Real-world clinical outcomes and healthcare costs in patients with Crohn's disease treated with vedolizumab versus ustekinumab in the United States.

OBJECTIVE: To compare real-world treatment persistence, dose escalation, rates of opportunistic or serious infections, and healthcare costs in patients with Crohn's disease (CD) receiving vedolizumab (VDZ) vs ustekinumab (UST) in the United States. METHODS: A retrospective observational study in adults with CD initiated on VDZ or UST on/after 26 September 2016, was performed using the IBM Truven Health MarketScan databases (1 January 2009-30 September 2018). Rates of treatment persistence, dose escalation, opportunistic or serious infection-related encounters, and healthcare costs per patient per month (PPPM) were evaluated. Entropy balancing was used to balance patient characteristics between cohorts. Event rates were assessed using weighted Kaplan-Meier analyses and compared between cohorts using log-rank tests. Healthcare costs were compared between cohorts using weighted 2-part models. RESULTS: 589 VDZ and 599 UST patients were included (172 [29.2%] and 117 [19.5%] were bio-naïve, respectively). After weighting, baseline characteristics were comparable between cohorts. No significant difference in rates of treatment persistence (12-month: VDZ, 76.5%; UST, 82.1%; p = .17), dose escalation (12-month: VDZ, 29.3%; UST, 32.7%; p = .97), or opportunistic or serious infection-related encounters were observed between VDZ and UST. Total mean healthcare costs were significantly lower for patients treated with VDZ vs UST (mean cost difference = -$5051 PPPM; p < .01). Findings were consistent in bio-naïve patients. CONCLUSIONS: In this real-world study, similar treatment persistence, dose escalation, and rates of opportunistic or serious infections were observed with VDZ- and UST-treated patients with CD. However, VDZ was associated with a significantly lower cost outlay for healthcare systems.

Crohn's disease (CD) causes inflammation in the digestive system. Vedolizumab (VDZ) and ustekinumab (UST) are therapies for patients with CD. Little is known about the clinical outcomes and healthcare costs of VDZ versus UST in the real world in the United States. We used health claims data and found that VDZ and UST had comparable real-world clinical outcomes. After 12 months of treatment, the proportions of patients with CD who stayed on treatment and those who needed to increase therapy dose were similar with VDZ and UST. The rate of infection was also similar between the two groups of patients. However, the monthly healthcare costs were $5051 less for patients treated with VDZ than with UST. This was mainly due to the lower cost of VDZ, which was almost half of that of UST. The lower treatment costs with VDZ may provide substantial savings for the healthcare system and patients specifically. Future cost-effectiveness studies on VDZ and UST are needed to aid treatment selection for patients with CD.

Safety of bone marrow derived mesenchymal stem cell extracellular vesicle injection for lumbar facet joint pain.

Aim: A 3-month pilot study to evaluate the safety of injecting a bone marrow-derived mesenchymal stem cell extracellular vesicle advanced investigational product (IP) into the lumbar facet joint space as a treatment for chronic low back pain. Methods: 20 healthy adults were treated with IP injections (0.5 ml/joint) and evaluated by three functional assessments 1, 3, 7, 14, 30, 60 and 90 days later. Results: No adverse effects or complications occurred across the 3-month follow-up. There were no reports of worsening pain. After 3 months group average scores improved significantly (p < 0.0001) in the Severity Index (65.04%), Interference Index (72.09%) and Oswestry Disability Index (58.43%) assessments. Conclusion: IP injections were safe and associated with significant functional improvements.

What is this article about? Bone marrow mesenchymal stem cell derived extracellular vesicles (BM-MSC EV), a novel biologic therapeutic candidate, are a safe and promising therapeutic intervention for patients with lumbar facet joint pain, a malady that manifests as persistent low back pain (LBP). 20 adult subjects with lumbar facet joint pain received a single injection of BM-MSC EV investigational product in the lumbar facet joint space. What were the results? Follow-up was conducted through in-office and virtual visits that included outcome measures to determine the safety and efficacy of this therapy. By the 3-month end point, follow-up was successful, and no complications or adverse events were noted. Significant improvements in all three assessments of pain and disability occurred throughout the study. What do the results of the study mean? The results are promising and suggest that BM-MSC EV may represent a revolutionary treatment option with durable efficacy and minimal safety risks. Randomized, controlled clinical studies into the application of BM-MSC EV in lumbar facet joint pain should be pursued to confirm the potential benefits of this novel intervention.

AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans.

BACKGROUND: Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human PKP2 gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival. METHODS: Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography. RESULTS: Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset. CONCLUSIONS: These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.

Salivary microbiome changes distinguish response to chemoradiotherapy in patients with oral cancer.

BACKGROUND: Oral squamous cell carcinoma (SCC) is associated with oral microbial dysbiosis. In this unique study, we compared pre- to post-treatment salivary microbiome in patients with SCC by 16S rRNA gene sequencing and examined how microbiome changes correlated with the expression of an anti-microbial protein. RESULTS: Treatment of SCC was associated with a reduction in overall bacterial richness and diversity. There were significant changes in the microbial community structure, including a decrease in the abundance of Porphyromonaceae and Prevotellaceae and an increase in Lactobacillaceae. There were also significant changes in the microbial community structure before and after treatment with chemoradiotherapy, but not with surgery alone. In patients treated with chemoradiotherapy alone, several bacterial populations were differentially abundant between responders and non-responders before and after therapy. Microbiome changes were associated with a change in the expression of DMBT1, an anti-microbial protein in human saliva. Additionally, we found that salivary DMBT1, which increases after treatment, could serve as a post-treatment salivary biomarker that links to microbial changes. Specifically, post-treatment increases in human salivary DMBT1 correlated with increased abundance of Gemella spp., Pasteurellaceae spp., Lactobacillus spp., and Oribacterium spp. This is the first longitudinal study to investigate treatment-associated changes (chemoradiotherapy and surgery) in the oral microbiome in patients with SCC along with changes in expression of an anti-microbial protein in saliva. CONCLUSIONS: The composition of the oral microbiota may predict treatment responses; salivary DMBT1 may have a role in modulating the oral microbiome in patients with SCC. After completion of treatment, 6 months after diagnosis, patients had a less diverse and less rich oral microbiome. Leptotrichia was a highly prevalent bacteria genus associated with disease. Expression of DMBT1 was higher after treatment and associated with microbiome changes, the most prominent genus being Gemella Video Abstract.

Early life exposure to broccoli sprouts confers stronger protection against enterocolitis development in an immunological mouse model of inflammatory bowel disease.

IMPORTANCE: To our knowledge, IL-10-KO mice have not previously been used to investigate the interactions of host, microbiota, and broccoli, broccoli sprouts, or broccoli bioactives in resolving symptoms of CD. We showed that a diet containing 10% raw broccoli sprouts increased the plasma concentration of the anti-inflammatory compound sulforaphane and protected mice to varying degrees against disease symptoms, including weight loss or stagnation, fecal blood, and diarrhea. Younger mice responded more strongly to the diet, further reducing symptoms, as well as increased gut bacterial richness, increased bacterial community similarity to each other, and more location-specific communities than older mice on the diet intervention. Crohn's disease disrupts the lives of patients and requires people to alter dietary and lifestyle habits to manage symptoms. The current medical treatment is expensive with significant side effects, and a dietary intervention represents an affordable, accessible, and simple strategy to reduce the burden of symptoms.

Skill transference and learning curves in novice learners: a randomized comparison of robotic and laparoscopic platforms.

BACKGROUND: While well-established protocols direct laparoscopic training, there remains a relative paucity of guidelines for robotic education. Furthermore, it is unknown how exposure to one platform influences trainees' proficiency in the other. This study aimed to compare and quantify (1) learning curves and (2) transference of skill between the two modalities in novice learners. METHODS: Thirty pre-clinical medical students were randomized into two groups. One group performed the peg-transfer task using the robot first, followed by laparoscopy, while the other group performed the same task laparoscopically first. Participants completed five repetitions with each methodology. Participants were timed and errors were recorded. We hypothesized that laparoscopic experience with the peg-transfer task would assist in completing the task robotically, and there would be a higher degree of skill transference from the laparoscopic to robotic platform. RESULTS: Peg-transfer task completion was consistently faster and more accurate with the robot compared to laparoscopy (p < 0.01). We observed a positive transference of skill from the laparoscopic to robotic platform. However, exposure to the robot-hindered students' ability to perform the task laparoscopically, evidenced by significantly increased time and errors when compared with baseline laparoscopic performance (p < 0.01). CONCLUSION: These findings encourage surgical residency programs to treat robotic and laparoscopic training as discrete entities and consider their unique learning curves and skill transference when designing an efficient curriculum. While these effects are observed in novices, future directions include uncovering the trends among resident trainees and practicing surgeons.

Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge.

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.

Simplifying Retroperitoneal Robotic Single-port Surgery: Novel Supine Anterior Retroperitoneal Access.

BACKGROUND: Multiport robotic surgery in the retroperitoneum is limited by the bulky robotic frame and clashing of instruments. Moreover, patients are placed in the lateral decubitus position, which has been linked to complications. OBJECTIVE: To assess the feasibility and safety of a supine anterior retroperitoneal access (SARA) technique with the da Vinci Single-Port (SP) robotic platform. DESIGN, SETTING, AND PARTICIPANTS: Between October 2022 and January 2023, 18 patients underwent surgery using the SARA technique for renal cancer, urothelial cancer, or ureteral stenosis. Perioperative variables were prospectively collected and outcomes were assessed. SURGICAL PROCEDURE: With the patient in a supine position, a 3-cm incision is made at the McBurney point and the abdominal muscles are dissected. Finger dissection is used to develop the retroperitoneal space for the da Vinci SP access port. After docking, the first step is to dissect retroperitoneal tissue to reveal the psoas muscle. This allows identification of the ureter, the inferior renal pole, and the hilum. MEASUREMENTS: A descriptive statistical analysis was performed. Data collected included demographics, operative time, warm ischemia time (WIT), surgical margin status, complications, length of hospital stay, 30-d Clavien-Dindo complications, and postoperative narcotic use. RESULTS AND LIMITATIONS: Twelve patients underwent partial nephrectomy (PN) and two each underwent pyeloplasty, radical nephroureterectomy, and radical nephrectomy. In the PN group, mean age was 57 yr (interquartile range [IQR] 30-73), median body mass index was 32 kg/m2 (IQR 17-58), and 25% had stage ≥3 chronic kidney disease. The median Charlson comorbidity index was 3 (IQR 0-7) and 75% of PN patients had an American Society of Anesthesiologists score ≥3. The median RENAL score was 5 (IQR 4-7). The median WIT was 25 min (IQR 16-48) and the median tumor size was 35 mm (IQR 16-50). The median estimated blood loss was 105 ml (IQR 20-400) and the median operative time was 160 min (IQR 110-200). Positive surgical margins were found in one patient. In the overall cohort, one patient was readmitted and managed conservatively; 83% of the PN group were discharged on the same day as their surgery, with the remainder discharged the next day. At 7 d after surgery, no patients reported narcotic use. CONCLUSIONS: The SARA approach is feasible and safe. Larger studies are needed to confirm this approach as a one-step solution for upper urinary tract surgery. PATIENT SUMMARY: We assessed initial outcomes of a novel approach for accessing the retroperitoneum (the space behind the abdominal cavity and in front of the back muscles and spine) during robot-assisted surgery in the upper urinary tract. The patient is placed on their back and surgery is performed with a single-port robot. Our results show that this approach was feasible and safe, with low complication rates, less postoperative pain, and earlier discharge. This is a promising start, but larger studies are needed to confirm our findings.

Beyond post-operative readmissions: analysis of the impact of unplanned readmissions during primary treatment of advanced-stage epithelial ovarian cancer on long-term oncology outcome.

BACKGROUND: Multiple studies have assessed post-operative readmissions in advanced ovarian cancer. OBJECTIVE: To evaluate all unplanned readmissions during the primary treatment period of advanced epithelial ovarian cancer, and the impact of readmission on progression-free survival. METHODS: This was a single institution retrospective study from January 2008 to October 2018. Χ2/Fisher's exact and t-test, or Kruskal-Wallis test were used. Multivariable Cox proportional hazard models were used to assess the effect of covariates in progression-free survival analysis. RESULTS: A total of 484 patients (279 primary cytoreductive surgery, 205 neoadjuvant chemotherapy) were analyzed. In total, 272 of 484 (56%; 37% primary cytoreductive surgery, 32% neoadjuvant chemotherapy, p=0.29) patients were readmitted during the primary treatment period. Overall, 42.3% of the readmissions were surgery related, 47.8% were chemotherapy related, and 59.6% were cancer related but not related to surgery or chemotherapy, and each readmission could qualify for more than one reason. Readmitted patients had a higher rate of chronic kidney disease (4.1% vs 1.0%, p=0.038). Post-operative, chemotherapy, and cancer-related readmissions were similar between the two groups. However, the percentage of inpatient treatment days due to unplanned readmission was twice as high for primary cytoreductive surgery at 2.2% vs 1.3% for neoadjuvant chemotherapy (p<0.001). Despite longer readmissions in the primary cytoreductive surgery group, Cox regression analysis demonstrated that readmissions did not affect progression-free survival (HR=1.22, 95% CI 0.98 to 1.51; p=0.08). Primary cytoreductive surgery, higher modified Frailty Index, grade 3 disease, and optimal cytoreduction were associated with longer progression-free survival. CONCLUSIONS: In this study, 35% of the women with advanced ovarian cancer had at least one unplanned readmission during the entire treatment time. Patients treated by primary cytoreductive surgery spent more days during readmission than those with neoadjuvant chemotherapy. Readmissions did not affect progression-free survival and may not be valuable as a quality metric.

