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.

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.

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.

A cross-sectional analysis on the effects of age on dual tasking in typically developing children.

Dual tasking is an integral part of everyday activities for children. Therefore, as with the other aspects of child development-motor, cognitive, perceptual, psychological, and behavioral-it is important to understand the maturation process of dual-tasking skills in children. Characterizing age-related changes in children's dual-task performance has been problematic, because differences in dual-tasking ability are confounded by age differences in abilities in the relevant single-task performances. The effect of age on dual-tasking ability was examined in 221 typically developing children aged 5-8 years using two motor-cognitive dual-task paradigms: walking while performing an n-back cognitive task, and drawing a trail while performing an n-back cognitive task. The test-retest reliability of the dual-task paradigm was examined by re-assessing 50 participants after 1 month. Individual differences in single-task performance were controlled for, so that any age differences in dual-task costs could not be attributed to differences in single-task performance. There were no age-related differences in dual-task cost of any task (p > 0.05). However, the dual-task cost of trail-making was significantly greater than the dual-task cost of walking when performed under similar cognitive loads (p < 0.0001). The intra-class correlation coefficient ranged from 0.71 to 0.92 for all dual-task performances. The results suggest that previously reported age differences in dual-task costs in young children may have been driven by developmental differences in single-task ability, and that general task coordination ability is comparable in children 5-8 years of age.

SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment.

BACKGROUND: Physical exercise, cognitive training, and vitamin D are low cost interventions that have the potential to enhance cognitive function and mobility in older adults, especially in pre-dementia states such as Mild Cognitive Impairment (MCI). Aerobic and progressive resistance exercises have benefits to cognitive performance, though evidence is somewhat inconsistent. We postulate that combined aerobic exercise (AE) and progressive resistance training (RT) (combined exercise) will have a better effect on cognition than a balance and toning control (BAT) intervention in older adults with MCI. We also expect that adding cognitive training and vitamin D supplementation to the combined exercise, as a multimodal intervention, will have synergistic efficacy. METHODS: The SYNERGIC trial (SYNchronizing Exercises, Remedies in GaIt and Cognition) is a multi-site, double-blinded, five-arm, controlled trial that assesses the potential synergic effect of combined AE and RT on cognition and mobility, with and without cognitive training and vitamin D supplementation in older adults with MCI. Two-hundred participants with MCI aged 60 to 85 years old will be randomized to one of five arms, four of which include combined exercise plus combinations of dual-task cognitive training (real vs. sham) and vitamin D supplementation (3 × 10,000 IU/wk. vs. placebo) in a quasi-factorial design, and one arm which receives all control interventions. The primary outcome measure is the ADAS-Cog (13 and plus modalities) measured at baseline and at 6 months of follow-up. Secondary outcomes include neuroimaging, neuro-cognitive performance, gait and mobility performance, and serum biomarkers of inflammation (C reactive protein and interleukin 6), neuroplasticity (brain-derived neurotropic factor), endothelial markers (vascular endothelial growth factor 1), and vitamin D serum levels. DISCUSSION: The SYNERGIC Trial will establish the efficacy and feasibility of a multimodal intervention to improve cognitive performance and mobility outcomes in MCI. These interventions may contribute to new approaches to stabilize and reverse cognitive-mobility decline in older individuals with MCI. TRIAL REGISTRATION: Identifier: NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676 .

A comparison of the impact of physical exercise, cognitive training and combined intervention on spontaneous walking speed in older adults.

BACKGROUND: Spontaneous walking speed (SWS) is one of the most important indicators of health in older adults. Studies have shown benefits of physical trainings on SWS in older adults but the impact of cognitive training and multidomain interventions remains understudied. AIMS: This original study aimed at comparing the impact of aerobic/resistance exercise, computerized cognitive training and the combination of both interventions compared with active control conditions on SWS in healthy older adults. METHODS: Ninety community-dwelling older adults were randomly assigned to four different combinations composed of two active interventions: physical aerobic/resistance and cognitive dual-task trainings, and two active control conditions: stretching exercises and computer lessons. The four combinations were the following: (1) aerobic/resistance and cognitive dual task (n = 28), (2) aerobic/resistance and computer lessons (n = 21), (3) stretching exercises and cognitive dual task and (n = 23), (4) stretching exercises and computer lessons (n = 18). Training sessions were held three times/week for three months. SWS for 30 s was assessed before and after the intervention. RESULTS: Repeated-measures ANOVA showed a main effect of time and a significant three-way interaction suggesting differential improvement in SWS according to training combinations. A clinical meaningful improvement in SWS was observed in groups 1-3 (0.08-0.14 m/s; effect sizes: small to moderate) but not in the active control group 4. DISCUSSION: Results of this study suggest that aerobic/resistance exercise and computerized dual-task training are two non-pharmacological interventions by which SWS, a functional vital sign, can be clinically improved in older adults. CONCLUSION: This original study pointed out different tools to prevent functional decline in older people.