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Necrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model. NEC was induced in newborn Sprague-Dawley rat pups for 4 days via formula feeding, hypoxia, and LPS. NEC pups received intraperitoneal (ip) injections of either saline or hPSC (NEC-hPSC) at 32 and 56 h into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum were assessed. Breastfed (BF) littermates were used as controls. NEC pups developed significant bowel dilation and fragility in the ileum. Further, NEC induced loss of normal villi-crypt morphology, disruption of epithelial proliferation and apoptosis, and loss of critical progenitor/stem cell and Paneth cell populations in the crypt. hPSC treatment improved macroscopic intestinal health with reduced ileal dilation and fragility. Histologically, hPSC administration had a significant reparative effect on the villi-crypt morphology and epithelium. In addition to a trend of decreased inflammatory marker expression, hPSC-NEC pups had increased epithelial proliferation and decreased apoptosis when compared with NEC littermates. Further, the intestinal stem cell and crypt niche that include Paneth cells, SOX9(+) cells, and LGR5(+) stem cells were restored with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage. NEW & NOTEWORTHY These studies demonstrate a human placental-derived stem cell (hPSC) therapeutic strategy for necrotizing enterocolitis (NEC). In an experimental model of NEC, hPSC administration improved macroscopic intestinal health, ameliorated epithelial morphology, and supported the intestinal stem cell niche. Our data suggest that hPSC are a potential therapeutic approach to attenuate established intestinal NEC damage. Further, we show hPSC are a novel research tool that can be utilized to elucidate critical neonatal repair mechanisms to overcome NEC.

Parkinson’s disease (PD) is one of the most common neurodegenerative disease, and is so far not considered curable. PD patients suffer from several motor and non-motor symptoms, including gastrointestinal dysfunctions and alterations of the enteric nervous system. Constipation and additional intestinal affections can precede the classical motor symptoms by several years. Recently, we reported effects of PD and related medications on the faecal bacterial community of 34 German PD patients and 25 age-matched controls. Here, we used the same collective and analysed the V6 and V7 hypervariable region of PCR-amplified, eukaryotic 18S rRNA genes using an Illumina MiSeq platform. In all, 53% (18) of the PD samples and 72% (18) of the control samples yielded sufficient amplicons for downstream community analyses. The PD samples showed a significantly lower alpha and a different beta eukaryotic diversity than the controls. Most strikingly, we observed a significantly higher relative abundance of sequence affiliated with the Geotrichum genus in the PD samples (39.7%), when compared to the control samples (0.05%). In addition, we observed lower relative abundances of sequences affiliated with Aspergillus/Penicillium, Charophyta/Linum, unidentified Opisthokonta and three genera of minor abundant zooflagellates in the PD samples. Our data add knowledge to the small body of data about the eukaryotic microbiota of PD patients and suggest a potential association of certain gut eukaryotes and PD.

To assess feasibility of a novel video directly observed therapy (DOT)-based digital asthma program intended to support correct inhaled corticosteroid (ICS) use among children. We conducted a 60-day pilot study among patients 2–18 years attending a primary care clinic with prescribed ICS and sub-optimally controlled asthma (recent hospitalization, ICS nonadherence, frequent rescue inhaler use, therapy escalation, or Asthma Control Test n = 247) and adherence issues (n = 107) prompted 543 communications; inadequate inspiration or holding breath were most common. Among 16 patients with engagement >7 days and >4 videos, median inhaler error rate (proportion of videos with ≥1 error) decreased from week 1 to week 2 (73% vs 8%, p ≤ 0.05) with median adherence >80%. Participants experienced the program as long, but easy to use; benefits included building routines, skill, and independence. This pilot study suggests high program acceptability among our cohort. High engagement with improved inhaler technique over the first 14 days suggests shorter implementation. Supplemental data for this article is available online at at

Eye diseases have a negative impact on the eyesight quality of the world population. The age-related macular degeneration (AMD) draws special attention since it is a chronic disorder characterized ...

Precision medicine has provided new perspectives in oncology, yielding research on the use of targeted therapies across different tumor types, regardless of their site of origin, a concept known as tissue-agnostic indication. Since 2017, the Food and Drug Administration (FDA) has approved the use of three different agents for tumor-agnostic treatment: pembrolizumab (for patients with microsatellite instability or high tumor mutational burden) and larotrectinib and entrectinib (both for use in patients harboring tumors with NTRK fusions). Importantly, the genomic alterations targeted by these agents are uncommon or rare in breast cancer, and little information exists regarding their efficacy in advanced breast cancer. In this review, we discuss the prevalence of these targets in breast cancer, their detection methods, the clinical characteristics of patients whose tumors have these alterations, and available data regarding the efficacy of these agents in breast cancer.

In der supportiven Onkologie werden zunehmend Verfahren aus dem Bereich der Naturheilkunde erganzend eingesetzt, um Nebenwirkungen zu lindern. Dieser Artikel beschreibt am Beispiel der oralen Mukositis, welche naturheilkundlichen Therapien sich in der Praxis bewahrt haben. In supportive oncology, methods from the field of naturopathy are increasingly being used to alleviate side effects. Using the example of oral mucositis, this article describes which naturopathic therapies have been successfully proven in practice.

