Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Effects of exogenous lactate on lipid, protein, and glucose metabolism-a randomized crossover trial in healthy males.

Lactate may inhibit lipolysis and thus enhance insulin sensitivity, but there is a lack of metabolic human studies. This study aimed to determine how hyperlactatemia affects lipolysis, glucose- and protein metabolism, and insulin sensitivity in healthy men. In a single-blind, randomized, crossover design, eight healthy men were studied after an overnight fast on two occasions: 1) during a sodium-lactate infusion (LAC) and 2) during a sodium-matched NaCl infusion (CTR). Both days consisted of a 3-h postabsorptive period followed by a 3-h hyperinsulinemic-euglycemic clamp (HEC). Lipolysis rate, endogenous glucose production (EGP), and delta glucose rate of disappearance (ΔRdglu) were evaluated using [9,10-3H]palmitate and [3-3H]glucose tracers. In addition, whole body- and forearm protein metabolism was assessed using [15N]phenylalanine, [2H4]tyrosine, [15N]tyrosine, and [13C]urea tracers. In the postabsorptive period, plasma lactate increased to 2.7 ± 0.5 mmol/L during LAC vs. 0.6 ± 0.3 mmol/L during CTR (P < 0.001). In the postabsorptive period, palmitate flux was 30% lower during LAC compared with CTR (84 ± 32 µmol/min vs. 120 ± 35 µmol/min, P = 0.003). During the HEC, palmitate flux was suppressed similarly during both interventions (P = 0.7). EGP, ΔRdglu, and M value were similar during LAC and CTR. During HEC, LAC increased whole body phenylalanine flux (P = 0.02) and protein synthesis (P = 0.03) compared with CTR; LAC did not affect forearm protein metabolism compared with CTR. Lactate infusion inhibited lipolysis by 30% under postabsorptive conditions but did not affect glucose metabolism or improve insulin sensitivity. In addition, whole body phenylalanine flux was increased. Clinical trial registrations: NCT04710875.NEW & NOTEWORTHY Lactate is a decisive intermediary metabolite, serving as an energy substrate and a signaling molecule. The present study examines the effects of lactate on substrate metabolism and insulin sensitivity in healthy males. Hyperlactatemia reduces lipolysis by 30% without affecting insulin sensitivity and glucose metabolism. In addition, hyperlactatemia increases whole body amino acid turnover rate.

The impact of CHOP versus bendamustine on bone mineral density in patients with indolent lymphoma enrolled in the GALLIUM study.

Standard CHOP treatment includes a high cumulative dose of prednisone, and studies have shown increased fracture risk following CHOP. It is unclear whether reductions in bone mineral density (BMD) are caused by glucocorticoids or by the combination with chemotherapy. Our objective was to determine the effect of obinutuzumab (G)/rituximab (R)-bendamustine versus G/R-CHOP on BMD in follicular lymphoma patients. Patients in this GALLIUM post hoc study were ≥60 years old and in complete remission at induction treatment completion (ITC), following treatment with G or R in combination with bendamustine or CHOP. To assess BMD, Hounsfield units (HU) were measured in lumbar vertebra L1 on annual computed tomography. Furthermore, vertebral compression fractures were recorded. Of 173 patients included, 59 (34%) received CHOP and 114 (66%) received bendamustine. At baseline, there was no difference in HU between groups. The mean HU decrease from baseline to ITC was 27.8 after CHOP and 17.3 after bendamustine, corresponding to a difference of 10.4 (95% CI: 3.2-17.6). Vertebral fractures were recorded in 5/59 patients receiving CHOP and in 2/114 receiving bendamustine. CHOP was associated with a significant greater decrease in BMD and more frequent fractures. These results suggest that prophylaxis against BMD loss should be considered.

Recommendations on the Use of Multiple Labels in Human Mass Balance Studies.

