Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping.

Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3' UTR harbors a miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null mdx52 mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated mdx52 with body-wide miR-146a deletion (146aX). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in 146aX vs. mdx52 muscles while skipped dystrophin transcript levels are unchanged supporting a post-transcriptional mechanism of action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.

Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

Key features of the innate immune response is mediated by the immunoproteasome in microglia.

Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.

The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.

Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.

Following the p63/Keratin5 basal cells in the sensory and non-sensory epithelia of the vomeronasal organ.

The vomeronasal organ (VNO) is a part of the accessory olfactory system, which detects pheromones and chemical factors that trigger a spectrum of sexual and social behaviors. The vomeronasal epithelium (VNE) shares several features with the epithelium of the main olfactory epithelium (MOE). However, it is a distinct neuroepithelium populated by chemosensory neurons that differ from the olfactory sensory neurons in cellular structure, receptor expression, and connectivity. The vomeronasal organ of rodents comprises a sensory epithelium (SE) and a thin non-sensory epithelium (NSE) that morphologically resembles the respiratory epithelium. Sox2-positive cells have been previously identified as the stem cell population that gives rise to neuronal progenitors in MOE and VNE. In addition, the MOE also comprises p63 positive horizontal basal cells, a second pool of quiescent stem cells that become active in response to injury. Immunolabeling against the transcription factor p63, Keratin-5 (Krt5), Krt14, NrCAM, and Krt5Cre tracing experiments highlighted the existence of horizontal basal cells distributed along the basal lamina of SE of the VNO. Single cell sequencing and genetic lineage tracing suggest that the vomeronasal horizontal basal cells arise from basal progenitors at the boundary between the SE and NSE proximal to the marginal zones. Moreover, our experiments revealed that the NSE of rodents is, like the respiratory epithelium, a stratified epithelium where the p63/Krt5+ basal progenitor cells self-replicate and give rise to the apical columnar cells facing the lumen of the VNO.

Studying Adherence to Reporting Standards in Kinesiology: A Post-publication Peer Review Brief Report.

To demonstrate how post-publication peer reviews-using journal article reporting standards-could improve the design and write-up of kinesiology research, the authors performed a post-publication peer review on one systematic literature review published in 2020. Two raters (1st & 2nd authors) critically appraised the case article between April and May 2021. The latest Journal Article Reporting Standards by the American Psychological Association relevant to the review were used: i.e., Table 1 (quantitative research standards) and Table 9 (research synthesis standards). A standard fully met was deemed satisfactory. Per Krippendorff's alpha-coefficient, inter-rater agreement was moderate for Table 1 (k-alpha = .57, raw-agreement = 72.2%) and poor for Table 9 (k-alpha = .09, raw-agreement = 53.6%). A 100% consensus was reached on all discrepancies. Results suggest the case article's Abstract, Methods, and Discussion sections required clarification or more detail. Per Table 9 standards, four sections were largely incomplete: i.e., Abstract (100%-incomplete), Introduction (66%-incomplete), Methods (75%-incomplete), and Discussion (66%-incomplete). Case article strengths included tabular summary of studies analyzed in the systematic review and a cautionary comment about the review's generalizability. The article's write-up gave detail to help the reader understand the scope of the study and decisions made by the authors. However, adequate detail was not provided to assess the credibility of all claims made in the article. This could affect readers' ability to obtain critical and nuanced understanding of the article's topics. The results of this critique should encourage (continuing) education on journal article reporting standards for diverse stakeholders (e.g., authors, reviewers).

Feasibility of paying people who use drugs cash to distribute naloxone within their networks.

INTRODUCTION: Immediate access to naloxone is needed to prevent fatal opioid-related overdoses in the presence of fentanyl analogs saturating the opioid supply. Peer models engage impacted populations who are not accessing naloxone through standard venues, yet compensating peers who utilize syringe service programs with cash stipends to distribute naloxone within networks of people who use drugs is not well described. METHODS: As part of the HEALing Communities Study, syringe service program-based interventions were developed in Holyoke and Gloucester, MA, which paid people who use drugs ("peers") cash to distribute naloxone. Early program outcomes were evaluated for the time each program was funded within the HCS study period. RESULTS: During 22 study-months of observation, peers in two communities distributed 1104 naloxone kits. The total cost of peer compensation for program delivery was $10,510. The rate of peer-distributed naloxone per 100 K population reached 109 kits/mo and 222 kits/mo in the two communities. Participating peers addressed gaps in harm reduction outreach and distributed naloxone and other harm reduction equipment to individuals who were not syringe service program participants, expanding organizational reach. Being compensated with unrestricted cash stipends supported dignity and acknowledged peers' work in overdose prevention. CONCLUSION: The underutilization of compensated peer models is often attributed to funding and organizational barriers. These programs demonstrate that providing cash stipends to peers is feasible and expanded naloxone distribution at two existing syringe service programs. Providing cash stipends for peers who engage in secondary naloxone distribution offers promise in delivering naloxone to people not accessing syringe services.

