Lebrikizumab monotherapy impacts on quality of life scores through improved itch and sleep interference in two Phase 3 trials.

BACKGROUND: Lebrikizumab improved itch, interference of itch on sleep, and quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD), in two Phase 3 trials at 16 weeks compared to placebo. OBJECTIVES: We assess improvements in itch and sleep interference due to itch and their impact on QoL measurements after treatment. METHODS: Data were analyzed from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) in patients with moderate-to-severe AD. QoL was evaluated using Dermatology Life Quality Index (DLQI) at Week 16 in patients (>16 years of age) who were itch responders/non-responders (defined as ≥4-point improvement in Pruritus Numeric Rating Scale) or Sleep-Loss Scale responders/non-responders (defined as ≥2-point improvement in itch interference on sleep). RESULTS: In ADvocate1 and ADvocate2, significantly greater proportions of itch responders had a clinically meaningful improvement in measures related to QoL (DLQI scores (0/1), ≤5 DLQI total score and ≥4-point DLQI improvement) compared to itch non-responders. In both studies, a significantly greater proportion of Sleep-Loss Scale responders, reported a DLQI score of (0/1), DLQI total score of ≤5 and DLQI improvement of ≥4 points compared to Sleep-Loss Scale non-responders. CONCLUSIONS: Improvement in itch and sleep interference due to itch is associated with improvement in the QoL of patients after treatment with lebrikizumab for moderate-to-severe AD.ClinicalTrials.gov registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2).

Innominate artery pseudoaneurysm from a Salter-Harris fracture of the sternoclavicular joint.

Fractures and dislocations of the sternoclavicular joint (SCJ) are uncommon, accounting for <5% of all shoulder girdle injuries. They are relatively more common in the pediatric population than in the adult population and can often present concurrently as a posteriorly displaced medial clavicular dislocation with a fracture through the unfused physis. It is especially important to recognize this injury, because its management and potential sequelae are very different from those for fractures of the clavicle shaft. This type of injury frequently requires closed or open operative management because fracture-dislocation of the SCJ can be associated with potentially serious complications such as pneumothorax, brachial plexus injury, vagus nerve injury, tracheal injury, and vascular compromise. Few case reports describe fracture-dislocation of the SCJ resulting in vascular injuries. We describe the case of a 17-year-old boy who sustained a blunt hockey injury resulting in a right physeal fracture-dislocation of the SCJ causing an innominate artery pseudoaneurysm. This was treated with excision of the pseudoaneurysm, bovine pericardial patch angioplasty repair of the innominate artery, and open reduction and internal fixation of the medial clavicular physeal fracture.

Most Online Resources for Home Suture Removal are Poor in Quality.

Introduction: At home suture or staple removal can be stressful for patients and may lead some to seek out additional instruction via online resources as an adjunct to what was explained to them by their provider. The purpose of this study was to examine the existing online resources available to patients who may be interested in or have been instructed to remove sutures at home after a simple procedure, such as a skin biopsy or excision. Methods: A systematic search was conducted using internet search engines to identify videos and webpages targeting at home suture removal instruction. The DISCERN instrument was used to evaluate the information quality of each included resource. Results: There was no statistically significant difference between average DISCERN scores for videos and webpage resources, and the majority were rated poor in quality. Conclusions: The online resources for at home suture and staple removal were often not comprehensive and were below the standard quality for written information. Health care providers should consider referring their patients to validated online sources for suture removal to prevent misinformation and improve patient safety.

Symptomatic peripheral artery disease increases risk of perioperative mortality following open abdominal aortic aneurysm repair.

