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KIFl A -associated neurological disorder (KAND ) encompasses a group of rare neurodegenerative conditions caused by variants in KIFl A, a gene that encodes an anterograde neuronal microtubule (MT) motor protein. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in sitico predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II. For a subset of variants, we generated recombinant proteins, which we used to assess transport in vivo by assessing neurite tip accumulation and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a different way to describe KAND subtypes to better capture the breadth of disease severity. [ABSTRACT FROM AUTHOR]

Purpose: The emergence of the novel SARS-CoV-2 pathogen and lethal COVID-19 disease pandemic poses major diagnostic challenges. The study aims to describe the spectrum and prevalence of thoracic and extrathoracic incidental findings in patients who have undergone 18F-FDG PET/CT during the first 3 weeks of the COVID-19 UK lockdown. Methods: This is a single-centre retrospective controlled observational study. 18F-FDG PET/CT scans (n = 160) acquired from 23/3/2020 to 9/4/2020 were retrospectively reviewed for incidental findings in the lungs and extrapulmonary sites (heart, nasal sinuses, parotid and salivary glands, colon, large vessels, renal cortex, brain, spleen and testes). A date-matched control group (n = 205) of patients from 2019 was used for comparison. Results: The total prevalence of suspicious findings was 26/160 (16.25%). Fifteen patients presented with incidental findings in the lungs, while eleven patients had only non-pulmonary incidental findings. There was a significant increase in the appearance of incidental 18F-FDG PET/CT findings during the 2nd week (OR = 3.8) and 3rd week (OR = 7.6) in relation to the 1st week. There was a significant increase in the average maximum standardised uptake values (SUVmax) in the parotid/salivary glands of patients scanned during week 2 in relation to week 1 (p = 0.036). There was no significant difference in the prevalence of incidental findings compared to the control group, but the number of pulmonary vs. extrathoracic findings was different between the two populations. Conclusion: The study provides a novel base of evidence to identify asymptomatic patients and those without symptoms strongly associated with COVID-19 with incidental 18F-FDG PET/CT findings suspicious of SARS-CoV-2 infection during the initial stages of the pandemic. [ABSTRACT FROM AUTHOR]

Abstract Background aims CD1d-restricted invariant natural killer (iNK) T cells are rare regulatory T cells that may contribute to the immune-regulation in allogeneic stem cell transplantation (ASCT). Here, we sought to develop an effective strategy to expand human iNK T cells for use in cell therapy to prevent graft-versus-host disease (GVHD) in ASCT. Methods Human iNK T cells were first enriched from peripheral blood mononuclear cells (PBMCs) using magnetic-activated cell sorting separation, then co-cultured with dendritic cells in the presence of agonist glycolipids, alpha-galactosylceramide, for 2 weeks. Results The single antigenic stimulation reliably expanded iNK T cells to an average of 2.8 × 107 per 5 × 108 PBMCs in an average purity of 98.8% in 2 weeks (N = 24). The expanded iNK T cells contained a significantly higher level of CD4+ and central memory phenotype (CD45RA−CD62L+) compared with freshly isolated iNK T cells, and maintained their ability to produce both Th-1 (interferon [IFN]γ and tumor necrosis factor [TNF]α) and Th-2 type cytokines (interleukin [IL]-4, IL-5 and IL-13) upon antigenic stimulation or stimulation with Phorbol 12-myristate 13-acetate/ionomycin. Interestingly, expanded iNK T cells were highly autoreactive and produced a Th-2 polarized cytokine production profile after being co-cultured with dendritic cells alone without exogenous agonist glycolipid antigen. Lastly, expanded iNK T cells suppressed conventional T-cell proliferation and ameliorated xenograft GVHD (hazard ratio, 0.1266; P < 0.0001). Conclusion We have demonstrated a feasible approach for obtaining ex vivo expanded, highly enriched human iNK T cells for use in adoptive cell therapy to prevent GVHD in ASCT. [ABSTRACT FROM AUTHOR]