Naming of nouns and verbs can be selectively impaired in neurological disorders, but the specificity of the neural and cognitive correlates of such dissociation remains unclear. Functional imaging and stroke research sought to identify cortical regions selectively recruited for nouns versus verbs, yet findings are inconsistent. The present study investigated this issue in neurodegenerative diseases known to selectively affect different brain networks, thus providing new critical evidence of network specificity. We examined naming performances on nouns and verbs in 146 patients with different neurodegenerative syndromes (Primary Progressive Aphasia - PPA, Alzheimer's disease - AD, and behavioral variant Frontotemporal Dementia - FTD) and 30 healthy adults. We then correlated naming scores with MRI-derived cortical thickness values as well as with performances in semantic and syntactic tasks, across all subjects. Results indicated that patients with the semantic variant PPA named significantly fewer nouns than verbs. Instead, nonfluent/agrammatic PPA patients named fewer verbs than nouns. Across all subjects, performance on nouns (adjusted for verbs) specifically correlated with cortical atrophy in left anterior temporal regions, and performance on verbs (adjusted for nouns) with atrophy in left inferior and middle frontal, inferior parietal and posterior temporal regions. Furthermore, lower lexical-semantic abilities correlated with deficits in naming both nouns and verbs, while lower syntactic abilities only correlated with naming verbs. Our results show that different neural and cognitive mechanisms underlie naming of specific grammatical categories in neurodegenerative diseases. Importantly, our findings showed that verb processing depends on a widespread perisylvian networks, suggesting that some regions might be involved in processing different types of action knowledge. These findings have important implications for early differential diagnosis of neurodegenerative disorders.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome caused by either TSC1 or TSC2 gene mutations. About 15% of TSC patients remain without genetic diagnosis by conventional analysis despite clinical evidence. It is important to identify somatic mosaics, as therapeutic options are now available in patients with TSC1 or TSC2 mutations. Here, we describe the clinical and genetic characteristics of four male TSC patients with low-level mosaicism. Patients presented at ages between 9 months and 32 years. Clinical manifestations varied considerably and included brain lesions in all four patients, cardiac rhabdomyomas in two young patients, skin involvement in two patients, and retinal hamartomas and renal angiomyolipomas in three patients. One patient presented with epileptic seizures and psychomotor delay. Low levels of mosaicism for TSC1 or TSC2 mutation were found in different tissue samples employing next generation sequencing and multiple ligation-dependent probe amplification. The five disease-associated variants, including one second-hit mutation, include three truncating mutations and one deletion in TSC2, and one truncating mutation in TSC1. Sanger sequencing, allele-specific oligonucleotide PCR (ASO-PCR), and droplet digital PCR were used to confirm and quantify the disclosed mutations. Genetic identification of low-level mosaicism for TSC remains challenging but is important for optimal surveillance and management.

Infectious agents can trigger autoimmune responses in a number of chronic inflammatory diseases. Lyme arthritis, which is caused by the tick-transmitted spirochaete Borrelia burgdorferi, is effectively treated in most patients with antibiotic therapy; however, in a subset of patients, arthritis can persist and worsen after the spirochaete has been killed (known as post-infectious Lyme arthritis). This Review details the current understanding of the pathogenetic events in Lyme arthritis, from initial infection in the skin, through infection of the joints, to post-infectious chronic inflammatory arthritis. The central feature of post-infectious Lyme arthritis is an excessive, dysregulated pro-inflammatory immune response during the infection phase that persists into the post-infectious period. This response is characterized by high amounts of IFNγ and inadequate amounts of the anti-inflammatory cytokine IL-10. The consequences of this dysregulated pro-inflammatory response in the synovium include impaired tissue repair, vascular damage, autoimmune and cytotoxic processes, and fibroblast proliferation and fibrosis. These synovial characteristics are similar to those in other chronic inflammatory arthritides, including rheumatoid arthritis. Thus, post-infectious Lyme arthritis provides a model for other chronic autoimmune or autoinflammatory arthritides in which complex immune responses can be triggered and shaped by an infectious agent in concert with host genetic factors.

Singleton-Merten syndrome (SMS) is a type I interferonopathy. In this report, we disclose the first-to the best of our knowledge-direct association of SMS with femoral head necrosis (FHN). The following case report presents the condition of a 38-year-old male suffering from SMS with FHN, characterized by acute symptoms and rapid disease progression. As per the recommendations of the Association Research Circulation Osseous (ARCO) and the S3-guidelines, we successfully treated the FHN with core decompression. Our histological results correlate with the changes described in medical literature in patients with SMS and MDA5-knockout in vivo experiments such as osteopenia, widened medullary cavity, and thin cortical bone. Moreover, the conducted immunohistochemistry shows strong CD56 positivity of the osteoblasts and osteocytes, as well as significant CD68 and CD163 positivity of the middle-sized osteoclasts. Collectively, these findings suggest an underlying syndrome in the FHN. A six-month post-operative follow-up revealed complete recovery with the absence of the initial symptoms and ability to resume normal daily activities. Taken together, our findings suggest that SMS is an additional cause of FHN in young adults. Early detection and adequate treatment using well-established joint-preserving techniques demonstrate a favorable improvement of the patient's clinical condition.

Background Asymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression. Objectives The objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naive PD. Methods From the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data. Results At baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time. Conclusions These findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

Purpose: To determine whether clinician-led immunization education with immediate onsite vaccination availability will increase pneumococcal immunizations during specialty care. Methods: We designed a controlled before and after QI project quasi-experimental design to retrospectively evaluate the QI effectiveness. The QI setting included two clinics. Clinic #1 was a part of the county hospital system and offered comprehensive care. Clinic #2 was a university clinic that hosted a private practice and a dermatology resident continuity clinic. 201 patients with planned or existing immunosuppressive medication regimens attending an initial or follow-up dermatology visit participated in the study. The intervention included clinician provided verbal immunization recommendations. Patients were then given the opportunity for immediate immunization. The main measure of outcome was pneumococcal immunization status after QI intervention. Results: Our analysis included 201 patients with planned or existing immunosuppressive medication regimens attending an initial or follow-up dermatology visit (aged 0-64 years [82.1%] ,aged ≥65 years [17.9%]; male [34.3%] female [65.6%%]). Of these, 146 [72.6%] were in the QI group and 55 [27.4%] in the comparison group. Our unadjusted analyses identified no significant group differences in immunization status at initial observation (p=0.329; Table 1). Of the 102 patients in the QI group with no pneumococcal immunizations at initial observation, 80.4% (95% CI: 71.4%, 87.1%) received at least one pneumonia vaccination by the final observation. For the 27 patients in the QI group with partial immunization at project initiation, 85.2% (95% CI: 65.9%, 94.5%) received at least one pneumonia vaccination. Overall, 81.4% (95% CI: 73.6, 87.3) of patients in the QI group without full immunization at initial observation received at least one vaccination by the final observation. Conclusion: These data demonstrate that immunization coverage in patients on immunosuppressive medications can be markedly improved by clinician recommendation with immediate availability of the pneumococcal vaccine during specialty care. Wider adoption of this model and its adaptation to other immunizations and settings is an important opportunity to reduce vaccine-preventable illness, including COVID-19, and improve population health.

