Time Trends, Regional Variation and Associations of Low-Allergy Formula Prescribing in England.

BACKGROUND: Cow's milk allergy (CMA) overdiagnosis appears to be increasing and is associated with excessive low-allergy formula prescription. We evaluated recent trends and regional variation in low-allergy formula prescribing for CMA in England, and assessed potential risk factors for higher prescribing rates. METHODS: Data on national and regional prescribing of low-allergy formulas were extracted from England's electronic prescription database using R. Region-level factors were evaluated for potential associations with regional low-allergy formula prescription rates using multivariate linear regression. Analysis of national prescribing trends covered 2007-2023, analysis of regional variation and region-level factors examined 2017-2019, prior to a re-organisation of the regional healthcare structure in England. RESULTS: Low-allergy formula prescribing increased from 6.1 to 23.3 L per birth nationally, between 2007 and 2023. Regional prescribing rate varied from 0.8 to 47.6 L per birth in 2017-2019. We found significant associations between regional low-allergy formula prescribing rate and regional prescribing rates for milk feed thickeners Gaviscon Infant and Carobel Instant (ß = 0.10, p < 0.01), and for other anti-reflux medications used in young children (ß = 0.89 p < 0.01). Inconsistent associations were seen with prescribing junior adrenaline auto-injectors and oral antibiotics. A model including these four variables accounted for 37% of regional variation in low-allergy formula prescribing rate. Region-level socio-economic deprivation, CMA guideline recommendations and paediatric allergy service provision were not associated with low-allergy formula prescribing. CONCLUSIONS: Low-allergy formula prescribing in England is increasing, varies significantly by region and is consistently associated with prescribing rates for milk feed thickeners and other anti-reflux medication for young children. Community prescribing behaviours may be important determinants of CMA overdiagnosis.

Prevalence and risk factors for milk allergy overdiagnosis in the BEEP trial cohort.

BACKGROUND: Cow's milk allergy (CMA) overdiagnosis in young children appears to be increasing and has not been well characterised. We used a clinical trial population to characterise CMA overdiagnosis and identify individual-level and primary care practice-level risk factors. METHODS: We analysed data from 1394 children born in England in 2014-2016 (BEEP trial, ISRCTN21528841). Participants underwent formal CMA diagnosis at ≤2 years. CMA overdiagnosis was defined in three separate ways: parent-reported milk reaction; primary care record of milk hypersensitivity symptoms; and primary care record of low-allergy formula prescription. RESULTS: CMA was formally diagnosed in 19 (1.4%) participants. CMA overdiagnosis was common: 16.1% had parent-reported cow's milk hypersensitivity, 11.3% primary care recorded milk hypersensitivity and 8.7% had low-allergy formula prescription. Symptoms attributed to cow's milk hypersensitivity in participants without CMA were commonly gastrointestinal and reported from a median age of 49 days. Low-allergy formula prescriptions in participants without CMA lasted a median of 10 months (interquartile range 1, 16); the estimated volume consumed was a median of 272 litres (26, 448). Risk factors for CMA overdiagnosis were high practice-based low-allergy formula prescribing in the previous year and maternal report of antibiotic prescription during pregnancy. Exclusive formula feeding from birth was associated with increased low-allergy formula prescription. There was no evidence that practice prescribing of paediatric adrenaline auto-injectors or anti-reflux medications, or maternal features such as anxiety, age, parity and socioeconomic status were associated with CMA overdiagnosis. CONCLUSION: CMA overdiagnosis is common in early infancy. Risk factors include high primary care practice-based low-allergy formula prescribing and maternal report of antibiotic prescription during pregnancy.

Exploring the challenges of avoiding collisions with virtual pedestrians using a dual-task paradigm in individuals with chronic moderate to severe traumatic brain injury.

