Upadacitinib Rapidly Improves Patient-Reported Outcomes in Atopic Dermatitis: 16-Week Results from Phase 3 Clinical Trials (Measure Up 1 and 2).

INTRODUCTION: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. METHODS: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). RESULTS: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2 weeks), increased through weeks 4-6, and were maintained through week 16. CONCLUSIONS: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422.

Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1­2 weeks. The extent of the improvements increased through weeks 4­6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis.

Revision of Harrington rod constructs: a single-center's experience with this homogenous adult spinal deformity population at a minimum 2-year follow-up.

PURPOSE: To evaluate radiographic and clinical outcomes following revision surgery after HRC fusions. METHODS: Single-institution, retrospective study of patients revised following HRC with minimum 2-year follow-up post-revision. Demographics, perioperative information, radiographic parameters, complications, and Oswestry disability index (ODI) scores were collected. Radiographic parameters included global alignment, coronal and sagittal measurements pre and postoperatively, as well as final follow-up time points. RESULTS: 26 patients were included with a mean follow-up of 3.3 ± 1.1 years. Mean age was 55.5 ± 7.8 years, BMI 25.2 ± 5.8, and 22 (85%) were females. Instrumented levels increased from 9.7 ± 2.8 to 16.0 ± 2.2. Five (19.2%) patients underwent lumbar pedicle subtraction osteotomies, and 23 (88.4%) had interbody fusions. Patients significantly improved in all radiographic parameters at immediate and final follow-up (p < 0.005), except for thoracic kyphosis and pelvic incidence (p > 0.05). Correction was maintained from immediate postop to final follow-up (p > 0.05). 20 (76.9%) of patients experienced a complication at some point within the follow-up period with the most common being a lumbar nerve root deficit (n = 7). However, only one patient had a nerve root deficit at final follow-up, that being a 4/5 unilateral anterior tibialis function. 5 (19.2%) patients required further revision within a mean of 1.8 ± 1.1 years. On average, patients had an improvement in ODI score by final follow-up (35.6 ± 16.8 vs 25.4 ± 19.8, p = 0.035). CONCLUSION: Patients revised for HRCs significantly improve, both clinically and radiographically by final follow-up. This group did have a propensity for distal lumbar root neurological issues, which were common but all patients except for one, recovered to full strength by two-year follow-up.

Early and Sustained Improvements in Symptoms and Quality of Life with Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: 52-Week Results from Two Phase III Randomized Clinical Trials (Measure Up 1 and Measure Up 2).

BACKGROUND: Atopic dermatitis is a chronic inflammatory disease characterized by increased itch, skin pain, poor sleep quality, and other symptoms that negatively affect patient quality of life. Upadacitinib, an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, is approved to treat moderate-to-severe atopic dermatitis. OBJECTIVE: We aimed to evaluate the effect of upadacitinib on patient-reported outcomes over 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis. METHODS: Data from two phase III monotherapy trials of upadacitinib (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422) were integrated. Changes in pruritus, pain, other skin symptoms, sleep, quality of life, mental health, and patient impression were evaluated. Patient-reported outcome assessments included the Worst Pruritus Numerical Rating Scale, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Atopic Dermatitis Symptom Scale, Atopic Dermatitis Impact Scale, Hospital Anxiety and Depression Scale, SCORing Atopic Dermatitis index, Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment. Minimal clinically important differences, achievement of scores representing minimal disease burden, and the change from baseline were evaluated in patients who received upadacitinib through week 52 and in patients who received placebo through week 16. RESULTS: This analysis included 1609 patients (upadacitinib 15 mg, N = 557; upadacitinib 30 mg, N = 567; placebo, N = 485). Baseline demographics and disease characteristics were generally similar across all arms. The proportion of patients treated with upadacitinib reporting improvements in itch increased rapidly by week 1, increased steadily through week 8, and was sustained through week 52. Patients receiving upadacitinib also experienced improvements in pain and other skin symptoms by week 1, which continued through week 16; improvements were maintained through week 52. Patient reports of improved sleep increased rapidly from baseline to week 1, increased steadily through week 32, and were sustained through week 52. Patients experienced quality-of-life improvements through week 8, which were maintained through week 52. By week 1, patients in both upadacitinib groups experienced rapid improvements in emotional state, and by week 12, patients also achieved meaningful improvements in anxiety and depression. Improvements in mental health continued steadily through week 32 and were maintained through week 52. Patients treated with upadacitinib 30 mg generally experienced improvements in patient-reported outcomes earlier than those treated with upadacitinib 15 mg. Through week 16, patients receiving upadacitinib experienced greater improvements versus those receiving placebo in all assessed patient-reported outcomes. CONCLUSIONS: Adults and adolescents with moderate-to-severe atopic dermatitis treated with once-daily upadacitinib 15 or 30 mg experienced early improvements in itch, pain, other skin symptoms, sleep, quality of life, and mental health that were sustained through week 52. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03569293 (13 August 2018) and NCT03607422 (27 July 2018).