The administration of radiolabeled drug candidates is considered the gold standard in absorption, distribution, metabolism, and excretion studies for small-molecule drugs since it allows facile and accurate quantification of parent drug, metabolites, and total drug-related material independent of the compound structure. The choice of the position of the radiolabel, typically 14C or 3H, is critical to obtain relevant information. Sometimes, a biotransformation reaction may lead to cleavage of a part of the molecule. As a result, only the radiolabeled portion can be followed, and information on the fate of the nonlabeled metabolite may be lost. Synthesis and administration of two or more radiolabeled versions of the parent drug as a mixture or in separate studies may resolve this issue but comes with additional challenges. In this paper, we address the questions that may be considered to help make the right choice whether to use a single or multiple radiolabel approach and discuss the pros and cons of different multiple-labeling strategies that can be taken as well as alternative methods that allow the nonlabeled part of the molecule to be followed. SIGNIFICANCE STATEMENT: Radiolabeled studies are the gold standard in drug metabolism research, but molecules can undergo cleavage with loss of the label. This often results in discussions around potential use of multiple labels, which seem to be occurring with increased frequency since an increasing proportion of the small-molecule drugs are tending towards larger molecular weights. This review provides insight and decision criteria in considering a multiple-label approach as well as pros and cons of different strategies that can be followed.

Hyperpolarized 13C magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: First investigations in a large animal model.

Early biomarkers of cerebral damage are essential for accurate prognosis, timely intervention, and evaluation of new treatment modalities in newborn infants with hypoxia and ischemia at birth. Hyperpolarized 13C magnetic resonance imaging (MRI) is a novel method with which to quantify metabolism in vivo with unprecedented sensitivity. We aimed to investigate the applicability of hyperpolarized 13C MRI in a newborn piglet model and whether this method may identify early changes in cerebral metabolism after a standardized hypoxic-ischemic (HI) insult. Six piglets were anesthetized and subjected to a standardized HI insult. Imaging was performed prior to and 2 h after the insult on a 3-T MR scanner. For 13C studies, [1-13C]pyruvate was hyperpolarized in a commercial polarizer. Following intravenous injection, images were acquired using metabolic-specific imaging. HI resulted in a metabolic shift with a decrease in pyruvate to bicarbonate metabolism and an increase in pyruvate to lactate metabolism (lactate/bicarbonate ratio, mean [SD]; 2.28 [0.36] vs. 3.96 [0.91]). This is the first study to show that hyperpolarized 13C MRI can be used in newborn piglets and applied to evaluate early changes in cerebral metabolism after an HI insult.

Epinephrine vs placebo in neonatal resuscitation: ROSC and brain MRS/MRI in term piglets.

BACKGROUND: We aimed to investigate the effect of epinephrine vs placebo on return of spontaneous circulation (ROSC) and brain magnetic resonance spectroscopy and imaging (MRS/MRI) in newborn piglets with hypoxic cardiac arrest (CA). METHODS: Twenty-five piglets underwent hypoxia induced by endotracheal tube clamping until CA. The animals were randomized to CPR + intravenous epinephrine or CPR + placebo (normal saline). The primary outcome was ROSC, and secondary outcomes included time-to-ROSC, brain MRS/MRI, and composite endpoint of death or severe brain MRS/MRI abnormality. RESULTS: ROSC was more frequent in animals treated with epinephrine than placebo; 10/13 vs 4/12, RR = 2.31 (95% CI: 1.09-5.77). We found no difference in time-to-ROSC (120 (113-211) vs 153 (116-503) seconds, p = 0.7) or 6-h survival (7/13 vs 3/12, p = 0.2). Among survivors, there was no difference between groups in brain MRS/MRI. We found no difference in the composite endpoint of death or severe brain MRS/MRI abnormality; RR = 0.7 (95% CI: 0.37-1.19). CONCLUSIONS: Resuscitation with epinephrine compared to placebo improved ROSC frequency after hypoxic CA in newborn piglets. We found no difference in time-to-ROSC or the composite endpoint of death or severe brain MRS/MRI abnormality. IMPACT: In a newborn piglet model of hypoxic cardiac arrest, resuscitation with epinephrine compared to placebo improved the rate of return of spontaneous circulation and more than doubled the 6-h survival. Brain MRS/MRI biomarkers were used to evaluate the effect of epinephrine vs placebo. We found no difference between groups in the composite endpoint of death or severe brain MRS/MRI abnormality. This study adds to the limited evidence regarding the effect and safety of epinephrine; the lack of high-quality evidence from randomized clinical trials was highlighted in the latest ILCOR 2020 guidelines, and newborn animal studies were specifically requested.

A unidirectional mapping of ICD-8 to ICD-10 codes, for harmonized longitudinal analysis of diseases.