BACKGROUND: Individuals with a moderate-to-severe traumatic brain injury (m/sTBI), despite experiencing good locomotor recovery six months post-injury, face challenges in adapting their locomotion to the environment. They also present with altered cognitive functions, which may impact dual-task walking abilities. Whether they present collision avoidance strategies with moving pedestrians that are altered under dual-task conditions, however, remains unclear. This study aimed to compare between individuals with m/sTBI and age-matched control individuals: (1), the locomotor and cognitive costs associated with the concurrent performance of circumventing approaching virtual pedestrians (VRPs) while attending to an auditory-based cognitive task and; (2) gaze behaviour associated with the VRP circumvention task in single and dual-task conditions. METHODOLOGY: Twelve individuals with m/sTBI (age = 43.3 ± 9.5 yrs; >6 mo. post injury) and 12 healthy controls (CTLs) (age = 41.8 ± 8.3 yrs) were assessed while walking in a virtual subway station viewed in a head-mounted display. They performed a collision avoidance task with VRPs, as well as auditory-based cognitive tasks (pitch discrimination and auditory Stroop), both under single and dual-task conditions. Dual-task cost (DTC) for onset distance of trajectory deviation, minimum distance from the VRP, maximum lateral deviation, walking speed, gaze fixations and cognitive task accuracy were contrasted between groups using generalized estimating equations. RESULTS: In contrast to CTLs who showed locomotor DTCs only, individuals with m/sTBI displayed both locomotor and cognitive DTCs. While both groups walked slower under dual-task conditions, only individuals with m/sTBI failed to modify their onset distance of trajectory deviation and maintained smaller minimum distances and smaller maximum lateral deviation compared to single-task walking. Both groups showed shorter gaze fixations on the approaching VRP under dual-task conditions, but this reduction was less pronounced in the individuals with m/sTBI. A reduction in cognitive task accuracy under dual-task conditions was found in the m/sTBI group only. CONCLUSION: Individuals with m/sTBI present altered locomotor and gaze behaviours, as well as altered cognitive performances, when executing a collision avoidance task involving moving pedestrians in dual-task conditions. Potential mechanisms explaining those alterations are discussed. Present findings highlight the compromised complex walking abilities in individuals with m/sTBI who otherwise present a good locomotor recovery.

Optimizing Lower Extremity Local Flap Reconstruction in Peripheral Vascular Disease.

BACKGROUND: Local flaps remain a valuable reconstructive tool as a means for limb salvage for patients with advanced arterial disease. Our single-center, retrospective cohort study aims to compare the outcomes of different patterns of blood flow affected by vascular disease to pedicles in local flap reconstruction of the foot and ankle. METHODS: A retrospective review of 92 patients and 103 flaps was performed. On angiograms, pattern of blood flow to the flap pedicle was determined to be direct inline flow (DF) or indirect flow (IF). Patterns of IF were either by arterial-arterial connections (AC) or unnamed randomized collaterals (RC). Primary outcomes were immediate flap success and limb salvage. Comparative analyses were performed using the χ2 and Fisher tests for categorical variables. RESULTS: Among all flaps, 73.8% (n = 76/103) had DF and 26.2% (n = 27/103) had IF. Both groups experienced similar rates of immediate flap success (DF = 97.3% vs IF = 92.6%, P = 0.281) and limb salvage (DF = 75.% vs IF = 66.7%, P = 0.403). However, the rate of contralateral amputation was significantly higher in the IF group (26.9% vs 5.3%, P = 0.006). When comparing the 3 distinct patterns of blood flow (DF vs AC vs RC), pedicled flaps were more commonly supplied by DF and AC, while random pattern flaps were more commonly supplied by RC (P = 0.042). CONCLUSIONS: Alternative routes of revascularization can maintain local flap viability and achieve similar rates of limb salvage but risks contralateral amputation. We found that pedicled and local muscle flaps require inline blood flow or blood supply by ACs. Meanwhile, random pattern flap can be supported by random collaterals.

Indocyanine Green Angiography for Detecting Quantitative Perfusion Changes in Deep Inferior Epigastric Perforator Flap Breast Reconstruction With Second Venous Drainage.

BACKGROUND: This study aims to compare perfusion dynamics using indocyanine green videoangiography before and after the creation of a second venous anastomosis between the superficial inferior epigastric vein and the retrograde internal mammary vein (IMV) in deep inferior epigastric perforator (DIEP) flap breast reconstructions. METHODS: Indocyanine green videoangiography performed during DIEP flap reconstructions was analyzed prospectively. The areas of interest were above the perforators with the highest intensity (complete perfusion), the most distal lateral edge of the flap (partial perfusion), and the next lowest intensity (ischemic). We compared the zone intensities before and after the second venous anastomosis, assessing venous drainage patency and functionality. Patient characteristics, operative details, and complications were collected. RESULTS: Seven patients (10 breasts) underwent DIEP reconstruction. Mean age was 54.5 ± 12.4 years. Mean operative duration was 575.5 ± 172.6 minutes. Donors included DIEV (n = 10, 100.0%), superficial inferior epigastric vein (n = 9, 90.0%), and superficial circumflex epigastric vein (n = 1, 10.0%). All DIEVs were anastomosed to the antegrade IMV (n = 10, 100.0%). Superficial inferior epigastric veins were anastomosed to the retrograde IMV (n = 10, 100.0%). Mean peak intensities of the complete perfusion zone before and after the second venous anastomosis were 160.7 ± 42.1 and 188 ± 42.1, respectively ( P = 0.163). Mean peak intensities of the partial perfusion zone were 100.8 ± 21.5 and 152 ± 31.5, respectively ( P < 0.001). Mean peak intensities of the ischemic zone were 90.4 ± 37.4 and 143.4 ± 45.3, respectively ( P = 0.012). CONCLUSION: These findings highlight the potential benefits of the super drainage technique in enhancing perfusion and reducing complications, emphasizing the need for further investigation and consideration of this technique in clinical practice.