OBJECTIVE: Peripheral artery disease (PAD) is associated with worse survival following abdominal aortic aneurysm (AAA) repair. However, little is known about the impact of PAD and sex on outcomes following open infrarenal AAA repair (OAR). METHODS: All elective open infrarenal AAA cases were queried from the Society for Vascular Surgery Vascular Quality Initiative from 2003 to 2022. PAD was defined as history of non-cardiac arterial bypass, non-coronary percutaneous vascular intervention (PVI), or non-traumatic major amputation. Cohorts were stratified by sex and history of PAD. Multivariable logistic regression and Cox proportional hazards models were constructed to assess the primary endpoints: 30-day and 5-year mortality, respectively. RESULTS: Of 4910 patients who underwent elective OAR, 3421 (69.7%) were men without PAD, 298 (6.1%) were men with PAD, 1098 (22.4%) were women without PAD, and 93 (1.9%) were women with PAD. Men with PAD had prior bypass (45%), PVI (62%), and amputation (6.7%). Women with PAD had prior bypass (32%), PVI (76%), and amputation (5.4%). Thirty-day mortality was significantly higher in men with PAD compared with men without PAD (4.4% vs 1.7%; P = .001) and in women with PAD compared with women without PAD (7.5% vs 2.4%; P = .01). After risk adjustment, when compared with men without PAD, women with PAD had nearly four times the odds of 30-day mortality (odds ratio, 3.86; 95% confidence interval [CI], 1.55-9.64; P = .004) and men with PAD had almost three times the odds of 30-day mortality (odds ratio, 2.77; 95% CI, 1.42-5.40; P = .003). Five-year survival was 87.8% in men without PAD, 77.8% in men with PAD, 85% in women without PAD, and 76.2% in women with PAD (P < .001). After risk adjustment, only men with PAD had an increased hazard of death at 5 years (hazard ratio, 1.52; 95% CI, 1.07-2.17; P = .019) compared with men without PAD. CONCLUSIONS: PAD is a potent risk factor for increased perioperative mortality in both men and women following OAR. In women, this equates to nearly four times the odds of perioperative mortality compared with men without PAD. Future study evaluating risk/benefit is needed to determine if women with PAD reflect a high-risk cohort that may benefit from a more conservative OAR threshold for treatment.

Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.

BACKGROUND: Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan. OBJECTIVES: To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods. METHODS: This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated. RESULTS: Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported. CONCLUSIONS: This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.

Characterizing the frequency and indications for repair of abdominal aortic aneurysms with diameters smaller than recommended by societal guidelines.

OBJECTIVE: Although the Society for Vascular Surgery recommends repair of abdominal aortic aneurysms (AAA) at 5.5 cm or greater in men and 5.0 cm or greater in women, AAA repair below these thresholds has been well-documented. There are clear indications for repair other than these strict size criteria, but the expected proportion of such repairs in one's practice has not been studied. We sought to characterize the indications for repairs of aneurysms below diameter recommendations at a single academic center. Using the assumption that this real-world experience would approximate that of other practices, we then used national data to extrapolate these findings. METHODS: A single-center retrospective review was conducted of all elective open AAA (oAAA) and endovascular aneurysm repair (EVAR) from 2010 to 2020 to assess the incidence of and indications for repair of aneurysms below diameter recommendations (defined as <5.5 cm in men and <5.0 cm in women). Reasons for these repairs were defined as (1) iliac aneurysm, (2) saccular morphology, (3) rapid expansion, (4) patient anxiety, (5) distal embolization, (6) other, and (7) no documented reason. The Vascular Quality Initiative (VQI) was queried for all asymptomatic oAAA and EVAR (2010-2020) and repairs below diameter recommendations were identified. Findings from the single-center analysis were applied to the VQI cohort to extrapolate estimates of reasons for repairs done nationally. In-hospital mortality and major adverse cardiac events (MACE) were compared between those below size recommendations and those meeting size recommendations. RESULTS: Of 456 elective AAA repairs at our center, 147 (32%) were below size recommendations. This finding was more common for EVAR (35% vs 28%). Reasons were: not documented (41%), iliac aneurysm (23%), saccular (10%), rapid expansion (10%), patient anxiety (7%), other (6%), and distal embolism (3%). Of 44,820 elective AAA repairs in the VQI, 17,057 (38%) were below size recommendations (40% EVAR, 26% oAAA). Patients who were repaired below size recommendations had lower in-hospital death (oAAA, 2.4% vs 4.6% [P < .0001]; EVAR, 0.3% vs 0.8% [P < .0001]). When single-center findings were applied to the VQI dataset, an estimated 10,064 repairs were performed nationally for acceptable indications other than size criteria. Conversely, there may have been 6993 repairs (with an associated 35 deaths) performed without documented indication. CONCLUSIONS: Repairs for AAA below the recommended diameter guidelines account for approximately one-third of all elective AAA procedures in both the VQI and our single-center experience. Assuming our practice is typical, nearly 60% of repairs below size recommendations meet the criteria for other clear reasons. The remaining 40% lack a documented reason, meaning that 13% of all elective AAA repairs were done for aneurysms below size recommendations without an acceptable indication. As awareness of overuse and underuse is heightened, these data help to estimate the expected proportion of repairs for less common pathologies. They also provide a potential baseline data point for efforts at decreasing overuse.

