After this, nothing happened.

The presence of COVID-19 means that the world will not return to a prior normal, but we cannot yet know into what future we will head. The world will have considerably changed from the one in which our subjectivities were first formed. Though curriculum may be the story we tell our children, the presence of this plague has made a severe break in that story. But curriculum might serve as the source of a radical hope that will lead us to a future we cannot yet imagine. In curriculum, we can attend to the world that has now passed, after which nothing happened, and from the scattered fragments of culture begin to construct new subjectivities and provide the space for the rebirth of culture that we cannot yet know or yet even imagine.

Update on Fibrocartilaginous Disease Clinical Examination.

This article provides an update on fibrocartilaginous disease clinical examination. Lesser metatarsophalangeal joint instability is a challenging entity for the foot and ankle surgeon. A correct diagnosis is crucial to instill an appropriate treatment plan that will result in a successful outcome and a satisfied patient. Insertional Achilles tendon disorders are common among active and inactive patients. There is also a high predilection for Achilles tendon pathology among athletes. In this article demographics and patient history, causative factors, differential diagnosis, physical examination, clinical tests, and radiographic evaluation are discussed for plantar plate disorders and insertional Achilles disorders.

Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis.

OBJECTIVE: We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS: This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS: Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION: Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial.

BACKGROUND: Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. METHODS: We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6-17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. FINDINGS: Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0.0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0.0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16-0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0.47); only two serious adverse events were reported, both in controls (p=0.50). INTERPRETATION: Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. FUNDING: Bristol-Myers Squibb.

Determinants of elevated pulse pressure in middle-aged and older subjects with uncomplicated systolic hypertension: the role of proximal aortic diameter and the aortic pressure-flow relationship.

BACKGROUND: Elevated pulse pressure (PP) is associated with increased cardiovascular risk and is thought to be secondary to elastin fragmentation with secondary collagen deposition and stiffening of the aortic wall, leading to a dilated, noncompliant vasculature. METHODS AND RESULTS: By use of calibrated tonometry and pulsed Doppler, arterial stiffness and pulsatile hemodynamics were assessed in 128 subjects with uncomplicated systolic hypertension (supine systolic pressure > or =140 mm Hg off medication) and 30 normotensive control subjects of comparable age and gender. Pulse-wave velocity was assessed from tonometry and body surface measurements. Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Effective aortic diameter was assessed by use of the water hammer equation. Hypertensives were heavier (P<0.001) and had higher PP (P<0.001), which was attributable primarily to higher Zc (P<0.001), especially in women. Pulse-wave velocity was higher in hypertensives (P=0.001); however, this difference was not significant after adjustment for differences in mean arterial pressure (MAP) (P>0.153), whereas increased Zc remained highly significant (P<0.001). Increased Zc in women and in hypertensive men was attributable to decreased effective aortic diameter, with no difference in wall stiffness at comparable MAP and body weight. CONCLUSIONS: Elevated PP in systolic hypertension was independent of MAP and was attributable primarily to elevated Zc and reduced effective diameter of the proximal aorta. These findings are not consistent with the hypothesis of secondary aortic degeneration, dilation, and wall stiffening but rather suggest that aortic function may play an active role in the pathophysiology of systolic hypertension.

Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study.

BACKGROUND: Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. METHODS AND RESULTS: We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be > or =160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Z(c)), a direct measure of the stiffness of the central aorta, was calculated from the ratio of changes in carotid pressure and aortic flow in early systole. Omapatrilat compared with enalapril produced greater reductions in peripheral (-8.2+/-12.2 versus -4.0+/-12.2 mm Hg, P<0.05) and central (-10.2+/-16.2 versus -3.2+/-16.9 mm Hg, P<0.01) pulse pressures and Z(c) (237+/-83 to 208+/-70 versus 225+/-87 to 231+/-94 dyne x s/cm(5), P<0.001); the latter remained significant (P<0.05) after adjusting for change in mean pressure. CONCLUSIONS: Greater reductions in pulse pressure and Z(c) in hypertensive subjects treated with omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms and underscore a potential role for pharmacological modulation of natriuretic peptides in the treatment of hypertension.

Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years.

OBJECTIVE: The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease-modifying antirheumatic drugs were previously established in a phase III study that included a 4-month open-label lead-in period, a 6-month double-blind withdrawal period, and a long-term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient-reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup. METHODS: Patients enrolled in the phase III trial could enter the open-label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double-blind period. RESULTS: One hundred fifty-three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient-years) of adverse events decreased during the LTE phase (433.61 events during the short-term phase [combined lead-in and double-blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time. CONCLUSION: Long-term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality-of-life benefits in patients with JIA.