Mechanistic insights into bone remodelling dysregulation by human viral pathogens.

Bone-related diseases (osteopathologies) associated with human virus infections have increased around the globe. Recent findings have highlighted the intricate interplay between viral infection, the host immune system and the bone remodelling process. Viral infections can disrupt bone homeostasis, contributing to conditions such as arthritis and soft tissue calcifications. Osteopathologies can occur after arbovirus infections such as chikungunya virus, dengue virus and Zika virus, as well as respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 and enteroviruses such as Coxsackievirus B. Here we explore how human viruses dysregulate bone homeostasis, detailing viral factors, molecular mechanisms, host immune response changes and bone remodelling that ultimately result in osteopathologies. We highlight model systems and technologies to advance mechanistic understanding of viral-mediated bone alterations. Finally, we propose potential prophylactic and therapeutic strategies, introduce 'osteovirology' as a research field highlighting the underestimated roles of viruses in bone-related diseases, and discuss research avenues for further investigation.

Assessing views and attitudes toward the use of extended reality and its implications in neurosurgical education: a survey of neurosurgical trainees.

OBJECTIVE: Extended reality (XR) systems, including augmented reality (AR), virtual reality (VR), and mixed reality, have rapidly emerged as new technologies capable of changing the way neurosurgeons prepare for cases. Thus, the authors sought to evaluate the perspectives of neurosurgical trainees on the integration of these technologies into neurosurgical education. METHODS: A 20-question cross-sectional survey was administered to neurosurgical residents and fellows to evaluate perceptions of the use of XR in neurosurgical training. Respondents evaluated each statement using a modified Likert scale (1-5). RESULTS: One hundred sixteen responses were recorded, with 59.5% of participants completing more than 90% of the questions. Approximately 59% of participants reported having institutional access to XR technologies. The majority of XR users (72%) believed it was effective for simulating surgical situations, compared with only 41% for those who did not have access to XR. Most respondents (61%) agreed that XR could become a standard in neurosurgical education and a cost-effective training tool (60%). Creating patient-specific anatomical XR models was considered relatively easy by 56% of respondents. Those with XR access reported finding it easier to create intraoperative models (58%) than those without access. A significant percentage (79%) agreed on the need for technical skill training outside the operating room (OR), especially among those without XR access (82%). There was general agreement (60%) regarding the specific need for XR. XR was perceived as effectively simulating stress in the OR. Regarding clinical outcomes, 61% believed XR improved efficiency and safety and 48% agreed it enhanced resection margins. Major barriers to XR integration included lack of ample training hours and/or time to use XR amid daily clinical obligations (63%). CONCLUSIONS: The data presented in this study indicate that there is broad agreement among neurosurgical trainees that XR holds potential as a training modality in neurosurgical education. Moreover, trainees who have access to XR technologies tend to hold more positive perceptions regarding the benefits of XR in their training. This finding suggests that the availability of XR resources can positively influence trainees' attitudes and beliefs regarding the utility of these technologies in their education and training.

Laparoscopic versus hybrid approach for treatment of incisional ventral hernia: a 5-10-year follow-up of the randomized controlled multicenter study.