Atopic dermatitis, or eczema, is a condition that causes painful itchy dry skin, which is burdensome for patients and has a negative impact on quality of life. These symptoms frequently lead to disruption of daily activities such as school and work, decreased self-confidence, social isolation, anxiety, depression, and sleep disturbance. Symptoms of atopic dermatitis, such as itch and sleep disturbance, can only be assessed by patients. Therefore, it is important to consider patients' perceptions of their symptoms and the related impact on their quality of life, especially when evaluating treatment benefits. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. In two clinical trials (Measure Up 1 and Measure Up 2), we investigated how treatment with upadacitinib (15-mg or 30-mg dose) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis would impact their symptoms and quality of life over a 1-year period. We measured changes over time in patients' assessments of itch, pain, other skin-related symptoms, sleep, daily activities, emotional state, mental health, and overall quality of life. Patients treated with upadacitinib experienced improvements in symptoms of atopic dermatitis and quality of life within the first 1­2 weeks of treatment. These improvements continued to steadily increase in the following weeks and lasted through 1 year of treatment. In conclusion, once-daily treatment with upadacitinib 15 or 30 mg led to early and lasting improvements in the well-being of patients with atopic dermatitis.

Knee flexion compensation in postoperative adult spinal deformity patients: implications for sagittal balance and clinical outcomes.

PURPOSE: To determine whether maintaining good sagittal balance with significant knee flexion (KF) constitutes a suboptimal outcome after adult spinal deformity (ASD) correction. METHODS: This single-center, single-surgeon retrospective study, assessed ASD patients who underwent posterior spinal fusion between 2014 and 2020. Inclusion criteria included meeting at least one of the following: PI-LL ≥ 25°, T1PA ≥ 20°, or CrSVA-H ≥ 2 cm. Those with lower-extremity contractures were excluded. Patients were classified into four groups based on their 6-week postoperative cranio-hip balance and KF angle, and followed for at least 2 years: Malaligned with Knee Flexion (MKF+) (CrSVA-H > 20 mm + KFA > 10), Malaligned without Knee Flexion (MKF-) (CrSVA-H > 20 mm + KFA < 10), Aligned without Knee Flexion (AKF-) (CrSVA-H < 20 mm + KFA < 10), and Aligned with Knee Flexion (AKF+) (CrSVA-H < 20 mm + KFA > 10). The primary outcomes of this study included one and two year reoperation rates. Secondy outcomes included clinical and patient reported outcomes. RESULTS: 263 patients (mean age 60.0 ± 0.9 years, 74.5% female, and mean Edmonton Frailty Score 3.3 ± 0.2) were included. 60.8% (160/263 patients) exhibited good sagittal alignment at 6-week postop without KF. Significant differences were observed in 1-year (p = 0.0482) and 2-year reoperation rates (p = 0.0374) across sub-cohorts, with the lowest and highest rates in the AKF- cohort (5%, n = 8) and MKF + cohort (16.7%, n = 4), respectively. Multivariable Cox regression demonstrated the AKF- cohort exhibited significantly better reoperation outcomes compared to other groups: AKF + (HR: 5.24, p = 0.025), MKF + (HR: 31.7, p < 0.0001), and MKF- (HR: 11.8, p < 0.0001). CONCLUSION: Our findings demonstrate that patients relying on knee flexion compensation in the early postoperative period have inferior outcomes compared to those achieving sagittal balance without knee flexion. When compared to malaligned patients, those with CrSVA-H < 20 mm and KFA > 10 degrees experience fewer early reoperations but similar delayed reoperation rates. This insight emphasizes the importance of considering knee compensation perioperatively when managing sagittal imbalance in clinical practice.

