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Individuals vary in their ability to perceive, as conscious sensations, signals like the beating of the heart. Tests of such interoceptive ability are, however, constrained in nature and reliability. Performance of the heartbeat tracking task, a widely used test of cardiac interoception, often corresponds well with individual differences in emotion and cognition, yet is susceptible to reporting bias and influenced by higher-order knowledge, e.g., of expected heart rate. The present study introduces a new way of assessing cardiac interoceptive ability, focusing on sensitivity to short-term, naturalistic changes in frequency of heartbeats. At rest, such heart rate variability typically reflects the dominant influence of respiration on vagus parasympathetic control of the sinoatrial pacemaker. We observed an overall tendency of healthy participants to report feeling fewer heartbeats during increases in heart rate, which we speculate reflects a reduction in heartbeat strength and salience during inspiratory periods when heart rate typically increases to maintain a stable cardiac output. Within-participant performance was more variable on this measure of cardiac interoceptive sensitivity relative to the "classic" heartbeat tracking task. Our findings indicate that cardiac interoceptive ability, rather than reflecting the veridical monitoring of subtle variations in physiology, appears to involve more interpolation wherein interoceptive decisions are informed by dynamic working estimates derived from the integration of afferent signaling and higher-order predictions.

To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P .001) than those without acute abnormalities.Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.ClinicalTrials.gov: NCT02811263.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background: Although pathogenic 22q11.2 deletions are an important cause of developmental delays and lifelong disease burden, their variable and complex clinical expression contributes to under-recognition, delayed molecular diagnosis and uncertainty about prevalence. We sought to estimate the contemporary live-birth prevalence of typical 22q11.2 deletions using a population-based newborn screening sample and to examine data available for associated clinical features. Methods: Using DNA available from an unbiased sample of about 12% of all dried blood spots collected for newborn screening in Ontario between January 2017 and September 2018, we prospectively screened for 22q11.2 deletions using multiplex quantitative polymerase chain reaction assays and conducted independent confirmatory studies. We used cross-sectional analyses to compare available clinical and T-cell receptor excision circle (TREC, used in newborn screening for severe combined immunodeficiency) data between samples with and without 22q11.2 deletions. Results: The estimated minimum prevalence of 22q11.2 deletions was 1 in 2148 (4.7 per 10 000) live births (95% confidence interval [CI] 2.5 to 7.8 per 10 000), based on a total of 30 074 samples screened, with 14 having confirmed 22q11.2 deletions. Of term singletons, samples with 22q11.2 deletions had significantly younger median maternal age (25.5 v. 32.0 yr, difference −6.5 yr, 95% CI −7 to −2 yr), a greater proportion with small birth weight for gestational age (odds ratio 7.00, 95% CI 2.36 to 23.18) and lower median TREC levels (108.9 v. 602.5 copies/3 μL, p < 0.001). Interpretation: These results indicate that the 22q11.2 deletion syndrome is one of the most common of rare genetic conditions and may be associated with relatively younger maternal ages and with prenatal growth abnormalities. The findings support the public health importance of early — prenatal and neonatal — diagnosis that would enable prompt screening for and management of well-known actionable features associated with 22q11.2 deletions.

Military personnel in combat roles often perform gait tasks with additional load, which can affect the contributions of joint mechanical work (positive and negative). Furthermore, different locomotion patterns can also affect joint specific work contributions. While mean behavior of joint work is important to understanding gait, changes in joint kinetic modulation, or the regulation/control of stride-to-stride joint work variability is necessary to elucidate locomotor system function. Suboptimal modulation exhibited as a stochastic time-series (large fluctuation followed by an opposite smaller fluctuation) could potentially affect locomotion efficiency and portend injury risk. It remains unclear how the locomotor system responds to a combination of load perturbations and varying locomotion patterns.What are the interactive effects of load magnitude and locomotion pattern on joint positive/negative work and joint work modulation in healthy, active, recruit-aged women?Eleven healthy, active, recruit-aged (18-33 years) women ran and forced-marched (walking at a velocity an individual would typically jog) in bodyweight (BW), an additional 25 % of BW (+25 %BW) and an additional 45 % of BW (+45 %BW) conditions at a velocity above their gait transition velocity. Joint work was calculated as the time integral of joint power. Joint work modulation was assessed with detrended fluctuation analysis (DFA) on consecutive joint work time-series.Joint work contributions shifted proximally for forced-marching demonstrated by lesser (p .001) positive/negative ankle work but greater (p = .001) positive hip work contributions compared to running. Running exhibited optimal positive ankle work modulation compared to forced-marching (p = .040). Knee and ankle negative joint work modulation was adversely impacted compared to the hip during forced-marching (p .001).Employing forced-marching gait while under loads of 25 and 45 % of BW reduces the ability of the plantar-flexors and knee extensors to optimally contribute to energy absorption and propulsion in recruit-aged women, potentially reducing metabolic efficiency and increasing injury risk.

Purpose Patellofemoral instability is a common cause of knee pain and dysfunction in paediatric and adolescent patients. The purpose of the study was to evaluate the frequency of patellar dislocations seen in emergency departments (EDs) and the rates of surgical procedures for patellar instability at paediatric hospitals in the United States between 2004 and 2014. Methods The Pediatric Health Information System database was queried for all paediatric patients who underwent surgery for patellar instability or were seen in the ED for acute patellar dislocation between 2004 and 2014. This was compared with the annual numbers of overall orthopaedic surgical procedures. Results Between 2004 and 2014, there were 3481 patellar instability procedures and 447 285 overall orthopaedic surgical procedures performed at the included institutions, suggesting a rate of 7.8 per 1000 orthopaedic surgeries. An additional 5244 patellar dislocations treated in EDs were identified. Between 2004 and 2014, the number of patellar instability procedures increased 2.1-fold (95% confidence interval (CI) 1.4 to 3.0), while orthopaedic surgical procedures increased 1.7-fold (95% CI 1.3 to 2.0), suggesting a 1.2-fold relative increase in patellar instability procedures, compared with total paediatric orthopaedic surgeries. Conclusion This study shows a significant rise in the rate of acute patellar instability treatment events in paediatric and adolescent patients across the country. Surgery for patellar instability also increased over the study period, though only slightly more than the rate of all paediatric orthopaedic surgical procedures. This may suggest that increasing youth sports participation may be leading to a spectrum of increasing injuries and associated surgeries in children. Level of Evidence IV