PURPOSE: In this long-term follow-up of a prospective, randomized, and multicenter study, we compare the results of a group receiving laparoscopic incisional ventral hernia repair using intraperitoneal onlay mesh (LG) to a group receiving a hybrid hernia repair where open closure of fascial defect was added to intraperitoneal mesh placement (HG). METHODS: Originally, 193 patients with 2-7 cm incisional hernias were randomly assigned to either the LG or HG during the 30-month recruitment period in 2012 to 2015. Long-term follow-up was conducted 5-10 years after surgery to evaluate hernia recurrence rate and quality of life (QoL). RESULTS: In all, 65 patients in the LG and 60 in the HG completed the long-term follow-up with a median follow-up period of 87 months. Recurrent hernia was detected in 11 of 65 patients (16.9%) in the LG and 10 of 60 patients (16.7%) in the HG (p > 0.9). Kaplan-Meier analysis demonstrated a recurrence rate approaching 20% in both groups, with similar curves. Three patients in the LG (4.6% and five patients in the HG (8.1%) had undergone re-operation due to recurrence (p = 0.48). There was no difference in patient-reported QoL measured using the SF-36 questionnaire. Mean pain scores were similar between groups, mean numeric rating scale (NRS) 0 to 10 being 1.1 in the LG and 0.7 in the HG (p = 0.43). CONCLUSION: Fascial closure did not reduce hernia recurrence rate in this study population, even though it has been shown to be beneficial and recommended in surgery guidelines. In the long term, recurrence rate for both groups is similar.

Prediction of preeclampsia in asymptomatic women.

Preeclampsia is a major cause of maternal and perinatal morbidity and mortality. It is important to identify women who are at high risk of developing this disorder in their first trimester of pregnancy to allow timely therapeutic intervention. The use of low-dose aspirin initiated before 16 weeks of gestation can significantly reduce the rate of preterm preeclampsia by 62 %. Effective screening recommended by the Fetal Medicine Foundation (FMF) consists of a combination of maternal risk factors, mean arterial pressure, uterine artery pulsatility index (UtA-PI) and placental growth factor (PLGF). The current model has detection rates of 90 %, 75 %, and 41 % for early, preterm, and term preeclampsia, respectively at 10 % false-positive rate. Similar risk assessment can be performed during the second trimester in all pregnant women irrespective of first trimester screening results. The use of PLGF, UtA-PI, sFlt-1 combined with other investigative tools are part of risk assessment.

Nursing students' satisfaction with the quality of clinical placement and their perceptions of preceptors competence: A prospective longitudinal study.

BACKGROUND: Previous studies have demonstrated that preceptor training programs enhance preceptor competence and effectiveness. However, there is little research that has investigated the link between preceptor training and the quality of clinical placement. AIM: This study sought to determine if preceptor training influences nursing students' satisfaction with the quality of their clinical placement and their perceptions of preceptor competence. DESIGN: Prospective longitudinal survey. METHODS: A total of 189 nursing students from two Nursing Training Colleges in the north of Ghana were surveyed before and after a preceptor training program using two validated questionnaires. Data were analyzed using descriptive statistics and paired samples t-test. RESULTS: There was a statistically significant increase in student satisfaction with the quality of their clinical placement following preceptors' participation in a preceptor training workshop (t(149) = 4.567, p < 0.001). Student perception of preceptor competence also had a statistically significant improvement following preceptor training, increasing from an average of 136.96 ± 21.45 at baseline to 156.49 ± 25.403 in the follow-up survey (t(142) = 6.731, p < 0.001). Furthermore, the percentage of students who perceived preceptors to be highly competent increased from 23.3 % at baseline to 53.8 % following the preceptor training. CONCLUSION: The findings from this study indicate that when supported by preceptors who themselves have had training in effective preceptorship, students are more likely to report higher quality clinical placement and perceive preceptors to be more competent.

Timed adoptive T cell transfer during chemotherapy in patients with recurrent platinum-sensitive epithelial ovarian cancer.