Purpose A previously published predictive model based on threshold parameters for erythrocyte sedimentation rate, c-reactive protein, and platelet count demonstrated that 40% of patients who underwent biopsy may not have required it. The current study was performed to evaluate the model's performance on an independent data set. Methods This is a retrospective consecutive series of patients undergoing temporal artery biopsy (TAB) in a single health region in Canada. The model was applied to a multicenter cohort of patients undergoing TAB by a variety of surgical services. A centralized pathological database serving multiple institutions and surgical services was used to identify patients undergoing TAB. Results Over a 7-year period, patients undergoing TAB were identified via a central pathological database. Those who had concurrent illnesses which would likely affect erythrocyte sedimentation rate, c-reactive protein, and platelet count, patients on steroids for >2 weeks by the time of biopsy, and those with missing serum markers were excluded. The previously developed model was applied to the 222 patients enrolled. The model correctly identified 29% of patients with a pretest probability of 0% for a positive biopsy and 9% with a pretest probability of 100%, suggesting that in total, 38% of patients could have avoided TAB. Conclusion The results of this independent data set support the previously published predictive formula. Utilizing a simple, clinically applicable predictive model of the pretest probabilities, approximately 38% of TAB currently being performed may be avoided. The results suggest that evaluation with a prospective multicentre study would be appropriate.

Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6–4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3–3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but—despite previously published data from cell culture models—does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.

Ann-Kathrin Rahm,1– 3 Dominik Gramlich,1– 3 Teresa Wieder,1,2 Mara Elena Müller,1– 3 Axel Schoeffel,1,2 Fadwa A El Tahry,1 Patrick Most,1,2 Tanja Heimberger,1,3 Steffi Sandke,1,3 Tanja Weis,1,3 Nina D Ullrich,4 Thomas Korff,4,5 Patrick Lugenbiel,1– 3 Hugo A Katus,1– 3 Dierk Thomas1– 3 1Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, 69120, Germany; 2HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Heidelberg, 69120, Germany; 3DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, 69120, Germany; 4Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Heidelberg, 69120, Germany; 5European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, GermanyCorrespondence: Dierk ThomasDepartment of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, 69120, GermanyTel +49 6221 568855Fax +49 6221 565514Email dierk.thomas@med.uni-heidelberg.deAim: Effective antiarrhythmic treatment of atrial fibrillation (AF) constitutes a major challenge, in particular, when concomitant heart failure (HF) is present. HF-associated atrial arrhythmogenesis is distinctly characterized by prolonged atrial refractoriness. Small-conductance, calcium-activated K+ (KCa, SK, KCNN) channels contribute to cardiac action potential repolarization and are implicated in AF susceptibility and therapy. The mechanistic impact of AF/HF-related triggers on atrial KCa channels is not known. We hypothesized that tachycardia, stretch, β-adrenergic stimulation, and hypoxia differentially determine KCa 2.1– 2.3 channel remodeling in atrial cells.Methods: KCNN1-3 transcript levels were assessed in AF/HF patients and in a pig model of atrial tachypacing-induced AF with reduced left ventricular function. HL-1 atrial myocytes were subjected to proarrhythmic triggers to investigate the effects on Kcnn mRNA and KCa channel protein.Results: Atrial KCNN1-3 expression was reduced in AF/HF patients. KCNN2 and KCNN3 suppression was recapitulated in the corresponding pig model. In contrast to human AF, KCNN1 remained unchanged in pigs. Channel- and stressor-specific remodeling was revealed in vitro. Lower expression levels of KCNN1/KCa 2.1 were linked to stretch and β-adrenergic stimulation. Furthermore, KCNN3/KCa 2.3 expression was suppressed upon tachypacing and hypoxia. Finally, KCNN2/KCa 2.2 abundance was specifically enhanced by hypoxia.Conclusion: Reduction of KCa 2.1– 2.3 channel expression might contribute to the action potential prolongation in AF complicated by HF. Subtype-specific KCa 2 channel remodeling induced by tachypacing, stretch, β-adrenergic stimulation, or hypoxia is expected to differentially determine atrial remodeling, depending on patient-specific activation of each triggering factor. Stressor-dependent KCa 2 regulation in atrial myocytes provides a starting point for mechanism-based antiarrhythmic therapy.Keywords: atrial fibrillation, calcium, KCa channel, KCNN, remodeling, SK channel

Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in presymptomatic mutation carriers. A 5-nucleotide sequence motif (GDCGG; D = G, A or U) was strongly enriched in these ALS-related microRNAs. We hypothesized that deregulation of protein(s) binding predominantly to this consensus motif was responsible for the ALS-linked microRNA fingerprint. Using microRNA pull-down assays combined with mass spectrometry followed by extensive biochemical validation, all members of the fragile X protein family, FMR1, FXR1 and FXR2, were identified to directly and predominantly interact with GDCGG microRNAs through their structurally disordered RGG/RG domains. Preferential association of this protein family with ALS-related microRNAs was confirmed by in vitro binding studies on a transcriptome-wide scale. Immunohistochemistry of lumbar spinal cord revealed aberrant expression level and aggregation of FXR1 and FXR2 in C9orf72- and FUS-linked familial ALS, but also patients with sporadic ALS. Further analysis of ALS autopsies and induced pluripotent stem cell-derived motor neurons with FUS mutations showed co-aggregation of FXR1 with FUS. Hence, our translational approach was able to take advantage of blood microRNAs to reveal CNS pathology, and suggests an involvement of the fragile X-related proteins in familial and sporadic ALS already at a presymptomatic stage. The findings may uncover disease mechanisms relevant to many patients with ALS. They furthermore underscore the systemic, extra-CNS aspect of ALS., Freischmidt et al. show direct interaction of fragile X proteins with a subset of microRNAs that share a common sequence motif and that are downregulated in the majority of patients with ALS. Neuropathology suggests contribution of the fragile X proteins to a convergent disease mechanism implicated in many cases of ALS.