Background: The improved outcomes and increased availability of surgery for congenital heart disease (CHD) over the last three decades have created a small but steadily increasing subset of patients with unique needs: children and adults with complex arrhythmias in the setting of structural cardiac abnormalities. Radiofrequency catheter ablation (RFCA) in these patients, and in small children with normal cardiac anatomy, is effective but challenging. An understanding of specific anatomical and electrophysiological characteristics of these patients and the technical challenges in addressing them are critical to the success of this therapy. Tools specifically designed for intracardiac diagnosis and therapy in anatomically complex and/or small hearts remain scarce. Aims: We report single-center results from an ongoing registry of all patients with congenital heart disease and all children with complex arrhythmias in which the Magnetic Navigation System (MNS) was used. Results: Included in this report are 12 patients with CHD in whom 17 tachyarrhythmias were treated, and 11 pediatric patients with normal cardiac anatomy who each had a single arrhythmia. The procedures' duration and the duration of fluoroscopy time as well as arrhythmia recurrence rates were comparable to those found in previous reports of procedures performed in adults with structurally normal hearts, and the incidence of complications was quite low. Discussion: In patients with complex congenital malformations, retrograde mapping of the pulmonary venous atrium was feasible, eliminating the need for puncture of the atrial septum, or surgically placed baffle in many cases. Moreover, the design of the catheter eliminated the need for multiple mapping and ablation catheters. Conclusion: Our findings suggest that RFCA using the MNS for arrhythmias after surgery for congenital heart disease and in pediatric patients is safe and effective. [ABSTRACT FROM AUTHOR]

Psychological hardiness encompasses three components: commitment, control, and challenge, and illustrates how individuals respond to stressors. Analyzing athletes' responses to wins and losses, depending on their psychological hardiness level, may provide insight of the impact of game outcome on student-athlete wellness. The purpose of this study was to examine postgame subjective wellness scores based on level of psychological hardiness following wins and losses in collegiate female lacrosse athletes. Players ( n = 17) took the Dispositional Resilience Scale Scale-15 (DRS-15) at the start of the academic year and were grouped based on hardiness level: above average (AH) and below average (BA). Participants took a daily wellness survey rating their overall wellness, energy level, muscle soreness, stress level, and sleep quality. RM-ANOVA indicated no difference in post-game wellness scores between hardiness groups ( Lambda (5,11) = 1.073, p = .426, ES = .328), by game outcome ( Lambda (5,11) = 2.361, p = .109, ES = .518), or an interaction between hardiness and outcome of game ( Lambda (5,11) = 1.421, p = .291, ES = .392). No hardiness group differences were found for overall wellness or sub-scores. These results show subjective wellness scores decrease collectively after a loss versus a win but refute prior studies as hardy players did not experience significantly less stress than their less hardy counterparts. Future studies should be conducted to assess wellness after differing game outcomes over many seasons to assist coaching staff on the subjective, psychological impacts of game.

Purpose: This study evaluated whether or not polysomnography (PSG) inter-scorer reliability (ISR) across sleep centres could be improved by external proficiency testing (EPT), or by EPT combined with method alignment training., Methods: Experienced scorers form 15 sleep centres were randomised to the following: (1) a control group, (2) a group that received a self-directed intervention of EPT reports (EPT Passive ) or (3) a group that received an active intervention of method alignment training and EPT reports (EPT Active ). Respiratory, arousal and sleep scoring ISR from sixteen PSG fragments were compared between groups across time., Results: Among 30 scorers, there were no ISR changes in controls between baseline (BL) and 6 months (6 m). Both EPT groups showed ISR improvement from BL to 6 m for respiratory, arousal and sleep scoring (p < 0.05). Respiratory scoring back-transformed mean (95CI) proportion of specific agreement (PSA) for the EPT Passive group improved from 0.78 (0.72-0.84) to 0.80 (0.74-0.86) and for the EPT Active group from 0.80 (0.74-0.85) to 0.82 (0.76-0.88). Arousal scoring PSA for the EPT Passive group improved from 0.72 (0.66-0.77) to 0.74 (0.69-0.79) and for the EPT Active group from 0.71 (0.65-0.76) to 0.77 (0.72-0.82). Sleep scoring kappa for the EPT Passive group improved from 0.64 (0.58-0.69) to 0.73 (0.68-0.77) and for the EPT Active group from = 0.75 (0.71-0.80) to 0.80 (0.76-0.85). Overall, poorer performers achieved greater improvement., Conclusion: External proficiency testing produced modest, statistically significant PSG inter-scorer reliability improvements among experienced scorers across sleep centres, with potential to improve clinical management of individual patients and increase research study statistical power., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A prototype infrared video bolometer (IRVB) was successfully deployed in the Mega Ampere Spherical Tokamak Upgrade (MAST Upgrade or MAST-U), the first deployment of such a diagnostic in a spherical tokamak. The IRVB was designed to study the radiation around the lower x-point, another first in tokamaks, and has the potential to estimate emissivity profiles with spatial resolution beyond what is achievable with resistive bolometry. The system was fully characterized prior to installation on MAST-U, and the results are summarized here. After installation, it was verified that the actual measurement geometry in the tokamak qualitatively matches the design; this is a particularly difficult process for bolometers and was done using specific features of the plasma itself. The installed IRVB measurements are consistent both with observations from other diagnostics, including magnetic reconstruction, visible light cameras, and resistive bolometry, as well as with the IRVB-designed view. Early results show that with conventional divertor geometry and only intrinsic impurities (for example, C and He), the progression of radiative detachment follows a similar path to that observed for large aspect ratio tokamaks: The peak of the radiation moves along the separatrix from the targets to the x-point and high-field side midplane with a toroidally symmetric structure that can eventually lead to strong effects on the core plasma inside the separatrix.