Comparison of the effects of omapatrilat and lisinopril on circulating neurohormones and cytokines in patients with chronic heart failure.

Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.

Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies).

BACKGROUND: Cardiovascular disease, the most common cause of death with a functioning graft among kidney transplant recipients, can be exacerbated by immunosuppressive drugs, particularly the calcineurin inhibitors. Belatacept, a selective co-stimulation blocker, may provide a better cardiovascular/metabolic risk profile than current immunosuppressants. METHODS: Cardiovascular and metabolic endpoints from two Phase III studies (BENEFIT and BENEFIT-EXT) of belatacept-based regimens in kidney transplant recipients were assessed at month 12. Each study assessed belatacept in more intensive (MI) and less intensive (LI) regimens versus cyclosporine A (CsA). These secondary endpoints included changes in blood pressure, changes in serum lipids, and the incidence of new-onset diabetes after transplant (NODAT). RESULTS: A total of 1209 patients were randomized and transplanted across the two studies. Mean systolic blood pressure was 6 to 9 mm Hg lower and mean diastolic blood pressure was 3 to 4 mm Hg lower in the MI and LI groups versus CsA (P ≤ 0.002) across both studies at month 12. Non-HDL cholesterol was lower in the belatacept groups versus CsA (P<0.01 MI or LI vs. CsA in each study). Serum triglycerides were lower in the belatacept groups versus CsA (P<0.02 MI or LI vs. CsA in each study). NODAT occurred less often in the belatacept groups versus CsA in a prespecified pooled analysis (P<0.05 MI or LI vs. CsA). CONCLUSIONS: At month 12, belatacept regimens were associated with better cardiovascular and metabolic risk profiles, with lower blood pressure and serum lipids and less NODAT versus CsA. The overall profile of belatacept will continue to be assessed over the 3-year trials.

Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies.

BACKGROUND: At 1 year, belatacept was associated with similar patient/graft survival, better renal function, and an improved cardiovascular/metabolic risk profile versus cyclosporine A (CsA) in the Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT) studies. Acute rejection was more frequent with belatacept in BENEFIT. Posttransplant lymphoproliferative disorder (PTLD)--specifically central nervous system PTLD--was observed more frequently in belatacept-treated patients. This analysis assesses outcomes from BENEFIT and BENEFIT-EXT after 2 years of treatment. METHODS: Patients received a more intensive (MI) or a less intensive (LI) regimen of belatacept or a CsA-based regimen. RESULTS: Four hundred ninety-three of 666 patients (74%) in BENEFIT and 347 of 543 (64%) in BENEFIT-EXT completed 2 years of treatment. The proportion of patients who survived with a functioning graft was similar across groups (BENEFIT: 94% MI, 95% LI, and 91% CsA; BENEFIT-EXT: 83% MI, 84% LI, and 83% CsA). Belatacept's renal benefits were sustained, as evidenced by a 16 to 17 mL/min (BENEFIT) and an 8 to 10 mL/min (BENEFIT-EXT) higher calculated glomerular filtration rate in the belatacept groups versus CsA. There were few new acute rejection episodes in either study between years 1 and 2. Because PTLD risk was highest in Epstein-Barr virus (EBV) (-) patients, an efficacy analysis of EBV (+) patients was performed and was consistent with the overall population results. There were two previously reported cases of PTLD in each study between years 1 and 2 in the belatacept groups. The overall balance of safety and efficacy favored the LI over the MI regimen. CONCLUSIONS: At 2 years, belatacept-based regimens sustained better renal function, similar patient/graft survival, and an improved cardiovascular/metabolic risk profile versus CsA; outcomes that were maintained in EBV (+) patients. No new safety signals emerged.

Abatacept improves health-related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis.