ZusammenfassungDas undifferenzierte pleomorphe Sarkom („undifferentiated pleomorphic sarcoma“ [UPS]) gehört zur Gruppe der Weichteilsarkome und macht fast 10 % aller Weichteilsarkome aus. Der Fall eines 49-jährigen Patienten wird vorgestellt, bei dem die kompartmentorientierte Resektion eines primären UPS im linken Musculus gluteus maximus mit adjuvanter Radiotherapie (60 Gy) durchgeführt wurde. Im Rahmen der Tumornachsorge (3 Jahre später) wurde eine lokoregionäre Metastase an einer ungewöhnlichen Lokalisation im M. quadratus femoris festgestellt, welche mittels einer In-toto-Resektion mit intraoperativer Radiotherapie (10 Gy) behandelt wurde. Der intra- und postoperative Verlauf gestalten sich komplikationslos ohne neurologische Defizite. Im Rahmen der Nachtuntersuchung 6 Monate postoperativ war der Patient tumor- und beschwerdefrei.

Emphysema-like-change of lung is one aspect of lung morbidity in children after congenital diaphragmatic hernia (CDH). This study aims to evaluate if the extent of reduced lung density can be quantified through pediatric chest CT examinations, if side differences are present and if emphysema-like tissue is more prominent after CDH than in controls. Thirty-seven chest CT scans of CDH patients (mean age 4.5 ± 4.0 years) were analyzed semi-automatically and compared to an age-matched control group. Emphysema-like-change was defined as areas of lung density lower than − 950 HU in percentage (low attenuating volume, LAV). A p-value lower than 0.05 was regarded as statistically significant. Hypoattenuating lung tissue was more frequently present in the ipsilateral lung than the contralateral side (LAV 12.6% vs. 5.7%; p 0.05), LAV in ipsilateral (p = 0.0002), but not in contralateral lung (p = 0.54), was higher in CDH than control. It is feasible to quantify emphysema-like-change in pediatric patients after CDH. In the ipsilateral lung, low-density areas are much more frequently present both in comparison to contralateral and to controls. Especially the ratio of LAV ipsilateral/contralateral seems promising as a quantitative parameter in the follow-up after CDH.

BackgroundLargest basal diameter (LBD) appears to have independent prognostic value in uveal melanoma (UM).MethodsAll patients undergoing plaque brachytherapy or enucleation for UM involving the choroid and/or ciliary body between 2012 and 2019.ResultsA total of 348 patients with a mean age of 60±14 years were included and followed for a mean of 40±26 months (3.3±2.2 years). On multivariate analysis, LBD >12 mm remained a significant independent predictor of metastasis for both class 1 (HR 21.90; 95% CI 2.69 to 178.02; p=0.004) and class 2 (HR 2.45; 95% CI, 1.03 to 5.83; p=0.04) tumours. Four prognostic groups were created: group 1 (class 1, LBD ConclusionsCombination of GEP and LBD allows separation of patients into four easy-to-use prognostic groups and was similar to a model combining AJCC stage with GEP.

Introduction Premenopausal women with intermediate-high risk HR+ breast cancer often receive near-complete estrogen deprivation with ovarian function suppression concurrent with an AI. Hypoestrogenemia is associated with cardiotoxicity, but the cardiovascular impact of this newer breast cancer treatment is largely unknown. With increases in survival rates and younger women being diagnosed, methods to monitor and predict cardiac damage due to OFS+AI therapy are needed. Left ventricle (LV) ejection fraction is currently used for monitoring cancer treatment-related cardiovascular degradation, and can detect major heart defects, but is insensitive to subclinical left ventricle function. Emerging methods include T1 mapping and estimation of myocardial strain to indicate fibrosis. We propose an extension of these methods by estimating cardiac tissue elasticity using LV wall deformation to drive a biomechanical model. Elasticity is a more functional and direct measurement of tissue response based on structural mechanics driven by patient-specific cardiac magnetic resonance imaging (CMR) data. Elasticity measurements may serve as a predictive biomarker of early AI-induced cardiac changes.MethodsThis study is a retrospective initial proof-of-concept correlative imaging study to an existing clinical study for the use of CMR to detect cardiovascular damage (ESPRIT). Two cohorts of premenopausal breast cancer patients either: (1) undergoing OFS+AI for HR+ breast cancer or (2) triple negative breast cancer (TNBC) patients that have already received chemotherapy, were imaged twice, 3-6 months apart using CINE CMR. TNBC patients serve as the control, with no expectation of further cancer treatment-related cardiac damage. Time steps during passive ventricular diastole were visually selected from CINE CMRs. Each slice was non-rigidly registered to estimate LV deformation during passive filling. Deformation was simulated on a finite element mesh of the LV based on linear elastic transverse isotropic mechanical equilibrium. Using an inverse problem formulation, simulated deformation was compared to model-calculated deformation to estimate the spatial tissue longitudinal and transverse elasticity. Elasticity maps of the LV at initial and final points are compared to determine regional stiffening of the LV wall, to be used as early biomarkers for LV fibrosis. ResultsIn this initial investigation, elasticity maps were analyzed for four patients (n=2 from each cohort). Passive LV tissue stiffening was observed in each AI patient, with 100% and 25% relative increases observed for longitudinal elasticity and 50% increases for transverse elasticity in the basal inferior region, and mid anterior region of the LV in each patient, respectively. No increases in stiffness of the LV were observed for TNBC patients. Ejection fraction remained consistent for all patients. ConclusionIn this proof-of-concept study, we demonstrate that elasticity maps indicate local stiffening of the LV using a biomechanical model-based elasticity imaging method that could be used to indicate cardiac dysfunction in breast cancer patients receiving AIs. Spatial elasticity mapping allows direct observation of structural mechanics to reveal specific areas of LV stiffening. Moving beyond traditional strain imaging, our method yields a functional measure of tissue stiffness to directly indicate cardiac fibrosis. This study demonstrates the use of biomechanical models to interpret CMR and provides potential for use of more advanced constitutive models. Our non-invasive biomechanical model-based elasticity imaging method shows significant promise to indicate early cardiac function deterioration, critical for premenopausal women undergoing extended cancer therapies. Citation Format: Caroline Elizabeth Miller, Jennifer Jordan, Alexandra Thomas, Jared Weis. Predicting cardiac dysfunction in breast cancer patients undergoing aromatase inhibitor treatment using biomechanical model-based elasticity imaging [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-21.