The aim of this study was to assess the temporal evolution of pulmonary 18 F-FDG uptake in patients with coronavirus disease 2019 (COVID-19) and post-COVID-19 lung disease (PCLD). Methods: Using our hospital's clinical electronic records, we retrospectively identified 23 acute COVID-19, 18 PCLD, and 9 completely recovered 18 F-FDG PET/CT patients during the 2 peaks of the U.K. pandemic. Pulmonary 18 F-FDG uptake was measured as a lung target-to-background ratio (TBR lung  = SUV max /SUV min ) and compared with temporal stage. Results: In acute COVID-19, less than 3 wk after infection, TBR lung was strongly correlated with time after infection ( r s  = 0.81, P < 0.001) and was significantly higher in the late stage than in the early stage ( P  = 0.001). In PCLD, TBR lung was lower in patients treated with high-dose steroids ( P  = 0.003) and in asymptomatic patients ( P < 0.001). Conclusion: Pulmonary 18 F-FDG uptake in COVID-19 increases with time after infection. In PCLD, pulmonary 18 F-FDG uptake rises despite viral clearance, suggesting ongoing inflammation. There was lower pulmonary 18 F-FDG uptake in PCLD patients treated with steroids., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Women with liver transplants may be at increased risk for adverse outcomes., Objective: The objectives of this study were to evaluate trends and provide recent data on outcomes for women with a liver transplant., Study Design: The National (Nationwide) Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project from 1998 to 2014 was used for this repeated cross-sectional analysis. Women aged between 15 and 54 years, with a history of liver transplant who underwent delivery, antepartum, or postpartum hospitalizations were identified. Temporal trends in deliveries of women with liver transplants were analyzed. The risk for severe maternal morbidity (SMM) excluding transfusion based on criteria from the Centers for Disease Control and Prevention (CDC), as well as for individual outcomes including hypertensive diseases of pregnancy, postpartum hemorrhage, placental abruption, liver rejection, cesarean delivery, preterm delivery, and coagulopathy during delivery hospitalizations were analyzed. Risks of SMM during antepartum and postpartum hospitalizations were also analyzed. An adjusted log-linear regression model for SMM during delivery hospitalizations including demographic factors, hospital characteristics, and underlying comorbidity was performed. The chi-squared or Fisher's exact test was used for comparisons. Temporal trends were analyzed with the Cochran-Armitage trend test. Population weights were applied to create national estimates., Results: From 1998 to 2014, an estimated 1165 births occurred by women with a liver transplant. The number of births occurring by women with liver transplants increased over the study period from 1.0 per 100,000 in 1998-2000 to 2.8 per 100,000 in 2012-2014 ( p  < .01). The risk for CDC SMM excluding transfusion was significantly higher during delivery hospitalizations among women with compared to without liver transplant (8.0 versus 0.5%, p  < .01, unadjusted risk ratio 15.4, 95% CI 12.7-18.6). Women with liver transplant were also at significantly higher risk for abruption (2.5 versus 1.0%, p  = .03), hypertensive diseases of pregnancy (27.8 versus 6.9%, p  < .01), postpartum hemorrhage (8.0 versus 2.8%, p  = .01), cesarean delivery (51.7 versus 29.5%, p  < .01), preterm delivery (27.5 versus 7.0%, p  < .01), and coagulopathy (3.1 versus 0.3%, p  < .01). A diagnosis of liver rejection was present during 4.1% of delivery hospitalizations for women with liver transplant. In the adjusted analysis for severe morbidity excluding transfusion risk was retained with liver transplant associated with increased likelihood of this adverse outcome (aRR 8.49, 95% CI 5.59-12.87). Women with liver transplants were at significantly higher likelihood of undergoing antepartum and postpartum admissions, and of experiencing SMM during these hospitalizations., Conclusion: In this analysis of antepartum, delivery, and postpartum hospitalizations, women with liver transplant were at significantly higher risk for both SMM during all hospitalizations and for a range of adverse outcomes including placental abruption, hypertensive diseases of pregnancy, postpartum hemorrhage, cesarean delivery, and coagulopathy delivery during delivery hospitalizations. While deliveries to women with liver transplant were rare, these births became more frequent over the study period.