Aged Lens Epithelial Cells Suppress Proliferation and Epithelial-Mesenchymal Transition-Relevance for Posterior Capsule Opacification.

Posterior capsule opacification (PCO) is a frequent complication after cataract surgery, and advanced PCO requires YAG laser (Nd: YAG) capsulotomy, which often gives rise to more complications. Lens epithelial cell (LEC) proliferation and transformation (i.e., epithelial-mesenchymal transition (EMT)) are two critical elements in PCO initiation and progression pathogenesis. While PCO marginally impacts aged cataract surgery patients, PCO incidences are exceptionally high in infants and children undergoing cataract surgery. The gene expression of lens epithelial cell aging and its role in the discrepancy of PCO prevalence between young and older people have not been fully studied. Here, we conducted a comprehensive differentially expressed gene (DEG) analysis of a cell aging model by comparing the early and late passage FHL124 lens epithelial cells (LECs). In vitro, TGFß2, cell treatment, and in vivo mouse cataract surgical models were used to validate our findings. We found that aged LECs decelerated rates of cell proliferation accompanied by dysregulation of cellular immune response and cell stress response. Surprisingly, we found that LECs systematically downregulated epithelial-mesenchymal transition (EMT)-promoting genes. The protein expression of several EMT hallmark genes, e.g., fibronectin, αSMA, and cadherin 11, were gradually decreased during LECs aging. We then confirmed these findings in vitro and found that aged LECs markedly alleviated TGFß2-mediated EMT. Importantly, we explicitly confirmed the in vitro findings from the in vivo mouse cataract surgery studies. We propose that both the high proliferation rate and EMT-enriched young LECs phenotypic characteristics contribute to unusually high PCO incidence in infants and children.

The Utility of Frequent Laboratory Monitoring for Patients on Tumor Necrosis Factor-Alpha Inhibitors in Dermatology.

Introduction: Tumor necrosis factor-alpha inhibitors (TNF-ai) are becoming increasingly common to use among patients with skin disease. To safely take these medications, it is recommended to monitor laboratory values routinely; however, the utility of this practice and the risk-benefit of frequent laboratory monitoring has not been explored fully in patients with skin disease. The purpose of this study was to evaluate the necessity of routine laboratory monitoring in patients taking a TNF-ai with a dermatological disease. Methods: Retrospective chart review evaluated laboratory abnormalities (complete blood counts and liver function tests) in adult patients who took a TNF-ai for a dermatologic disease at The University of Kansas Hospital. Results: There were 27 patients included for a total of 45 entries. The most common skin disease was hidradenitis suppurativa (23/45) and infliximab (22/45) was most the commonly used medication. Of the 45 entries, there were only seven patients that developed abnormal monitoring laboratory values related to initiation of TNF-ai. These abnormalities were transient and most frequently occurred after 12 months, with 2 of the 45 resulting in no discontinuation or dose reduction of TNF-ai. One patient discontinued medication due to anemia that did not improve after medication withdrawal. Conclusions: Laboratory abnormalities due to TNF-ai were infrequent and when they did occur were transient and mild. The study was limited by the small sample size of patients, and larger prospective studies are needed to evaluate these findings fully. However, dermatologists may be able to employ less frequent laboratory monitoring safely for patients on TNF-ai.