A Comparative Analysis of Patient-Reported Outcomes Following Free Tissue Transfer, Partial Foot Amputation, and Below-Knee Amputation in High-Risk Limb Salvage Patients.

BACKGROUND: The surgical decision for limb-salvage with free tissue transfer (FTT), partial foot amputation (PFA), or below-knee amputation (BKA) for complex lower extremity (LE) wounds hinges on several factors, including patient choice and baseline function. However, patient-reported outcome measures (PROMs) on LE function, pain, and QoL for chronic LE wound interventions are limited. Thus, the study aim was to compare PROMs in patients who underwent FTT, PFA, or BKA for chronic LE wounds. METHODS: PROMs were collected via QR code for all adult chronic LE wound patients who presented to a tertiary wound center between June 2022 and June 2023. A cross-sectional analysis of patients who underwent FTT, PFA, or BKA was conducted. The 12-Item Short Survey (SF-12), PROM Information System Pain Intensity (PROMIS-3a), and Lower Extremity Functional Scale (LEFS) were completed at 1, 3, and 6 months and 1, 3, and 5 years postoperatively. Patient demographics, comorbidities, preoperative characteristics, and amputation details were collected. RESULTS: Of 200 survey sets, 71 (35.5%) underwent FTT, 51 (25.5%) underwent PFA, and 78 (39.0%) underwent BKA. Median postoperative time points of survey completion between FTT (6.2 months, IQR: 23.1), PFA (6.8 months, IQR: 15.5), and BKA (11.1 months, IQR: 21.3) patients were comparable (P = 0.8672). Most patients were male (n = 92, 76.0%) with an average age and body mass index (BMI) of 61.8 ± 12.6 years and 30.3 ± 7.0 kg/m2, respectively. Comorbidities for FTT, PFA, and BKA patients included diabetes mellitus (DM; 60.6% vs 84.2% vs 69.2%; P = 0.165), peripheral vascular disease (PVD; 48.5% vs 47.4% vs 42.3%; P = 0.790), and chronic kidney disease (CKD; 12.1% vs 42.1% vs 30.8%; P = 0.084). No significant differences were observed between FTT, PFA, and BKA patients in mean overall PROMIS-3a T-scores (49.6 ± 14.8 vs 54.2 ± 11.8 vs 49.6 ± 13.7; P = 0.098), LEFS scores (37.5 ± 18.0 vs 34.6 ± 18.3 vs 38.5 ± 19.4; P = 0.457), or SF-12 scores (29.6 ± 4.1 vs 29.5 ± 2.9 vs 29.0 ± 4.0; P = 0.298). CONCLUSION: Patients receiving FTT, PFA, or BKA for chronic LE wounds achieve comparable levels of LE function, pain, and QoL postoperatively. Patient-centered functionally based surgical management for chronic LE wounds using interdisciplinary care, preoperative medical optimization, and proper patient selection optimizes postoperative PROMs.

Positive Bacterial Cultures on Spinal Wound Closure Do Not Predict Postoperative Outcomes.

BACKGROUND: Complex surgical back wounds represent significant morbidity in patients who have undergone spinal procedures requiring closure or revision by plastic surgeons. This study aimed to assess the utility of bacterial wound culture data for predicting surgical outcomes of wound management. METHODS: This study is a single-institution retrospective review of consecutive patients who required plastic surgery intervention for wound infection following spinal procedures between the years 2010 and 2021 (n = 70). Statistical analysis was performed for demographics, comorbidities, perioperative laboratory studies, and treatment methods. The primary outcomes of interest were rate of postoperative complications after soft tissue reconstruction and reconstructive failure. The secondary outcome of interest was time to healing in number of days. RESULTS: The overall complication rate after wound closure was 31.4%, with wound infection in 12.9%, seroma in 10%, dehiscence in 12.9%, and hematoma in 1.4%. Increasing number of debridements before wound closure increased the likelihood of a surgical complication of any kind (odds ratio [OR], 1.772; 95% confidence interval [CI], 1.045-3.002). Positive wound cultures before reconstruction were associated with development of seroma only (OR, 0.265; 95% CI, 0.078-0.893). Use of incisional vacuum-assisted closure devices significantly decreased the odds of postoperative wound dehiscence (OR, 0.179; 95% CI, 0.034-0.904) and increased odds of healing (hazard ratio, 3.638; 95% CI, 1.547-8.613). CONCLUSIONS: Positive wound cultures were not significantly associated with negative outcomes after complex closure or reconstruction of infected spinal surgical wounds. This finding emphasizes the importance of clinical judgment with a multidisciplinary approach to complex surgical back wounds over culture data for wound closure timing.