KIF1A-associated neurological disorder (KAND) encompasses a group of rare neurodegenerative conditions caused by variants in KIF1A ,a gene that encodes an anterograde neuronal microtubule (MT) motor protein. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II. For a subset of variants, we generated recombinant proteins, which we used to assess transport in vivo by assessing neurite tip accumulation and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a different way to describe KAND subtypes to better capture the breadth of disease severity., Competing Interests: Declaration of interests The authors declare no competing interests.

Background/aim: Systematic reporting using qualitative evaluation of PET/computed tomography (CT) results has been demonstrated to be very accurate and reproducible in posttherapy assessment of lung cancer (so-called Hopkins criteria). Our aim was to test, in a different cohort of patients, the Hopkins criteria for assessment of therapeutic response in lung cancer and to compare the results with those obtained using a semi-quantitative evaluation of uptake., Methods: This is a retrospective study. A total of 85 patients with known lung cancer who underwent fluorine-18 fluorodeoxyglucose PET/CT assessment within 24 weeks (mean 7.9 weeks) of completion of treatment were included. Treatments included surgical resection, chemotherapy, radiation therapy, immunotherapy or combinations thereof. PET/CT interpretation was done by two nuclear medicine physicians, and discrepancies were resolved by a third interpreter. Studies were scored both according to the Hopkins criteria using qualitative assessment of tracer uptake for the primary tumour, locoregional disease in the mediastinum and distant metastatic sites and by applying the same five-point score using a semi-quantitative measure, maximum standardized uptake value. Overall scores of 1, 2 and 3 were considered negative for residual disease, while scores of 4 and 5 were considered positive. Patients were followed up for a median of 18.5 months (range 2-139 months). Kaplan-Meier plots with a Mantel-Cox log-rank test were performed, considering death as the endpoint. Inter-reader variability was assessed using percent agreement and kappa statistics., Results: The Cohen κ coefficient analysis showed substantial agreement between the two interpreters on the five-point Hopkins criteria scoring, with a κ of 0.73. There was almost perfect agreement between the interpreters with respect to classification as positive or negative according to the Hopkins criteria, with a κ of 0.89. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the Hopkins criteria were 88.5% [95% confidence interval (CI) 80.6-96.5%), 79.2% (95% CI 63.2-95.1%), 91.5% (95% CI 84.4-98.6%), 73.1% (95% CI 61.8-84.4%) and 85.9% (95% CI 78.5-93.3%), respectively. There was almost perfect agreement between the qualitative and semi-quantitative scoring with a κ of 0.87, with sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the semi-quantitative Hopkin's criteria of 86.9% (95% CI 78.4-95.4%), 79.2% (95% CI 62.9-95.4%), 91.4% (95% CI 84.2-98.6%), 70.4% (95% CI 58.6-82.1%) and 84.7% (95% CI 80.8-92.4%), respectively., Conclusion: The use of Hopkins criteria for posttherapy assessment in patients with lung cancer represents an easy and reproducible method with substantial to almost perfect interobserver agreement and high positive predictive value and accuracy; moreover, it is easily understood by referring physicians. Additionally, there was no significant difference when applying a semi-quantitative measure to the same five-point score.

The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35-40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name "Radiomic Prognostic Vector" (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.