Specific Forms of Graphene Quantum Dots Induce Apoptosis and Cell Cycle Arrest in Breast Cancer Cells.

Graphene quantum dots (GQDs), nanomaterials derived from graphene and carbon dots, are highly stable, soluble, and have exceptional optical properties. Further, they have low toxicity and are excellent vehicles for carrying drugs or fluorescein dyes. Specific forms of GQDs can induce apoptosis and could be used to treat cancers. In this study, three forms of GQDs (GQD (nitrogen:carbon = 1:3), ortho-GQD, and meta-GQD) were screened and tested for their potential to inhibit breast cancer cell (MCF-7, BT-474, MDA-MB-231, and T-47D) growth. All three GQDs decreased cell viability after 72 h of treatment and specifically affected breast cancer cell proliferation. An assay for the expression of apoptotic proteins revealed that p21 and p27 were up-regulated (1.41-fold and 4.75-fold) after treatment. In particular, ortho-GQD-treated cells showed G2/M phase arrest. The GQDs specifically induced apoptosis in estrogen receptor-positive breast cancer cell lines. These results indicate that these GQDs induce apoptosis and G2/M cell cycle arrest in specific breast cancer subtypes and could potentially be used for treating breast cancers.

Maribavir Pharmacokinetics and Safety in Participants With Moderate Hepatic Impairment: A Phase 1, Open-Label, Single-Dose, Parallel Group Study.

Maribavir, an orally bioavailable antiviral, has shown superior activity against posttransplant cytomegalovirus infection compared with conventional antivirals. It is primarily metabolized in the liver. This open-label, single-center study evaluated the effect of hepatic impairment on the pharmacokinetics of maribavir in nontransplant participants. A single 200-mg dose of maribavir was administered orally under fasting conditions to participants with moderate hepatic impairment (Child-Pugh class B) (n = 10) and healthy controls (n = 10) matched for age, weight, sex, and smoking status. Compared with participants with normal hepatic function, maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 to infinity values for maribavir in participants with moderate hepatic impairment were 1.346-fold (90%CI of geometric mean ratio, 1.091-1.660) and 1.261-fold (0.889-1.787) higher, respectively. However, Cmax and AUC values for unbound maribavir were comparable. For VP 44469, the main metabolite of maribavir, the Cmax and AUC from time 0 to infinity values were 1.190-fold (0.836-1.693) and 1.309-fold (1.007-1.702) higher, respectively, in participants with moderate hepatic impairment. In total, 7 mild treatment-emergent adverse events were reported, all in the moderate hepatic impairment group. Dysgeusia was the most frequently reported treatment-emergent adverse event, at a frequency of 50%. These results indicated that total maribavir concentrations were mildly increased in participants with moderate hepatic impairment, while unbound concentrations were unaffected. Similar maribavir pharmacokinetics in participants with moderate hepatic impairment and normal hepatic function suggest that dose adjustment may not be required for patients with moderate hepatic impairment.

E-cigarettes may serve as a gateway to conventional cigarettes and other addictive drugs.