BACKGROUND: The presence of T cells and suppressive myeloid cells in epithelial ovarian cancer (EOC) correlate with good and bad clinical outcome, respectively. This suggests that EOC may be sensitive to adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL), provided that immunosuppression by myeloid-derived suppressor cells and M2 macrophages is reduced. Platinum-based chemotherapy can alleviate such immunosuppression, potentially creating a window of opportunity for T cell-based immunotherapy. METHODS: We initiated a phase I/II trial (NCT04072263) in patients with recurrent platinum-sensitive EOC receiving TIL during platinum-based chemotherapy. TILs were administered 2 weeks after the second, third and fourth chemotherapy course. Patients were treated in two cohorts with or without interferon-α (IFNa), as conditioning and TIL support regimen. The primary endpoint was to evaluate the feasibility and safety according to CTCAE V.4.03 criteria and the clinical response and immune modulatory effects of this treatment were evaluated as secondary endpoints. RESULTS: Sixteen patients were enrolled. TIL could be successfully expanded for all patients. TIL treatment during chemotherapy without IFNa (n=13) was safe but the combination with IFNa added to the chemotherapy-induced toxicity with 2 out of 3 patients developing thrombocytopenia as dose-limiting toxicity. Fourteen patients completed treatment with a full TIL cycle and were further evaluated for clinical and immunological response. Platinum-based chemotherapy resulted in reduction of circulating myeloid cell numbers and IL-6 plasma levels, confirming its immunosuppression-alleviating effect. Three complete (CR), nine partial responses and two stable diseases were recorded, resulting in an objective response rate of 86% (Response Evaluation Criteria In Solid Tumors V.1.1). Interestingly, progression free survival that exceeded the previous platinum-free interval was detected in two patients, including an exceptionally long and ongoing CR in one patient that coincided with sustained alleviation of immune suppression. CONCLUSION: TIL therapy can be safely combined with platinum-based chemotherapy but not in combination with IFNa. The chemotherapy-mediated reduction in immunosuppression and the increase in platinum-free interval for two patients warrants further exploration of properly-timed TIL infusions during platinum-based chemotherapy, possibly further benefiting from IL-2 support, as a novel treatment option for EOC patients.

Development of an Electronic Health Record-Based Algorithm for Predicting Lung Cancer Screening Eligibility in the Population-Based Research to Optimize the Screening Process Lung Research Consortium.

PURPOSE: Lung cancer screening (LCS) guidelines in the United States recommend LCS for those age 50-80 years with at least 20 pack-years smoking history who currently smoke or quit within the last 15 years. We tested the performance of simple smoking-related criteria derived from electronic health record (EHR) data and developed and tested the performance of a multivariable model in predicting LCS eligibility. METHODS: Analyses were completed within the Population-based Research to Optimize the Screening Process Lung Consortium (PROSPR-Lung). In our primary validity analyses, the reference standard LCS eligibility was based on self-reported smoking data collected via survey. Within one PROSPR-Lung health system, we used a training data set and penalized multivariable logistic regression using the Least Absolute Shrinkage and Selection Operator to select EHR-based variables into the prediction model including demographics, smoking history, diagnoses, and prescription medications. A separate test data set assessed model performance. We also conducted external validation analysis in a separate health system and reported AUC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy metrics associated with the Youden Index. RESULTS: There were 14,214 individuals with survey data to assess LCS eligibility in primary analyses. The overall performance for assigning LCS eligibility status as measured by the AUC values at the two health systems was 0.940 and 0.938. At the Youden Index cutoff value, performance metrics were as follows: accuracy, 0.855 and 0.895; sensitivity, 0.886 and 0.920; specificity, 0.896 and 0.850; PPV, 0.357 and 0.444; and NPV, 0.988 and 0.992. CONCLUSION: Our results suggest that health systems can use an EHR-derived multivariable prediction model to aid in the identification of those who may be eligible for LCS.

A Bibliometric Analysis of the Rise of ChatGPT in Medical Research.

The rapid emergence of publicly accessible artificial intelligence platforms such as large language models (LLMs) has led to an equally rapid increase in articles exploring their potential benefits and risks. We performed a bibliometric analysis of ChatGPT literature in medicine and science to better understand publication trends and knowledge gaps. Following title, abstract, and keyword searches of PubMed, Embase, Scopus, and Web of Science databases for ChatGPT articles published in the medical field, articles were screened for inclusion and exclusion criteria. Data were extracted from included articles, with citation counts obtained from PubMed and journal metrics obtained from Clarivate Journal Citation Reports. After screening, 267 articles were included in the study, most of which were editorials or correspondence with an average of 7.5 +/- 18.4 citations per publication. Published articles on ChatGPT were authored largely in the United States, India, and China. The topics discussed included use and accuracy of ChatGPT in research, medical education, and patient counseling. Among non-surgical specialties, radiology published the most ChatGPT-related articles, while plastic surgery published the most articles among surgical specialties. The average citation number among the top 20 most-cited articles was 60.1 +/- 35.3. Among journals with the most ChatGPT-related publications, there were on average 10 +/- 3.7 publications. Our results suggest that managing the inevitable ethical and safety issues that arise with the implementation of LLMs will require further research exploring the capabilities and accuracy of ChatGPT, to generate policies guiding the adoption of artificial intelligence in medicine and science.

Individuals Eligible for Lung Cancer Screening Less Likely to Receive Screening When Enrolled in Health Plans With Deductibles.