Purpose: The aim of this multi-center study was to discover and validate radiomics classifiers as image-derived biomarkers for risk stratification of non-small-cell lung cancer (NSCLC)., Patients and Methods: Pre-therapy PET scans from a total of 358 Stage I-III NSCLC patients scheduled for radiotherapy/chemo-radiotherapy acquired between October 2008 and December 2013 were included in this seven-institution study. A semi-automatic threshold method was used to segment the primary tumors. Radiomics predictive classifiers were derived from a training set of 133 scans using TexLAB v2. Least absolute shrinkage and selection operator (LASSO) regression analysis was used for data dimension reduction and radiomics feature vector (FV) discovery. Multivariable analysis was performed to establish the relationship between FV, stage and overall survival (OS). Performance of the optimal FV was tested in an independent validation set of 204 patients, and a further independent set of 21 (TESTI) patients., Results: Of 358 patients, 249 died within the follow-up period [median 22 (range 0-85) months]. From each primary tumor, 665 three-dimensional radiomics features from each of seven gray levels were extracted. The most predictive feature vector discovered (FVX) was independent of known prognostic factors, such as stage and tumor volume, and of interest to multi-center studies, invariant to the type of PET/CT manufacturer. Using the median cut-off, FVX predicted a 14-month survival difference in the validation cohort (N = 204, p = 0.00465; HR = 1.61, 95% CI 1.16-2.24). In the TESTI cohort, a smaller cohort that presented with unusually poor survival of stage I cancers, FVX correctly indicated a lack of survival difference (N = 21, p = 0.501). In contrast to the radiomics classifier, clinically routine PET variables including SUV max , SUV mean and SUV peak lacked any prognostic information., Conclusion: PET-based radiomics classifiers derived from routine pre-treatment imaging possess intrinsic prognostic information for risk stratification of NSCLC patients to radiotherapy/chemo-radiotherapy.

Poor sanitation could pose greater risk for enteric pathogen transmission at higher human population densities because of greater potential for pathogens to infect new hosts through environmentally mediated and person-to-person transmission. We hypothesized that incidence and prevalence of diarrhea, enteric protozoans, and soil-transmitted helminth infections would be higher in high-population-density areas compared with low-population-density areas, and that poor sanitation would pose greater risk for these enteric infections at high density compared with low density. We tested our hypotheses using 6 years of clinic-based diarrhea surveillance (2007-2013) including 4,360 geolocated diarrhea cases tested for 13 pathogens and a 2010 cross-sectional survey that measured environmental exposures from 204 households (920 people) and tested 701 stool specimens for enteric parasites. We found that population density was not a key determinant of enteric infection nor a strong effect modifier of risk posed by poor household sanitation in this setting., (© The American Society of Tropical Medicine and Hygiene.)

Foreign-born persons in the United States seeking to adjust their status to permanent resident must undergo screening for tuberculosis (TB) disease. Screening is performed by civil surgeons (CS) following technical instructions by the Centers for Disease Control and Prevention. From 2011 to 2012, 1,369 practicing CS in California, Texas, and New England were surveyed to investigate adherence to the instructions. A descriptive analysis was conducted on 907 (66%) respondents. Of 907 respondents, 739 (83%) had read the instructions and 565 (63%) understood that a chest radiograph is required for status adjustors with TB symptoms; however, only 326 (36%) knew that a chest radiograph is required for immunosuppressed status adjustors. When suspecting TB disease, 105 (12%) would neither report nor refer status adjustors to the health department; 91 (10%) would neither start treatment nor refer for TB infection. Most CS followed aspects of the technical instructions; however, educational opportunities are warranted to ensure positive patient outcomes.

In 2008, a large Salmonella outbreak caused by contamination of the municipal drinking water supply occurred in Alamosa, Colorado. The objectives of this assessment were to determine the full economic costs associated with the outbreak and the long-term health impacts on the community of Alamosa. We conducted a postal survey of City of Alamosa (2008 population: 8,746) households and businesses, and conducted in-depth interviews with local, state, and nongovernmental agencies, and City of Alamosa healthcare facilities and schools to assess the economic and long-term health impacts of the outbreak. Twenty-one percent of household survey respondents (n = 369/1,732) reported diarrheal illness during the outbreak. Of those, 29% (n = 108) reported experiencing potential long-term health consequences. Most households (n = 699/771, 91%) reported municipal water as their main drinking water source at home before the outbreak; afterwards, only 30% (n = 233) drank unfiltered municipal tap water. The outbreak's estimated total cost to residents and businesses of Alamosa using a Monte Carlo simulation model (10,000 iterations) was approximately $1.5 million dollars (range: $196,677-$6,002,879), and rose to $2.6 million dollars (range: $1,123,471-$7,792,973) with the inclusion of outbreak response costs to local, state and nongovernmental agencies and City of Alamosa healthcare facilities and schools. This investigation documents the significant economic and health impacts associated with waterborne disease outbreaks and highlights the potential for loss of trust in public water systems following such outbreaks.