Literature regarding medial collateral ligament (MCL) injuries is focused on adults with superficial MCL disruptions. However, children follow different injury patterns, with avulsion fractures at ligament attachment sites occurring commonly. Such avulsions have not been characterized for pediatric MCL injuries. To elucidate imaging findings, and review management and outcomes of pediatric MCL avulsion fractures. We conducted a 10-year retrospective review of knee magnetic resonance (MR) imaging reports for patients younger than 16 years old diagnosed with acute MCL avulsion fracture. MR imaging was reviewed to confirm and characterize the components of the avulsion (perichondrium without or with cartilage, and/or bone) and to identify additional knee injuries. Radiographs, if available, from the time of injury were reviewed. Clinical management and patient outcomes were recorded. Eighteen patients (13 boys, 5 girls) incurred an acute MCL avulsion fracture. All avulsions involved the deep MCL attachment: 17 meniscofemoral and 1 meniscotibial component. Two avulsions also included the superficial MCL attachment. Nine boys had non-osseous avulsions, all radiographically occult. All girls had radiographically apparent avulsions. Three girls and three boys sustained associated knee derangements, most commonly anterior cruciate ligament (ACL) injury (n=4). All MCL avulsions were initially treated conservatively; one child required subsequent surgery for ongoing pain. Pediatric MCL avulsion fractures in this study uniformly involve the attachment of the deep MCL and can be entirely non-osseous, particularly in boys who lag in skeletal maturity, making these injuries radiographically occult. MR imaging may be required to recognize these avulsions, which can impact the duration of rest and knee bracing.

Doege-Potter syndrome is a rare paraneoplastic syndrome that is often diagnosed incidentally during the workup of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia secondary to excessive production of partially processed IGF-II hormone from a solitary fibrous tumor (SFT). Often these tumors are intrathoracic, benign, and asymptomatic. Occasionally they present as a paraneoplastic event; hypertrophic osteoarthropathy in Pierre-Marie-Bamberger syndrome and hypoglycemia in Doege-Potter syndrome. The NAB2-STAT6 gene fusion is the hallmark of the SFT. Complete surgical resection of the tumor often results in resolution of symptoms and cure in most cases. Here we present the case of an 83-year-old non-diabetic female with recurrent syncopal events who was diagnosed with the Doege-Potter syndrome secondary to a SFT of pleura. Her tumor was positive for NAB2-STAT6 gene fusion on RT-PCR. Following the resection of the giant tumor mass, she became symptom-free within 24 h, and has remained asymptomatic at 4 months follow-up.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. Early detection and appropriate treatment and management of COPD can lower morbidity and perhaps mortality. Clinicians in the primary care setting provide the majority of COPD care and are pivotal in the diagnosis and management of COPD. In this review, we provide an overview of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 report, with a focus on the management of COPD in the primary care setting. We discuss the pathophysiology of COPD; describe COPD risk factors, signs, and symptoms that may facilitate earlier diagnosis of COPD; and reinforce the importance of spirometry use in establishing the diagnosis of COPD. Disease monitoring, as well as a review of the 2020 GOLD treatment recommendations, is also discussed. Patients and families are important partners in COPD management; therefore, we outline simple steps that may assist them in caring for those affected by COPD. Finally, we discuss nonpharmacological treatment options for COPD, COPD monitoring tools that may aid in the evaluation of disease progression and response to therapy, and the importance of developing a COPD action plan on an individualized basis.

OBJECTIVE: To evaluate the association between retinopathy of prematurity and vitreous findings in premature infants detected by handheld spectral-domain optical coherence tomography. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Consecutive sample of 92 premature infants requiring retinopathy of prematurity screening at two academic neonatal intensive care units, between July 2015 and March 2018. METHODS: Infants underwent handheld spectral domain optical coherence tomography at the time of routine retinopathy of prematurity examinations. Two masked, trained graders analyzed right eye vitreoretinal findings including semi-automated quantification of punctate hyperreflective vitreous opacities within 5 foveal/parafoveal B-scans (Vitreous Opacity Ratio). MAIN OUTCOME MEASURES: Excluding post-treatment data, vitreous findings were compared to clinical retinopathy of prematurity diagnoses. RESULTS: Agreement between image graders for all vitreoretinal findings was 91% (kappa=0.86 [95% confidence interval, 0.82–0.90], P

In a population-based study, we found that computed tomography (CT)-based bone density and strength measures from the thoracic spine predicted new vertebral fracture as well as measures from the lumbar spine, suggesting that CT scans at either the thorax or abdominal regions are useful to assess vertebral fracture risk. Prior studies have shown that computed tomography (CT)-based lumbar bone density and strength measurements predict incident vertebral fracture. This study investigated whether CT-based bone density and strength measurements from the thoracic spine predict incident vertebral fracture and compared the performance of thoracic and lumbar bone measurements to predict incident vertebral fracture. This case-control study of community-based men and women (age 74.6 ± 6.6) included 135 cases with incident vertebral fracture at any level and 266 age- and sex-matched controls. We used baseline CT scans to measure integral and trabecular volumetric bone mineral density (vBMD) and vertebral strength (via finite element analysis, FEA) at the T8 and L2 levels. Association between these measurements and vertebral fracture was determined by using conditional logistic regression. Sensitivity and specificity for predicting incident vertebral fracture were determined for lumbar spine and thoracic bone measurements. Bone measurements from T8 and L2 predicted incident vertebral fracture equally well, regardless of fracture location. Specifically, for predicting vertebral fracture at any level, the odds ratio (per 1-SD decrease) for the vBMD and strength measurements at L2 and T8 ranged from 2.0 to 2.7 (p

Background The use of kinetic impact projectiles (KIPs) for crowd-control has increased worldwide. Despite having been created as non-lethal weapons, significant damage to several organs, including the eye, has been reported. In this study, we investigated cases of ocular trauma from KIPs during the civil unrest in Chile. To our knowledge, this is the largest case series recorded in international literature. Methods We included all patients who sought care or were referred to the Eye Trauma Unit, a national referral centre in Santiago, Chile, during the civil unrest from October 18 to November 30, 2019. We reviewed paper medical records and extracted data on suspected cause of trauma, type of trauma, visual acuity and sociodemographic data. Results We included 259 patients, out of which in 182 cases (70.5%) KIPs were the suspected cause. Cases by KIPs were predominantly male (86.6%), young (median age 26.3, interquartile range 22.0–31.4) and living in the Metropolitan Region. Eighty-nine patients (48.9%) had severe visual impairment or were blind at the first examination. The trauma was an open-globe injury in 20.3% of cases and 13 cases required evisceration of the ocular content. Compared to other causes of ocular trauma, KIPs were related to a more severe loss of visual acuity and a higher frequency of open-globe injuries. Conclusions The use of KIPs during a period of civil unrest in Chile resulted in severe ocular trauma, visual impairment and permanent disability. KIPs should be avoided as a method of crowd-control.