Electronic cigarettes (e-cigarettes) are devices that allow the user to inhale nicotine in a vapor, and are primarily marketed as a means of quitting smoking and a less harmful replacement for traditional cigarette smoking. However, further research is needed to determine if vaping nicotine via e-cigarettes can be effective. Conversely, nicotine has been considered a gateway drug to alcohol and other addictive drugs and e-cigarettes containing nicotine may have the same effects. Previous reports have shown that e-cigarette use may open the gate for the use of other drugs including conventional cigarettes, cannabis, opioids, etc. The increasing prevalence of e-cigarettes, particularly among youth and adolescents in the last decade have led to an increase in the dual use of e-cigarettes with alcohol, cannabis, and other illicit drug use like heroin and 3-4-methylenedioxymethamphetamine (MDMA). The advent of e-cigarettes as a device to self-administer addictive agents such as cocaine and synthetic cathinones may bring about additional adverse health effects associated with their concurrent use. This review aims to briefly describe e-cigarettes and their different generations, and their co-use with other addictive drugs as well as the use of the device as a tool to self-administer addictive drugs, such as cocaine, etc.

A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine.

There is currently no licensed vaccine for respiratory syncytial virus (RSV). Here, we assess the effect of RSV fusion protein (F) conformation on B cell responses in a post hoc comparison of samples from the DS-Cav1 [prefusion (pre-F)] and MEDI7510 [postfusion (post-F)] vaccine clinical trials. We compared the magnitude and quality of the serological and B cell responses across time points and vaccines. We measured RSV A and B neutralization, F-binding immunoglobulin G titers, and competition assays at week 0 (before vaccination) and week 4 (after vaccination) to evaluate antibody specificity and potency. To compare B cell specificity and activation, we used pre-F and post-F probes in tandem with a 17-color immunophenotyping flow cytometry panel at week 0 (before vaccination) and week 1 (after vaccination). Our data demonstrate that both DS-Cav1 and MEDI7510 vaccination robustly elicit F-specific antibodies and B cells, but DS-Cav1 elicited antibodies that more potently neutralized both RSV A and B. The superior potency was mediated by antibodies that bind antigenic sites on the apex of pre-F that are not present on post-F. In the memory (CD27+) B cell compartment, vaccination with DS-Cav1 or MEDI7510 elicited B cells with different epitope specificities. B cells preferentially binding the pre-F probe were activated in DS-Cav1-vaccinated participants but not in MEDI7510-vaccinated participants. Our findings emphasize the importance of using pre-F as an immunogen in humans because of its deterministic role in eliciting highly potent neutralizing antibodies and memory B cells.

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma.

Ferroptosis is a type of iron-dependent cell death pertaining to an excess of lipid peroxidation. It has been suggested that sorafenib-an anti-angiogenic medication for hepatocellular carcinoma (HCC)-induces ferroptosis, but the underlying mechanism for this remains largely unknown. We employed siRNA-mediated gene silencing to investigate the role of Src homology region 2 domain-containing phosphatase-1 (SHP-1), following sorafenib treatment, in cystine/glutamate-antiporter-system-Xc--regulated cystine uptake. Co-immunoprecipitation was also performed to examine the interactions between MCL1, beclin 1 (BECN1), and solute carrier family 7 member 11 (SLC7A11), which functions as the catalytic subunit of system Xc-. The results of this study showed that sorafenib enhanced the activity of SHP-1, dephosphorylated STAT3, downregulated the expression of MCL1 and, consequently, reduced the association between MCL1 and BECN1. In contrast, increased binding between BECN1 and SLC7A11 was observed following sorafenib treatment. The elevated interaction between BECN1 and SLC7A11 inhibited the activity of system Xc-, whereas BECN1 silencing restored cystine intake and protected cells from ferroptosis. Notably, ectopic expression of MCL1 uncoupled BECN1 from SLC7A11 and rescued cell viability by attenuating lipid peroxidation. The results revealed that ferroptosis could be induced in HCC via SHP-1/STAT3-mediated downregulation of MCL1 and subsequent inhibition of SLC7A11 by increased BECN1 binding.

Single-Port Robotic Surgery: General Principles and Troubleshooting.

The da Vinci single-port (SP) system (Intuitive Surgical, Sunnyvale, CA) is the newest robotic platform released and approved for use in the urologist's armimentarium. This article (and complementary video) aims to summarize the most common problems that have been encountered at the University of Illinois at Chicago when using the SP system. Moreover, solutions to these issues will be presented.

Elicitation of pneumovirus-specific B cell responses by a prefusion-stabilized respiratory syncytial virus F subunit vaccine.

