Jmjd3 fl/fl Cd19 cre/+ ] [dKO]) led to a significant increase in plasma cell (PC) formation after stimulation with the T cell-independent Ags LPS and NP-Ficoll. This phenotype occurred in a UTX-dependent manner as UTX single-knockout mice, but not JMJD3 single-knockout mice, mimicked the dKO. Although UTX- and JMJD3-deficient marginal zone B cells showed increased proliferation, dKO follicular B cells also showed increased PC formation. PCs from dKO mice upregulated genes associated with oxidative phosphorylation and exhibited increased spare respiratory capacity. Mechanistically, deletion of Utx and Jmjd3 resulted in higher levels of H3K27me3 at proapoptotic genes and resulted in reduced apoptosis of dKO PCs in vivo. Furthermore, UTX regulated chromatin accessibility at regions containing ETS and IFN regulatory factor (IRF) transcription factor family motifs, including motifs of known repressors of PC fate. Taken together, these data demonstrate that the H3K27me3 demethylases restrain B cell differentiation., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Purpose: Buprenorphine is an effective medication treatment for opioid use disorder (MOUD) but access is difficult for patients, especially in rural locations. To improve access, legislation, including the Comprehensive Addiction and Recovery Act (2016) and the Substance Use Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities (SUPPORT) Act (2018), extended the ability to get a Drug Enforcement Administration (DEA) waiver to prescribe buprenorphine to treat opioid use disorder (OUD) to numerous types of clinicians. This study updates the distribution of waivered clinicians as of July 2020 and notes regional and geographic differences., Methods: Using the July 2020 Drug Enforcement Administration list of providers with a waiver to prescribe buprenorphine to treat OUD, we assigned waivered clinicians to counties in one of four geographic categories. We calculated the number of counties in each category that did not have a waivered clinician, available treatment slots, and the county provider to population ratios., Findings: The number of DEA-waivered clinicians more than doubled between December 2017 and July 2020 from 37,869 to 98,344. The availability of a clinician with a DEA waiver to provide MOUD has increased across all geographic categories. Nearly two-thirds of all rural counties (63.1%) had at least one clinician with a DEA waiver but more than half of small and remote rural counties lacked one. There were also significant differences in access by the US Census Division., Conclusions: Overall, MOUD access has improved, but small rural communities still experience treatment disparities and there is significant regional variation., (© 2021 National Rural Health Association.)