The current study examined whether a brief text messaging intervention compared to an assessment only/no treatment control would differentially increase protective behavioral strategies (PBS) that were associated with reducing negative alcohol-related negative consequences during football game weekends. Eligible participants (n = 161) were college students who had at least one drinking occasion in the past 30 days. Participants completed a baseline assessment prior to the experimental weekend before being randomly assigned to receive either a text-message condition that instructed students to use PBS or an assessment only/no treatment condition. Participants in the text messaging condition received a message on Thursday, Friday, and Saturday of a game weekend. Follow-up assessments were completed within 3 days following the experimental weekend. After controlling for amount of use, results suggest that for game day, those in the text-messaging condition reported significantly higher utilization of PBS and significantly lower negative alcohol-related consequences as compared with the assessment only/no treatment condition. Overall, the results highlight the importance of text messaging as an alternative intervention method that minimizes harm associated with drinking during football game weekends.

Background context The North American Spine Society's (NASS) Evidence Based Clinical Guideline for the Diagnosis and Treatment of Low Back Pain features evidence-based recommendations for diagnosing and treating adult patients with nonspecific low back pain. The guideline is intended to reflect contemporary treatment concepts for nonspecific low back pain as reflected in the highest quality clinical literature available on this subject as of February 2016. PURPOSE The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with nonspecific low back pain. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition. Study design This is a guideline summary review. Methods This guideline is the product of the Low Back Pain Work Group of NASS’ Evidence-Based Clinical Guideline Development Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questions to address in the guideline. The literature search strategy was developed in consultation with medical librarians. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in webcasts and in-person recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guideline was submitted to an internal and external peer review process and ultimately approved by the NASS Board of Directors. Results Eighty-two clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature. Conclusions The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with nonspecific low back pain. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at https://www.spine.org/ResearchClinicalCare/QualityImprovement/ClinicalGuidelines.aspx

BACKGROUND: To determine the prevalence and severity of acute kidney injury (AKI) at different time frames in relation to gestational age (GA) and birthweight (BW) in extremely low gestational age neonates (ELGAN). Our hypothesis is that ELGAN with lower GA and lower BW have higher AKI rates. METHODS: 923 ELGAN enrolled in the Preterm Erythropoietin Neuroprotection Trial were evaluated from birth until death or hospital discharge. AKI was defined according to kidney disease: improving global outcomes (KDIGO) definition from clinically-derived serum creatinine (SCr) measurements. Severe AKI was defined as stage 2 or higher. RESULTS: For the entire cohort, 351/923 (38.0%, CI = 34.8–41.3%) had at least one episode of stage 1 or higher AKI and 168/923 (18.2%, CI = 15.7–20.7%) had at least one episode of severe (stage 2 or higher) AKI. The prevalence of AKI stage 1 or higher for the entire cohort during the early (days 3–7), middle (days 8–14) and late follow-up period (after day 14) was 112/923 (12.1%, CI = 10.0–14.3%), 142/891 (15.9%, CI = 13.5–18.4%) and 249/875 (28.5%, CI = 25.4–31.5%), respectively. The rates of severe AKI during the hospital course were 27.8%, 21.9%, 13.6%, and 9.4% for the 24, 25, 26 and 27 week GA groups respectively. AKI rates were significantly higher with decreasing GA and decreasing BW for stated time trends (all p < 0.01 using tests for trend). CONCLUSIONS: AKI is relatively common in ELGAN during their initial hospital course, and is associated with lower GA and BW.

Background: Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality. Methods and results: A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%). Conclusion: A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

Background:Preclinical studies suggest that for complete midsubstance anterior cruciate ligament (ACL) injuries, a suture repair of the ACL augmented with a protein implant placed in the gap between the torn ends (bridge-enhanced ACL repair [BEAR]) may be a viable alternative to ACL reconstruction (ACLR).Hypothesis:We hypothesized that patients treated with BEAR would have a noninferior patient-reported outcomes (International Knee Documentation Committee [IKDC] Subjective Score; prespecified noninferiority margin, –11.5 points) and instrumented anteroposterior (AP) knee laxity (prespecified noninferiority margin, +2-mm side-to-side difference) and superior muscle strength at 2 years after surgery when compared with patients who underwent ACLR with autograft.Study Design:Randomized controlled trial; Level of evidence, 1.Methods:One hundred patients (median age, 17 years; median preoperative Marx activity score, 16) with complete midsubstance ACL injuries were enrolled and underwent surgery within 45 days of injury. Patients were randomly assigned to receive either BEAR (n = 65) or autograft ACLR (n = 35 [33 with quadrupled semitendinosus-gracilis and 2 with bone–patellar tendon–bone]). Outcomes—including the IKDC Subjective Score, the side-to-side difference in instrumented AP knee laxity, and muscle strength—were assessed at 2 years by an independent examiner blinded to the procedure. Patients were unblinded after their 2-year visit.Results:In total, 96% of the patients returned for 2-year follow-up. Noninferiority criteria were met for both the IKDC Subjective Score (BEAR, 88.9 points; ACLR, 84.8 points; mean difference, 4.1 points [95% CI, –1.5 to 9.7]) and the side-to-side difference in AP knee laxity (BEAR, 1.61 mm; ACLR, 1.77 mm; mean difference, –0.15 mm [95% CI, –1.48 to 1.17]). The BEAR group had a significantly higher mean hamstring muscle strength index than the ACLR group at 2 years (98.2% vs 63.2%; P < .001). In addition, 14% of the BEAR group and 6% of the ACLR group had a reinjury that required a second ipsilateral ACL surgical procedure ( P = .32). Furthermore, the 8 patients who converted from BEAR to ACLR in the study period and returned for the 2-year postoperative visit had similar primary outcomes to patients who had a single ipsilateral ACL procedure.Conclusion:BEAR resulted in noninferior patient-reported outcomes and AP knee laxity and superior hamstring muscle strength when compared with autograft ACLR at 2-year follow-up in a young and active cohort. These promising results suggest that longer-term studies of this technique are justified.Registration:NCT02664545 (ClinicalTrials.gov identifier)