Introduction Pathological formation of fibrosis, is an important feature in many diseases. Fibrosis in liver and pancreas has been associated to metabolic disease including type 1 and 2 diabetes. The current methods for detecting and diagnosing fibrosis are either invasive, or their sensitivity to detect fibrosis in early stage is limited. Therefore, it is crucial to develop non-invasive methods to detect, stage and study the molecular processes that drive the pathology of liver fibrosis. The peptide LRELHLNNN was previously identified as a selective binder to collagen type I with an affinity of 170 nM. Radiolabelled LRELHLNNN thus constitute a potential PET tracer for fibrosis. Method LRELHLNNN was conjugated to a DOTA/NOTA moiety via a PEG2-linker. DOTA-PEG2-LRELHLNNN was labelled with Gallium-68 and NOTA- PEG2-LRELHLNNN with aluminium fluoride-18. Biodistribution of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN was performed in healthy rats ex vivo and in vivo. The 68Ga-labelled analogue was evaluated in a mouse model of liver fibrosis by PET/MRI-imaging. The human predicted dosimetry of the tracers was extrapolated from rat ex vivo biodistribution studies at 10, 20, 40, 60, 120, 180 min (only fluoride-18) post-injection. Results The peptides were successfully radiolabelled with gallium-68 and aluminium fluoride-18, respectively. The biodistribution of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN was favorable showing rapid clearance and low background binding in organs where fibrosis may develop. Binding of [68Ga]Ga-DOTA-PEG2-LRELHLNNN to fibrotic liver was higher than surrounding tissues in mice with induced hepatic fibrosis. However, the binding was in the range of SUV 0.3, indicating limited targeting of the tracer to liver. The extrapolated human predicted dosimetric profiles of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN were beneficial, potentially allowing at least three PET examinations annually. Conclusions We describe the modification, radiolabelling and evaluation of the collagen type I binding peptide LRELHLNNN. The resulting radiotracer analogues demonstrated suitable biodistribution and dosimetry. [68Ga]Ga-DOTA-PEG2-LRELHLNNN exhibited binding to hepatic fibrotic lesions and is a promising tool for PET imaging of fibrosis. Advances in knowledge Validation of a new collagen targeting PET tracer. Implications for patient care Early, non-invasive diagnosis and stratification of fibrosis in order to improve the diagnosis, staging and treatment of patients with diseases involving fibrosis.

The thymus prevents autoimmune diseases through mechanisms that operate in the cortex and medulla, comprising positive and negative selection and the generation of regulatory T-cells (Tregs). Egress from the thymus through the perivascular space (PVS) to the blood is another possible checkpoint, as shown by some autoimmune/immunodeficiency syndromes. In polygenic autoimmune diseases, subtle thymic dysfunctions may compound genetic, hormonal and environmental cues. Here, we cover (a) tolerance-inducing cell types, whether thymic epithelial or tuft cells, or dendritic, B- or thymic myoid cells; (b) tolerance-inducing mechanisms and their failure in relation to thymic anatomic compartments, and with special emphasis on human monogenic and polygenic autoimmune diseases and the related thymic pathologies, if known; (c) polymorphisms and mutations of tolerance-related genes with an impact on positive selection (e.g. the gene encoding the thymoproteasome-specific subunit, PSMB11), promiscuous gene expression (e.g. AIRE, PRKDC, FEZF2, CHD4), Treg development (e.g. SATB1, FOXP3), T-cell migration (e.g. TAGAP) and egress from the thymus (e.g. MTS1, CORO1A); (d) myasthenia gravis as the prototypic outcome of an inflamed or disordered neoplastic ‘sick thymus’.

Transforming growth factor-beta (TGFβ) is a highly potent immunosuppressive cytokine. Although TGFβ is a tumor suppressor in early/premalignant cancer lesions, the cytokine has several tumor-promoting effects in advanced cancer; abrogation of the antitumor immune response is one of the most important tumor-promoting effects. As several immunoregulatory mechanisms have recently been shown to be targets of specific T cells, we hypothesized that TGFβ is targeted by naturally occurring specific T cells and thus could be a potential target for immunomodulatory cancer vaccination. Hence, we tested healthy donor and cancer patient T cells for spontaneous T-cell responses specifically targeting 38 20-mer epitopes derived from TGFβ1. We identified numerous CD4(+) and CD8(+) T-cell responses against several epitopes in TGFβ. Additionally, several ex vivo responses were identified. By enriching specific T cells from different donors, we produced highly specific cultures specific to several TGFβ-derived epitopes. Cytotoxic CD8(+) T-cell clones specific for both a 20-mer epitope and a 9-mer HLA-A2 restricted killed epitope peptide were pulsed in HLA-A2(+) target cells and killed the HLA-A2(+) cancer cell lines THP-1 and UKE-1. Additionally, stimulation of THP-1 cancer cells with cytokines that increased TGFβ expression increased the fraction of killed cells. In conclusion, we have shown that healthy donors and cancer patients harbor CD4(+) and CD8(+) T cells specific for TGFβ-derived epitopes and that cytotoxic T cells with specificity toward TGFβ-derived epitopes are able to recognize and kill cancer cell lines in a TGFβ-dependent manner.