The "Sandwich" Extended Pedicle Subtraction Osteotomy for the Treatment of Fixed Sagittal Malalignment: Technical Description, Case Series, and Early Results With 2-Year Outcomes.

BACKGROUND AND OBJECTIVES: Adult spinal deformity (ASD) with fixed sagittal malalignment (FSM) may require a pedicle subtraction osteotomy (PSO) for greater focal lordosis and restoration of global alignment. Despite growing trends in minimizing PSOs given their associated high risks, a considerable portion of patients with ASD still require a lumbar PSO most commonly because of iatrogenic flat back deformity. The purpose of this article is to describe a modified extended PSO technique with additional anterior column support coined the "sandwich" extended PSO (SE-PSO) to promote arthrodesis and report the outcomes in a consecutive case series. METHODS: Patients with ASD treated with a lumbar SE-PSO at a single institution from 2015 to 2020 were analyzed. Complications, radiographic data, and patient-reported outcomes were compared preoperatively, at immediate postoperative follow-up, and at a 2-year postoperative follow-up (FU). RESULTS: Fourteen patients who underwent revision operations for FSM were included. Improvements in segmental lordosis across the PSO site (14.8 ± 6.8 vs 39.9 ± 7.1, P < .0001), overall lumbar lordosis (14.6 ± 15.4 vs 44.6 ± 12.1, P < .0001), sacral slope (21.0 ± 10.5 31.1 ± 10.7, P = .0150), C7 sagittal vertical axis (140.1 ± 59.0 mm vs 35.9 ± 28.5, P < .0001), and spinopelvic mismatch (52.5 ± 21.3 vs 18.6 ± 14.1, P = .0001) were obtained in all patients. Eight patients experienced perioperative complications, with intraoperative durotomy being the most common (n = 7). Eight patients had a 2-year FU and demonstrated improvements in their segmental lordosis across the PSO site (14.3 ± 7.0 vs 41.3 ± 7.3, P = .0003), overall lumbar lordosis (8.7 ± 17.8 vs 46.1 ± 14.2, P = .0014), sacral slope (19.1 ± 12.8 vs 32.3 ± 12.5, P = .0479), C7 sagittal vertical axis (173.6 ± 54.4 mm vs 35.8 ± 30.0, P < .0001), and spinopelvic mismatch (63.0 ± 19.7 vs 21.1 ± 18.3, P < .0001), all of which were maintained at final FU (P > .05). At 2 years, a significant increase in Scoliosis Research Society-22r total score (2.5 ± 0.8 vs 3.6 ± 0.7, P = .0023 was reported. There were no reports of symptomatic pseudarthrosis or mechanical complications. CONCLUSION: SE-PSO is an effective technique to correct FSM and is associated with low complications, improved patient-reported outcomes, and spinopelvic parameters that are maintained at 2 years.

Aggregate Response Benefit in Skin Clearance and Itch Reduction With Upadacitinib or Dupilumab in Patients With Moderate-to-Severe Atopic Dermatitis.

