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SummaryBackgroundFilgotinib, an oral, once‐daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis.AimsThe aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long‐term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535).MethodsIn this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double‐blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non‐responders received open‐label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health‐related quality of life (HRQoL). We compared safety and efficacy between achievers and non‐achievers of a multi‐component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements.ResultsData for completers (n = 250) and non‐responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as‐observed proportion of FIL200‐treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non‐responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid‐free pMCS remission than non‐achievers, up to LTE week 96.ConclusionsFilgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long‐term benefit–risk profile. FIL200‐treated CDC achievers had better long‐term outcomes than non‐achievers.

Abstract Background Filgotinib (FIL), an oral, once-daily, Janus kinase 1 inhibitor, was approved for Ulcerative Colitis (UC) treatment after the phase 2b/3 SELECTION trial (NCT02914522). In SELECTION, a greater proportion of FIL200 mg (FIL200)-treated than placebo-treated patients achieved comprehensive disease control (CDC), a stringent multi-component endpoint. We examined the long-term outcomes of achieving CDC in patients continuing on FIL200 in the ongoing long-term extension (LTE) study SELECTIONLTE (NCT02914535). Methods This interim analysis included adult patients with UC who completed SELECTION and received ≤144 weeks of FIL200 in the LTE (up to data cut-off 24/02/22). CDC (biomarker remission, endoscopic improvement, IBDQ remission and partial Mayo Clinic Score [pMCS] remission achieved concurrently) was assessed at SELECTION week 58 (LTE baseline [BL]). Mean pMCS and IBDQ score, use of corticosteroids (CS) and incidence of TEAEs and serious TEAEs in the LTE were compared between SELECTION CDC achievers and non-achievers. A mixed model for repeated measures was fitted on pMCS and IBDQ score, with CDC achiever status, study visit and the interaction between CDC achiever status and study visit as fixed effects; p values were nominal. Results We analysed 148 patients (CDC achievers, n=41; CDC non-achievers, n=107). Mean pMCS was stable in CDC achievers (0.44, LTE BL; 0.50, LTE week 144) and decreased in CDC non-achievers (1.49, LTE BL; 0.77, LTE week 144; Figure). Mean IBDQ score was stable in CDC achievers (204.05, LTE BL; 197.21, LTE week 144) and increased in CDC non-achievers (181.55, LTE BL; 196.37, LTE week 144; Figure). There was a significant beneficial effect of achieving CDC on pMCS and IBDQ score overall (pMCS: fixed effect estimate: −0.5542, p=0.0025; IBDQ score: fixed effect estimate: 13.1585, p=0.0042). There was a significant interaction between achieving CDC and study visit for IBDQ score (p=0.0183), with the benefit of achieving CDC lessening by week 144. Generally, a lower proportion of CDC achievers used CS than non-achievers; 2.4–7.3% of CDC achievers used CS vs 1.9–15.9% of CDC non-achievers. Incidence of TEAEs and serious TEAEs were stable over time and similar between CDC achievers and non-achievers. Conclusion Follow-up for ~3 years showed high levels of long-term benefit with continued FIL200 treatment. Achieving comprehensive disease control at the end of the randomized trial with FIL200 was associated with long-term efficacy, improved HRQoL and low overall use of CS. This may demonstrate the value of filgotinib-induced achievement of CDC in UC disease course. The safety profile of FIL200 was consistent between CDC achievers and non-achievers, suggesting an acceptable long-term benefit–risk profile.

AbstractBackgroundAPOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).MethodGeneration of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.ResultHere we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.ConclusionWe identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.