Hemoglobin A1c monitoring practices before lower extremity bypass in patients with diabetes vary broadly and do not predict outcomes.

OBJECTIVE: Hemoglobin A1c (HbA1c) is used as a marker of glycemic control, but the role of HbA1c before lower extremity bypass (LEB) in patients with diabetes remains unclear. We sought to characterize patients with diabetes undergoing LEB with and without HbA1c monitoring and to determine if HbA1c monitoring practices correlate with better outcomes. METHODS: The Vascular Quality Initiative was queried for all LEB in patients with diabetes (2010-2020). Patients with diabetes were characterized based on therapy: diet-controlled, noninsulin medication use, or insulin use. Glycemic control was characterized by preoperative HbA1c within 6 months of surgery: unknown control (no HbA1c), well-controlled (HbA1c <7%), poorly-controlled (HbA1c 7%-10%), and uncontrolled (HbA1c >10%). Centers with >5 LEB/y were stratified into terciles according to rate of HbA1c monitoring. The unadjusted associations between glycemic control and in-hospital major adverse limb events, major adverse cardiac events, and mortality were assessed with univariate methods. The independent association of center-level HbA1c monitoring with 5-year survival and 3-year amputation-free survival (AFS) was determined with Kaplan-Meier analyses and Cox regression modeling, adjusted for differences in patient characteristics and center volume. RESULTS: Of 16,092 patients with diabetes undergoing LEB, 4055 (25%) did not have a documented HbA1c. Insulin use was less common in no A1c (48%) and well-controlled diabetes (39%) compared with poorly controlled (67%) and uncontrolled diabetes (78%) (P < .01). In univariate analyses, glycemic control was not associated with differences for in-hospital major adverse limb events, major adverse cardiac events, or mortality. Of 162 centers, HbA1c monitoring practices varied widely (range: 12.5%-100% of LEB). The 3-year AFS and 5-year survival were worse in the highest monitoring tercile vs the lowest (73.6% vs 77.3%, P < .01, 72.1% vs 77.5%, P < .01, respectively). On multivariable analyses, centers in the highest tercile of monitoring had the greatest hazard of AFS (hazard ratio: 1.21, 95% confidence interval: 1.1-1.3, P < .001) and overall mortality (hazard ratio: 1.19, 95% confidence interval: 1.1-1.3, P < 0.001), compared with the centers in the lowest tercile of monitoring. CONCLUSIONS: Patients with diabetes and no preoperative HbA1c monitoring do not have worse LEB outcomes compared with those with HbA1c monitoring. Preoperative HbA1c monitoring varies widely, suggesting broad differences in practice and documentation. Centers with the highest rates of monitoring demonstrated inferior outcomes, likely due to other confounding unmeasured variables. These findings indicate that HbA1c monitoring before LEB, unto itself, should not be used as a measure of surgical quality.

Trends in General Surgery Operative Experience Obtained by Integrated Vascular Surgery Residents.

