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The benefits of a comprehensive enhanced recovery after surgery (ERAS) program for patients with congenital heart disease are largely unknown. This study evaluated adherence and to outcomes of a recently implemented enhanced recovery program (ERP) in congenital cardiac surgery.Patients undergoing elective procedures for simple and moderately complex congenital cardiac surgery have followed institutional ERP guidelines since October 2018. Adherence to guidelines over a 12-month period (P2) was compared with implementation data (P1, 5 months). The association of outcomes with continuous time was estimated using linear regression.Among 559 patients (representing 40% of the cardiac surgical volume) following the ERP over a period of 17 months, no differences in patient characteristics were observed between periods, except a higher incidence of previous operations in P2. Adherence to many aspects of guidelines improved from P1 to P2. The following improvements were notable: operating room extubation, 27% in P2 vs16% in P1 (P = .006); and a decrease in median ventilation time, 6.0 hours (interquartile range [IQR], 0-9.2 hours) in P2 vs 7.6 hours (IQR, 3.8-12.3 hours) in P1 (P = .002). In addition, there was a reduction in opioids, reported as oral morphine equivalents, that was most significant for intraoperative oral morphine equivalents: 5.00 mg/kg (IQR, 3.11-7.60 mg/kg) in P2 vs 6.05 mg/kg (IQR, 3.77-9.78 mg/kg) in P1 (P = .001). There was no difference in overall intensive care unit and postoperative lengths of stay, except in lower-risk surgical procedures. Surgical outcomes were similar in the 2 periods.An enhanced recovery program reduced the use of opioids, led to more extubation in the operating room, and reduced mechanical ventilation duration in patients undergoing congenital cardiac surgery.

Objective The leadless cardiac pacemaker is typically implanted percutaneously and has been widely used for patients who have already undergone valve surgery. We sought to determine the feasibility and safety of implanting the leadless pacemaker under direct visualization during valve surgery. Methods We performed a retrospective analysis of consecutive adult patients (n = 15) who underwent implantation of a leadless pacemaker under direct visualization at the time of valve surgery. Indications for single-chamber pacing were sick sinus syndrome with pauses (53.3%), atrial fibrillation with slow ventricular rates (13.3%) or complete heart block (6.6%), and elevated risk for postoperative heart block (26.6%). Leadless pacemaker performance and pacing percentage were assessed. Results Patients' age was 67.5 ± 17 years, 6 patients (40%) were male, and 14 patients (93%) had atrial fibrillation. Isolated tricuspid valve replacement was performed in 5 patients (33.3%), and the remainder underwent multivalve surgery that included concomitant tricuspid valve repair/replacement. In 93% of the patients (n = 14), the immediate post–cardiopulmonary bypass pacing thresholds were normal (≤2.0 V at 0.24 ms) and normalized in the remaining patient by the next morning. The impedance/sensing values were normal and stable through follow-up (151 ± 119 days) in all patients. Reliable leadless pacemaker performance allowed for deferral of temporary epicardial wires in 11 patients (73%). There were no procedural complications or device malfunction. Conclusions Leadless cardiac pacemaker implantation during valve surgery is feasible and safe. This hybrid approach to pacing may simplify the perioperative management of patients undergoing valve surgery who have an indication for single-chamber pacing.

BACKGROUND: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial. METHODS: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. 84 participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence. RESULTS: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants. CONCLUSION: Together these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD. NATIONAL CLINICAL TRIAL: NCT03449979, “Single Session of tACS in a Depressive Episode (SSDE)” https://www.clinicaltrials.gov/ct2/show/NCT03449979

Medicinal plants are fundamental to health sovereignty, providing vital healthcare and livelihood options for rural mountain communities. We conducted 284 interviews with 416 participants in Badakhshan Province of northeastern Afghanistan focusing on the collection, use, sale, and management of medicinal plants. Participants identified 48 plants within 45 categories of treatment and prevention. The greatest number of plants were used to treat hypertension (14 plants), followed by kidney aids (12), analgesics (11), gastrointestinal aids (11), and dermatological aids (9). Comparisons with hospital records suggest that medicinal plants treat common ailments and preempt the need for some hospital visits. In addition, medicinal plants provide a source of livelihood for approximately 25% of participants. Many gatherers are concerned about the impacts of harvesting on medicinal plant resources. Collaborative research and knowledge exchange are necessary to enhance health sovereignty and community-based stewardship that sustain medicinal plant diversity in the context of increasing commercialization.

Conventional histopathology is the primary means of melanoma diagnosis. Both architectural and cytologic features aid in discrimination of melanocytic nevi from melanoma. Communication between the clinician and pathologist regarding the history, examination, differential diagnosis, prior biopsy findings, method of sampling, and specimen orientation is critical to an accurate diagnosis. A melanoma pathology report includes multiple prognostic indicators to guide surgical and medical management. In challenging cases, immunohistochemistry and molecular diagnostics may be of benefit.

BACKGROUND AND OBJECTIVES The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection. METHODS Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT). RESULTS Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p

Objective/background Adults with multiple sclerosis (MS) often present with conditions that mimic restless legs syndrome (RLS), thereby adding complexity into the assessment of RLS severity. The current gold-standard measures of RLS severity rely on a fixed seven-day time frame, which limits the ability of these measures for studying acute changes in RLS severity. The present study examined if subjective and objective scores from the suggested immobilization test (SIT) provide a valid and reliable acute measure of RLS severity in persons with MS. Patients/methods Participants with MS and RLS (n = 20) and MS without RLS (n = 20) were matched by age, gender, and disability. All participants completed validated questionnaires for RLS severity followed by the SIT, conducted at 18:00 (±15 min) on the same day of the week for two consecutive weeks. Participants wore accelerometer devices for seven nights to capture periodic limb movements (PLMs) during the night. Results Self-reported RLS severity during the SIT had excellent construct validity and convergent validity, but moderate test-retest reliability. Device-measured PLMs, while not themselves a direct measure of RLS severity, were significantly associated with PLMs during the night and had excellent test-retest reliability during the SIT in adults with MS. Conclusions Our results suggest that the SIT represents a valid acute measure for capturing self-reported sensory aspects of RLS severity and should be considered in future research and clinical practice as a standardized acute measure of subjective RLS severity in adults with MS who present with RLS.

Objective A significant number of epileptic patients fail to respond to available anticonvulsive medications. To find new anticonvulsive medications, we evaluated FDA‐approved drugs not known to be anticonvulsants. Using zebrafish larvae as an initial model system, we found that the opioid antagonist naltrexone exhibited an anticonvulsant effect. We validated this effect in three other epilepsy models and present naltrexone as a promising anticonvulsive candidate. Methods Candidate anticonvulsant drugs, determined by our prior transcriptomics analysis of hippocampal tissue, were evaluated in a larval zebrafish model of human Dravet syndrome (scn1Lab mutants), in wild‐type zebrafish larvae treated with the pro‐convulsant drug pentylenetetrazole (PTZ), in wild‐type C57bl/6J acute brain slices exposed to PTZ, and in wild‐type mice treated with PTZ in vivo. Abnormal locomotion was determined behaviorally in zebrafish and mice and by field potential in neocortex layer IV/V and CA1 stratum pyramidale in the hippocampus. Results The opioid antagonist naltrexone decreased abnormal locomotion in the larval zebrafish model of human Dravet syndrome (scn1Lab mutants) and wild‐type larvae treated with the pro‐convulsant drug PTZ. Naltrexone also decreased seizure‐like events in acute brain slices of wild‐type mice, and the duration and number of seizures in adult mice injected with PTZ. Significance Our data reveal that naltrexone has anticonvulsive properties and is a candidate drug for seizure treatment.