Background: In patients with moderate-to-severe atopic dermatitis (AD), greater skin clearance and itch reduction are associated with more pronounced improvements in quality of life (QoL). Objective: To characterize the aggregate response benefit with upadacitinib versus dupilumab or placebo in patients with moderate-to-severe AD. Methods: Degree of skin clearance and itch response in 3 phase 3 studies (Heads Up [NCT03738397] and Measure Up 1/2 [integrated; NCT03569293/NCT03607422]) were assessed by the Eczema Area and Severity Index (EASI) and Worst Pruritus Numerical Rating Scale (WP-NRS), respectively, using mutually exclusive categories. The aggregate response benefit with upadacitinib over dupilumab or placebo was determined by summing incremental differences for each EASI or WP-NRS category across the full distribution of patient responses. Results: Comparisons across EASI improvement threshold distributions, EASI severity levels, and WP-NRS categories demonstrated an aggregate response benefit favoring upadacitinib over dupilumab as early as week 4 and continuing at weeks 16 and 24. Similar trends were observed for upadacitinib 15 and 30 mg versus placebo. Conclusions: The aggregate response benefit in skin clearance and itch reduction favored upadacitinib 30 mg over dupilumab and upadacitinib 15 or 30 mg over placebo. These benefits may translate to overall greater improvements in patient QoL.

Clinical and Immunologic Correlates of Vasodilatory Shock Among Ebola Virus-Infected Nonhuman Primates in a Critical Care Model.

BACKGROUND: Existing models of Ebola virus infection have not fully characterized the pathophysiology of shock in connection with daily virologic, clinical, and immunologic parameters. We implemented a nonhuman primate critical care model to investigate these associations. METHODS: Two rhesus macaques received a target dose of 1000 plaque-forming units of Ebola virus intramuscularly with supportive care initiated on day 3. High-dimensional spectral cytometry was used to phenotype neutrophils and peripheral blood mononuclear cells daily. RESULTS: We observed progressive vasodilatory shock with preserved cardiac function following viremia onset on day 5. Multiorgan dysfunction began on day 6 coincident with the nadir of circulating neutrophils. Consumptive coagulopathy and anemia occurred on days 7 to 8 along with irreversible shock, followed by death. The monocyte repertoire began shifting on day 4 with a decline in classical and expansion of double-negative monocytes. A selective loss of CXCR3-positive B and T cells, expansion of naive B cells, and activation of natural killer cells followed viremia onset. CONCLUSIONS: Our model allows for high-fidelity characterization of the pathophysiology of acute Ebola virus infection with host innate and adaptive immune responses, which may advance host-targeted therapy design and evaluation for use after the onset of multiorgan failure.

Ebola virus shed glycoprotein is toxic to human T, B, and natural killer lymphocytes.

Lymphocyte depletion is a distinctive feature of Ebola virus (EBOV) disease. The ectodomain of EBOV glycoprotein (GP) is cleaved off the surface of infected cells into circulation as shed GP. To test the hypothesis that shed GP induces lymphocyte death, we cultured primary human B, NK, or T cells with shed GP in vitro. We found that shed GP dependably decreased B, NK, and T cell viability across donors. B and NK cells exhibited higher susceptibility than T cells. Continuous monitoring revealed shed GP began to kill B and NK cells by 4 h and T cells by 5 h. We also demonstrated that shed GP-induced lymphocyte death can be both caspase dependent and caspase independent. Our data are evidence that the cytotoxic effect of shed GP on lymphocytes may contribute to EBOV disease and highlight the need for further research to clarify mechanisms of shed GP-induced death.

The role of Janus kinase signaling in the pathology of atopic dermatitis.

Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The pathology of AD includes complex interactions involving abnormalities in immune and skin barrier genes, skin barrier disruption, immune dysregulation, microbiome disturbance, and other environmental factors. Many of the cytokines involved in AD pathology, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and IFN-γ, signal through the Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathway. The JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2; the STAT family includes STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6. Activation of the JAK-STAT pathway has been implicated in the pathology of several immune-mediated inflammatory diseases, including AD. However, the exact mechanisms of JAK-STAT involvement in AD have not been fully characterized. This review aims to discuss current knowledge about the role of the JAK-STAT signaling pathway and, specifically, the role of JAK1 in the pathology and symptomology of AD.

Pulmonary Co-Infections Detected Premortem Underestimate Postmortem Findings in a COVID-19 Autopsy Case Series.

Bacterial and fungal co-infections are reported complications of coronavirus disease 2019 (COVID-19) in critically ill patients but may go unrecognized premortem due to diagnostic limitations. We compared the premortem with the postmortem detection of pulmonary co-infections in 55 fatal COVID-19 cases from March 2020 to March 2021. The concordance in the premortem versus the postmortem diagnoses and the pathogen identification were evaluated. Premortem pulmonary co-infections were extracted from medical charts while applying standard diagnostic definitions. Postmortem co-infection was defined by compatible lung histopathology with or without the detection of an organism in tissue by bacterial or fungal staining, or polymerase chain reaction (PCR) with broad-range bacterial and fungal primers. Pulmonary co-infection was detected premortem in significantly fewer cases (15/55, 27%) than were detected postmortem (36/55, 65%; p < 0.0001). Among cases in which co-infection was detected postmortem by histopathology, an organism was identified in 27/36 (75%) of cases. Pseudomonas, Enterobacterales, and Staphylococcus aureus were the most frequently identified bacteria both premortem and postmortem. Invasive pulmonary fungal infection was detected in five cases postmortem, but in no cases premortem. According to the univariate analyses, the patients with undiagnosed pulmonary co-infection had significantly shorter hospital (p = 0.0012) and intensive care unit (p = 0.0006) stays and significantly fewer extra-pulmonary infections (p = 0.0021). Bacterial and fungal pulmonary co-infection are under-recognized complications in critically ill patients with COVID-19.

Adult spinal deformity patients revised for pseudarthrosis have comparable two-year outcomes to those not undergoing any revision surgery.

PURPOSE: This study aimed to evaluate whether adult spinal deformity patients undergoing revision for symptomatic pseudarthrosis have comparable two-year outcomes as patients who do not experience pseudarthrosis. METHODS: Patients whose indexed procedure was revision for pseudarthrosis (pseudo) were compared with patients who underwent a primary procedure and did not have pseudarthrosis by 2Y post-op (non-pseudo). Patients were propensity-matched (PSM) based on baseline (BL) sagittal alignment, specifically C7SVA and CrSVA-Hip. Key outcomes were 2Y PROs (SRS and ODI) and reoperation. All patients had a minimum follow-up period of two years. RESULTS: A total of 224 patients with min 2-year FU were included (pseudo = 42, non-pseudo = 182). Compared to non-pseudo, pseudo-patients were more often female (P = 0.0018) and had worse BL sagittal alignment, including T1PA (P = 0.02], C2-C7 SVA [P = 0.0002], and CrSVA-Hip [P = 0.004]. After 37 PSM pairs were generated, there was no significant difference in demographics, BL and 2Y alignment, or operative/procedural variables. PSM pairs did not report any significantly different PROs at BL. Consistently, at 2Y, there were no significant differences in PROs, including SRS function [3.9(0.2) vs 3.7(0.2), P = 0.44], pain [4.0 (0.2) vs. 3.57 (0.2), P = 0.12], and ODI [25.7 (5.2) vs 27.7 (3.7), P = 0.76]. There were no differences in 1Y (10.8% vs 10.8%, P > 0.99) and 2Y (13.2% vs 15.8%, P = 0.64) reoperation, PJK rate (2.6% vs 10.5%, P = 0.62), or implant failure (2.6% vs 10.5%, P = 0.37). Notably, only 2 patients (5.4%) had recurrent pseudarthrosis following revision. Kaplan-Meier curves indicated that patients undergoing intervention for pseudarthrosis had comparable overall reoperation-free survival (log-rank test, χ2 = 0.1975 and P = 0.66). CONCLUSIONS: Patients undergoing revision for pseudarthrosis have comparable PROs and clinical outcomes as patients who never experienced pseudarthrosis. Recurrence of symptomatic pseudarthrosis was infrequent.