OBJECTIVE: When the integrated vascular surgery training pathway was introduced, training was comprised of nearly equal amounts of core general surgery and vascular surgery experience. However, specific requirements for case numbers or types were not defined. Over time, the time spent on core general surgery requirements has been reduced, most recently in 2018, from 24 to 18 months. We sought to determine trends in general surgery case volume and type over the past 10 years for vascular surgery residents. METHODS: We conducted a retrospective review of the Accreditation Council for Graduate Medical Education case log data for integrated vascular surgery graduates from 2012-2018. We evaluated trends in mean numbers of cases, categorized as general surgery open (GS-open), general surgery laparoscopic (GS-laparoscopic), vascular surgery open (VS-open), and vascular surgery endovascular (VS-endo). Cases were also categorized by anatomic region as head/neck, thoracic, or abdominal. RESULTS: The mean number of total head/neck, thoracic, or abdominal cases logged by graduating integrated vascular surgery trainees was 263.5. This total, as well as the proportion of general surgery cases (35%-38%, p = 0.99) has remained constant over time. The type of general surgery cases has changed significantly, with an upward trend in the mean number of GS-open cases and downward trend in mean GS-laparoscopic cases (GS-open p = 0.006, GS-laparoscopic p = 0.048). Among head/neck and thoracic subgroups, no significant changes were observed, while in the abdominal subgroup, there has been a significant increase in GS-open over time (p = 0.005). Additionally, the number of open vascular abdominal aortic cases has remained stable, with an average of 36.82 per graduating trainee per year. CONCLUSIONS: In the 10 years since the introduction of integrated vascular surgery programs, total case volume and proportion of general surgery cases have remained remarkably stable. The type of general surgery cases has shifted though, with a decrease in GS-laparoscopic cases, replaced primarily by open abdominal cases. These changes likely reflect integrated vascular residents actively seeking out these opportunities during their core rotations and a willingness by general surgery partners to provide these opportunities. At the program level, these data may help guide program directors' choices about the specific core rotations they incorporate into their curriculum. At the national level, this information may contribute to future discussions regarding the optimal number of core general surgery rotation requirements.

Explantation of infected thoracic endovascular aortic repair.

Prosthetic graft infection is a rare and serious complication of thoracic endovascular aortic repair associated with high mortality and posing unique challenges for treatment. The prosthetic graft infection is often identified late as patients present with mild nonspecific symptoms. We describe the successful medical management and surgical explantation of an infected thoracic endograft with an aorta-bronchial fistula, using an inline reconstruction with an antibiotic-soaked synthetic graft. In this report, we provide an example of a patient with an infected thoracic endograft and how inline reconstruction combined with appropriate medical management is an acceptable treatment strategy.

Early Onset of Clinical Improvement with Ixekizumab in a Randomized, Open-label Study of Patients with Moderate-to-severe Plaque Psoriasis.

Objective: The purpose of this study was to evaluate the speed of onset of clinical response to ixekizumab (IXE) and assess the progression of visible improvement in patients with moderate-to-severe plaque psoriasis. Design: This was an interventional, randomized, open-label, Phase IIIb clinical trial. Setting: This was a single center study at the Mount Sinai School of Medicine. Participants: Twelve patients were randomized at a ratio of 1:1 to receive 80mg of ixekizumab every two (IXE Q2W) or four (IXE Q4W) weeks following a starting dose of 160mg of ixekizumab. After Week 12, all patients received 80mg IXE Q4W through Week 44. Measurements: Clinical response was measured using the Patient's Global Assessment (PatGA), the Psoriasis Area and Severity Index (PASI), the static Physician's Global Assessment (sPGA), and the Itch Numeric Rating Scale (Itch NRS). Sequential patient photographs were taken at regular intervals during the study to evaluate visible improvement in plaque psoriasis. Results: The median time to an improvement of at least 1 point or 2 points from baseline in PatGA score was 5.0 and 10.0 days for patients randomized to IXE Q2W and 6.0 and 13.5 days for patients randomized to IXE Q4W. All patients achieved at least a 50- or 75-percent improvement in PASI from baseline by Weeks 2 and 4, respectively. At least half of the patients achieved at least a 4-point improvement from baseline in Itch NRS by Day 14. Improvement in disease was visibly evident within one week of treatment in patient photographs. Conclusion: Ixekizumab results in a rapid and visible improvement in plaque psoriasis in as early as one week of treatment.

Stroke-like migraine attacks after radiation therapy: A misnomer?