The robotic-assisted free jejunal flap for neovaginal canal creation in gender-affirming vaginoplasties.

INTRODUCTION: One of the biggest challenges with gender-affirming vaginoplasty was the creation of a long-lasting, durable, patent, and self-lubricating neovaginal canal that allowed for spontaneous, pain-free sexual intercourse. The jejunum was a durable, physiologic, and intestinal option to create the neovaginal canal that minimizes the adverse effects of skin graft, peritoneal, and colonic vaginoplasties. Free jejunal vaginoplasties had been performed in cis females for congenital genitourinary anomalies like Mullerian agenesis or after gynecologic-oncologic surgery but had yet to be reported for gender-affirming vaginoplasties. The purpose of this report was to present a technique for a physiologic, intestinal, gender-affirming vaginoplasty without the disadvantages of colonic vaginoplasties. PATIENTS AND METHODS: This report presented six patients, all natal males who identified as female, undergoing robotic-assisted free jejunal flap gender-affirming vaginoplasty. Mean age was 35.8 years (range: 21-66). Mean body mass index was 33.2 kg/m2 (range: 28.0-41.0). The proximal aspect of the neovaginal canal was created intra-abdominally by elevating peritoneal flaps from the posterior bladder wall to be reflected downward into the external neovaginal canal. The jejunal flap was harvested. The greater saphenous vein was harvested to create an arteriovenous loop between the flap vessels and the recipient femoral artery in an end-to-side fashion and a branch of the femoral vein. The jejunal flap was passed intra-abdominally through the groin incision and then trans-peritoneally into the neovaginal canal. The jejunal segment was inset to the proximal peritoneal flaps and the distal inverted penoscrotal skin of the neovaginal introitus. RESULTS: Mean length of the harvest jejunal segment was 19.2 cm (range: 15-20). Mean time to ambulation, foley removal, and first vaginal dilation were 3.3 (range: 3-4), 4.0 (range: 3-5), and 4.5 days (range: 4-6), respectively. By a mean follow-up duration of 8.0 months (range: 1-14), mean vaginal depth and diameter were 7.0 and 1.3 cm (range: 1.0-1.5), respectively. Two (33.3%) patients experienced postoperative complications, including groin hematoma (n = 1, 16.7%) and reoperation for correction of dehiscence of the jejunal flap to the vaginal introitus (n = 1, 16.7%). CONCLUSION: Gender-affirming surgeons should consider a free vascularized segment of jejunum as an option to line the neovaginal canal in the correct patients.

Muscle versus Fascia Free Tissue Transfer for Treatment of Chronic Osteomyelitis in the Comorbid Population.

BACKGROUND: In patients with chronic lower extremity (LE) wounds, chronic osteomyelitis confers additional complexity to achieving adequate treatment. Previous reviews demonstrate increased rates of osteomyelitis recurrence in patients who receive muscle flaps compared with fasciocutaneous flaps for LE limb salvage; however, these studies were not limited to atraumatic populations who receive exclusively free flaps. Thus, this study compared rates of recurrence in chronic osteomyelitis patients undergoing LE reconstruction with fasciocutaneous versus muscle free flaps. METHODS: Patients undergoing free tissue transfer (FTT) between July 2011 and July 2021 were retrospectively reviewed. Patients were stratified into fasciocutaneous and muscle free flap groups. Primary outcomes included osteomyelitis recurrence, flap complications, limb salvage, and ambulatory status. RESULTS: Forty-eight patients with pathologic diagnosis of chronic osteomyelitis of the wound bed were identified, of which 58.3% received fasciocutaneous (n = 28) and 41.7% received muscle flaps (n = 20). The most common comorbidities included diabetes mellitus (n = 29, 60.4%), peripheral neuropathy (n = 27, 56.3%) and peripheral vascular disease (n = 24, 50.0%). Methicillin-resistant or methicillin -sensitive Staphylococcus aureus were the most common pathogen in 18.7% (n = 9) of procedures. The majority of patients underwent a median of three debridements followed by negative pressure wound therapy prior to receiving FTT. At a median follow-up of 16.6 months, the limb salvage and ambulatory rates were 79.2 (n = 38) and 83.3% (n = 40), respectively. The overall rate of microsurgical flap success was 93.8% (n = 45). Osteomyelitis recurred in 25% of patients (n = 12) at a median duration of 4.0 months. There were no significant differences in rates of osteomyelitis recurrence, flap complications, limb salvage, ambulation, and mortality. On multivariate analysis, flap composition remained a nonsignificant predictor of osteomyelitis recurrence (odds ratio: 0.975, p = 0.973). CONCLUSION: This study demonstrates that flap composition may not influence recurrence of osteomyelitis following free flap reconstruction of chronic LE wounds, suggesting that optimal flap selection should be based on wound characteristics and patient goals.