Background Prevalence and etiology of unconsciousness are uncertain in hospitalized patients with coronavirus disease 2019 (COVID-19). We tested the hypothesis that increased inflammation in COVID-19 precedes coma, independent of medications, hypotension, and hypoxia. Methods We retrospectively assessed 3203 hospitalized patients with COVID-19 from March 2 through July 30, 2020, in New York City with the Glasgow Coma Scale and systemic inflammatory response syndrome (SIRS) scores. We applied hazard ratio (HR) modeling and mediation analysis to determine the risk of SIRS score elevation to precede coma, accounting for confounders. Results We obtained behavioral assessments in 3203 of 10,797 patients admitted to the hospital who tested positive for SARS-CoV-2. Of those patients, 1054 (32.9%) were comatose, which first developed on median hospital day 2 (interquartile range [IQR] 1–9). During their hospital stay, 1538 (48%) had a SIRS score of 2 or above at least once, and the median maximum SIRS score was 2 (IQR 1–2). A fivefold increased risk of coma (HR 5.05, 95% confidence interval 4.27–5.98) was seen for each day that patients with COVID-19 had elevated SIRS scores, independent of medication effects, hypotension, and hypoxia. The overall mortality in this population was 13.8% (n = 441). Coma was associated with death (odds ratio 7.77, 95% confidence interval 6.29–9.65) and increased length of stay (13 days [IQR 11.9–14.1] vs. 11 [IQR 9.6–12.4]), accounting for demographics. Conclusions Disorders of consciousness are common in hospitalized patients with severe COVID-19 and are associated with increased mortality and length of hospitalization. The underlying etiology of disorders of consciousness in this population is uncertain but, in addition to medication effects, may in part be linked to systemic inflammation. Supplementary Information The online version contains supplementary material available at 10.1007/s12028-021-01256-7.

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

Objective. The objective of this brief report is to review an assessment paradigm for conducting virtual neuropsychological pre‐surgical evaluations in the context of the COVID‐19 pandemic. Methods. A multidisciplinary epilepsy team at a Level 4 epilepsy center within a large children's academic medical center convened to discuss the challenges and possible solutions for Phase II evaluations for pediatric patients with pharmacoresistant epilepsy during the COVID‐19 pandemic. The neuropsychologists explored evidence‐based methods of virtual evaluation and developed a systematic decision‐making process for youth requiring a Phase II evaluation. Results. We propose models of assessment which prioritize teleneuropsychology when possible to reduce the risk of infection: (1) evaluation with directly administered tests through a completely virtual format; (2) virtual/in‐person hybrid evaluation; and (3) clinical observation/interview in a virtual format supplemented by survey data. These models are illustrated by three cases. Significance. Using virtual assessment models, the team was able to meet the urgent patient care needs and collect useful data while minimizing the risk of virus spread. The paradigms presented may be useful examples for other multidisciplinary surgical teams interested in incorporating teleneuropsychology into their practices.

Background This study compares outcomes of conventional and less-invasive (LI) approaches for aortic valve replacement (AVR) using The Society of Thoracic Surgeons database. Methods Between 2011 and 2017, we identified 122,474 patients undergoing isolated primary AVR. Patients were categorized into 3 groups: (1) full sternotomy (FS) (n = 98,549; 78%), (2) partial sternotomy (PS) (n = 17,306; 15%), and (3) right thoracotomy (RT) (n = 6619; 7%). Results The rate of LI-AVR increased from 17% in 2011 to 23% in 2016 (P Conclusions Less-invasive AVR is associated with an operative mortality and postoperative stroke rate similar to that of FS. Less-invasive AVRs should serve as a benchmark for comparison between transcatheter aortic valve replacement and surgical AVR in low-risk patients.

Malaria continues to pose a severe threat to over half of the world's population each year. With no long-term, effective vaccine available and a growing resistance to antimalarials, there is a need for innovative methods of Plasmodium treatment. Recent evidence has pointed to a role of the composition of the gut microbiota in the severity of Plasmodium infection in both animal models and human studies. Further evidence has shown that the gut microbiota influences the adaptive immune response of the host, the arm of the immune system necessary for Plasmodium clearance, sustained Plasmodium immunity, and vaccine efficacy. Together, this illustrates the future potential of gut microbiota modulation as a novel method of preventing severe malaria.

Background Deltoid compartment syndrome is a rare entity. The purpose of this study was to report a recent case and perform a systematic literature review. Methods Patient data were gathered from chart review and clinical encounters. For the review, the MEDLINE, Embase, and Ovid databases were queried for deltoid compartment syndrome cases. Seventeen articles reporting on 18 patients with deltoid compartment syndrome were included. Results Including our patient, 9 of 19 patients (47.4%) presented with compartment syndrome limited to the deltoid. Most patients presented with additional affected compartments, most commonly in the ipsilateral arm (7 of 19, 37%). Isolated deltoid involvement often resulted from iatrogenic injury; of 10 iatrogenic reports, 8 involved only the deltoid. Of 19 cases, 5 (26%) occurred in powerlifters, climbers, or anabolic steroid or testosterone injectors. In 13 of 19 cases (68%), the patients were men aged 18-36 years, and only 1 female case (5%) was reported. Prolonged recumbence owing to substance abuse was documented in 6 of 19 cases (32%). Conclusion Deltoid compartment syndrome is rare, with only 19 reported cases, including our patient. Men are more commonly affected, and isolated deltoid compartment syndrome occurs in about 50% of reported cases. More than half of cases are iatrogenic, secondary to prolonged lateral decubitus positioning, injections, and surgical interventions about the shoulder. Prolonged recumbence from intoxication is also a common etiology. Providers should be aware of and recognize deltoid compartment syndrome to facilitate urgent surgical management.

Delayed gastric emptying (DGE) is a frequent complication after pancreaticoduodenectomy (PD) that impairs recovery and quality of life. The purpose of this study was to assess the impact risk-stratified pancreatectomy clinical pathways (RSPCPs) had on delayed gastric emptying (DGE) and identify factors associated with DGE in a contemporary period. A single-institution, prospective database was queried for consecutive PDs during July 2011–November 2019. Using international definitions, DGE rates were compared between periods before and after RSPCPs were implemented in 2016, classifying patients according to their postoperative pancreatic fistula (POPF) risk. Risk factors were analyzed to identify modifiable targets. Among 724 elective PDs, 552 (76%) were for adenocarcinoma and 172 (24%) for other diagnoses. Of the 197 (27%) patients with DGE, 119 (16%) had type A, 41 (6%) type B, and 38 (5%) type C. In the overall cohort, DGE rates were higher with pylorus-preserving vs. classic hand-sewn reconstruction (odds ratio [OR] − 1.84; p < 0.001), postoperative abscess (OR − 2.54; p = 0.003), and non-white patients (p = 0.007), but lower after implementation of RSPCPs (OR − 0.34, p < 0.001). In the 374 patients treated with RSPCPs, only 17% (n = 65/374) developed DGE. Patients with protocol-compliant NGT removal ≤ 48 h were less likely to experience DGE (OR − 1.46, p = 0.042). Our data suggest that implementation of preoperatively assigned RSPCPs as a care bundle was the most important factor in decreasing DGE. These gains were accentuated in patients who underwent early nasogastric tube removal and had a classic hand-sewn gastro-jejunostomy reconstruction. Application of these modifiable factors is generalizable with low implementation barriers.