OBJECTIVE: To understand the frequency of electrographic and clinical seizures in patients with stroke-like migraine attacks after radiation therapy (SMART), and determine whether SMART warrants comprehensive electroencephalographic (EEG) monitoring and aggressive seizure management. METHODS: We searched our magnetic resonance brain imaging report database for all patients between January 2013 and December 2015 for suspected SMART syndrome. Clinical inclusion criteria were further applied as follows: inpatient adults (>18 years of age) with history of cranial radiation presenting with acute neurologic deficits as primary admission reason who lacked evidence of recurrent or new brain malignancy, stroke, or infectious agents in cerebrospinal fluid. Six patients were identified. All 6 patients underwent prolonged video EEG monitoring as part of our standard protocol. RESULTS: All patients but 1 were found to have multiple or prolonged electrographic seizures consistent with status epilepticus during video EEG monitoring. Their neurological deficit and/or mental status change improved in parallel with resolution of the seizure activity. SIGNIFICANCE: SMART is likely a misnomer that underestimates the significance of seizures and status epilepticus in the pathophysiology and clinical presentation of the syndrome. Systematic continuous EEG monitoring and appropriate seizure management is warranted to reduce symptom duration and optimize clinical outcome.

Patient and Provider Characteristics Associated With Optimal Post-Fracture Osteoporosis Management.

Despite an estimated 2 million osteoporosis (OP)-related fractures annually, quality of care for post-fracture OP management remains low. This study aimed to identify patient and provider characteristics associated with achieving or not achieving optimal post-fracture OP management, as defined by the current HEDIS quality measure. The study included women 67 to 85 years of age, with ≥1 fracture, and continuous enrollment in a Humana insurance plan. The study identified a higher percentage of black women in the not achieved group (6.2% vs 5.4%; P < .0001) and Hispanic women in the achieved group (3.0% vs 1.3%; P < .0001). The not achieved group largely included patients residing in the South and urban and suburban areas. The majority of providers were primary care or OP-related specialty, and 66% did not achieve the 4-star OP rating. The study findings can guide development of predictive models to identify at-risk women to improve post-fracture OP management.

Abnormal environmental light exposure in the intensive care environment.

PURPOSE: We sought to characterize ambient light exposure in the intensive care unit (ICU) environment to identify patterns of light exposure relevant to circadian regulation. METHODS: A light monitor was affixed to subjects' bed at eye level in a modern intensive care unit and continuously recorded illuminescence for at least 24h per subject. Blood was sampled hourly and measured for plasma melatonin. Subjects underwent hourly vital sign and bedside neurologic assessments. Care protocols and the ICU environment were not modified for the study. RESULTS: A total of 67,324 30-second epochs of light data were collected from 17 subjects. Light intensity peaked in the late morning, median 64.1 (interquartile range 19.7-138.7) lux. The 75th percentile of light intensity exceeded 100lx only between 9AM and noon, and never exceeded 150lx. There was no correlation between melatonin amplitude and daytime, nighttime or total light exposure (Spearman's correlation coefficients all <0.2 and p>0.5). CONCLUSIONS: Patients' environmental light exposure in the intensive care unit is consistently low and follows a diurnal pattern. No effect of nighttime light exposure was observed on melatonin secretion. Inadequate daytime light exposure in the ICU may contribute to abnormal circadian rhythms.

Effect of Ixekizumab Treatment on Work Productivity for Patients With Moderate-to-Severe Plaque Psoriasis: Analysis of Results From 3 Randomized Phase 3 Clinical Trials.