Comparison of minimally invasive decompression alone versus minimally invasive short-segment fusion in the setting of adult degenerative lumbar scoliosis: a propensity score-matched analysis.

OBJECTIVE: Patients with degenerative lumbar scoliosis (DLS) and neurogenic pain may be candidates for decompression alone or short-segment fusion. In this study, minimally invasive surgery (MIS) decompression (MIS-D) and MIS short-segment fusion (MIS-SF) in patients with DLS were compared in a propensity score-matched analysis. METHODS: The propensity score was calculated using 13 variables: sex, age, BMI, Charlson Comorbidity Index, smoking status, leg pain, back pain, grade 1 spondylolisthesis, lateral spondylolisthesis, multilevel spondylolisthesis, lumbar Cobb angle, pelvic incidence minus lumbar lordosis, and pelvic tilt in a logistic regression model. One-to-one matching was performed to compare perioperative morbidity and patient-reported outcome measures (PROMs). The minimal clinically important difference (MCID) for patients was calculated based on cutoffs of percentage change from baseline: 42.4% for Oswestry Disability Index (ODI), 25.0% for visual analog scale (VAS) low-back pain, and 55.6% for VAS leg pain. RESULTS: A total of 113 patients were included in the propensity score calculation, resulting in 31 matched pairs. Perioperative morbidity was significantly reduced for the MIS-D group, including shorter operative duration (91 vs 204 minutes, p < 0.0001), decreased blood loss (22 vs 116 mL, p = 0.0005), and reduced length of stay (2.6 vs 5.1 days, p = 0.0004). Discharge status (home vs rehabilitation), complications, and reoperation rates were similar. Preoperative PROMs were similar, but after 3 months, improvement was significantly higher for the MIS-SF group in the VAS back pain score (-3.4 vs -1.2, p = 0.044) and Veterans RAND 12-Item Health Survey (VR-12) Mental Component Summary (MCS) score (+10.3 vs +1.9, p = 0.009), and after 1 year the MIS-SF group continued to have significantly greater improvement in the VAS back pain score (-3.9 vs -1.2, p = 0.026), ODI score (-23.1 vs -7.4, p = 0.037), 12-Item Short-Form Health Survey MCS score (+6.5 vs -6.5, p = 0.0374), and VR-12 MCS score (+7.6 vs -5.1, p = 0.047). MCID did not differ significantly between the matched groups for VAS back pain, VAS leg pain, or ODI scores (p = 0.38, 0.055, and 0.072, respectively). CONCLUSIONS: Patients with DLS undergoing surgery had similar rates of significant improvement after both MIS-D and MIS-SF. For matched patients, tradeoffs were seen for reduced perioperative morbidity for MIS-D versus greater magnitudes of improvement in back pain, disability, and mental health for patients 1 year after MIS-SF. However, rates of MCID were similar, and the small sample size among the matched patients may be subject to patient outliers, limiting generalizability of these results.

Efficacy and Safety of Upadacitinib Treatment in Adolescents With Moderate-to-Severe Atopic Dermatitis: Analysis of the Measure Up 1, Measure Up 2, and AD Up Randomized Clinical Trials.