Interest in symptoms of sluggish cognitive tempo (SCT) has led to a number of studies evaluating how these symptoms respond to treatment commonly utilized in youths with symptoms of ADHD. No study to date, however, has examined the extent to which symptoms of SCT predict behavioral treatment response in youths across multiple domains of functioning. The current preliminary investigation integrates a number of methodological (e.g., direct observations) and analytic (e.g., Poisson regression) refinements to evaluate the extent to which symptoms of SCT predict treatment responses across multiple domains including behavioral (e.g., interruptions, rule violations), social (e.g., social skills, negative verbalizations), and severe behavioral difficulties (e.g., intentional aggression) above and beyond other demographic characteristics (e.g., symptom severity, Full Scale Intelligence Quotient [FSIQ]). A relatively small sample of 37 children, aged six to 12 years ( M = 8.03, SD = 1.83, 35 males: 2 females) attending an eight week multi-component intensive behavioral treatment program for youths with behavioral difficulties participated in the current study. Baseline parental perceptions of SCT were collected prior to the initiation of treatment. Results from this preliminary investigation revealed that pre-treatment SCT symptoms only predicted a less robust treatment response to time out which was associated also with parent’s perceptions of underlying working memory problems. Results revealed also that pre-treatment SCT symptoms failed to predict paraprofessional counselor’s and teacher’s improvement ratings of both rule following and social skills following treatment. Notably, other potential predictors (e.g., symptom severity, FSIQ) also largely failed to predict behavioral treatment response.

Made available in DSpace on 2022-04-28T19:29:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-01 Medical Research Council Canada National Institute for Health Research Objectives: To develop consensus definitions for the core outcome set for pre-eclampsia. Study design: Potential definitions for individual core outcomes were identified across four formal definition development initiatives, nine national and international guidelines, 12 Cochrane systematic reviews, and 79 randomised trials. Eighty-six definitions were entered into the consensus development meeting. Ten healthcare professionals and three researchers, including six participants who had experience of conducting research in low- and middle-income countries, participated in the consensus development process. The final core outcome set was approved by an international steering group. Results: Consensus definitions were developed for all core outcomes. When considering stroke, pulmonary oedema, acute kidney injury, raised liver enzymes, low platelets, birth weight, and neonatal seizures, consensus definitions were developed specifically for low- and middle-income countries because of the limited availability of diagnostic interventions including computerised tomography, chest x-ray, laboratory tests, equipment, and electroencephalogram monitoring. Conclusions: Consensus on measurements for the pre-eclampsia core outcome set will help to ensure consistency across future randomised trials and systematic reviews. Such standardization should make research evidence more accessible and facilitate the translation of research into clinical practice. Video abstract can be available at: www.dropbox.com/s/ftrgvrfu0u9glqd/6.%20Standardising%20definitions%20in%20teh%20pre-eclampsia%20core%20outcome%20set%3A%20a%20consensus%20development%20study.mp4?dl=0. Nuffield Department of Primary Care Health Sciences University of Oxford Institute for Women’s Health University College London Department of Women and Children’s Health School of Life Course Sciences King’s College London Department of Obstetrics and Gynecology Amsterdam UMC Academic Medical Center Academic Neonatal Medicine Imperial College London Department of Renal Medicine St George Hospital and University of New South Wales Department of Obstetrics and Gynaecology Feinberg School of Medicine Northwestern University Health Services Research Unit Nuffield Department of Population Health University of Oxford Cedars-Sinai Medical Center London North West University Healthcare NHS Trust Women’s Health Care Research Group Department of Obstetrics and Gynaecology Monash University Department of Obstetrics and Gynaecology University of Adelaide Women’s Health Research Unit Barts and The London School of Medicine and Dentistry School of Health and Related Research University of Sheffield MRC North West Hub for Trials Methodology Research Department of Biostatistics University of Liverpool Centro Rosarino de Estudios Perinatales Chelsea and Westminster Hospital NHS Foundation Trust Babcock University Ailem Academic Counselling KU Leuven Universidad Nacional de Colombia Northwell Health University of Oxford Université de Montréal University of Montreal Hospital Centre Ondokuz Mayıs University Prince Sultan Military Medical City Postgraduate Institute of Medical Education and Research King's Fertility Fetal Medicine Research Institute University Hospital Limerick Drexel University University of Aberdeen University of Groningen University of Auckland Haaglanden Medisch Centrum Nottingham University Medical School Utrecht University King Edward Memorial Hospital for Women Imperial College Healthcare NHS Trust Jean-Verdier Hospital Downland Practice University of Campinas Université Lyon University of North Carolina School of Medicine South Ural State Medical University Stellenbosch University Irish Neonatal Health Alliance University of Rzeszow Royal Brisbane and Women’s Hospital Nottingham University Hospitals NHS Trust University Hospitals of Leicester North Bristol NHS Trust University of Nottingham Soroka University Medical Center Ben Gurion University of the Negev St George’s University Hospitals NHS Foundation Trust Hospitalsenhed Midt University of Glasgow Amsterdam Universitair Medische Centra All India Institute of Medical Sciences Patna Luton and Dunstable University Hospital Khyber Medical University Institution of Medical Sciences Midwife Mid Essex Hospitals NHS Trust University of Oulu University of Michigan Bastyr University Irish Nurses and Midwives Organisation University of Toronto Barts Health NHS Trust University Hospitals Plymouth NHS Trust Burnet Institute Aga Khan University Medical University of Graz Homerton University Hospital NHS Foundation Trust Mount Royal University Université de Paris Royal Surrey County Hospital University Hospital Southampton NHS Foundation Trust University of Washington School of Nursing Evelina London Children's Hospital Neonatal Unit University of Sydney University of Leicester Academic Hospital of Udine NHS Borders Weill Cornell Medical College University of Dundee University of Edinburgh South Australian Health and Medical Research Institute University of Sheffield Monash University and Monash Health United Lincolnshire Hospitals NHS Trust University of Kwa Zulu-Natal Beatrix Hospital Keele University Government Medical College Institut Catala de la Salut. IdiapJgol University College London National Center for Child Health and Development Basavatarakam Indo-American Cancer Hospital and Research Institute Axon Anaesthesia Associates Pennine Acute Hospitals NHS Trust St George's University of London Norfolk and Norwich University Hospital Jichi Medical University School of Medicine São Paulo State University National Institute of Public Health University of Kyrenia King Edward Memorial Hospital Amsterdam University Centres University of British Columbia Chulalongkorn University University of Brescia University Of British Columbia University of Montreal Women's Clinic of Tartu University Hospital Universidade Federal de São Paulo Université de Sherbrooke University Hospital of Wales University of Iowa King's College London Westmead Hospital Princess Royal Maternity Leipzig University Centre Hospitalier Public du Cotentin Lewisham and Greenwich NHS Trust Juntendo University Faculty of Medicine Western Sydney University National Institute of Health Research University of Washington Baylor College of Medicine Capelle aan den Ijssel Sanatorio Anchorena Oxford University Hospitals NHS Foundation Trust University of Leeds Institute of Medical Sciences UPMC Magee Womens Hospital Penn Medicine Princeton Health University of North Carolina at Chapel Hill São Paulo State University