No definite consensus exists for the clearance of the cervical spine (C-spine) after blunt trauma, despite many validated algorithms, recommendations and guidelines. We intend to answer the most relevant questions with which physicians are confronted when clearing C-spines after blunt trauma in emergency departments (EDs). To exclude significant C-spine injuries we designed an algorithm to be compatible with clinical practice, to simplify patient management and avoid unrewarding evaluation. We conducted an exploratory PubMed search including articles published from January 2000 to October 2018. Keywords used were “cervical spine”, “injury”, “clearance”, “Canadian C-spine Rule”, “CCR” and “national emergency x-radiography utilization study”. Clinical and experimental studies were included in a detailed review. We based our literature review on 33 articles. While answering fundamental triage questions from daily clinical practice, the current literature is discussed in detail. We designed an algorithm for the C-spine clearance suitable for any trauma centre with a high-quality multiplanar reconstruction computerized tomography (CT) scan continuously available. The high sensitivity of the Canadian C-spine Rule (CCR) prevents missing C-spine injuries while limiting the amount of unnecessary radiologic examinations. Plain radiographs were fully abandoned for C-spine clearance. A negative CT scan is sufficient to clear the majority of C-spine injuries and allows for collar removal. In case of motor symptoms or radio-clinical discrepancy, the advice of a specialized spine surgeon must be requested. Magnetic resonance imaging must not be routinely used. Neck pain despite negative imaging is not a reason to delay removal of stiff cervical collars. Cite this article: EFORT Open Rev 2020;5:253-259. DOI: 10.1302/2058-5241.5.190047

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) is a truly novel, multifaceted disease that has negatively impacted the lives of many including the pregnant women. We present a 34-year-old pregnant patient at 35 weeks with SARS-COV-2 requiring emergent cesarean section under general endotracheal anesthesia and a prolonged postoperative course in the ICU with multiple end organ function derangement of this disease. After nearly 1 month, she was discharged home. Her baby did not have any manifestations of SARS-COV-2 and was able to go home after 5 days.

Symptomatic lumbar spinal stenosis is a leading cause of pain and mobility limitation in older adults. It is clinically believed that patients with lumbar spinal stenosis adopt a flexed trunk posture or bend forward and alter their gait pattern to improve tolerance for walking. However, a biomechanical assessment of spine posture and motion during walking is broadly lacking in these patients. The purpose of this study was to evaluate lumbar spine and pelvic sagittal angles and lumbar spine compressive loads in standing and walking and to determine the effect of pain and neurogenic claudication symptoms in patients with symptomatic lumbar spinal stenosis. Seven participants with symptomatic lumbar spinal stenosis, aged 44–82, underwent a 3D opto-electronic motion analysis during standing and walking trials in asymptomatic and symptomatic states. Passive reflective marker clusters (four markers each) were attached to participants at T1, L1, and S2 levels of the spine, with additional reflective markers at other spinal levels, as well as the head, pelvis, and extremities. Whole-body motion data was collected during standing and walking trials in asymptomatic and symptomatic states. The results showed that the spine was slightly flexed during walking, but this was not affected by symptoms. Pelvic tilt was not different when symptoms were present, but suggests a possible effect of more forward tilt in both standing (p = 0.052) and walking (p = 0.075). Lumbar spine loading during symptomatic walking was increased by an average of 7% over asymptomatic walking (p = 0.001). Our results did not show increased spine flexion (adopting a trunk-flexed posture) and only indicate a trend for a small forward shift of the pelvis during both symptomatic walking and standing. This suggests that provocation of symptoms in these patients does not markedly affect their normal gait kinematics. The finding of increased spine loading with provocation of symptoms supports our hypothesis that spine loading plays a role in limiting walking function in patients with lumbar spinal stenosis, but additional work is needed to understand the biomechanical cause of this increase.

OBJECTIVES To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P

Objectives To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. Study design The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. Results One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. Conclusions Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

Acknowledgements: The authors would like to acknowledge Drs. Matthew Milewski, Yi-Meng Yen, and Adam Yanke for their contributions. Background: Surgical decision-making and pre-operative planning for children and adolescents with patellofemoral instability relies heavily on skeletal maturity status. In order to be clinically useful, radiologic assessments of skeletal maturity must demonstrate acceptable interrater reliability and accuracy. Purpose: The purpose of this study was to evaluate the interrater reliability among surgeons of varying experience levels and specialty training backgrounds when evaluating skeletal maturity in the distal femur and proximal tibia of children and adolescents with patellofemoral instability. Study Design: Cross-sectional study Methods: Six fellowship-trained orthopedic surgeons (4 pediatric orthopedic, 2 sports medicine) who perform a high volume of patellofemoral instability surgery examined 20 blinded and randomized knee radiographs and MR images. They assessed these images for clinically relevant growth (open physis) or clinically insignificant growth (closing/closed physis) remaining in the distal femoral and proximal tibial physes. Fleiss’s kappa was calculated for each measurement. After initial ratings, raters discussed consensus methods to improve reliability and assessed the images again in order to determine if training and new criteria improved interrater reliability. Results: Reliability for initial assessments of distal femoral and proximal tibial physeal status was poor (Kappa range: 0.01 – 0.58). After consensus building, all assessments demonstrated almost perfect interrater reliability (Kappa = 0.99 for all measurements). Conclusion: Surgical decision-making and pre-operative planning for children and adolescents with patellofemoral instability relies heavily on radiologic assessment of skeletal maturity. This study found that initial interrater reliability of physeal status and clinical decision making was unacceptably low. However, with the addition of new criteria, a consensus-building process, and training, these variables became highly reliable. Clinical Relevance: Lack of assessment reliability can jeopardize patient care, both when determining surgical indications as well as choosing an appropriate procedure based upon skeletal maturity. Surgeons should focus on using reliable imaging metrics in children and adolescents with patellofemoral instability, and measurements that remain unreliable after consensus building and training should be removed from clinical decision-making algorithms. What is known about the subject: Treatment of patellofemoral instability heavily relies on skeletal maturity status. Physeal assessments of the knee must be reliable and clinically relevant to ensure optimal patient care. What this study adds to existing knowledge: Physeal assessment of the knee without training can be unreliable among fellowship trained orthopedic surgeons. With consensus building and training in the use of the methods described in this manuscript, physeal assessments can demonstrate almost perfect reliability.