At-home computerized executive-function training to improve cognition and mobility in normal-hearing adults and older hearing aid users: a multi-centre, single-blinded randomized controlled trial.

BACKGROUND: Hearing loss predicts cognitive decline and falls risk. It has been argued that degraded hearing makes listening effortful, causing competition for higher-level cognitive resources needed for secondary cognitive or motor tasks. Therefore, executive function training has the potential to improve cognitive performance, in turn improving mobility, especially when older adults with hearing loss are engaged in effortful listening. Moreover, research using mobile neuroimaging and ecologically valid measures of cognition and mobility in this population is limited. The objective of this research is to examine the effect of at-home cognitive training on dual-task performance using laboratory and simulated real-world conditions in normal-hearing adults and older hearing aid users. We hypothesize that executive function training will lead to greater improvements in cognitive-motor dual-task performance compared to a wait-list control group. We also hypothesize that executive function training will lead to the largest dual-task improvements in older hearing aid users, followed by normal-hearing older adults, and then middle-aged adults. METHODS: A multi-site (Concordia University and KITE-Toronto Rehabilitation Institute, University Health Network) single-blinded randomized controlled trial will be conducted whereby participants are randomized to either 12 weeks of at-home computerized executive function training or a wait-list control. Participants will consist of normal-hearing middle-aged adults (45-60 years old) and older adults (65-80 years old), as well as older hearing aid users (65-80 years old, ≥ 6 months hearing aid experience). Separate samples will undergo the same training protocol and the same pre- and post-evaluations of cognition, hearing, and mobility across sites. The primary dual-task outcome measures will involve either static balance (KITE site) or treadmill walking (Concordia site) with a secondary auditory-cognitive task. Dual-task performance will be assessed in an immersive virtual reality environment in KITE's StreetLab and brain activity will be measured using functional near infrared spectroscopy at Concordia's PERFORM Centre. DISCUSSION: This research will establish the efficacy of an at-home cognitive training program on complex auditory and motor functioning under laboratory and simulated real-world conditions. This will contribute to rehabilitation strategies in order to mitigate or prevent physical and cognitive decline in older adults with hearing loss. TRIAL REGISTRATION: Identifier: NCT05418998. https://clinicaltrials.gov/ct2/show/NCT05418998.

Implications of Single-Vessel Runoff on Long-Term Outcomes of Free Tissue Transfer for Lower Extremity Reconstruction.

BACKGROUND: Patients with complex lower extremity (LE) wounds and single-vessel LE runoff (1-VRO) are often considered for amputation. While more challenging, free tissue transfer (FTT) is a means for limb salvage. This study aims to demonstrate the feasibility of limb salvage with FTT in patients with 1-VRO. METHODS: Patients undergoing FTT by a single surgeon between 2011 and 2021 were retrospectively reviewed. Data collected included demographics, wound characteristics, vascular status, and operative details. Patients were divided into cohorts based on 1- versus 3-VRO of tibial vessel inflow. Outcomes of interest included postoperative complications such as flap necrosis, flap success, limb salvage, and ambulatory status. RESULTS: A total of 188 patients underwent FTT to LE, with 25 patients (13.3%) having 1-VRO. Patients with 1-VRO had a comparable prevalence of diabetes (56.0% vs. 50.0%, p = 0.569) and end-stage renal disease (8.0% vs. 3.7%, p = 0.319). Osteomyelitis was more common in the 1-VRO group (80.0% vs. 60.1%, p = 0.056). FTT donor sites and flap composition were similar between cohorts. At mean follow-up of 21.2 months (interquartile range 24.5:5.6, 30.1 months), limb salvage rates were similar between cohorts (84.0% vs. 91.4%, p = 0.241), with no significant differences in ambulatory status or mortality. Higher complication rates occurred in the 1-VRO cohort (48.0% vs. 21.5%, p = 0.004), of which partial flap necrosis was more prevalent in the 1-VRO group (8.0% vs. 1.2%, p = 0.029). There was no difference in flap success rates between groups (p = 0.805). More postflap angiograms were performed in the 1-VRO group (32.0% vs. 9.2%, p = 0.001), but there was no difference in need for repeat percutaneous endovascular intervention between groups. CONCLUSION: This study demonstrates that FTT reconstruction to the LE remains a reliable reconstruction option for limb salvage in patients with single-vessel supply to the LE. Reliance on advanced perioperative management and patient optimization is effective at reducing negative outcomes.