Periodic revisions of the international classification of diseases (ICD) ensure that the classification reflects new practices and knowledge; however, this complicates retrospective research as diagnoses are coded in different versions. For longitudinal disease trajectory studies, a crosswalk is an essential tool and a comprehensive mapping between ICD-8 and ICD-10 has until now been lacking. In this study, we map all ICD-8 morbidity codes to ICD-10 in the expanded Danish ICD version. We mapped ICD-8 codes to ICD-10, using a many-to-one system inspired by general equivalence mappings such that each ICD-8 code maps to a single ICD-10 code. Each ICD-8 code was manually and unidirectionally mapped to a single ICD-10 code based on medical setting and context. Each match was assigned a score (1 of 4 levels) reflecting the quality of the match and, if applicable, a "flag" signalling choices made in the mapping. We provide the first complete mapping of the 8596 ICD-8 morbidity codes to ICD-10 codes. All Danish ICD-8 codes representing diseases were mapped and 5106 (59.4%) achieved the highest consistency score. Only 334 (3.9%) of the ICD-8 codes received the lowest mapping consistency score. The mapping provides a scaffold for translation of ICD-8 to ICD-10, which enable longitudinal disease studies back to and 1969 in Denmark and to 1965 internationally with further adaption.

Mild Neurocognitive Disorder, Social Engagement, and Falls Among Older Primary Care Patients.

OBJECTIVES: (1) To estimate the association between social engagement (SE) and falls; (2) To examine the relation between mild neurocognitive disorder (MNCD) and falls by different levels of SE. DESIGN: We performed a secondary data analysis using prospective cohort study design. SETTING: Primary care. PARTICIPANTS: A total of 425 older adult primary care patients at risk for mobility decline (N=425). As previously reported, at baseline, 42% of participants exhibit MNCD. MAIN OUTCOME MEASURES: The outcome variable was the number of falls during 2 years of follow-up. Exposure variables at baseline included (1) MNCD identified using a cut-off of 1.5 SD below the age-adjusted mean on at least 2 measures within a cognitive performance battery and (2) SE, which was assessed using the social component of the Late-Life Function and Disability Instrument. High SE was defined as having a score ≥ median value (≥49 out of 100). All models were adjusted for age, sex, education, marital status, comorbidities, and pain status. RESULTS: Over 2 years of follow-up, 48% of participants fell at least once. MNCD was associated with a higher rate of falls, adjusting for the covariates (Incidence Rate Ratio=1.6, 95% confidence interval: 1.1-2.3). There was no significant association between MNCD and the rate of falls among people with high SE. In participants with low SE (having a score less than 49.5 out 100), MNCD was associated with a higher rate of falls as compared with participants with no neurocognitive disorder (No-NCD). CONCLUSIONS: Among participants with low SE, MNCD was associated with a higher rate of falls, but not among participants with high SE. The findings suggest that high SE may be protective against falls among older primary care patients with MNCD.

Shared and distinct factors underlying in-hospital mobility of older adults in Israel and Denmark (97/100).

BACKGROUND: Low in-hospital mobility is widely acknowledged as a major risk factor in acquiring hospital-associated disabilities. Various predictors of in-hospital low mobility have been suggested, among them older age, disabling admission diagnosis, poor cognitive and physical functioning, and pre-hospitalization mobility. However, the universalism of the phenomena is not well studied, as similar risk factors to low in-hospital mobility have not been tested. METHODS: The study was a secondary analysis of data on in-hospital mobility that investigated the relationship between in-hospital mobility and a set of similar risk factors in independently mobile prior to hospitalization older adults, hospitalized in acute care settings in Israel (N = 206) and Denmark (N = 113). In Israel, mobility was measured via ActiGraph GT9X and in Denmark by ActivPal3 for up to seven hospital days. RESULTS: Parallel multivariate analyses revealed that a higher level of community mobility prior to hospitalization and higher mobility ability status on admission were common predictors of a higher number of in-hospital steps, whereas the longer length of hospital stay was significantly correlated with a lower number of steps in both samples. The risk of malnutrition on admission was associated with a lower number of steps, but only in the Israeli sample. CONCLUSIONS: Despite different assessment methods, older adults' low in-hospital mobility has similar risk factors in Israel and Denmark. Pre-hospitalization and admission mobility ability are robust and constant risk factors across the two studies. This information can encourage the development of both international standard risk evaluations and tailored country-based approaches.

Comparison of convolutional neural networks for classification of vocal fold nodules from high-speed video images.