Background: Adolescent dancers may be a high-risk population for patellofemoral instability (PFI), but the condition remains under-investigated, to date, in this sub-group of athletes. Purpose: The purpose of this study was to (1) investigate the descriptive epidemiology of PFI in adolescent dancers, (2) analyze the efficacy of various patellar stabilization procedures within this population, and (3) compare PFI in dancers to a larger control group of matched, non-dancer athletes. Methods: A retrospective review of athletes, ages 10 to 19, who presented to a single tertiary care center with PFI between 2008 and 2017 was performed. Based on each patient’s primary sport, the cohort was divided into a dancer and a non-dancer control group. Demographics, clinical and radiologic features, surgical stabilization technique, and postoperative course and clinical outcomes were collected. Independent categorical groups were tested using chi squared and Fisher exact tests. Results: 258 adolescent athletes were included, 41 of whom were dancers, all females. This group was therefore matched with a control group of similarly aged, all-female athletes with PFI (Table 1). 54 athletes had bilateral PFI, yielding 285 knees for analysis. There was no difference between dancer and non-dancer athletes’ age, BMI, laterality, mechanism of injury, nor number of preoperative instability events. However, dancers had lower Dejour Classifications (p=0.044), smaller patella inclination angles (20.9±8.14 versus 25.0±9.84; p=0.004), and smaller Caton-Deschamps Indices (1.18±0.161 versus 1.25±0.189; p=0.041). Among dancers, there was no association between surgical stabilization technique and rates of recurrent instability (p=0.418) nor re-stabilization procedures (p=1.0) (Table 2). However, dancers who underwent tibial tubercle osteotomy (TTO) had higher rates of subsequent, non-stabilization procedures (66.7%), all for implant removal, compared to those undergoing isolated medial retinacular repairs (MRP) (3.8%) (pConclusions: Female dancers with PFI have similar demographic and clinical features as other female athletes with PFI, but have lower rates or less severe trochlear dysplasia, lateral tilt and patella alta. Therefore, the ligamentous laxity inherent in dancers may be a more powerful risk factor for PFI than other non-modifiable risk factors. Notably, the TTO was a powerful stabilization procedure for this sub-population with low rates of recurrent instability episodes and no revision stabilization procedures performed. Rates of implant removal surgery following TTO may be substantial, though this may be technique or surgeon dependent. Tables/Figures: [Table: see text][Table: see text]

Background: Historically, the most commonly utilized technique to address recurrent patellofemoral instability (PFI) was a combined proximal and distal realignment, specifically the tibial tubercle osteotomy (TTO) with a proximal medial retinacular plication/reefing/tightening/repair (MRP). Rising interest in the medial patellofemoral ligament reconstruction (MPFLR) over the last decade, now frequently performed as a more powerful isolated proximal realignment procedure, has prompted debate over the optimal technique to treat this common condition. Hypothesis/Purpose: The study hypothesis was that no difference would be detected in recurrent PFI rates or revision surgery rates between patients who underwent TTO-MRP vs. MPFLR. Methods: With cohorts derived from a large, single-center PFI database of 523 patients who underwent a variety of stabilization procedures, 114 eligible MPFLR patients were matched to 109 TTO patients based on age, gender, BMI, and TT-TG distance. Propensity score matching was conducted using logistic regression models to produce 1:1 matching, and a caliper of 0.2 standard deviations of the estimated propensity score was used to for the nearest neighbor matching algorithm. Final matching procedure resulted in 84 MPFLR patients and 84 TTO patients. These were compared on demographics and post-operative clinical results. Results: Demographic and radiologic comparisons of the cohorts are shown in Table 1, with the only difference between groups being an expected higher rate of patients with open physes in the MPFLR cohort. Table 2 shows the TTO-MRP group had longer follow up times, but comparable rates of return to sports. The MPFLR group had a higher rate of recurrent instability, but not to a significant degree, and a significantly higher incidence of revision patellar stabilization surgery (pConclusion: The TTO-MRP shows equivalent or superior results to the MPFLR for treatment of PFI. However, implant removal may be common with TTO, though this may be somewhat technique-dependent. In the current landscape of increasing interest and utilization of MPFLR as an all-encompassing PFI surgery, the influence of distal bony realignment to minimize recurrence should not be underappreciated. Tables/Figures: [Table: see text][Table: see text]

Lisch corneal dystrophy is a rare corneal disease characterized by the distinctive feature of highly vacuolated cells. Although this feature is important, the nature of these vacuoles within corneal cells remains unknown. Here, we sought to analyze corneal cells from a patient diagnosed with Lisch dystrophy to characterize the vacuoles within these cells. Analyses using histopathology examination, confocal microscopy, and transmission electron microscopy were all consistent with previous descriptions of Lisch cells. Importantly, the vacuoles within these cells appeared to be autophagosomes and autolysosomes, and could be stained with an anti-microtubule-associated protein 1A/1B-light chain 3 (LC3) antibody. Taken together, these findings indicate that the vacuoles we observed within superficial corneal cells of a patient with Lisch corneal dystrophy constituted autophagosomes and autolysosomes; this finding has not been previously reported and suggests a need for further analyses to define the role of autophagy in this ocular disease. RESUMO A distrofia corneana de Lisch é uma doença rara, caracterizada principalmente pela presença de células altamente vacuoladas. Embora esta característica seja importante, a natureza desses vacúolos dentro das células da córnea permanece des conhecida. Aqui, procuramos analisar as células da córnea de um paciente diagnosticado com distrofia de Lisch para caracte rizar os vacúolos dentro dessas células. Análises utilizando exame histopatológico, microscopia confocal e microscopia eletrônica de transmissão foram todas consistentes com descrições previas de células de Lisch. Importante, os vacúolos dentro dessas células pareciam ser autofagossomos e autolisossomos, e po deriam ser corados com um anticorpo proteico 1A/1B-cadeia leve 3 (LC3) da proteína anti-microtúbulo associado a microtúbulos. Em conjunto, esses achados indicam que os vacúolos observados nas células superficiais da córnea de um paciente com distrofia corneana de Lisch constituíram autofagossomos e autolisossomos. Esse achado não foi relatado anteriormente e sugere a necessidade de mais análises para definir o papel da autofagia nessa doença ocular.

Objective This study aimed to evaluate the association between acute kidney injury (AKI) and bronchopulmonary dysplasia (BPD) in infants born Study Design Present study is a secondary analysis of premature infants born at Results Moderate or severe BPD occurred in 214 of 546 (39%) infants, while death occurred in 32 of 546 (6%); the composite of moderate or severe BPD/death occurred in 246 of 546 (45%). For infants born ≤29 weeks of gestation, the adjusted odds ratio (OR) of AKI and the primary outcome was 1.15 (95% confidence interval [CI] = 0.47–2.86; p = 0.76). Infants born between 29 and 32 weeks of gestation with AKI had four-fold higher odds of moderate or severe BPD/death that remained after controlling for multiple factors (adjusted OR = 4.21, 95% CI: 2.07–8.61; p Conclusion Neonates born between 29 and 32 weeks who develop AKI had a higher likelihood of moderate or severe BPD/death than those without AKI. Further studies are needed to validate our findings and evaluate mechanisms of multiorgan injury.