Although The Bethesda System for Reporting Cervical Cytopathology does not mandate reporting of endocervical glandular involvement (EGI) in Papanicolaou test specimens with high-grade squamous intraepithelial lesions (HSIL), several studies have suggested that EGI diagnosed on surgical specimens is associated with higher rates of residual or recurrent dysplasia. When suspected, EGI is reported for Papanicolaou test specimens at our institution, but the performance of this diagnosis has not been assessed.The archives were queried for Papanicolaou test specimens with a diagnosis of HSIL-EGI (2006-2017). All follow-up surgical pathology specimens within a year of the Papanicolaou test diagnosis were evaluated for cytologic-histologic correlation. This same query was repeated for all surgical pathology specimens with a diagnosis of HSIL-EGI. All preceding Papanicolaou test diagnoses within a year were assessed for cytologic-histologic correlation. Twenty Papanicolaou test specimen glass slides were reviewed by 6 observers to assess for interobserver variability.Patients with HSIL-EGI on surgical specimens were more likely to have a preceding Papanicolaou diagnosis of HSIL and atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) (32.3% versus 25.5%, P = 0.03, and 16.7% versus 11.8%, P = 0.04, respectively). Patients with an HSIL-EGI diagnosis on a Papanicolaou test were significantly more likely to have HSIL-EGI detected on a follow-up histology (41.6% versus 24.0%, P0.001). Interobserver concordance was poor for the assignment of EGI in Papanicolaou test specimens.Overall, the diagnosis of HSIL-EGI on Papanicolaou test specimens is complicated by poor sensitivity and interobserver concordance.

Profound increases (>15 mmHg) in arterial carbon dioxide (i.e., hypercapnia) reduce renal blood flow. However, a relatively brief and mild hypercapnia can occur in patients with sleep apnea or in those receiving supplemental oxygen therapy during an acute exacerbation of chronic obstructive pulmonary disease. We tested the hypothesis that a brief, mild hypercapnic exposure increases vascular resistance in the renal and segmental arteries. Blood velocity in 14 healthy adults (26 ± 4 yr; 7 women, 7 men) was measured in the renal and segmental arteries with Doppler ultrasound while subjects breathed room air (Air) and while they breathed a 3% CO2, 21% O2, 76% N2 gas mixture for 5 min (CO2). The end-tidal partial pressure of CO2 ([Formula: see text]) was measured via capnography. Mean arterial pressure (MAP) was measured beat to beat via the Penaz method. Vascular resistance in the renal and segmental arteries was calculated as MAP divided by blood velocity. [Formula: see text] increased with CO2 (Air: 45 ± 3, CO2: 48 ± 3 mmHg, P < 0.01), but there were no changes in MAP ( P = 0.77). CO2 decreased blood velocity in the renal (Air: 35.2 ± 8.1, CO2: 32.2 ± 7.3 cm/s, P < 0.01) and segmental (Air: 24.2 ± 5.1, CO2: 21.8 ± 4.2 cm/s, P < 0.01) arteries and increased vascular resistance in the renal (Air: 2.7 ± 0.9, CO2: 3.0 ± 0.9 mmHg·cm−1·s, P < 0.01) and segmental (Air: 3.9 ± 1.0, CO2: 4.4 ± 1.0 mmHg·cm−1·s, P < 0.01) arteries. These data provide evidence that the kidneys are hemodynamically responsive to a mild and acute hypercapnic stimulus in healthy humans.

Light-adapted (LA) electroretinograms (ERGs) from 90 individuals with autism spectrum disorder (ASD), mean age (13.0 ± 4.2), were compared to 87 control subjects, mean age (13.8 ± 4.8). LA-ERGs were produced by a random series of nine different Troland based, full-field flash strengths and the ISCEV standard flash at 2/s on a 30 cd m−2 white background. A random effects mixed model analysis showed the ASD group had smaller b- and a-wave amplitudes at high flash strengths (p

STUDY OBJECTIVES: Sleep problems are a common consequence of multiple sclerosis; however, there is limited evidence regarding the agreement between device-measured and self-reported sleep parameters in adults with multiple sclerosis. The present study examined the agreement between self-reported and device-measured parameters of sleep quality in a sample of adults with multiple sclerosis. METHODS: Participants (n = 49) completed a 7-day sleep diary and wore a wrist-worn ActiGraph GT3×+ (ActiGraph Corp., Pensecola, FL) for seven consecutive nights to quantify self-reported and device-measured sleep parameters, respectively. RESULTS: There was a significant discrepancy between self-reported and device-measured parameters of total time in bed (mean difference = 19.8 [51.3] min), sleep onset latency (mean difference = 22.2 [19.5] min), and frequency of awakenings during the night (mean difference = 12.8 [6.8]). Intraclass correlation estimates indicated poor agreement between methods on most parameters, except for total time in bed (intraclass correlation = 0.80). Bland-Altman plots suggested that total time in bed and total sleep time had acceptable levels of agreement and linear regression analyses indicated that sleep onset latency (F = 113.91, B = −1.34, P < .001), number of awakenings (F = 543.34, B = 1.85, P < .001), and sleep efficiency (F = 18.39, B = −0.77, P < .001) had significant proportional bias. CONCLUSIONS: Our results draw attention to the discrepancies between sleep parameter measurements and highlight the importance of including both self-report and device-measured outcomes for a complete and accurate representation of sleep in adults with multiple sclerosis. CITATION: Cederberg KLJ, Mathison BG, Schuetz ML, Motl RW. Discrepancies between self-reported and device-measured sleep parameters in adults with multiple sclerosis. J Clin Sleep Med. 2022;18(2):415–421.

BACKGROUND The metabolism of normal prostate relies on glycolysis, with prostate cancer having reduced glycolysis and increased aerobic metabolism. Advanced glycation end products (AGEs) accumulate in tissues as a result of age and glycolytic rate. Differential AGE levels were recently observed in prostate cancer tissues. Herein we sought to quantify AGEs in benign and cancer prostate tissue in a diverse cohort of patients. METHODS Levels of the AGE Ne-(carboxylethyl)lysine (CML) were quantified by immunohistochemistry (IHC) in a tissue microarray which consisted of 3 cores from tumor and 2 cores from benign areas from 118 patients (87 African American and 31 European American). Ancestry informative markers for African Ancestry were available for 79 patients. Epithelial and stromal areas were quantified separately using an E-cadherin mask. CML levels were compared with clinical grade group and ancestry by mixed linear effect models. Age, prostate-specific antigen (PSA) levels, body mass index (BMI), and hemoglobin A1C were included as covariates. RESULTS CML levels were lower in areas of the tumor, for both epithelium and surrounding stroma, compared with benign, but did not significantly change with tumor grade group. Age, PSA levels, BMI, and hemoglobin A1C did not associate with CML levels. CML levels were inversely associated with the percentage of African Ancestry in all tissues. CONCLUSIONS The low CML levels in cancer may reflect the reduced glycolytic state of the tissue. The inverse relationship between African Ancestry and CML levels in both benign and cancer areas suggests a state of reduced glycolysis. It is yet to be determined whether altered glycolysis and CML levels are bystanders or drivers of carcinogenesis.