IMPORTANCE: Therapies that reduce psoriasis symptoms may improve work productivity. OBJECTIVE: To assess the effect of ixekizumab therapy on work productivity, measured by the Work Productivity and Activity Impairment-Psoriasis (WPAI-PSO). DESIGN, SETTING, AND PARTICIPANTS: Three multicenter, randomized double-blind phase 3 trials conducted during the following periods: December 2011 through August 2014 (UNCOVER-1), May 2012 through April 2015 (UNCOVER-2), and August 2012 through July 2014 (UNCOVER-3). Adult outpatients with moderate-to-severe chronic plaque psoriasis were included. INTERVENTIONS: In UNCOVER-1, patients were randomized 1:1:1 to subcutaneous placebo or 80 mg ixekizumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 12 weeks; UNCOVER-2 and UNCOVER-3 also had an etanercept arm (50 mg twice weekly). Maintenance of initial ixekizumab response was evaluated in UNCOVER-1 and UNCOVER-2 during a randomized withdrawal period following week 12 through week 60. The WPAI-PSO questionnaire was administered at baseline and week 12 for all patients and at weeks 24, 36, 52, and 60 for patients in UNCOVER-1 and UNCOVER-2. MAIN OUTCOMES AND MEASURES: Change in work productivity from baseline as measured by WPAI-PSO scores. RESULTS: Across trials, 5101 patients consented; 3866 were randomized (mean [SD] age, UNCOVER-1, 45.7 [12.9] y, 68.1% male; UNCOVER-2: 45.0 [13.0] y, 67.1% male; UNCOVER-3: 45.8 [13.1] y, 68.2% male). At week 12 in UNCOVER-1, the ixekizumab Q4W and ixekizumab Q2W groups showed significantly greater improvements in WPAI-PSO scores (least squares mean change from baseline [SE]) relative to placebo: absenteeism (-3.5 [0.87], P < .001; -2.6 [0.84], P = .003, respectively, vs 0.2 [0.88]), presenteeism (-18.8 [1.28], P < .001; -18.3 [1.24], P < .001, vs 0.5 [1.30]), work productivity loss (-20.6 [1.38], P < .001; -19.8 [1.33], P < .001, vs -0.8 [1.40]), and activity impairment (-24.5 [1.18], P < .001; -25.2 [1.15], P < .001, vs 0.8 [1.18]). Similar results were obtained for UNCOVER-2 and UNCOVER-3, with the exception of absenteeism with ixekizumab Q4W in UNCOVER-2. Additionally, ixekizumab-treated patients showed significantly greater improvements in WPAI-PSO scores vs etanercept-treated patients: UNCOVER-2: presenteeism, work productivity loss, activity impairment (P < .001 both doses), UNCOVER-3: activity impairment (ie, regular activities outside of work) (ixekizumab Q2W; P = .009). Improvements in WPAI-PSO scores at week 12 were sustained to at least week 60. CONCLUSIONS AND RELEVANCE: Ixekizumab-treated patients reported short- and long-term improvements in work productivity, which could lead to reduced productivity-related cost burden in patients with psoriasis. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01474512, NCT01597245, NCT01646177.

Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy.

The hallmarks of Alzheimer's disease (AD) are the aggregates of amyloid-ß (Aß) peptides and tau protein. Autophagy is a major cellular pathway leading to the removal of aggregated proteins. We have reported recently that autophagy was responsible for amyloid precursor protein cleaved C-terminal fragment (APP-CTF) degradation and amyloid ß clearance in an Atg5-dependent manner. Here we aimed to elucidate the molecular mechanism by which autophagy mediates the degradation of APP-CTF and the clearance of amyloid ß. Through affinity purification followed by mass spectrum analysis, we identified adaptor protein (AP) 2 together with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) as binding proteins of microtubule-associated protein 1 light chain 3 (LC3). Further analysis showed that AP2 regulated the cellular levels of APP-CTF. Knockdown of AP2 reduced autophagy-mediated APP-CTF degradation. Immunoprecipitation and live imaging analysis demonstrated that AP2 and PICALM cross-link LC3 with APP-CTF. These data suggest that the AP-2/PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-marked autophagic degradation pathway. This molecular mechanism linking AP2/PICALM and AD is consistent with genetic evidence indicating a role for PICALM as a risk factor for AD.

Amyloid-ß oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons.

Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-ß oligomers (AßOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AßOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AßOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3ß, downstream targets of CaN, prevents BDNF transport defects induced by AßOs. We further show that AßOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AßO-induced BDNF transport disruption.