Phase II study of enzalutamide in androgen receptor positive, recurrent, high- and low-grade serous ovarian cancer.

OBJECTIVES: We sought to determine the safety and efficacy of the oral androgen receptor antagonist enzalutamide in patients with previously treated, recurrent, AR-positive (AR+) ovarian cancer. METHODS: This was a single-institution phase II study of patients with AR+ ovarian cancer with measurable disease with 1-3 prior lines of chemotherapy; patients were screened for enrollment from 11/2013-7/2018. Following consent, archival tissue was evaluated for AR+. Enrolled patients received daily enzalutamide 160 mg until progression of disease or treatment discontinuation. Adverse events were graded by CTCAE v4.0. Co-primary endpoints were 6-month progression-free survival (PFS6) and overall response rate (ORR) by RECIST 1.1 criteria. RESULTS: During the study period, 160 patients were screened and 59 (45 high-grade serous [HGS] and 14 low-grade serous [LGS]) consented to treatment on study. There was 1 confirmed and 1 unconfirmed partial response. The ORR was 1.7% (90% CI: 0.2-100%). The overall PFS6 rate (as binary) was 22% (90% CI: 15.1-100%). The 6-month PFS rate (as time to event) was 19.8% for HGS patients (90% CI: 12.7-100%) and 38.5% (90% CI: 21.7%-100%) for LGS patients. Grade 3 toxicities occurred in 6 patients (one toxicity (Grade 3 rash) was considered a dose-limiting toxicity). One patient died of cardiac arrest after 42 days on treatment of a cardiac arrest not attributed to study drug. CONCLUSIONS: The study met its primary endpoint, with a PFS6 rate of 22% (n = 13); however, the overall response rate was low. Enzalutamide was well tolerated and may be a potential treatment option in select patients.

Neurological Complications and Clinical Outcomes of Infective Endocarditis.

OBJECTIVES: The aim of this study is to explore the clinical features associated with neurological complications of infective endocarditis (IE) and to assess the impact of neurological complications on clinical outcomes. MATERIALS AND METHODS: The frequency of relevant clinical features was compared in a case series of IE patients with and without neurological complications admitted to a single health care system from 2015 to 2019. Variables with significant differences (p ≤ 0.05) in baseline characteristics in univariate logistic regression models were entered into multivariable models along with age to determine associations with neurological complications, unfavorable discharge outcomes (modified Rankin score ≥ 3), and in-hospital mortality. RESULTS: 260 patients with a mean age of 51 (±18) years and 103 (40%) females were included. Neurological complications occurred in 165 (63%) patients, with the most common being septic emboli (66 patients, 25%). In the regression analyses, antiplatelet usage (aOR 1.87, 95% CI [1.05-3.32]) and mitral valve vegetations (aOR 2.66, 95% CI [1.22-5.79]) were independently associated with neurological complications. Territorial infarction (aOR 4.13, 95% CI [1.89-9.06]) and encephalopathy (aOR 3.95, 95% CI [1.19-13.05]) were associated with an increased risk of unfavorable outcome, while cardiac surgery was associated with a lower risk of both unfavorable outcome (aOR 0.40, 95% CI [0.22-0.71]) and in-hospital mortality (aOR 0.18, 95% CI [0.09-0.35]). CONCLUSIONS: Neurological complications are common in IE patients and are associated with mitral valve endocarditis and antiplatelet usage. Of the neurological complications, territorial infarcts and encephalopathy are associated with unfavorable discharge outcomes.

Expression of DEspR in acute intracerebral hemorrhage.

OBJECTIVES: Neuroinflammation and secondary injury play a central role in the pathophysiology of intracerebral hemorrhage. The dual endothelin-1/VEGFsignal-peptide receptor (DEspR) has been reported to mediate the inflammatory response after acute brain injury in a rodent model. We performed a pilot study to assess the expression of DEspR on circulating leukocytes in patients who presented with spontaneous intracerebral hemorrhage (ICH). MATERIALS AND METHODS: We performed a prospective observational study of patients presenting to two academic medical centers with ICH. Normal healthy volunteers (NHV) were also recruited for sample analysis. Whole blood was obtained, and flow cytometry was performed to examine DEspR expression on neutrophils, monocytes, and lymphocytes. RESULTS: A total of 19 patients were included in analysis. Median ICH volume was 39 cm3 [IQR 19 cm3, 73 cm3] and median ICH score was 2 [IQR 2, 3]. DEspR expression was more abundant on neutrophils (median 2.4% [IQR 0.5%, 5.8%], p = 0.0064) and monocytes (median 4.4% [IQR 1.7%, 15.8%], p = 0.003) relative to lymphocytes (median 0.9% [IQR 0.2%, 3.3%]). ICH patients had higher DEspR expression in all leukocytes relative to NHV (p < 0.05 for all). Among ICH patients, those with a medical history of hypertension showed higher DEspR expression on neutrophils and monocytes (p = 0.018) compared to those without hypertension. CONCLUSIONS: In this pilot study, DEspR is expressed on circulating neutrophils and monocytes in humans after ICH, with higher levels of expression in those with hypertension. Future work in larger cohorts should examine the relationship of DEspR expression with neuroinflammatory endpoints and long-term outcome.