Background: Diet modification has the potential to influence glycemic control and diabetes outcome in patients with type 1 diabetes (T1D). This cross-sectional study aimed to assess types of diets being reported by patients with T1D and documented in the Diabetes Patients Follow-Up Registry (DPV). Methods: The DPV registry was screened for additional free text entries containing information about certain diets and/or physician-based diagnoses requiring special diets e. g. celiac disease. Descriptive analysis and unadjusted comparisons between patients with T1D following at least one special diet and controls (T1D without diet) were performed. Results: Overall, 113,894 patients with T1D of all ages were included. In 2.3% (n = 2,595; median age 11.3 yrs [Q1; Q3: 7.0; 15.2]), at least one kind of diet was documented. These patients were significantly younger at diabetes onset than controls (median age 7.5 yrs [Q1; Q3: 3.9; 11.4] vs. 11.1 yrs [6.6; 16.7]; p < 0.001) and showed a significantly lower BMI-SDS (median [Q1; Q3]: 0.220 [−0.427;0.812] vs. 0.450 [−0.211;1.088]). Diet was more often reported in females (55.7% vs. 44.3%, p < 0.001). The three most common diets were gluten-free diet due to celiac disease, low-protein diet, and lactose-restricted diet due to lactoseintolerance. A combination of two diagnoses in one patient (n = 44, 1.7% of the entire diet group) was predominantly intolerance to both fructose and lactose. Among all diet subgroups the highest BMI-SDS was found in the group diets for weight loss. Conclusions: This study revealed a wide range of eating habits in patients with T1D. A special diet was more frequently documented in females. The main reason for adhering to a diet was a concomitant disease. As any diet modification could impact glycemic control, health care providers should be encouraged to regularly ask their patients about their eating habits and provide training and support by specialized dietitians.

The use of surgical meshes to reinforce damaged internal soft tissues has been instrumental for successful hernia surgery; a highly prevalent condition affecting yearly more than 20 million patients worldwide. Intraperitoneal adhesions between meshes and viscera are one of the most threatening complications, often implying reoperation or side effects such as chronic pain and bowel perforation. Despite recent advances in the optimization of mesh porous structure, incorporation of anti-adherent coatings or new approaches in the mesh fixation systems, clinicians and manufacturers are still pursuing an optimal material to improve the clinical outcomes at a cost-effective ratio. Here, bacterial nanocellulose (BNC), a bio-based polymer, is evaluated as a soft tissue reinforcement material regarding mechanical properties and in vivo anti-adhesive performance. A double-layer BNC laminate proved sufficient to meet the standards of mechanical resistance for abdominal hernia reinforcement meshes. BNC-polypropylene (BNC-PP) composites incorporating a commercial mesh have also been prepared. The in vivo study of implanted BNC patches in a rabbit model demonstrated excellent anti-adherent characteristics of this natural nanofibrous polymer 21-days after implantation and the animals were asymptomatic after the surgery. BNC emerges as a novel and versatile hernioplasty biomaterial with outstanding mechanical and anti-adherent characteristics., Authors acknowledge financial support from the Spanish Ministry of Science and Innovation through the RTI2018-096273-B-I00 project, the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (CEX2019-000917-S) and the Generalitat de Catalunya 2017SGR765 grant. Authors are also grateful for the PhD scholarships of I. A-S. (BE-2017-076734) and S. R-S. (BES-2016-077533) and the 2019LLAV00046 project. The ICMAB members participate in the CSIC Interdisciplinary Platform for Sustainable Plastics towards a Circular Economy, SUSPLAST, and in the Aerogels COST ACTION (CA 18125). This work has been performed within the framework of the doctoral program in materials science of UAB (I. A-S. and S. R-S.). We acknowledge the support by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI) to cover the publication fee.

Introduction: Immunosuppressive therapies increase risk of infections 2-fold when compared to naive individuals; however, an observational study found that only 4% of patients with psoriasis who were on or planned to start immunosuppressive therapy were immunized with pneumococcus. Factors positively influencing vaccination uptake include having vaccines available same day in clinic and education about vaccines. Negative influences include no recommendation from the treating clinician and no insurance. Failure to vaccinate occurs by overlooking indication and an uncertainty as to who is responsible for vaccination. Since the early 2000’s, vaccinations have been offered in pharmacies. This could result in additional confusion regarding vaccination responsibility. As a result of not being immunized, patients on immunosuppressive medications experience higher rates of preventable infections. We observed that many of our patients’ immunizations were incomplete and sought to increase immunization uptake through a quality improvement (QI) project beginning in Fall 2019. We evaluated the project’s approach of providing education with immediate onsite immunization availability relative to standard care to determine if vaccination uptake per CDC guidelines can be increased. Methods: We compared acceptance of CDC recommended pneumococcal immunization for patients on immunosuppressive therapy who were and were not subject to the QI project at the 2 urban dermatology clinics. Patients in the comparison group were under the care of other dermatologists. All patients in the QI group were educated on benefits of immunizations and offered immediate immunizations. Those who had never received the PCV13 or PPSV23 were defined as unimmunized. Patients who had received either vaccination were partially immunized. Patients who received both were completely immunized. We collected demographics and immunization status for all patients. Using Stata 14.2 [StataCorp, College Station, TX], we compared immunization status at baseline and final observations for patients in the QI and comparison groups using a multivariable ordered logit model, and used multiple logistic regression to examine receipt of a vaccination within the QI group. Results: The QI (N=146) and comparison groups (N=55) did not differ significantly on sociodemographic or clinical characteristics, including baseline immunization. After adjusting for patient characteristics, baseline immunization rates for fully, partially, and unimmunized patients were 9.2%, 28.7%, and 62.1% for the comparison group and 7.7%, 26.1%, and 66.3% for the QI group, respectively. Immunization statuses within the comparison group did not change over time, but at final observation 40.6%, 43.2%, and 16.1% of the QI group were fully, partially, and unimmunized, respectively (Table 1; p