Importance: Atopic dermatitis onset usually occurs in childhood. Persistence of disease into adolescence and adulthood is common. It is important to evaluate new treatment options in adolescents because of the high unmet need in this population. Objective: To assess the efficacy and safety of upadacitinib to treat moderate-to-severe atopic dermatitis in adolescents. Design, Setting, and Participants: Prespecified analysis of adolescents enrolled in 3 randomized, double-blind, placebo-controlled phase 3 clinical trials in more than 20 countries across Europe, North and South America, Oceania, the Middle East, and the Asia-Pacific region from July 2018 through December 2020. Participants were adolescents aged 12 to 17 years with moderate-to-severe atopic dermatitis. Data analysis was performed from April to August 2021. Interventions: Patients were randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo alone (Measure Up 1 and Measure Up 2) or with topical corticosteroids (AD Up). Main Outcomes and Measures: Safety and efficacy, including at least a 75% improvement in the Eczema Area and Severity Index from baseline and validated Investigator Global Assessment for Atopic Dermatitis score of 0 (clear) or 1 (almost clear) at week 16 (coprimary end points). Results: A total of 552 adolescents (290 female; 262 male) were randomized. Mean (SD) age was 15.4 (1.8), 15.5 (1.7), and 15.3 (1.8) years for adolescents in Measure Up 1, Measure Up 2, and AD Up, respectively. In Measure Up 1, Measure Up 2, and AD Up, respectively, a greater proportion of adolescents (% [95% CI]) achieved at least 75% improvement in the Eczema Area and Severity Index at week 16 with upadacitinib 15 mg (73% [63%-84%], 69% [57%-81%], 63% [51%-76%]), and upadacitinib 30 mg (78% [68%-88%], 73% [62%-85%], 84% [75%-94%]), than with placebo (12% [4%-20%], 13% [5%-22%], 30% [19%-42%]; nominal P < .001 for all comparisons vs placebo). Similarly, a greater proportion of adolescents treated with upadacitinib achieved a validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 at week 16 and improvements in quality of life with upadacitinib than with placebo. Upadacitinib was generally well tolerated in adolescents. Acne was the most common adverse event, and all acne events were mild or moderate. Conclusions and Relevance: In this analysis of 3 randomized clinical trials, upadacitinib was an effective treatment for adolescents with moderate-to-severe atopic dermatitis, with an acceptable safety profile. Trial Registration: ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1), NCT03607422 (Measure Up 2), and NCT03568318 (AD Up).

Comparison of Perioperative Complications After Anterior-Posterior Versus Posterior-Anterior-Posterior Cervical Fusion: A Retrospective Review of 153 Consecutive Cases.

BACKGROUND: Although published data support the utilization of circumferential fusion to treat select cervical spine pathologies, it is unclear whether the posterior-anterior-posterior (PAP) fusion has increased risks compared with the anterior-posterior fusion. OBJECTIVE: To evaluate the differences in perioperative complications between the 2 circumferential cervical fusion approaches. METHODS: One hundred fifty-three consecutive adult patients who underwent single-staged circumferential cervical fusion for degenerative pathologies from 2010 to 2021 were retrospectively reviewed. Patients were stratified into the anterior-posterior ( n = 116) and PAP ( n = 37) groups. The primary outcomes assessed were major complications, reoperation, and readmission. RESULTS: Although the PAP group was older ( P = .024), predominantly female ( P = .024), with higher baseline neck disability index ( P = .026), cervical sagittal vertical axis ( P = .001), and previous cervical operation rate ( P < .00001), the major complication, reoperation, and readmission rates were not significantly different from the 360° group. Although the PAP group had higher urinary tract infection ( P = .043) and transfusion ( P = .007) rates, higher estimated blood loss ( P = .034), and longer operative times ( P < .00001), these differences were insignificant after the multivariable analysis. Overall, operative time was associated with older age (odds ratio [OR] 17.72, P = .042), atrial fibrillation (OR 158.30, P = .045), previous cervical operation (OR 5.05, P = .051), and lower baseline C1 - 7 lordosis (OR 0.93, P = .007). Higher estimated blood loss was associated with older age (OR 1.13, P = .005), male gender (OR 323.31, P = .047), and higher baseline cervical sagittal vertical axis (OR 9.65, P = .022). CONCLUSION: Despite some differences in preoperative and intraoperative variables, this study suggests both circumferential approaches have comparable reoperation, readmission, and complication profiles, all of which are high.