OBJECTIVE: To assess health-related quality of life (HRQOL) in abatacept-treated children/adolescents with juvenile idiopathic arthritis (JIA). METHODS: In this phase III, double-blind, placebo-controlled trial, subjects with active polyarticular course JIA and an inadequate response/intolerance to ≥1 disease-modifying antirheumatic drug (including biologics) received abatacept 10 mg/kg plus methotrexate (MTX) during the 4-month open-label period (period A). Subjects achieving the American College of Rheumatology Pediatric 30 criteria for improvement (defined "responders") were randomized to abatacept or placebo (plus MTX) in the 6-month double-blind withdrawal period (period B). HRQOL assessments included 15 Child Health Questionnaire (CHQ) health concepts plus the physical (PhS) and psychosocial summary scores (PsS), pain (100-mm visual analog scale), the Children's Sleep Habits Questionnaire, and a daily activity participation questionnaire. RESULTS: A total of 190 subjects from period A and 122 from period B were eligible for analysis. In period A, there were substantial improvements across all of the CHQ domains (greatest improvement was in pain/discomfort) and the PhS (8.3 units) and PsS (4.3 units) with abatacept. At the end of period B, abatacept-treated subjects had greater improvements versus placebo in all domains (except behavior) and both summary scores. Similar improvement patterns were seen with pain and sleep. For participation in daily activities, an additional 2.6 school days/month and 2.3 parents' usual activity days/month were gained in period A responders with abatacept, and further gains were made in period B (1.9 versus 0.9 [P = 0.033] and 0.2 versus -1.3 [P = 0.109] school days/month and parents' usual activity days/month, respectively, in abatacept- versus placebo-treated subjects). CONCLUSION: Improvements in HRQOL were observed with abatacept, providing real-life tangible benefits to children with JIA and their parents/caregivers.

Evaluation of ultrasound-guided extracorporeal shock wave therapy (ESWT) in the treatment of chronic plantar fasciitis.

Thirty patients (39 heels) were evaluated to determine the success of ultrasound-guided ESWT for treatment of recalcitrant plantar fasciitis. All patients had been diagnosed and treated for plantar fasciitis for greater than 6 months and had failed at least 3 conservative treatment modalities. Each patient received 3800 shockwaves into the treated heel using the Dornier Epos Ultra ESWT machine. The average postoperative follow-up was 124 days (range, 33 to 255). Written subjective surveys evaluated pre- and posttreatment pain levels using a visual analog scoring system. The mean pretreatment score was 8.51 (range, 5 to 10), which improved to a mean follow-up score of 3.75 (range, 0 to 10). This represents an improvement in the mean VAS of 4.76, which is statistically significant ( P = .0002). Twenty-five of 30 patients reported some degree of improvement, with 5 experiencing no change. These early results indicate ultrasound-guided ESWT may be a useful tool in the treatment armamentarium for chronic plantar fasciitis.

Treatment of recalcitrant intermetatarsal neuroma with 4% sclerosing alcohol injection: a pilot study.

The purpose of this investigation was to conduct a prospective trial to assess the effectiveness of a 4% sclerosing alcohol injection in a small group of patients with intermetatarsal neuromas who had failed previous conservative therapies including corticosteroid injections. Six patients with 8 neuromas were followed for a mean 346 days. A weekly series of 3-9 injections containing 1 mL of the 4% alcohol sclerosing solution were given based on patient response to treatment. Pre- and posttreatment surveys consisting of both objective and subjective findings including a visual analog pain scale were collected. The average pretreatment visual analog pain rating was 7.5 +/- 1.14. The average posttreatment visual analog pain rating was 1.38 +/- 2.39 with an average reduction of 6.13. The average reported improvement in symptoms was 73%. Five of the 6 patients would recommend the treatment to a friend or family member. No complications were encountered. Two neuromas in 2 patients failed the sclerosing injection course: 1 ultimately responded to antiinflammatory use and the other underwent excision.

Evaluation of the anterior and middle talocalcaneal articular facets and the Evans osteotomy.

The purpose of this study was to determine the occurrence of discrete anterior and middle talocalcaneal facets and the distance of these facets from the anterior border of the calcaneus as it relates to the Evans osteotomy. Seven hundred sixty-eight calcanei were examined from the human osteology archive at the Cleveland Museum of Natural History. Measurements taken included: 1) distance from the proximal border of the anterior facet to the anterior border of the calcaneus (DTAF), 2) distance from the distal border of the middle facet to the anterior border of the calcaneus (DTMF), and 3) width of facet separation (WFS). The results revealed that 310 of 755 (41.06%) had discrete anterior and middle facets and 423 of 755 (56.03%) had a conjoined facet. In those with discrete facets, the mean DTAF, DTMF, and WFS were 11.04 mm, 15.47 mm, and 3.85 mm, respectively. In those with discrete facets, an osteotomy begun between 11.5 mm and 15 mm from the calcaneocuboid joint should pass between the anterior and middle facets and avoid damaging these articular surfaces. This information may aid the foot and ankle surgeon in patient selection and in attaining optimal surgical outcome for the Evans lateral column lengthening procedure.