OBJECTIVES: Deep learning is in this study used through convolutional neural networks (CNN) to the determination of vocal fold nodules. Through high-speed video (HSV) images and computer-assisted tools, a comparison of convolutional neural network models and their accuracy will be presented. METHODS: The data have been collected by an Ear Nose Throat (ENT) specialist with a 90° rigid scope in the years from 2007 to 2019, where 15.732 high-speed videos have been collected from 7909 patients. A total of 4000 images have been carefully selected, 2000 images were of normal vocal folds and 2000 images were of vocal folds with varying degrees of vocal fold nodules. These images were then split into training-, validation-, and testing-data set, for use with a CNN model with 5 layers (CNN5) and compared to other models: VGG19, MobileNetV2, and Inception-ResNetV2. To compare the neural network models, the following evaluation metrics have been calculated: accuracy, sensitivity, specificity, precision, and negative predictive values. RESULTS: All the trained CNN models have shown high accuracy when applied to the test set. The accuracy is 97.75%, 83.5%, 91.5%, and 89.75%, for CNN5, VGG19, MobileNetV2, and InceptionResNetV2, respectively. CONCLUSIONS: Precision was identified as the most relevant performance metric for a study that focuses on the classification of vocal fold nodules. The highest performing model was MobilNetV2 with a precision of 97.7%. The average accuracy across all 4 neural networks was 90.63% showing that neural networks can be used for classifying vocal fold nodules in a clinical setting.

Three months of melatonin treatment reduces insulin sensitivity in patients with type 2 diabetes-A randomized placebo-controlled crossover trial.

The use of the sleep-promoting hormone melatonin is rapidly increasing as an assumed safe sleep aid. During the last decade, accumulating observations suggest that melatonin affects glucose homeostasis, but the precise role remains to be defined. We investigated the metabolic effects of long-term melatonin treatment in patients with type 2 diabetes including determinations of insulin sensitivity and glucose-stimulated insulin secretion. We used a double-blinded, randomized, placebo-controlled, crossover design. Seventeen male participants with type 2 diabetes completed (1) 3 months of daily melatonin treatment (10 mg) 1 h before bedtime (M) and (2) 3 months of placebo treatment 1 h before bedtime (P). At the end of each treatment period, insulin secretion was assessed by an intravenous glucose tolerance test (0.3 g/kg) (IVGTT) and insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp (insulin infusion rate 1.5 mU/kg/min) (primary endpoints). Insulin sensitivity decreased after melatonin (3.6 [2.9-4.4] vs. 4.1 [3.2-5.2] mg/(kg × min), p = .016). During the IVGTT, the second-phase insulin response was increased after melatonin (p = .03). In conclusion, melatonin treatment of male patients with type 2 diabetes for 3 months decreased insulin sensitivity by 12%. Clinical use of melatonin treatment in dosages of 10 mg should be reserved for conditions where the benefits will outweigh the potential negative impact on insulin sensitivity.

Solid-phase synthesis and biological evaluation of piperazine-based novel bacterial topoisomerase inhibitors.

There is an emerging global need for new and more effective antibiotics against multi-resistant bacteria. This situation has led to massive industrial investigations on novel bacterial topoisomerase inhibitors (NBTIs) that target the vital bacterial enzymes DNA gyrase and topoisomerase IV. However, several of the NBTI compound classes have been associated with inhibition of the hERG potassium channel, an undesired cause of cardiac arrhythmia, which challenges medicinal chemistry efforts through lengthy synthetic routes. We herein present a solid-phase strategy that rapidly facilitates the chemical synthesis of a promising new class of NBTIs. A proof-of-concept library was synthesized with the ability to modulate both hERG affinity and antibacterial activity through scaffold substitutions.

Variations in physical activity and sedentary behavior during and after hospitalization in acutely admitted older medical patients: a longitudinal study.