Histopathology and SARS-CoV-2 Cellular Localization in Eye Tissues of COVID-19 Autopsies.

Ophthalmic manifestations and tissue tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in association with coronavirus disease 2019 (COVID-19), but the pathology and cellular localization of SARS-CoV-2 are not well characterized. The objective of this study was to evaluate macroscopic and microscopic changes and investigate cellular localization of SARS-CoV-2 across ocular tissues at autopsy. Ocular tissues were obtained from 25 patients with COVID-19 at autopsy. SARS-CoV-2 nucleocapsid gene RNA was previously quantified by droplet digital PCR from one eye. Herein, contralateral eyes from 21 patients were fixed in formalin and subject to histopathologic examination. Sections of the droplet digital PCR-positive eyes from four other patients were evaluated by in situ hybridization to determine the cellular localization of SARS-CoV-2 spike gene RNA. Histopathologic abnormalities, including cytoid bodies, vascular changes, and retinal edema, with minimal or no inflammation in ocular tissues were observed in all 21 cases evaluated. In situ hybridization localized SARS-CoV-2 RNA to neuronal cells of the retinal inner and outer layers, ganglion cells, corneal epithelia, scleral fibroblasts, and oligodendrocytes of the optic nerve. In conclusion, a range of common histopathologic alterations were identified within ocular tissue, and SARS-CoV-2 RNA was localized to multiple cell types. Further studies will be required to determine whether the alterations observed were caused by SARS-CoV-2 infection, the host immune response, and/or preexisting comorbidities.

Decompression Alone in the Setting of Adult Degenerative Lumbar Scoliosis and Stenosis: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis.OBJECTIVESSurgical decompression alone for patients with neurogenic leg pain in the setting of degenerative lumbar scoliosis (DLS) and stenosis is commonly performed, however, there is no summary of evidence for outcomes. METHODS: A systematic search of English language medical literature databases was performed for studies describing outcomes of decompression alone in DLS, defined as Cobb angle >10˚, and 2-year minimum follow-up. Three outcomes were examined: 1) Cobb angle progression, 2) reoperation rate, and 3) ODI and overall satisfaction. Data were pooled and weighted averages were calculated to summarize available evidence. RESULTS: Across 15 studies included in the final analysis, 586 patients were examined. Average preoperative and postoperative Cobb angles were 17.6˚ (Range: 12.7 - 25˚) and 18.0 (range 14.1 - 25˚), respectively. Average change in Cobb angle was an increase of 1.8˚. Overall rate of reoperation ranged from 3 to 33% with an average of 9.7%. Average ODI before surgery, after surgery, and change in scores were 56.4%, 27.2%, and an improvement of 29% respectively. Average from 8 studies that reported patient satisfaction was 71.2%. CONCLUSIONS: Current literature on decompression alone in the setting of DLS is sparse and is not high quality, limited to patients with small magnitude of lumbar coronal Cobb angle, and heterogenous in the type of procedure performed. Based on available evidence, select patients with DLS who undergo decompression alone had minimal progression of Cobb angle, relatively low reoperation rate, and favorable patient-reported outcomes.

SARS-CoV-2 infection and persistence in the human body and brain at autopsy.

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19.

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes," remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19.

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as "COVID toes", remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients. Summary: NET formation and degradation are dysregulated in pediatric and symptomatic adult patients with various complications of COVID-19, in association with disease severity. NET degradation impairments are multifactorial and associated with natural inhibitors of DNase 1, G-actin and anti-DNase1L3 and anti-NET antibodies. Infection with the Omicron variant is associated with decreased levels of NETs when compared to other SARS-CoV-2 strains.