Background Post-traumatic headache is very common after a mild traumatic brain injury. Post-traumatic headache may persist for months to years after an injury in a substantial proportion of people. The pathophysiology underlying post-traumatic headache remains unknown but is likely distinct from other headache disorders. Identification of brain areas activated in acute and persistent phases of post-traumatic headache can provide insights into the underlying circuits mediating headache pain. We used an animal model of mild traumatic brain injury-induced post-traumatic headache and c-fos immunohistochemistry to identify brain regions with peak activity levels across the acute and persistent phases of post-traumatic headache. Methods Male and female C57BL/6 J mice were briefly anesthetized and subjected to a sham procedure or a weight drop closed-head mild traumatic brain injury . Cutaneous allodynia was assessed in the periorbital and hindpaw regions using von Frey filaments. Immunohistochemical c-fos based neural activity mapping was then performed on sections from whole brain across the development of post-traumatic headache (i.e. peak of the acute phase at 2 days post- mild traumatic brain injury), start of the persistent phase (i.e. >14 days post-mild traumatic brain injury) or after provocation with stress (bright light). Brain areas with consistent and peak levels of c-fos expression across mild traumatic brain injury induced post-traumatic headache were identified and included for further analysis. Results Following mild traumatic brain injury, periorbital and hindpaw allodynia was observed in both male and female mice. This allodynia was transient and subsided within the first 14 days post-mild traumatic brain injury and is representative of acute post-traumatic headache. After this acute post-traumatic headache phase, exposure of mild traumatic brain injury mice to a bright light stress reinstated periorbital and hindpaw allodynia for several hours – indicative of the development of persistent post-traumatic headache. Acute post-traumatic headache was coincident with an increase in neuronal c-fos labeling in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and the nucleus accumbens. Neuronal activation returned to baseline levels by the persistent post-traumatic headache phase in the spinal nucleus of the trigeminal caudalis and primary somatosensory cortex but remained elevated in the nucleus accumbens. In the persistent post-traumatic headache phase, coincident with allodynia observed following bright light stress, we observed bright light stress-induced c-fos neural activation in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens. Conclusion Examination of mild traumatic brain injury-induced changes in peak c-fos expression revealed brain regions with significantly increased neural activity across the acute and persistent phases of post-traumatic headache. Our findings suggest mild traumatic brain injury-induced post-traumatic headache produces neural activation along pain relevant pathways at time-points matching post-traumatic headache-like pain behaviors. These observations suggest that the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens may contribute to both the induction and maintenance of post-traumatic headache.

Summary Background Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC). Aim To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long‐term extension study SELECTIONLTE (NCT02914535). Methods Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11‐week SELECTION induction study, the 47‐week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure‐adjusted incidence rates (EAIRs) per 100 censored patient‐years of exposure with 95% confidence intervals were reported for treatment‐emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status. Results This interim analysis included 1348 patients representing 3326.2 patient‐years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic‐experienced than biologic‐naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib. Conclusion FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age. ClinicalTrials.gov Identifiers (NCT numbers) NCT02914522, NCT02914535.

Abstract The utilization of sports ultrasound in the clinical practice of sports medicine physicians is growing rapidly. Simultaneously, ultrasound is being increasingly implemented as a teaching tool in undergraduate medical education. However, a sports ultrasound curriculum for medical students has not been previously described. In this article, we describe methods as well as barriers to implementing a sports ultrasound curriculum at the medical school level. Recommended content for the curriculum also is discussed. While educational goals and resources will vary among institutions, this article may serve as a general roadmap for the creation of a successful curriculum.

Abstract Background and aims Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE. Methods A total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years. Results The TRI-SCORE was low (≤3) in 32%, intermediate (4–5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P < .0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87%, and 79%, respectively, P = .0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71%, and 71%, respectively, P = .13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81%, and 71%, respectively, P = .009). In the high TRI-SCORE category, survival was not different to conservative management in the surgical and successful repair group (61% and 68% vs 58%, P = .26 and P = .18 respectively). Conclusions Survival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.