Objective This study aimed to evaluate the association between acute kidney injury (AKI) and lung outcomes in infants born ≥32 weeks of gestational age (GA). Study Design Secondary analysis of infants ≥32 weeks of GA in the assessment of worldwide acute kidney injury epidemiology in neonates (AWAKEN) retrospective cohort (n = 1,348). We used logistic regression to assess association between AKI and a composite outcome of chronic lung disease (CLD) or death at 28 days of age and linear regression to evaluate association between AKI and duration of respiratory support. Results CLD occurred in 82/1,348 (6.1%) infants, while death occurred in 22/1,348 (1.6%); the composite of CLD/death occurred in 104/1,348 (7.7%). Infants with AKI had an almost five-fold increased odds of CLD/death, which remained after controlling for GA, maternal polyhydramnios, multiple gestations, 5-minute Apgar's score, intubation, and hypoxic–ischemic encephalopathy (adjusted odds ratio [OR] = 4.9, 95% confidence interval [CI]: 3.2–7.4; p Conclusion AKI is associated with CLD/death and longer duration of respiratory support in infants born at ≥32 weeks of GA. Further prospective studies are needed to elucidate the pathophysiologic relationship.

Phosphatidylethanolamine (PE) N-methyltransferase (PEMT) accounts for ∼30% of hepatic phosphatidylcholine (PC) biosynthesis. Pemt-/- mice fed a high-fat diet are protected against diet-induced obesity (DIO) and insulin resistance (IR) but develop nonalcoholic fatty liver disease (NAFLD) associated with a decreased PC:PE ratio. We investigated whether the lack of hepatic PEMT or the lack of PEMT in other tissues (where it is expressed at low levels) is responsible for or contributes to the protection against DIO and IR in Pemt-/- mice. Furthermore, we investigated whether decreasing PEMT expression with antisense oligonucleotides (ASOs) would result in metabolic benefits in both lean and obese mice without negatively impacting liver health. We both restored hepatic PEMT in Pemt-/- mice via adeno-associated virus delivery and decreased hepatic PEMT with ASOs in wild-type and ob/ob mice. Weight gain, insulin sensitivity, and indices of liver function were determined. We report that the protection against DIO and IR and the development of NAFLD is dependent on hepatic PEMT activity. NAFLD, associated with a significant decrease in the hepatic PC:PE ratio, was exacerbated by PEMT deficiency in obese mice, suggesting that phospholipid insufficiency promotes NAFLD progression during obesity or overnutrition. Hepatic PEMT is critical for maintaining phospholipid balance, which is crucial for a healthy liver.-Wan, S., van der Veen, J. N., Bakala N'Goma, J.-C., Nelson, R. C., Vance, D. E., Jacobs, R. L. Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance.

PURPOSE Individuals who are obese, and older individuals, exhibit gait alterations that may result, in part, from walking with greater effort relative to their maximum strength capacity. The goal of this study was to investigate obesity-related and age-related differences in relative effort during gait. METHODS Four groups of women completed the study, including 10 younger healthy-weight, 10 younger obese, 10 older healthy-weight, and 9 older obese women. The protocol included strength measurements at the hip, knee, and ankle in both flexion and extension, and gait trials under self-selected and constrained (1.5 m·s gait speed and 0.65-m step length) conditions. Relative effort was calculated as the ratio of joint torques during gait, and strength from a subject-specific model that predicted strength as a function of joint angle. RESULTS Relative effort during self-selected gait was higher among women who were obese in knee extension (P = 0.028) and ankle plantar flexion (P = 0.013). Although both joint torques and strength were higher among women who were obese, these increases in relative effort were attributed to greater obesity-related increases in joint torques than strength. Relative effort was also higher among older women in hip flexion (P < 0.001) and knee extension (P = 0.008), and attributed to age-related strength loss. Results were generally similar between self-selected and constrained gait, indicating the greater relative effort among women who were obese and older women was not attributed to differences in gait spatiotemporal characteristics. CONCLUSIONS Women who were obese, as well as older women, walk with greater relative effort. These results may help explain the compromised walking ability among these individuals.

Context: Recent epidemiology studies indicated a steady increase of anterior cruciate ligament (ACL) injury in young athletes. ACL reconstruction (ACLR) is currently a standard of care, but the eff...

Newborns with hypoxic–ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities correlate with MRI brain injury and with response to treatment. Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system. Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality. Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE.

Hyperthermia therapy (HT) raises tissue temperature to 40–45°C for up to 60 minutes. Hyperthermia is one of the most potent sensitizers of radiation therapy (RT). Ultrasound-mediated HT for radiosensitization has been used clinically since the 1960s. Recently, magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU), which has been approved by the United States Food and Drug Administration for thermal ablation therapy, has been adapted for HT. With emerging clinical trials using MRgHIFU HT for radiosensitization, there is a pressing need to review the ultrasound HT technology. The objective of this review is to overview existing HT technology, summarize available ultrasound HT devices, evaluate clinical studies combining ultrasound HT with RT, and discuss challenges and future directions.

Background: Primary repair of the anterior cruciate ligament (ACL) augmented with a tissue engineered scaffold to facilitate ligament healing is a technique under development for patients with ACL injuries. The size (the amount of tissue) and signal intensity (the quality of tissue) of the healing ligament as visualized on magnetic resonance imaging (MRI) have been shown to be related to its strength in large animal models. Hypothesis: Both modifiable and nonmodifiable risk factors could influence the size and signal intensity of the repaired ligament in patients at 6 months after surgery. Study Design: Case series; Level of evidence, 4. Methods: 62 patients (mean age, 19.4 years; range, 14-35 years) underwent MRI of the knee 6 months after ACL repair augmented with an extracellular matrix scaffold. The signal intensity (normalized to cortical bone) and average cross-sectional area of the healing ligament were measured from the MRI stack obtained by use of a gradient echo sequence. Associations between these 2 measures and patient characteristics, which included demographic, clinical, and anatomic features, were determined by use of multivariable regression analysis. Results: A larger cross-sectional area of the repaired ligament at 6 months was associated with male sex, older age, and the performance of a larger notchplasty ( P < .05 for all associations). A lower signal intensity at 6 months, indicating greater similarity to normal ligament, was associated with a smaller tibial slope and greater side-to-side difference in quadriceps strength 3 months after surgery. Other factors, including preoperative body mass index, mechanism of injury, tibial stump length, and Marx activity score, were not significantly associated with either MRI parameter at 6 months. Conclusion: Modifiable factors, including surgical notchplasty and slower recovery of quadriceps strength at 3 months, were associated with a larger cross-sectional area and improved signal intensity of the healing ACL after bridge-enhanced ACL repair in this preliminary study. Further studies to determine the optimal size of the notchplasty and the most effective postoperative rehabilitation strategy after ACL repair augmented by a scaffold are justified. Registration: NCT02664545 (ClinicalTrials.gov identifier).