BACKGROUND Restless legs syndrome (RLS) is a sleep disorder present in as many as 26% of persons with multiple sclerosis (MS) and can be associated with cognitive function. The present study examined the relationships between RLS symptoms (severity, frequency, occurrence) and cognitive function in adults with MS who have RLS. METHODS Twenty-two participants attended 1 laboratory session and completed the International Restless Legs Syndrome Study Group Rating Scale (IRLS), the Restless Legs Syndrome-6 Scale, and then the Brief International Cognitive Assessment for Multiple Sclerosis battery consisting of the Symbol Digit Modalities Test; California Verbal Learning Test, Second Edition; and Brief Visuospatial Memory Test–Revised. RESULTS Nonparametric bivariate correlations indicated that worse IRLS total severity was associated with slower processing speed (ρ = −0.42), worse verbal memory (ρ = −0.63), and worse visual memory (ρ = −0.61); worse RLS severity at falling asleep was associated with worse verbal memory (ρ = −0.45) and worse visual memory (ρ = −0.55); and worse RLS severity during the day while active was associated with slower processing speed (ρ = −0.58), worse verbal memory (ρ = −0.52), and worse visual memory (ρ = −0.60). CONCLUSIONS These results suggest that those with more severe RLS, including worse symptoms at falling asleep and during the day while active, might experience worse cognitive function, particularly processing speed and memory. Future research should evaluate whether treatment of RLS symptoms can offer new opportunities for managing cognitive dysfunction in adults with MS.

Zika virus (ZIKV) is a mosquito-borne flavivirus that became widely recognized due to the epidemic in Brazil in 2015. Since then, there has been nearly a 20-fold increase in the incidence of microcephaly and birth defects seen among women giving birth in Brazil, leading the Centers for Disease Control and Prevention (CDC) to officially declare a causal link between prenatal ZIKV infection and the serious brain abnormalities seen in affected infants. Here, we used a unique rat model of prenatal ZIKV infection to study three possible long-term outcomes of congenital ZIKV infection: (1) behavior, (2) cell proliferation, survival, and differentiation in the brain, and (3) immune responses later in life. Adult offspring that were prenatally infected with ZIKV exhibited motor deficits in a sex-specific manner, and failed to mount a normal interferon response to a viral immune challenge later in life. Despite undetectable levels of ZIKV in the brain and serum in these offspring at P2, P24, or P60, these results suggest that prenatal exposure to ZIKV results in lasting consequences that could significantly impact the health of the offspring. To help individuals already exposed to ZIKV, as well as be prepared for future outbreaks, we need to understand the full spectrum of neurological and immunological consequences that could arise following prenatal ZIKV infection.

Background: Patients with a history of alcohol use disorder are at an increased risk of hematoma expansion following intracranial hemorrhage (ICH) due to the effects of alcohol on platelet aggregation. Desmopressin (DDAVP) improves platelet aggregation and may decrease hematoma expansion in patients with ICH. However, DDAVP may also increase the risk of hyponatremia and thrombotic events. Evidence is limited regarding the safety and efficacy of DDAVP in alcohol use (AU)-associated ICH. Methods: This was a retrospective chart review of adult patients with radiographic evidence of ICH and a confirmed or suspected history of alcohol use upon admission. Patients were categorized into groups based on DDAVP administration. Safety outcomes included hyponatremia (serum sodium Results: In total, 52 patients were included in the safety analysis (27 DDAVP and 25 non-DDAVP). Although hyponatremia was numerically higher in the DDAVP group, there was no significant difference between groups (19.2% vs 4.2%, P = 0.192). Thrombotic complications were similar between the DDAVP and non-DDAVP groups (11.1% vs. 8%, P = 1.0). Thirty-nine patients met criteria for hemostatic efficacy analysis. There was no difference in hematoma expansion between the DDAVP and non-DDAVP groups (23.1% vs 34.6%, P = 0.71) and these findings were consistent after adjusting for differences in baseline characteristics (OR 0.63, 95% CI 0.1-3.3). Conclusion: The administration of DDAVP was not associated with adverse safety events, but did not significantly reduce the incidence of hematoma expansion in patients with AU-associated ICH.

Introduction:Preventing complications of stroke such as post-stroke aspiration pneumonia (PSAP) may improve stroke outcomes in resource-limited settings. We investigated the incidence and associated mortality of PSAP in Zambia.Methods:We conducted a prospective cohort study of adults with stroke at University Teaching Hospital (Lusaka, Zambia) between 12/2019-3/2020. NIH Stroke Scale, Glasgow Coma Scale, Modified Rankin Scale scores, and nine indicators of possible PSAP were collected serially over each participant’s admission. PSAP was defined as ≥4 indicators present, and possible PSAP as 2-3 present. T-tests and chi-square tests were used to compare clinical parameters across PSAP groups. Logistic regression was used to assess the relative effects of age, sex, PSAP status, and initial stroke severity on inpatient mortality.Results:We enrolled 125 participants. Mean age was 60±16 years, 61% were female, 55% of strokes were ischemic, and baseline NIH Stroke Scale was 19.7±8.7. Thirty-eight (30%) had PSAP, and 32 (26%) had possible PSAP. PSAP was associated with older age and more adverse stroke severity scores. Fifty-nine percent of participants with PSAP died, compared to 39% with possible PSAP and 8% with no PSAP. PSAP status independently predicted inpatient mortality after controlling for age, sex, and initial stroke severity. Swallow screening was not performed for any participant.Conclusion:PSAP is common and life-threatening in Zambia, especially among older participants with severe stroke presentations. PSAP was associated with significantly increased mortality independent of initial stroke severity, suggesting that interventions to mitigate PSAP may improve stroke outcomes in Zambia and other resource-limited settings.

BackgroundLeft frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial.MethodsIn this current study, we aimed to replicate such successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence.ResultsIn agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants.ConclusionTogether these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD.National Clinical TrialNCT03449979, “Single Session of tACS in a Depressive Episode (SSDE)” https://www.clinicaltrials.gov/ct2/show/NCT03449979

Objective To determine whether children with Down syndrome (DS) receive higher doses of opioid medications compared with children without DS for repair of complete atrioventricular canal (CAVC). Design A retrospective chart review of children with and without DS who underwent primary repair of CAVC. The exclusion criteria included unbalanced CAVC and patients undergoing biventricular staging procedures. The primary outcome was oral morphine equivalents (OME) received in the first 24 hours after surgery. The secondary outcomes included intraoperative OME, OME at 48 and 72 hours, nonopioid analgesic and sedative medications received, pain scores, time to extubation, and length of stay. Setting A pediatric academic medical center in the United States. Participants One hundred thirty-one patients with DS and 24 without, all Interventions Not applicable. Measurements and Main Results Patients with DS were older than patients without DS (median 96.3 days [interquartile range {IQR} 70.7-128.2] v 75.9 days [IQR 49.8-107.3], p = 0.033) but otherwise not statistically different in the baseline characteristics. There was no difference in OME received in the first 24 hours postoperatively between groups (3.01 mg/kg [IQR 1.23-5.43] v 3.57 mg/kg [IQR 1.54-7.06], p = 0.202). OME at 48 and 72 hours was lower in the DS group compared with the control group. Similar amounts of opioid and non-opioid analgesics and sedatives were otherwise given to both groups of patients. Median pain scores did not differ between groups. Conclusions These results suggested that patients with DS undergoing CAVC repair do not have increased opioid requirements compared with a similar control group.