BACKGROUND: In 2015, the Centers for Medicare & Medicaid Services and commercial insurance plans began covering lung cancer screening (LCS) without patient cost-sharing for all plans. We explore the impact of enrolling into a deductible plan on the utilization of LCS services despite having no out-of-pocket cost requirement. METHODS: This retrospective study analyzed data from the Population-based Research to Optimize the Screening Process Lung Consortium. Our cohort included non-Medicare LCS-eligible individuals enrolled in managed care organizations between February 5, 2015, and February 28, 2019. We estimate a series of sequential logistic regression models examining utilization across the sequence of events required for baseline LCS. We report the marginal effects of enrollment into deductible plans compared with enrollment in no-deductible plans. RESULTS: The total effect of deductible plan enrollment was a 1.8 percentage-point (PP) decrease in baseline LCS. Sequential logistic regression results that explore each transition separately indicate deductible plan enrollment was associated with a 4.3 PP decrease in receipt of clinician visit, a 1.7 PP decrease in receipt of LCS order, and a 7.0 PP decrease in receipt of baseline LCS. Reductions persisted across all observable races and ethnicities. CONCLUSIONS: These findings suggest individuals enrolled in deductible plans are more likely to forgo preventive LCS services despite requiring no out-of-pocket costs. This result may indicate that increased cost-sharing is associated with suboptimal choices to forgo recommended LCS. Alternatively, this effect may indicate individuals enrolling into deductible plans prefer less health care utilization. Patient outreach interventions at the health plan level may improve LCS.

Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of High-Grade Anal Intraepithelial Neoplasia in HIV+ Men.

PURPOSE: Anal cancer is increasing in HIV+ men who have sex with men (MSM). Treatment options for its precursor, high-grade anal intraepithelial neoplasia (HGAIN), are suboptimal. In this phase I to II dose-finding study, we assessed the safety and efficacy of the human papillomavirus type 16 (HPV16) synthetic long peptide vaccine (SLP-HPV-01) in HIV+ MSM with HPV16-positive HGAIN. PATIENTS AND METHODS: Four dosage schedules (1-5-10; 5-10-20; 10-20-40; and 40-40-40-40 µg) of SLP-HPV-01 were administered intradermally with a 3-week interval in 10 patients per dose level (DL). In each dose group, 5 patients also received 1 µg/kg pegylated IFNα-2b subcutaneously. Primary endpoints were safety and regression of HGAIN at 3, 6, and 12 months. RESULTS: Eighty-one of 134 screened patients (60%) had HPV16-negative HGAIN lesions, leaving 53 eligible patients. Thirteen patients were excluded, leaving 40 men. The vaccine was well tolerated. One patient developed a generalized rash. The highest dosage level induced the strongest immune responses. There was no indication for stronger reactivity in the IFNα groups. Up to 18 months of follow-up, 8/38 intention-to-treat patients had a complete clinical and histologic response and one had a partial response (in total 9/38, 23.7%). At the highest dosage level, the clinical response was 4/10 (40%). Stronger immune responses were detected among clinical responders. CONCLUSIONS: The highest DL is safe, immunogenic, and associated with clinical responses to HPV16-induced lesions. However, as the majority of HGAIN is caused by the other HPV types, further studies should aim at pan-HPV vaccination to prevent or treat HGAIN.

Vamorolone improves Becker muscular dystrophy and increases dystrophin protein in bmx model mice.

There is no approved therapy for Becker muscular dystrophy (BMD), a genetic muscle disease caused by in-frame dystrophin deletions. We previously developed the dissociative corticosteroid vamorolone for treatment of the allelic, dystrophin-null disease Duchenne muscular dystrophy. We hypothesize vamorolone can treat BMD by safely reducing inflammatory signaling in muscle and through a novel mechanism of increasing dystrophin protein via suppression of dystrophin-targeting miRNAs. Here, we test this in the bmx mouse model of BMD. Daily oral treatment with vamorolone or prednisolone improves bmx grip strength and hang time phenotypes. Both drugs reduce myofiber size and decrease the percentage of centrally nucleated fibers. Vamorolone shows improved safety versus prednisolone by avoiding or reducing key side effects to behavior and growth. Intriguingly, vamorolone increases dystrophin protein in both heart and skeletal muscle. These data indicate that vamorolone, nearing approval for Duchenne, shows efficacy in bmx mice and therefore warrants clinical investigation in BMD.