The frequency of knee arthroscopy procedures is increasing in pediatric and adolescent patients. In general, complications after these procedures in adolescents are uncommon. The purposes of this study are to report the incidence of venous thromboembolism (VTE) in adolescent patients after knee arthroscopy procedures, as well identify risk factors in this patient population.Medical records were reviewed in all pediatric and adolescent patients (≤19 y) who underwent an arthroscopic knee procedure from 2010 to 2014 and were diagnosed with a symptomatic VTE in the postoperative period. Demographic features were recorded, and included age, sex, body mass index, clinical characteristics (diagnosis, type of surgical intervention, tourniquet time), VTE risk factors [family history of VTE, obesity (body mass index30), oral contraceptive use, and smoking use/exposure] and treatment (anticoagulation type/duration).Out of 2783 patients who underwent knee arthroscopy during the 5-year study period, 7 patients (3 males, 4 females, mean age, 16.9 y, range, 15 to 18) developed a symptomatic postoperative VTE (incidence, 0.25%, 95% confidence interval, 0.11%-0.54%). There were 6 unilateral deep venous thrombosis, and 1 bilateral deep venous thrombosis. Arthroscopic procedures performed in this cohort included anterior cruciate ligament reconstruction (3), isolated lateral release (1), meniscectomy (2), and patellar realignment with arthroscopic lateral release, open tibial tubercle osteotomy, and open proximal medial retinacular reefing (1). VTE was diagnosed an average of 9 days following surgery (range, 3 to 16). All patients were initially treated with low-molecular-weight heparin, and 2 were converted to warfarin. Mean duration of anticoagulation treatment was 64 days (range, 28 to 183). All patients had at least 1 identifiable medical or surgical risk factor, including oral contraceptive use (2), smoking (2), obesity (2), an arthroscopically assisted open procedure (4), or tourniquet time60 minutes (3).VTE after adolescent knee arthroscopy has not been well described. The incidence is ∼0.25%. Previously established risk factors for VTE were present in 100% of the affected population. Low-molecular-weight heparin was used to successfully treat this complication.Level IV.

Data correlating dried blood spots (DBS) and plasma concentrations for neonatal biomarkers of brain injury are lacking. We hypothesized that candidate biomarker levels determined from DBS can serve as a reliable surrogate for plasma levels. In the context of a phase II multi-center trial evaluating erythropoietin for neuroprotection in neonatal encephalopathy (NE), DBS were collected at enrollment (

Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt-/- mice fed a high-fat diet are protected from obesity and whole-body insulin resistance. However, Pemt-/- mice develop severe nonalcoholic steatohepatitis (NASH). Because NASH is often associated with hepatic insulin resistance, we investigated whether the increased insulin sensitivity in Pemt-/- mice was restricted to nonhepatic tissues or whether the liver was also insulin sensitive. Strikingly, the livers of Pemt-/- mice compared with those of Pemt+/+ mice were not insulin resistant, despite elevated levels of hepatic triacylglycerols and diacylglycerols, as well as increased hepatic inflammation and fibrosis. Endogenous glucose production was lower in Pemt-/- mice under both basal and hyperinsulinemic conditions. Experiments in primary hepatocytes and hepatoma cells revealed improved insulin signaling in the absence of PEMT, which was not due to changes in diacylglycerols, ceramides, or gangliosides. On the other hand, the phospholipid composition in hepatocytes seems critically important for insulin signaling such that lowering the PC:phosphatidylethanolamine (PE) ratio improves insulin signaling. Thus, treatments to reduce the PC:PE ratio in liver may protect against the development of hepatic insulin resistance.-Van der Veen, J. N., Lingrell, S., McCloskey, N., LeBlond, N. D., Galleguillos, D., Zhao, Y. Y., Curtis, J. M., Sipione, S., Fullerton, M. D., Vance, D. E., Jacobs, R. L. A role for phosphatidylcholine and phosphatidylethanolamine in hepatic insulin signaling.

Phosphatidylethanolamine N-methyltransferase (PEMT) is a hepatic integral membrane protein localized to the endoplasmic reticulum (ER). PEMT catalyzes approximately 30% of hepatic phosphatidylcholine (PC) biosynthesis. Pemt(-/-) mice fed a high-fat diet (HFD) develop steatohepatitis. Interestingly, portions of the ER located close to the canaliculus are enriched in PEMT. Phospholipid balance and asymmetrical distribution by adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) on the canalicular membrane is required for membrane integrity and biliary processes. We hypothesized that PEMT is an important supplier of PC to the canaliculus and that PEMT activity is critical for the maintenance of canalicular membrane integrity and bile formation following HFD feeding when there is an increase in overall hepatic PC demand. Pemt(+/+) and Pemt(-/-) mice were fed a chow diet, an HFD, or a choline-supplemented HFD. Plasma and hepatic indices of liver function and parameters of bile formation were determined. Pemt(-/-) mice developed cholestasis, i.e, elevated plasma bile acid (BA) concentrations and decreased biliary secretion rates of BAs and PC, during HFD feeding. The maximal BA secretory rate was reduced more than 70% in HFD-fed Pemt(-/-) mice. Hepatic ABCB11/bile salt export protein, responsible for BA secretion, was decreased in Pemt(-/-) mice and appeared to be retained intracellularly. Canalicular membranes of HFD-fed mice contained fewer invaginations and displayed a smaller surface area than Pemt(+/+). mice. Choline supplementation (CS) prevented and reversed the development of HFD-induced cholestasis. Conclusion: We propose that hepatic PC availability is critical for bile formation. Dietary CS might be a potential noninvasive therapy for a specific subset of patients with cholestasis.

Interoceptive processes in Tourette syndrome may foster the premonitory urges that commonly precede tics. Twenty-one adults with TS and 22 controls completed heartbeat tracking and discrimination tasks. Three dimensions of interoception were examined: objective accuracy, metacognitive awareness, and subjective (self-report) sensibility. Trait interoceptive prediction error was calculated as the discrepancy between accuracy and sensibility. Participants with TS had numerically lower interoceptive accuracy on the heartbeat tracking task, and increased self-reported interoceptive sensibility. While these group differences were not significant, the discrepancy between lower interoceptive accuracy and heightened sensibility, i.e. the trait interoceptive prediction error, was significantly greater in TS compared to controls. This suggests a heightened higher-order sensitivity to bodily sensations in TS, relative to a noisier perceptual representation of afferent bodily signals. Moreover, interoceptive sensibility predicted the severity of premonitory sensations and tics. This suggests interventions that work to align dimensions of interoceptive experience in TS hold therapeutic potential.