Introduction: Angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin receptor blocker (ARB) discontinuation during acute heart failure (AHF) is associated with increased mortality following hospitalization. Although the etiology of acute kidney injury (AKI) in type 1 cardiorenal syndrome (CRS) has been linked to renal venous congestion, ACE-I/ARB withdrawal (AW) theoretically promotes renal function recovery. ACE-I/ARBs are dose-reduced or withheld in approximately half of patients with CRS, but the subsequent impact on renal function remains largely uninvestigated. This study compared AW to ACE-I/ARB continuation (AC) during CRS. Methods: This was a retrospective, single-center chart review. Patients aged 18-89 years admitted from April 2018 to August 2019 with AHF and AKI were identified using discharge ICD-10 codes. All patients were treated with an ACE-I/ARB before admission. Key exclusion criteria included shock, pregnancy, and end-stage renal disease. The primary endpoint was change in serum creatinine (SCr) from admission through 72 hours. Data were analyzed utilizing chi-square and Mann-Whitney U tests with SPSS software. Results: A total of 111 admissions were included. AW occurred in 68 patients upon admission. AW patients presented with a higher blood urea nitrogen ( P = 0.034), higher SCr ( P = 0.021), and lower ejection fraction ( P = 0.04). Median SCr change from admission to 72 hours did not differ between groups (AW −0.1 mg/dL vs AC 0.0 mg/dL, P = 0.05). There was no difference in SCr reduction ≥0.3 mg/dL at 72 hours, 30-day readmissions, or ACE-I/ARB prescription at discharge. Conclusions: In patients with type 1 CRS, AW was not associated with improved renal function at 72 hours. A larger sample size is necessary to confirm these results.

The objective of this study was to develop mathematically described characteristic tracheobronchial bifurcations that are representative of aerosol transport and deposition in the intermediate airways of children with cystic fibrosis (CF), where bronchiectasis is a major contributor to changes in lung anatomy. Realistic airway models in the region of bifurcations B4-B7 were extracted from CT scans of children that were scored as having either low (CT-Low) or moderate (CT-Mod) CF lung disease and served as a basis for comparison with characteristic models. Aerosol deposition characteristics in these CT-extracted models were compared with a previously developed baseline stochastic individual path model (Baseline SIP), based on mathematically defined physiologically realistic bifurcations (PRBs), and new characteristic PRB geometries with modifications made to account for the CF disease state. The Baseline SIP models provided a poor approximation of aerosol deposition in the scan-extracted geometries, as expected. In contrast, the new characteristic (modified) PRB geometries adequately captured deposition consistent with the scan-extracted geometries across the two disease states considered for multiple particle sizes and inhalation flow rates. This was surprising considering that the modified PRB geometries, which can be mathematically specified, only captured an expanded bifurcation region and extended carinal curvature, both representative of bronchiectasis, and neglected asymmetry, surface roughness and non-circular branch cross-sections. In conclusion, the new characteristic PRB geometries adequately captured the deposition characteristics of scan-extracted airway models and can be implemented to represent airway structures in the intermediate and likely deeper lung regions of children with CF for future complete-airway modeling studies. Copyright © 2021 American Association for Aerosol Research

Alexithymia-a trait associated with difficulties understanding one's own emotions-is theorized to stem from deficits in interoceptive awareness, or the ability to detect, accurately monitor, and regulate internal bodily processes. The present meta-analysis analyzed all studies that empirically examined the relationship between alexithymia and interoceptive awareness. Across 66 independent samples (N = 7,146), alexithymia had a small, negative correlation with interoceptive awareness (r = -.162, p = .001, 95% CI [-.252, -.068]), but additional analyses revealed that the strength and directionality of this association was heavily influenced by the specific interoceptive awareness components measured (e.g., interoceptive accuracy vs. sensibility) and the methods used to measure interoceptive awareness (e.g., objective vs. self-report measures). The strength of this relationship was also moderated by diagnosis of participants such that alexithymia was moderately associated with interoceptive awareness in samples with psychiatric and developmental disorders, but the relationship was nonsignificant in healthy, typically developing samples. Results suggest interoception may represent a shared transdiagnostic vulnerability that underlies atypical emotional processing in a variety of disparate clinical populations but that current operationalization and measurement of interoceptive awareness continues to create confusion and inconsistency in the literature. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Fragmented care following elective surgery has been associated with poor outcomes. The association between fragmented care and outcomes in patients undergoing transcatheter aortic valve implantation (TAVI) is unknown. We examined patients who underwent TAVI from 2011 to 2015 at 374 sites in the STS/ACC TVT Registry, linked to Center for Medicare and Medicaid Services claims data. Fragmented care was defined as at least one readmission to a site other than the implanting TAVI center within 90 days after discharge, whereas continuous care was defined as readmission to the same implanting center. We compared adjusted 1-year outcomes, including stroke, bleeding, heart failure, mortality, and all-cause readmission in patients who received fragmented versus continuous care. Among 8,927 patients who received a TAVI between 2011 and 2015, 27.4% were readmitted within 90 days of discharge. Most patients received fragmented care (57.0%). Compared with the continuous care group, the fragmented care group was more likely to have severe chronic lung disease, cerebrovascular disease, and heart failure. States that had lower TAVI volume per Center for Medicare and Medicaid Services population had greater fragmentation. Patients living 30 minutes from their TAVI center had an increased risk of fragmented care 1.07 (confidence interval [CI] 1.06 to 1.09, p 0.001). After adjustment for comorbidities and procedural complications, fragmented care was associated with increased 1-year mortality (hazards ratio 1.18, CI 1.04 to 1.35, p = 0.010) and all-cause readmission (hazards ratio 1.08, CI 1.00 to 1.16, p = 0.051. In conclusion, fragmented readmission following TAVI is common, and is associated with increased 1-year mortality and readmission. Efforts to improve coordination of care may improve these outcomes and optimize long-term benefits yielded from TAVI.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an “age-suppressing” hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.

Women with HIV are more likely to have a history of traumatic and stressful life experiences. The current study examines experiences of traumatic and stressful life events, issues co-occurring with experiences of trauma, and intergenerational family dynamics regarding trauma and psychological well-being in women with HIV. The study was guided by the theoretical approach of an integrative translational model that incorporates trauma-related factors into a psychosocial framework. Data were collected from interviews with 20 women with HIV and analyzed for thematic categories. Thematic analysis indicated that traumatic life events of women with HIV included experiences of loss, sexual assault, and homelessness. Women with HIV also experienced issues co-occurring with trauma, including substance use and mental illness. The current study adds to the existing body of research by including an analysis of intergenerational family dynamics and psychological well-being. Implications for health care professionals and recommendations for translating research into practice are also discussed. [ Journal of Psychosocial Nursing and Mental Health Services, 57 (4), 23–31.]

A right-sided pneumonectomy after induction therapy for non-small cell lung cancer (NSCLC) has been shown to be associated with significant perioperative risk. We examined the effect of laterality on long-term survival after induction therapy and pneumonectomy using the National Cancer Data Base.Perioperative and long-term outcomes of patients who underwent pneumonectomy after induction chemotherapy, with or without radiotherapy, from 2004 to 2014 in the National Cancer Data Base were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis.During the study period, 1,465 patients (right, 693 [47.3%]; left, 772 [52.7%]) met inclusion criteria. Right-sided pneumonectomy was associated with significantly higher 30-day (8.2% [57 of 693] vs 4.2% [32 of 772], p0.01) and 90-day mortality (13.6% [94 of 693] vs 7.9% [61 of 772], p0.01), and right-sided pneumonectomy was a predictor of higher 90-day mortality (odds ratio, 2.23; p0.01). However, overall 5-year survival between right and left pneumonectomy was not significantly different in unadjusted (37.6% [95% confidence interval {CI}, 0.34 to 0.42] vs 35% [95% CI, 0.32 to 0.39], log-rank p = 0.94) or multivariable analysis (hazard ratio, 1.07; 95% CI, 0.92 to 1.25; p = 0.40). A propensity score-matched analysis of 810 patients found no significant differences in 5-year survival between the right-sided versus left-sided groups (34.7% [95% CI, 0.30 to 0.40] vs 34.1%, [95% CI, 0.29 to 0.39], log-rank p = 0.86).In this national analysis, right-sided pneumonectomy after induction therapy was associated with a significantly higher perioperative but not worse long-term mortality compared to a left-sided procedure.