BACKGROUND: Inactivity is frequent among older patients during hospitalization. It is unknown how patients' daily activity pattern (diurnal profile) vary between hospitalization and after discharge. This study aims to describe and compare the distribution of physical activity and sedentary behavior in acutely hospitalized older patients during hospitalization and after discharge. METHODS: We included data on 80 patients (+65 years) admitted with acute medical illness from the STAND-Cph trial. Physical activity and sedentary behavior were measured as daily number of steps, uptime (walking/standing) and sedentary behavior (lying/sitting) with an activity monitor (activPAL3, PAL Technologies Ltd). The patients wore the monitor for three periods of one week: during hospitalization, after discharge, and four weeks after discharge. RESULTS: The patients' median age was 80 years [IQR: 75;88], 68% were female and the median De Morton Mobility Index (DEMMI) was 57 [IQR: 48;67]. The daily median uptime was 1.7 h [IQR: 1;2.8] during hospitalization, 4.0 h [IQR: 2.7;5.4] after discharge and 4.0 h [IQR: 2.8;5.8] four weeks after discharge. The daily median number of steps was 728 [IQR: 176;2089], 2207 [IQR: 1433;3148], and 2622 [IQR: 1714;3865], respectively, and median daily sedentary behavior was 21.4 h (IQR: 20.7;22.4), 19.5 h (IQR: 18.1;21.0) and 19.6 h (IQR: 18.0;20.8), respectively. During hospitalization, a small activity peak was observed between 9-11 AM without any notable variation after. At discharge and four weeks after discharge, a peak in physical activity was seen between 9-12 AM and at 5 PM. CONCLUSION: Older hospitalized patients spend most of their time being sedentary with their highest activity between 9-11 AM. Daily activity doubles after discharge with one extra peak in the afternoon. Daily routines might be disrupted, and older patients have the potential to be more physically active during hospitalization. Interventions that encourage physical activity during hospitalization are warranted.

Co-designing implementation strategies for the WALK-Cph intervention in Denmark aimed at increasing mobility in acutely hospitalized older patients: a qualitative analysis of selected strategies and their justifications.

BACKGROUND: Selecting appropriate strategies to target barriers to implementing interventions represents a considerable challenge in implementation research and practice. The aim was to investigate what categories of implementation strategies were selected by health care practitioners and their managers in a co-design process and how they justified these strategies aimed at facilitating the implementation of the WALK-Cph intervention. METHODS: The study used a qualitative research design to explore what implementation strategies were selected and the justifications for selecting these strategies. Workshops were used because this qualitative method is particularly well suited for studying co-design processes that involve substantial attention to social interaction and the context. Data were 1) analyzed deductively based on the Proctor et al. taxonomy of implementation strategies, 2) categorized in accordance with the ERIC compilation of implementation strategies by Powell et al., and 3) analyzed to examine the justification for the selected strategies by the Proctor et al. framework for justifications of implementation strategies. RESULTS: Thirteen different types of implementation strategies were chosen across two hospitals. The deductive analysis showed that selection of implementation strategies was based on pragmatic and theoretical justifications. The contents of the two types of justifications were thematized into nine subthemes. CONCLUSION: This study contributes with knowledge about categories and justification of implementation strategies selected in a co-design process. In this study, implementation strategies were selected through pragmatic and theoretical justifications. This points to a challenge in balancing strategies based on practice-based and research-based knowledge and thereby selection of strategies with or without proven effectiveness.

Cost-effectiveness of a transdiagnostic psychotherapy program for youth with common mental health problems.

OBJECTIVES: Our objective was to evaluate the cost-effectiveness of the transdiagnostic psychotherapy program Mind My Mind (MMM) for youth with common mental health problems using a cost-utility analysis (CUA) framework and data from a randomized controlled trial. Furthermore, we analyzed the impact of the choice of informant for both quality-of-life reporting and preference weights on the Incremental Cost-Effectiveness Ratio (ICER). METHODS: A total of 396 school-aged (6-16 years) youth took part in the 6-month trial carried out in Denmark. CUAs were carried out for the trial period and four one-year extrapolation scenarios. Costs were based on a combination of budget and self-reported costs. Youths and parents were asked to report on the youth's quality-of-life three times during the trial using the Child Health Utility 9D (CHU9D). Parental-reported CHU9D was used in the base case together with preference weights of a youth population. Analyses using self-reported CHU9D and preference weights of an adult population were also carried out. RESULTS: The analysis of the trial period resulted in an ICER of €170,465. The analyses of the one-year scenarios resulted in ICERs between €23,653 and €50,480. The ICER increased by 24% and 71% compared to the base case when using self-reported CHU9D and adult preference weights, respectively. CONCLUSION: The MMM intervention has the potential to be cost-effective, but the ICER is dependent on the duration of the treatment effects. Results varied significantly with the choice of informant and the choice of preference weights indicating that both factors should be considered when assessing CUA involving youth.