Introduction: Both conservative and liberal transfusion thresholds, in regard to hematocrit and hemoglobin levels, have been widely studied with varying outcomes. The aim of this study was to evaluate if transfusion administered peri- (anytime during the admission), pre-, intra-, or postoperatively an its association with morbidity and mortality in the geriatric population undergoing hip surgery. Methods: This study was an institutional review board approved retrospective analysis of data collected from 841 patients at a single urban institution who underwent surgical repairs for hip fractures from 2008 to 2010. Results: Our analysis included data from 841 surgical patients. Mean patient age was 83, 74% were female, 48% received spinal anesthesia while 52% underwent general anesthesia. Out of 841 patients, 425 were transfused during the perioperative period. Most transfusions occurred postoperatively. Perioperative, intraoperative and postoperative transfusion was associated with an increase in post-operative AKI. Intraoperative blood transfusion was associated with an increase in morbidity (11.6% increased to 22.2%) by 1.9 fold, AKI (3.9% increased to 11.1%) by 2.8 fold, as well as an increase in mortality (5.2 increased to 15.6%) within 60 days by 3 fold. Conclusions: This may suggest that patients transfused prior to surgery, despite having met a specific trigger hemoglobin level earlier, may have been treated before deteriorating to a point that would cause future systemic implications.

Purpose To evaluate the targetability of late-stage cervical cancer by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-induced hyperthermia (HT) as an adjuvant to radiation therapy (RT). Methods Seventy-nine cervical cancer patients (stage IIIB–IVA) who received RT with lesions visible on positron emission tomography-computed tomography (PET-CT) were retrospectively analyzed for targetability using a commercially-available HT-capable MRgHIFU system. Targetability was assessed for both primary targets and/or any metastatic lymph nodes using both posterior (supine) and anterior (prone) patient setups relative to the transducer. Thirty-four different angles of rotation along subjects’ longitudinal axis were analyzed. Targetability was categorized as: (1) Targetable with/without minimal intervention; (2) Not targetable. To determine if any factors could be used for prospective screening of patients, potential associations between demographic/anatomical factors and targetability were analyzed. Results 72.15% primary tumors and 33.96% metastatic lymph nodes were targetable from at least one angle. 49.37% and 39.24% of primary tumors could be targeted with patient laying in supine and prone positions, respectively. 25°–30° rotation and 0° rotation had the highest rate of the posterior and anterior targetability, respectively. The ventral depth of the tumor and its distance to the coccyx were statistically correlated with the anterior and posterior targetability, respectively. Conclusion Most late-stage cervical cancer primaries were targetable by MRgHIFU HT requiring either no/minimal intervention. A rotation of 0° or 25°–30° relative to the transducer might benefit anterior and posterior targetability, respectively. Certain demographic/anatomic parameters might be useful in screening patients for treatability.

Background/Purpose: Supracondylar humerus (SCH) fractures are the second most common pediatric fracture. Displaced SCH fractures are typically treated with closed reduction and percutaneous pinning (CRPP) and pins are removed in clinic at three to four weeks post-surgery. No studies to our knowledge quantify the physiological and behavioral response to pin removal. Therefore, the purpose of this study was to quantify the anxiety experienced undergoing pin removal following CRPP for SCH fractures. Methods: We prospectively enrolled 53 patients (3-8 years) treated for SCH fracture with CRPP between July 24, 2018 and …

Desmoid-type fibromatosis (DF) is a rare soft tissue lesion with an annual incidence of 2 to 4 per million population and peak incidence occurring at approximately 4.5 years of age. While benign, the tumor has a locally aggressive infiltrative growth pattern and a high rate of recurrence. Given the functional and aesthetic implications of excision and reconstruction in the facial skeleton, novel medical treatment options are highly desirable. We describe the case of a 3-year-old boy who presented with an enlarging, asymptomatic mass involving the left mandible. Biopsy revealed an immunohistochemical profile consistent with DF. Despite the high likelihood of recurrence, conservative, mandible-sparing en bloc resection and limited mandibulectomy were performed. Pathological and immunohistochemical analysis of the resection specimen revealed DF with grossly positive margins and elevated expression of angiotensin II type 1 receptor. Postoperative medical treatment with the angiotensin receptor blocker losartan was initiated. The patient remains medically stable and disease progression-free on repeat imaging at 20 months post-resection. We describe for the first time the successful use of the angiotensin blocker losartan following conservative surgery for management of DF.

Background: Small-diameter semitendinosus-gracilis tendon autografts may be encountered intraoperatively during anterior cruciate ligament reconstruction (ACLR); these have been shown to be at increased risk of graft rupture. One option that surgeons have pursued to reduce the theoretical failure rate of these smaller-diameter grafts is augmenting them with allograft material, thereby forming a larger-diameter hybrid autograft-allograft construct. Purpose/Hypothesis: The purpose of this study was to compare outcomes in adolescent athletes of primary ACLR using a hybrid autologous hamstring tendon and soft tissue allograft construct versus ACLR using small-diameter hamstring tendon autograft. The hypothesis was that the hybrid hamstring autograft-allograft construct would provide superior short-term results. Study Design: Cohort study; Level of evidence, 3. Methods: We performed a retrospective analysis of 47 patients aged between 12 and 20 years who underwent hybrid graft ACLR (mean diameter, 9.1 mm) at a single institution. Electronic medical records including clinic notes, radiographic images, operative notes, and pathology reports were reviewed for study analysis. A control group of 64 patients who underwent small-diameter hamstring reconstruction (mean diameter, 7.1 mm) without allograft supplementation was compiled. Corresponding clinical, radiographic, and surgical characteristics were collected for the control group to allow for comparative analysis. Results: Mean follow-up was 2.7 years for the hybrid cohort and 2.3 years for the control group. Despite a significantly larger mean graft diameter in the hybrid group as compared with the control group ( P < .001), no significant difference in retear rate was seen between cohorts (hybrid, 9%; control, 13%; P = .554). Patients with hybrid anterior cruciate ligament constructs also underwent a comparable number of reoperations overall ( P = .838). Functionally, all patients with adequate follow-up returned to sports, with no significant difference in time to return to sports between the groups ( P = .213). Radiographically, hybrid graft constructs did not undergo a significantly larger degree of tunnel lysis ( P = .126). Conclusion: A cohort of adolescents with hybrid anterior cruciate ligament grafts was shown to have retear rates and overall clinical results comparable with those of a control group that received small-diameter hamstring tendon autografts alone.