Gait variability across neurodegenerative and cognitive disorders: Results from the Canadian Consortium of Neurodegeneration in Aging (CCNA) and the Gait and Brain Study.

INTRODUCTION: Gait impairment is common in neurodegenerative disorders. Specifically, gait variability-the stride-to-stride fluctuations in distance and time-has been associated with neurodegeneration and cognitive impairment. However, quantitative comparisons of gait impairments across the cognitive spectrum of dementias have not been systematically investigated. METHODS: Older adults (N = 500) with subjective cognitive impairment, Parkinson disease (PD), mild cognitive impairment (MCI), PD-MCI, Alzheimer's disease (AD), PD-dementia, Lewy body dementia, and frontotemporal dementia, as well cognitive normal controls, who were assessed for their gait and cognitive performance. RESULTS: Factor analyses grouped 11 quantitative gait parameters and identified four independent gait domains: rhythm, pace, variability, and postural control, for group comparisons and classification analysis. Among these domains, only high gait variability was associated with lower cognitive performance and accurately discriminated AD from other neurodegenerative and cognitive conditions. DISCUSSION: Our findings indicate that high gait variability is a marker of cognitive-cortical dysfunction, which can help to identify Alzheimer's disease dementia.

Microemboli After Successful Thrombectomy Do Not Affect Outcome but Predict New Embolic Events.

Background and Purpose- We aimed to determine if microemboli after endovascular thrombectomy correlate with unfavorable outcomes despite successful recanalization. Methods- This is a prospective multicenter study of consecutive patients with ischemic stroke and occlusion of anterior circulation vessels (terminal internal carotid or main trunk of the middle cerebral artery/first-order branch of the main trunk of the middle cerebral artery segments of middle cerebral artery) after successful thrombectomy (modified Treatment In Cerebral Ischemia grades 2b-3). Microembolic signals (MES) were assessed by 30 minutes of transcranial Doppler monitoring within 72 hours of the last-seen-well time. Major outcomes included modified Rankin Scale at 90 days and infarct volume on head computed tomography at 24 hours. We also assessed early outcomes based on National Institutes of Health Stroke Scale variation and recurrence of stroke, transient ischemic attack, or systemic embolism within 90 days. Results- Among 111 patients, MES were detected in 43 (39%), with a median rate of 4 counts/h (interquartile range 2-12). The occurrence of MES was not associated with a significant difference in modified Rankin Scale (ordinal shift analysis, adjusted odds ratio, 1.06 [95% CI, 0.48-2.34] P=0.85) nor in functional independence (modified Rankin Scale, 0-2: adjusted odds ratio, 0.52 [95% CI, 0.19-1.39] P=0.19). Patients with and without MES had similar infarct volumes (adjusted beta, 11.2 [95% CI, -46.6 to +22.9] P=0.51) on 24-hour computed tomography. MES did predict new embolic events (adjusted Cox hazard ratio, 6.78 [95% CI, 1.63-27.8] P=0.01). Conclusions- MES detected by transcranial Doppler following endovascular treatment of anterior circulation occlusions do not predict clinical or radiological outcome. However, such emboli are an independent marker of recurrent embolic events within 90 days.

Dysregulation of miR-431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis.

The level of microRNA (miR)-431 was found to be markedly up-regulated in intestinal tissue of necrotizing enterocolitis (NEC). The objective of this study was to identify the target gene of miR-431 and to investigate the role of the miR-431-FOXA1 axis in the pathophysiology of NEC. The target gene of miR-431 was identified by in silico target prediction bioinformatics, luciferase assay, and Western blotting. Effects of miR-431 on downstream expression signals, cell proliferation, and apoptosis were investigated by overexpression in Caco-2 cells upon stimulation by LPS or lipoteichoic acid (LTA). FOXA1 was identified as the target gene of miR-431. Overexpression of miR-431 in Caco-2 cells significantly inhibited FOXA1, ESRRG, and HNF4A and activated IL-6, LGR5, NFKB2, PLA2G2A, PRKCZ, and TNF. IL-8 and - 10 were enhanced when costimulated with LPS or LTA. These potential downstream genes were also significantly dysregulated in primary NEC tissues compared with surgical-control tissues. Overexpression of miR-431 significantly decreased proliferation and increased apoptosis of Caco-2 cells. A proposed network of miR-431-FOXA1 interaction with LPS and LTA receptors demonstrates dysregulation of transcription factors, inflammatory mediators, epithelium tight junction regulators, and cell proliferation and apoptosis signals. The miR-431-FOXA1 axis could in part be responsible for the intensification of the inflammatory response in NEC tissues and contribute to the proinflammatory pathophysiology.-Wu, Y. Z., Chan, K. Y. Y., Leung, K. T., Lam, H. S., Tam, Y. H., Lee, K. H., Li, K., Ng, P. C. Dysregulation of miR-431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis.