Systematic identification and stratification of help-seeking school-aged youth with mental health problems: a novel approach to stage-based stepped-care.

We investigated whether a novel visitation model for school-aged youth with mental health problems based on a stage-based stepped-care approach facilitated a systematic identification and stratification process without problems with equity in access. The visitation model was developed within the context of evaluating a new transdiagnostic early treatment for youth with anxiety, depressive symptoms, and/or behavioural problems. The model aimed to identify youth with mental health problems requiring an intervention, and to stratify the youth into three groups with increasing severity of problems. This was accomplished using a two-phase stratification process involving a web-based assessment and a semi-structured psychopathological interview of the youth and parents. To assess problems with inequity in access, individual-level socioeconomic data were obtained from national registers with data on both the youth participating in the visitation and the background population. Altogether, 573 youth and their parents took part in the visitation process. Seventy-five (13%) youth had mental health problems below the intervention threshold, 396 (69%) were deemed eligible for the early treatment, and 52 (9%) had symptoms of severe mental health problems. Fifty (9%) youth were excluded for other reasons. Eighty percent of the 396 youth eligible for early treatment fulfilled criteria of a mental disorder. The severity of mental health problems highlights the urgent need for a systematic approach. Potential problems in reaching youth of less resourceful parents, and older youth were identified. These findings can help ensure that actions are taken to avoid equity problems in future mental health care implementations.

Clinical feasibility and impact of fully automated multiparametric PET imaging using direct Patlak reconstruction: evaluation of 103 dynamic whole-body 18F-FDG PET/CT scans.

PURPOSE: Functional imaging by standard whole-body (WB) 18F-flurodeoxyglucose (FDG) positron emission tomography (PET) is an integrated part of disease diagnostics. Recently, a clinical dynamic whole-body (D-WB) FDG PET/CT scanning protocols has been developed allowing for quantitative imaging of tissue metabolic rate of FDG (MRFDG). It was the purpose of this retrospective study to evaluate whether MRFDG imaging is feasible in a clinical setting and whether it improves lesion detectability. METHODS: One hundred nine patients representing a broad range of referral indications for FDG PET/CT were invited to undergo a D-WB FDG PET/CT scan. Two sets of images were produced: parametric images and standard static SUV images. Both sets of images were reviewed visually, and 310 individual lesions were quantitatively analysed using the target-to-background (TBR) and contrast-to-noise (CNR) metrics. RESULTS: One hundred three out of 109 patients completed the D-WB FDG PET/CT scan. There was no difference in the number of pathological lesions identified visually on the MRFDG and the SUV images, whereas MRFDG images yielded 4 fewer false positives than the SUV images. Quantitatively, MRFDG TBR was significantly higher than SUV TBR in 299/310 lesions, and better MRFDG CNR was found to facilitate the challenging reading of lesions with low SUV TBR. CONCLUSION: D-WB FDG PET/CT is feasible in a clinical setting and produces MRFDG images of good visual quality and superior lesion contrast. In addition, MRFDG images complement the standard SUV images providing better quantification and enhanced image reading. However, although MRFDG also reduced the number of false-positive findings, no additional malignant lesions were identified. The technique therefore appears to be best suited for select patient groups or possibly treatment response evaluation.

High-grade B-cell lymphomas with MYC and BCL2 translocations lack tumor-associated macrophages and PD-L1 expression: A possible noninflamed subgroup.