Thymomas exhibit a unique genomic landscape, comprising the lowest on average total mutational burden among adult human cancers; a unique point mutation in the GTF2I gene in WHO type A and AB thymomas (and rarely others); almost unique KMT2A-MAML2 translocations in rare WHO type B2 and B3 thymomas; a unique YAP1-MAML2 translocation in almost all metaplastic thymomas; and unique miRNA profiles in relation to GTF2I mutational status and WHO histotypes. While most thymomas can be diagnosed solely on the basis of morphological features, mutational analyses can solve challenging differential diagnostic problems. No molecular biomarkers have been identified that predict the response of unresectable thymomas to chemotherapy or agents with known molecular targets. Despite the common and strong expression of PDL1 in thymomas, immune checkpoint inhibitors are rarely applicable due to the poor predictability of common, life-threatening autoimmune side effects that are related to the unrivaled propensity of thymomas towards autoimmunity.

This commentary describes the transition to remote delivery of cognitive-behavioral therapy (CBT) for anxiety in children with autism spectrum disorder (ASD) who participates in a clinical trial during the COVID-19 pandemic. The effects of COVID-19 on children’s anxiety and on the family functioning are discussed. Modifications to CBT necessitated by telehealth delivery were aimed at maximizing engagement of children and their parents while maintaining treatment fidelity and adhering to the research protocol. Treatment targets were updated to address new sources of anxiety and CBT exposure exercises were modified to accommodate the new reality of quarantine restrictions. If the COVID-19 pandemic continues to affect treatment delivery it may require a widespread utilization of telehealth for treating anxiety in children with ASD. Supplementary information The online version of this article (10.1007/s10803-020-04845-1) contains supplementary material, which is available to authorized users.

Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα–treated patients not attaining CHR (P = .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment.

Cognitive impairment after a stroke has a direct impact on patients’ disability. In particular, impairment of Executive Functions (EFs) interferes with re-adaptation to daily life. The aim of this study was to explore whether adding a computer-based training on EFs to an ordinary rehabilitation program, regardless of the specific brain damage and clinical impairment (motor, language, or cognitive), could improve rehabilitation outcomes in patients with stroke. An EF training was designed to have minimal motor and expressive language demands and to be applied to a wide range of clinical conditions. A total of 37 stroke patients were randomly assigned to two groups: a training group, which performed the EF training in addition to the ordinary rehabilitation program (treatment as usual), and a control group, which performed the ordinary rehabilitation exclusively. Both groups were assessed before and after the rehabilitation program on neuropsychological tests covering multiple cognitive domains, and on functional scales (Barthel index, Functional Independence Measure). The results showed that only patients who received the training improved their scores on the Attentional Matrices and Phonemic Fluency tests after the rehabilitation program. Moreover, they showed a greater functional improvement in the Barthel scale as well. These results suggest that combining an EF training with an ordinary rehabilitation program potentiates beneficial effects of the latter, especially in promoting independence in activities of daily living.

Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p =.0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.

Purpose Diagnosis and classification of primary progressive aphasia (PPA) requires confirmation of specific speech and language symptoms, highlighting the important role of speech-language pathologists in the evaluation process. The purpose of this case report is to inform speech-language pathologists regarding current practices for diagnostic assessment in PPA, describing standard approaches as well as complementary, state-of-the-art procedures that may improve diagnostic precision. Method We describe the diagnostic evaluation of a 49-year-old woman with complaints of progressive word-finding difficulty. She completed standard neurological, neuropsychological, and speech-language evaluations, as well as magnetic resonance and positron emission tomography imaging of her brain. In addition, a history of developmental speech, language, and learning abilities was obtained, as well as genetic testing and assessment of cerebrospinal fluid biomarkers. We discuss the evaluation results in the context of the most current research related to PPA diagnosis. Conclusion Detailed behavioral assessment, thorough intake of symptom history and neurodevelopmental differences, multimodal neuroimaging, and comprehensive examination of genes and biomarkers are of paramount importance for detecting and characterizing PPA, with ramifications for early behavioral and/or pharmacological intervention. Supplemental Material https://doi.org/10.23641/asha.12771113

Background Herpes simplex virus type 1 (HSV-1) is frequently detected in the BAL fluid of patients on mechanical ventilation. Research Question The aim of the study was to investigate whether antiviral therapy is associated with improved overall survival within 30 days. Study Design and Methods This was a retrospective cohort study in four ICUs between January 2011 and December 2017. All adult patients on mechanical ventilation with a respiratory tract infection with positive polymerase chain reaction testing for HSV-1 in the BAL were included. Patients already receiving antiviral agents on the day BAL was performed were excluded. We performed uni- and multivariable Cox and logistic regression modeling. Results Overall, 306 patients were included in the analysis. Among them, 177 patients (57.8%) received antiviral therapy (90.9% acyclovir, 6.2% ganciclovir, 2.9% both). The overall 30-day mortality rate was 42.4% (n = 75) in the antiviral treatment group and 50.4% (n = 65) in the control group. The adjusted hazard ratio (HR) for the primary outcome was 0.62 (95% CI, 0.44-0.87; P = .005), indicating better overall survival within 30 days for the antiviral-treated group than for the untreated group. This benefit was also present in the subgroup of patients without immunosuppression (n = 246; adjusted HR, 0.53; 95% CI, 0.36-0.78; P = .001). Overall, the median lengths of hospital stay (31 vs 24 days, P = .002) and ICU stay (24 vs 17 days, P Interpretation These data suggest that detection of HSV-1 in the BAL of patients on mechanical ventilation may be of clinical significance and that specific antiviral treatment may improve clinical outcomes. However, this needs to be proven in multicenter randomized controlled trials before implementation into the clinical routine.