Background Delayed hemolytic transfusion reactions (DHTRs) are serious complications of RBC transfusion that can occur in previously alloimmunized patients. Patients who require episodic transfusions during heightened inflammatory states, such as patients with sickle cell disease (SCD), are particularly prone to alloimmunization and developing DHTRs with hyperhemolysis. While efforts to mitigate these hemolytic episodes via immunosuppressive drugs can be employed, the relative efficacy of various treatment options remains incompletely understood. Case reports In this study, we explored five patients with SCD and multiple RBC alloantibodies who received various forms of immunosuppressive therapy in an attempt to prevent or treat severe DHTRs. Results The clinical course for these five patients provides insight into the difficulty of effectively treating and preventing DHTRs in patients with SCD with currently available immunosuppressive therapies. Conclusion Based on our experience, and the current literature, it is difficult to predict the potential impact of various immunosuppressive therapies when seeking to prevent or treat DHTRs. Future mechanistic studies are needed to identify the optimal treatment options for DHTRs in the presence or absence of distinct alloantibodies in patients with SCD.

Background Vitamin D, a hormone that acts through the nuclear vitamin D receptor (VDR), upregulates antitumorigenic microRNA in prostate epithelium. This may contribute to the lower levels of aggressive prostate cancer (PCa) observed in patients with high serum vitamin D. The small noncoding RNA (ncRNA) landscape includes many other RNA species that remain uncharacterized in prostate epithelium and their potential regulation by vitamin D is unknown. Methods Laser capture microdissection (LCM) followed by small‐RNA sequencing was used to identify ncRNAs in the prostate epithelium of tissues from a vitamin D‐supplementation trial. VDR chromatin immunoprecipitation‐sequencing was performed to identify vitamin D genomic targets in primary prostate epithelial cells. Results Isolation of epithelium by LCM increased sample homogeneity and captured more diversity in ncRNA species compared with publicly available small‐RNA sequencing data from benign whole prostate. An abundance of PIWI‐interacting RNAs (piRNAs) was detected in normal prostate epithelium. The obligate binding partners of piRNAs, PIWI‐like (PIWIL) proteins, were also detected in prostate epithelium. High prostatic vitamin D levels were associated with increased expression of piRNAs. VDR binding sites were located near several ncRNA biogenesis genes and genes regulating translation and differentiation. Conclusions Benign prostate epithelium expresses both piRNA and PIWIL proteins, suggesting that these small ncRNA may serve an unknown function in the prostate. Vitamin D may increase the expression of prostatic piRNAs. VDR binding sites in primary prostate epithelial cells are consistent with its reported antitumorigenic functions and a role in ncRNA biogenesis.

ObjectiveTo test the hypothesis that, in the context of robotic therapy designed to enhance proprioceptive feedback via a Hebbian model, integrity of both somatosensory and motor systems would be important in understanding interparticipant differences in treatment-related motor gains.MethodsIn 30 patients with chronic stroke, behavioral performance, neural injury, and neural function were quantified for somatosensory and motor systems. Patients then received a 3-week robot-based therapy targeting finger movements with enhanced proprioceptive feedback.ResultsHand function improved after treatment (Box and Blocks score increase of 2.8 blocks, p = 0.001) but with substantial variability: 9 patients showed improvement exceeding the minimal clinically important difference (6 blocks), while 8 patients (all of whom had >2-SD greater proprioception deficit compared to 25 healthy controls) showed no improvement. In terms of baseline behavioral assessments, a somatosensory measure (finger proprioception assessed robotically) best predicted treatment gains, outperforming all measures of motor behavior. When the neural basis underlying variability in treatment response was examined, somatosensory-related variables were again the strongest predictors. A multivariate model combining total sensory system injury and sensorimotor cortical connectivity (between ipsilesional primary motor and secondary somatosensory cortices) explained 56% of variance in treatment-induced hand functional gains (p = 0.002).ConclusionsMeasures related to the somatosensory network best explained interparticipant differences in treatment-related hand function gains. These results underscore the importance of baseline somatosensory integrity for improving hand function after stroke and provide insights useful for individualizing rehabilitation therapy.ClinicalTrials.gov identifier:NCT02048826.

Summary The fibromuscular stroma of the prostate regulates normal epithelial differentiation and contributes to carcinogenesis in vivo. We developed and characterized a human 3D prostate organoid co-culture model that incorporates prostate stroma. Primary prostate stromal cells increased organoid formation and directed organoid morphology into a branched acini structure similar to what is observed in vivo. Organoid branching occurred distal to physical contact with stromal cells, demonstrating non-random branching. Stroma-induced phenotypes were similar in all patients examined, yet they maintained inter-patient heterogeneity in the degree of response. Stromal cells expressed growth factors involved in epithelial differentiation, which was not observed in non-prostatic fibroblasts. Organoids derived from areas of prostate cancer maintained differential expression of alpha-methylacyl-CoA racemase and showed increased viability and passaging when co-cultured with stroma. The addition of stroma to epithelial cells in vitro improves the ability of organoids to recapitulate features of the tissue and enhances the viability of organoids., Graphical Abstract, Highlights • Co-culture with human primary prostate stroma improves epithelial organoid viability • Stromal cell contact in co-culture directs epithelial organoid branching • Prostate stromal cells express morphogenic factors unique from non-prostate fibroblasts • Co-culture with stroma maintains AMACR and increases survival of cancer derived-organoids, Bioengineering; Biological Sciences; Cell Biology; Tissue Engineering

An adult male snapping turtle with marked palpebral edema and multifocal skin ulceration was found alive in a marsh in southern Ontario in summer 2017. The turtle was transported to a rehabilitation facility and died 4 d after arrival. The carcass was submitted to the Canadian Wildlife Health Cooperative for post-mortem examination. Gross lesions included ulcerative conjunctivitis, necrotizing stomatitis, and splenomegaly. Microscopically, this corresponded to multisystemic fibrinonecrotizing vasculitis and severe fibrinous splenic necrosis. Liver tissue tested positive for frog virus 3-like ranavirus and negative for herpesvirus via polymerase chain reaction. The gross and microscopic lesions were consistent with previous reports of ranavirus infection in turtles and were severe enough to have been the cause of death in this case. This is the first report of morbidity and mortality in a common snapping turtle with a ranavirus infection, and the first reported case of ranavirus infection in a reptile in Canada. Ranaviruses are considered to be an emerging infectious disease in chelonians as they are increasing in distribution, prevalence, and host range.

Guided by a community-based participatory research and systems-based approach, this 3-year mixed-methods case study describes the experiences and capacity development of a Community-Academic Advisory Board (CAB) formed to adapt, implement, and evaluate an evidence-based childhood obesity treatment program in a medically underserved region. The CAB included community, public health, and clinical (n = 9) and academic partners (n = 9). CAB members completed capacity evaluations at 4 points. Partners identified best practices that attributed to the successful execution and continued advancement of project goals. The methodological framework and findings can inform capacity development and sustainability of emergent community-academic collaborations.