Neurological toxicities associated with chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.

Adverse Birth Outcomes and Birth Telomere Length: A Systematic Review and Meta-Analysis.

OBJECTIVES: To synthesize previous findings on the difference in birth telomere length between newborns with and without intrauterine growth restriction (IUGR) or with and without preterm birth. STUDY DESIGN: We systematically searched 3 databases (PubMed, Embase, and Web of Science) for publications that examined the relationships of IUGR or preterm birth with birth telomere length. We conducted meta-analysis to pool the estimated difference in birth telomere length either between IUGR and non-IUGR or between preterm birth and full-term birth. Subgroup analyses were conducted by tissues (newborn blood vs placenta) and techniques used for telomere length measurement (quantitative polymerase chain reaction [qPCR] vs telomere restriction fragment). RESULTS: We included 11 articles on comparing birth telomere length between IUGR (combined n = 227) and non-IUGR (n = 1897) and 7 articles on comparing birth telomere length between preterm birth (n = 182) and full-term birth (n = 1320). We found IUGR was associated with shorter birth telomere length only when birth telomere length was measured in placenta (pooled standardized mean difference [SMD] = -0.85; 95% CI -1.13 to -0.57; IUGR/non-IUGR n = 87/173), but not in newborn blood (pooled SMD = 0.00, 95% CI -0.18 to 0.19; IUGR/non-IUGR n = 148/1733). Birth telomere length was significantly longer in preterm birth than in full-term birth when birth telomere length was measured by qPCR (pooled SMD = 0.40, 95% CI 0.18-0.63; preterm birth/full-term birth n = 137/682) but not by telomere restriction fragment (pooled SMD = 0.05, 95% CI -0.29 to 0.38; preterm birth/full-term birth n = 44/444). CONCLUSIONS: IUGR is associated with shorter placental telomere length and preterm birth is associated with longer birth telomere length measured by qPCR.

Plasma miR-1290 Is a Novel and Specific Biomarker for Early Diagnosis of Necrotizing Enterocolitis-Biomarker Discovery with Prospective Cohort Evaluation.

OBJECTIVE: To discover specific circulating microRNA (miRNA) biomarkers for the early differentiation of necrotizing enterocolitis (NEC) from neonatal sepsis and inflammatory conditions. STUDY DESIGN: The study comprised 3 distinct phases: differential microarray analysis to compare plasma miRNA expression profiles of NEC vs sepsis and non-NEC/nonsepsis cases, a case-control study to quantify dysregulated miRNAs as potential specific biomarkers of NEC, and a prospective cohort study to assess the diagnostic usefulness of the best miRNA biomarker(s). RESULTS: A distinct miRNA expression profile was observed in the NEC compared with the sepsis and non-NEC/nonsepsis groups. miR-1290, miR-1246, and miR-375 were discovered to be specific biomarkers of NEC in the case-control study. In the cohort study (n = 301), plasma miR-1290 (day 0; >220 copies/µL) provided the greatest diagnostic usefulness for identifying both mild medical and severe surgical NEC cases. Of 20 infants with miR-1290 >650 copies/µL, 15 were diagnosed with NEC. Incorporating C-reactive protein (day 1; >15.8 mg/L) for cases with intermediate levels (220-650 copies/µL) in a 2-stage algorithm further optimized the diagnostic profile with a sensitivity of 0.83, a specificity of 0.96, a positive predictive value of 0.75, and a negative predictive value of 0.98. Importantly, 7 of 36 infants with NEC (19.4%) could be diagnosed 7.8-32.2 hours earlier (median, 13.3 hours) using miR-1290. CONCLUSIONS: Plasma miR-1290 is a novel and specific biomarker that can effectively differentiate NEC cases from neonatal sepsis. miR-1290 facilitates neonatologists to confidently and timely reach a decision for early transfer of sick infants with NEC from community-based hospitals to tertiary surgical centers.