Respiratory syncytial virus (RSV) is a substantial cause of morbidity and mortality globally. A candidate RSV prefusion (pre-F)-stabilized subunit vaccine, DS-Cav1, has previously been shown to elicit potent and durable neutralizing activity in a phase 1 clinical trial in healthy adults. Here, we used fluorescently labeled probes and flow cytometry to evaluate the antigen specificity and phenotype of RSV F-specific B cells longitudinally after DS-Cav1 immunization. Peripheral blood mononuclear cells (PBMCs) collected at time points before the first immunization through the end of the trial at 44 weeks were assessed by flow cytometry. Our data demonstrate a rapid increase in the frequency of pre-F-specific IgG+ and IgA+ B cells after the first immunization and a modest increase after a second immunization at week 12. Nearly all F-specific B cells down-regulated CD21 and up-regulated the proliferation marker CD71 after the first immunization, with less pronounced activation after the second immunization. Memory B cells (CD27+CD21+) specific for pre-F remained elevated above baseline at 44 weeks after vaccination. DS-Cav1 vaccination also activated human metapneumovirus (HMPV) cross-reactive B cells capable of binding prefusion-stabilized HMPV F protein and increased HMPV F-binding antibodies and neutralizing activity for HMPV in some participants. In summary, vaccination with RSV pre-F resulted in the expansion and activation of RSV and HMPV F-specific B cells that were maintained above baseline for at least 10 months and could contribute to long-term pneumovirus immunity.

Human pluripotent stem cell-derived myogenic progenitors undergo maturation to quiescent satellite cells upon engraftment.

Human pluripotent stem cell (hPSC)-derived myogenic progenitor cell (MPC) transplantation is a promising therapeutic approach for a variety of degenerative muscle disorders. Here, using an MPC-specific fluorescent reporter system (PAX7::GFP), we demonstrate that hPSC-derived MPCs can contribute to the regeneration of myofibers in mice following local injury and in mice deficient of dystrophin (mdx). We also demonstrate that a subset of PAX7::GFP MPCs engraft within the basal lamina of regenerated myofibers, adopt a quiescent state, and contribute to regeneration upon reinjury and in mdx mouse models. This subset of PAX7::GFP MPCs undergo a maturation process and remodel their molecular characteristics to resemble those of late-stage fetal MPCs/adult satellite cells following in vivo engraftment. These in-vivo-matured PAX7::GFP MPCs retain a cell-autonomous ability to regenerate and can repopulate in the niche of secondary recipient mice, providing a proof of principle for future hPSC-based cell therapy for muscle disorders.

Sports and trauma as risk factors for Motor Neurone Disease: New Zealand case-control study.

OBJECTIVES: To assess whether sports, physical trauma and emotional trauma are associated with motor neurone disease (MND) in a New Zealand case-control study (2013-2016). METHODS: In total, 321 MND cases and 605 population controls were interviewed collecting information on lifetime histories of playing sports, physical trauma (head injury with concussion, spine injury) and emotional trauma (14 categories). ORs were estimated using logistic regression adjusting for age, sex, ethnicity, socioeconomic status, education, smoking status, alcohol consumption and mutually adjusting for all other exposures. RESULTS: Head injury with concussion ≥3 years before diagnosis was associated with MND (OR 1.51, 95% CI: 1.09-2.09), with strongest associations for two (OR 4.01, 95% CI: 1.82-8.86), and three or more (OR 2.34, 95% CI: 1.00-5.45) head injuries. Spine injury was not associated with MND (OR 0.81, 95% CI: 0.48-1.36). Compared to never playing sports, engaging in sports throughout childhood and adulthood increased MND risk (OR 1.81, 95% CI: 1.01-3.25), as was more than 12 years playing football/soccer (OR 2.35, 95% CI: 1.19-4.65). Reporting emotionally traumatic events in more than three categories was associated with MND (OR 1.88, 95% CI: 1.17-3.03), with physical childhood abuse the only specific emotional trauma associated with MND (OR 1.82, 95% CI: 1.14-2.90), particularly for those reporting longer abuse duration (OR(5-8 years) 2.26, 95% CI: 1.14-4.49; OR(>8 years) 3.01, 95% CI: 1.18-7.70). For females, having witnessed another person being killed, seriously injured or assaulted also increased MND risk (OR 2.68, 95% CI: 1.06-6.76). CONCLUSIONS: This study adds to the evidence that repeated head injury with concussion, playing sports in general, and playing football (soccer) in particular, are associated with an increased risk of MND. Emotional trauma, that is physical abuse in childhood, may also play a role.