Objective Epilepsy treatment falls short in ~30% of cases. A better understanding of epilepsy pathophysiology can guide rational drug development in this difficult to treat condition. We tested a low‐cost, drug‐repositioning strategy to identify candidate epilepsy drugs that are already FDA‐approved and might be immediately tested in epilepsy patients who require new therapies. Methods Biopsies of spiking and nonspiking hippocampal brain tissue from six patients with unilateral mesial temporal lobe epilepsy were analyzed by RNA‐Seq. These profiles were correlated with transcriptomes from cell lines treated with FDA‐approved drugs, identifying compounds which were tested for therapeutic efficacy in a zebrafish seizure assay. Results In spiking versus nonspiking biopsies, RNA‐Seq identified 689 differentially expressed genes, 148 of which were previously cited in articles mentioning seizures or epilepsy. Differentially expressed genes were highly enriched for protein–protein interactions and formed three clusters with associated GO‐terms including myelination, protein ubiquitination, and neuronal migration. Among the 184 compounds, a zebrafish seizure model tested the therapeutic efficacy of doxycycline, metformin, nifedipine, and pyrantel tartrate, with metformin, nifedipine, and pyrantel tartrate all showing efficacy. Interpretation This proof‐of‐principle analysis suggests our powerful, rapid, cost‐effective approach can likely be applied to other hard‐to‐treat diseases.

Background and Purpose: Social networks influence human health and disease through direct biological and indirect psychosocial mechanisms. They have particular importance in neurologic disease because of support, information, and healthy behavior adoption that circulate in networks. Investigations into social networks as determinants of disease risk and health outcomes have historically relied on summary indices of social support, such as the Lubben Social Network Scale–Revised (LSNS-R) or the Stroke Social Network Scale (SSNS). We compared these 2 survey tools to personal network (PERSNET) mapping tool, a novel social network survey that facilitates detailed mapping of social network structure, extraction of quantitative network structural parameters, and characterization of the demographic and health parameters of each network member. Methods: In a cohort of inpatient and outpatient stroke survivors, we administered LSNS-R, SSNS, and PERSNET in a randomized order to each patient. We used logistic regression to generate correlation matrices between LSNS-R scores, SSNS scores, and PERSNET’s network structure (eg, size and density) and composition metrics (eg, percent kin in network). We also examined the relationship between LSNS-R-derived risk of social isolation with PERSNET-derived network size. Results: We analyzed survey responses for 67 participants and found a significant correlation between LSNS-R, SSNS, and PERSNET-derived indices of network structure. We found no correlation between LSNS-R, SSNS, and PERSNET-derived metrics of network composition. Personal network mapping tool structural and compositional variables were also internally correlated. Social isolation defined by LSNS-R corresponded to a network size of Conclusions: Personal network mapping tool is a valid index of social network structure, with a significant correlation to validated indices of perceived social support. Personal network mapping tool also captures a novel range of health behavioral data that have not been well characterized by previous network surveys. Therefore, PERSNET offers a comprehensive social network assessment with visualization capabilities that quantifies the social environment in a valid and unique manner.

Concussions have been shown to result in autonomic dysfunction and altered cerebral vascular function. We tested the hypothesis that concussed athletes (CA) would have altered cerebral vascular function during acute decreases and increases in blood pressure compared to healthy controls (HC). Ten CA (age: 20 ± 2 y, 7 females) and 10 HC (age: 21 ± 2 y, 6 females) completed 5 min of lower body negative pressure (LBNP; −40 mmHg) and 5 min of lower body positive pressure (LBPP; 20 mmHg). Protocols were randomized and separated by 10 min. Mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) were continuously recorded. Cerebral vascular resistance (CVR) was calculated as MAP/MCAv. Values are reported as change from baseline to the last minute achieved (LBNP) or 5 min (LBPP). There were no differences in baseline values between groups. During LBNP, there were no differences in the change for MAP (CA: −23 ± 18 vs. HC: −21 ± 17 cm/s; P = 0.80) or MCAv (CA: −13 ± 8 vs. HC: −18 ± 9 cm/s; P = 0.19). The change in CVR was different between groups (CA: −0.08 ± 0.26 vs. HC: 0.18 ± 0.24 mmHg/cm/s; P = 0.04). Total LBNP time was lower for CA (204 ± 92 s) vs. HC (297 ± 64 s; P = 0.04). During LBPP, the change in MAP was not different between groups (CA: 13 ± 6 vs. HC: 10 ± 7 mmHg; P = 0.32). The change in MCAv (CA: 7 ± 6 vs. HC: −4 ± 13 cm/s; P = 0.04) and CVR (CA: −0.06 ± 0.27 vs. HC: 0.38 ± 0.41 mmHg/cm/s; P = 0.03) were different between groups. CA exhibited impaired tolerance to LBNP and had a different cerebral vascular response to LBPP compared to HC.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38–97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20–30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

The objective was to assess the effectiveness and safety of peripheral regional anesthesia in congenital cardiac surgical patients undergoing thoracotomy for aortic coarctation.A retrospective chart review of pediatric patients (18 years) who underwent surgical repair of congenital heart diseases via thoracotomy between September 2013 and July 2018 was done. Among patients who underwent coarctation repair, a propensity score was used to match patients who received a regional catheter (C) versus traditional medical treatment only (M).A single center children's hospital.The median age was 172 days (IQR 64-1315) in group C and 176 days (IQR 71-1146) in group M (SMD = 0.07). The median weight was 6.8 kg (IQR 4.8-13.6) in group C and 7.7 kg (4.6-17.4) in group M (SMD = 0.003).Outcomes assessed were postoperative hospital length of stay, median pain scores in the first 24 and 48 hours, and total morphine equivalent use in the first 24 and 48 hours. Complications related to the catheters were reviewed. The median oral morphine equivalent dose administered in the first 24 hours was lower in group C than group M (0.8 mg/kg, IQR 0.5-1.1 vs. 1.4 mg/kg, IQR 0.9-1.7, p = 0.019). There were no major complications related to the catheters, including hematoma.Peripheral regional catheters may be used to reduce opioid requirements in patients after CoA repair. Due to the low risk of these catheters, they should be considered as part of a pain management strategy for pediatric patients undergoing thoracotomy and should be incorporated into strategies to improve outcomes.

ImportanceThe effects of SARS-CoV-2 infection on immune responses during pregnancy have not been systematically evaluated.ObjectiveTo assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women.DesignImmune responses to SARS-CoV-2 were analyzed using samples from pregnant and non-pregnant women who had either tested positive or negative for SARS-CoV-2. We measured, proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) receptor expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we measured anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood.SettingJohns Hopkins Hospital (JHH)ParticipantsPregnant women were recruited through JHH outpatient obstetric clinics and the JHH Labor & Delivery unit. Non-pregnant women were recruited after receiving outpatient SARS-CoV-2 testing within Johns Hopkins Health System, USA. Adult non-pregnant women with positive RT-PCR results for SARS-CoV-2, within the age range of 18-48 years, were included in the study.ExposuresSARS-CoV-2Main Outcomes and MeasuresParticipant demographic characteristics, antibody titers, cytokine mRNA expression, and FcRn receptor expression.ResultsSARS-COV-2 positive pregnant women expressed more IL1β, but not IL6, in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test, with similar patterns observed in the fetal side of placentas, particularly among asymptomatic pregnant women. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of nAb was inhibited by SARS-CoV-2 infection during pregnancy.Conclusions and RelevanceSARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.

PURPOSE: Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths. METHODS: In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place. RESULTS: Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%. CONCLUSION: Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.