Objectives: The purpose of this study was to assess return to play (RTP), patient-reported outcomes (PRO), and reoperation rates following patellofemoral stabilization surgeries (PSS) for recurrent patellar instability (RPI) in a cohort of competitive wrestlers. Methods: All competitive wrestlers with a history of an RPI and subsequent PSS at a single institution between 2000 and 2020 were identified. Primary PSS ranged from MPFL reconstruction (n = 31; 50%) or MPFL repair (n = 22; 33.5%), and other PSS (n = 9; 14.5%) in the form of tibial tubercle osteotomy (TTO), lateral retinaculum release (LRR), and medial retinaculum reefing (MRR). Exclusion criteria included revision PSS, or concomitant anterior cruciate ligament reconstruction or multi ligament knee injury. All patients were contacted for determination of reinjury rates, current sport status, and PROs. Surgical failure defined as subsequent patellar dislocation despite operative management or need for secondary PSS. Results: Ultimately, 62 knees in 56 wrestlers were included at a mean follow-up time of 6.6 years (range, 2.0 – 18.8 years). RTP occurred in 55.3% of wrestlers at a mean of 8.8 ± 6.7 months. Among the PSS no differences were observed between rates of RTP (P = .676), postoperative pain (P = .176), Tegner activity level (P = .801), International Knee Documentation Committee (P = .378), Lysholm (P = .402), or Kujala scores (P = .370). Recurrent patellar instability was the most common complication in 21% of knees. Among PSS types, MPFL reconstruction had the lowest rate of RPI (6.5% vs. 27.3% vs. 55.6%; P = .005), and surgical failure (9.7% vs. 31.8% vs. 55.6%; P = .008). Kaplan-Meier survivorship free from surgical failure of the entire cohort was 91.9% at 1 year, 77.7% at 5 years, and 65.7% at 15 years. MPFL reconstruction had the highest survivorship when compared to MPFL repair and other PSS up to 10 years after the index surgery (90.3% vs. 64.1% vs. 27.8%; P = .048). Conclusions: Recurrent patellar instability remains a concern for competitive wrestlers after PSS. MPFL reconstruction may serve as a more durable surgical treatment option with lower rates of RPI and failure when compared to other PSS up to 10 years after surgery. [Table: see text]

Background: The extent to which recurrent patellar instability (RPI) affects wrestlers has not been thoroughly examined. Purpose: To assess return to wrestling (RTW), patient-reported outcomes, and reoperation rates after patellofemoral stabilization surgery (PFSS) for RPI in a cohort of competitive wrestlers. Study Design: Cohort study; Level of evidence, 3. Methods: All competitive wrestlers with a history of RPI and subsequent PFSS performed at a single institution between 2000 and 2020 were identified. Primary PFSS procedures included medial patellofemoral (MPFL) reconstruction (n = 31; 50%); MPFL repair (n = 22; 35.5%); or other PFSS (n = 9; 14.5%), such as tibial tubercle osteotomy, lateral retinacular release, and/or medial retinacular reefing. Exclusion criteria included revision PFSS or concomitant anterior cruciate ligament reconstruction or multiligament knee injury. Surgical failure was defined as subsequent patellar dislocation despite operative management or need for secondary PFSS. Results: Ultimately, 62 knees in 56 wrestlers with a mean age of 17.0 years (range, 14.0-22.8 years) were included at a mean follow-up of 6.6 years (range, 2.0-18.8 years). RTW occurred in 55.3% of wrestlers at a mean ± SD 8.8 ± 6.7 months. Among PFSS types, no differences were observed in rates of RTW ( P = .676), postoperative pain ( P = .176), Tegner activity level ( P = .801), International Knee Documentation Committee ( P = .378), Lysholm ( P = .402), or Kujala scores ( P = .370). RPI was the most common postoperative complication (n = 13; 21.0%). MPFL reconstruction had the lowest rate of RPI (6.5% vs 27.3% [repair] vs 55.6% [other]; P = .005) and surgical failure (9.7% vs 31.8% [repair] vs 55.6% [other]; P = .008). Kaplan-Meier survivorship free from surgical failure of the entire cohort was 91.9% at 1 year, 77.7% at 5 years, and 65.7% at 15 years. MPFL reconstruction had the highest survivorship when compared with MPFL repair and other PFSS up to 10 years after the index surgery (90.3% vs 64.1% vs 27.8%; P = .048). Conclusion: RPI remains a concern for competitive wrestlers after PFSS. MPFL reconstruction may serve as a more durable surgical treatment option with lower rates of RPI and failure when compared with other PFSS procedures at up to 10 years after surgery.