We investigated the intratumoral source of PD-L1 expression and the infiltration of tumor-associated macrophages (TAMs) in large B-cell lymphomas (LBCLs) with or without MYC-translocation, as well as possible correlations to BCL2-and BCL6-translocations and cell of origin (COO). One-hundred and twenty-six patient samples were studied in a cohort enriched for MYC-translocated tumors with 34 samples carrying this translocation. Demonstration of intratumoral distribution and cellular source of PD-L1 was enabled by immunohistochemical (IHC) dual staining specifically highlighting PD-L1 expression in lymphoma B-cells with antibodies against PD-L1 and PAX5. Additional IHC with antibodies against CD68 and CD163 identified TAMs. We found that CD68-positive TAMs were the main source of PD-L1 protein expression in contrast to lymphoma B cells which rarely expressed PD-L1. Semiquantitative IHC demonstrated a significant correlation between CD68 and PD-L1 protein expression. Unsupervised hierarchical analysis of PD-L1, CD68, and CD163 IHC data subsequently demonstrated three potential clusters defined by expression of the three biomarkers. Cluster A consisted of patient samples with significantly lower expression of PD-L1, CD68, and CD163, but also significantly higher prevalence of BCL2-translocation and MYC-BCL2-double-hit (DH) compared to the other two clusters. In cluster C we found a significant accumulation of BCL6 translocated tumors. This cluster in contrast had the highest protein expression of PD-L1, CD68, and CD163. Cluster B tumors had an intermediate expression of the three biomarkers, but no accumulation of the specific genetic translocations. Our data, which were based on morphological analysis, immunophenotyping and genotyping by fluorescence in situ hybridization were in line with new concepts of LBCL taxonomy integrating genetic, phenotypical, and immunological characteristics with identification of new subgroups where MYC translocation and MYC-BCL2 DH may identify a noninflamed subtype. These findings may furthermore hold significant predictive value especially regarding immune checkpoint blockade therapy, but further molecular characterization should be done to substantiate this hypothesis.

Neonatal jaundice and autism spectrum disorder: a systematic review and meta-analysis.

BACKGROUND: Two meta-analyses concluded that jaundice was associated with an increased risk of autism. We hypothesize that these findings were due to methodological limitations of the studies included. Neonatal jaundice affects many infants and risks of later morbidity may prompt physicians towards more aggressive treatment. METHODS: To conduct a systematic literature review and a meta-analysis of the association between neonatal jaundice and autism with particular attention given to low risk of bias studies. Pubmed, Scopus, Embase, Cochrane, and Google Scholar were searched for publications until February 2019. Data was extracted by use of pre-piloted structured sheets. Low risk of bias studies were identified through predefined criteria. RESULTS: A total of 32 studies met the inclusion criteria. The meta-analysis of six low risk of bias studies showed no association between neonatal jaundice and autism; cohort studies risk ratio 1.09, 95% CI, 0.99-1.20, case-control studies odds ratio 1.29 95% CI 0.95, 1.76. Funnel plot of all studies suggested a high risk of publication bias. CONCLUSIONS: We found a high risk of publication bias, selection bias, and potential confounding in all studies. Based on the low risk of bias studies there was no convincing evidence to support an association between neonatal jaundice and autism. IMPACT: Meta-analysis of data from six low risk of bias studies indicated no association between neonatal jaundice and autism spectrum disorder. Previous studies show inconsistent results, which may be explained by unadjusted confounding and selection bias. Funnel plot suggested high risk of publication bias when including all studies. There is no evidence to suggest jaundice should be treated more aggressively to prevent autism.

Adaptations and modifications to a co-designed intervention and its clinical implementation: a qualitative study in Denmark.

BACKGROUND: There is a long-standing debate in implementation research on whether adaptations to evidence-based interventions (EBIs) are desirable in health care. If an intervention is adapted and not delivered as conceived and planned, it is said to have low fidelity. The WALK-Cph project was developed based on the assumption that involving stakeholders in co-design processes would facilitate the fidelity of an intervention to increase the mobility of acutely admitted older medical patients and its implementation in two hospitals in Denmark. The purpose of this study is to describe and analyse adaptations and modifications that were made to the co-designed WALK-Cph intervention and its implementation. METHODS: This study used a qualitative design. An ethnographic field study was performed using participant observations, workshops and semi-structured interviews. Data were analysed twice using the Framework Method. The first analysis was based on the frameworks from Stirman, Moore and Proctor. The second analysis, a retrospective modifications analysis, was based on the Adaptation-Impact Framework. RESULTS: Many different types of adaptations and modifications were made to the WALK-Cph intervention and its implementation plan. Most of the modifications were made on the contents of the intervention. In total, 44 adaptations and modifications were made, of which 21 were planned (adaptations) and 23 were made haphazardly (modifications). Most of the content and context adaptations and modifications made on the intervention had a mixed result regarding enhanced fidelity. The retrospective modifications analysis showed that modifications were ongoing and both situationally and contextually shaped. CONCLUSIONS: Although an extensive co-design process was carried out to facilitate the fidelity of the WALK-Cph intervention, this study showed that many adaptations and modifications were still made to both the intervention and its implementation plan. It could indicate that the co-design process had a small effect or that adaptations and modifications are ongoing and both situationally and contextually shaped, which challenge the assumption and the desire to be able to plan and control changes.