Antibiotic resistance is a part of bacterial evolution and therefore unavoidable. Scarcity of novel treatment options requires prudent use of available antibiotics in order to decelerate the spread of resistance. This is the aim of antibiotic stewardship (ABS) programmes. The implementation of strategies that optimize antibiotic prescription and therapy necessitates the deployment of personnel as well as of structural resources. Necessary requirements for staff and strategies based on their evidence are described in the updated German S3 ABS Guideline. In the future, patients with infectious diseases will benefit from accelerated microbiological diagnostics as early adequate treatment not only reduces antibiotic consumption but also improves patient outcome. In addition, training of infectious disease specialists will substantially contribute to enhanced quality of care of patients with infectious disease.

Our aim was to explore change in kyphosis and vertebral fracture incidence following 8 months of high-intensity resistance and impact training (HiRIT) or machine-based isometric axial compression (IAC) training in men with osteopenia and osteoporosis. HiRIT and IAC improved posture. HiRIT participants did not experience progression or incident vertebral fracture. IAC participants did experience progression and incident vertebral fracture. The Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation for Men (LIFTMOR-M) trial examined efficacy and safety of an eight-month, supervised, high-intensity progressive resistance and impact training (HiRIT) program compared with machine-based isometric axial compression (IAC) training in middle-aged and older men with low areal bone mineral density (aBMD). The primary purpose of the current work was to explore change in thoracic kyphosis and incident fracture from vertebral morphology following eight-months of HiRIT or IAC training. The secondary purpose was to explore change in clinical kyphosis measures for HiRIT, IAC and a non-randomized, matched control group. Men (≥ 45 yrs), with low aBMD, were recruited and randomized to HiRIT or IAC, or designated control. Clinical measures of thoracic kyphosis with inclinometry were determined. Cobb angle of kyphosis and vertebral fracture assessment using the Genant semi-quantitative method were determined from lateral thoracolumbar DXA (Medix DR, Medilink, France). Per-protocol (n = 40) and intention-to-treat (n = 93) analyses were conducted. Forty participants (HiRIT n = 20, IAC n = 20; 66.1 ± 7.8 yrs.; lumbar spine T-score − 0.1 ± 0.8; femoral neck T-score − 1.5 ± 0.5) underwent clinical kyphosis measures and thoracolumbar DXA at baseline and follow-up. No between-group differences were detected in kyphosis change, however, within-group improvements in neutral (HiRIT − 2.3 ± 0.8°; IAC − 2.5 ± 0.8°) and ‘standing tall’ (HiRIT − 2.4 ± 0.8°; IAC − 2.0 ± 0.8°) postures were observed (p

This paper presents the results of a qualitative study designed to explore and identify the resources that probation officers need to implement specialized mental health probation caseloads, a promising practice that enhances mental health treatment engagement and reduces recidivism among people with mental illnesses. Our research team conducted a directed content analysis guided by the Practical, Robust Implementation and Sustainability Model (PRISM) to analyze qualitative interviews with 16 specialty mental health probation officers and their supervising chiefs. Results indicated five components and resources related to multiple PRISM constructs: (1) meaningfully reduced caseload sizes (intervention design), (2) officers’ ability to build rapport and individualize probation (organizational staff characteristics), (3) specialized training that is offered regularly (implementation and sustainability infrastructure), (4) regular case staffing and consultation (implementation and sustainability infrastructure), and (5) communication and collaboration with community-based providers (external environment). Agencies implementing specialized mental health probation approaches should pay particular attention to selecting officers and chiefs and establishing the infrastructure to implement and sustain specialty mental health probation.

Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.

Purpose: To report the outcomes of bypass grafting (BG) vs endovascular therapy (EVT) in patients with non-dialysis-dependent chronic kidney disease (CKD) and chronic limb-threatening ischemia (CLTI). Materials and Methods: The CRITISCH Registry is a prospective, national, interdisciplinary, multicenter registry evaluating the current practice of all available treatment options in 1200 consecutive CLTI patients. For the purposes of this analysis, only the 337 patients with non-dialysis-dependent CKD treated by either BG (n=86; median 78 years, 48 men) or EVT (n=251; median age 80 years, 135 men) were analyzed. The primary composite outcome was amputation-free survival (AFS); secondary outcomes were overall survival (OS) and amputation-free time (AFT). All outcomes were evaluated in Cox proportional hazards models; the results are reported as the hazard ratio (HR) and 95% confidence interval (CI). Results: The Cox regression analysis revealed a significantly greater hazard of amputation or death after BG (HR 1.78, 95% CI 1.05 to 3.03, p=0.028). The models for AFT and overall survival also suggested a higher hazard for BG, but the differences were not significant (AFT: HR 1.66, 95% CI 0.78 to 3.53, p=0.188; OS: HR 1.41, 95% CI 0.80 to 2.47, p=0.348). The absence of runoff vessels (HR 1.73, 95% CI 1.15 to 2.60, p=0.008) was associated with a decreased AFS. The likelihood of amputation was higher in male patients (HR 2.21, 95% CI 1.10 to 4.45, p=0.027) and was associated with a lack of runoff vessels (HR 1.95, 95% CI 0.96 to 3.95, p=0.065) and myocardial infarction (HR 3.74, 95% CI 1.23 to 11.35, p=0.020). Death was more likely in patients without runoff vessels (HR 1.76, 95% CI 1.11 to 2.80, p=0.016) and those with a higher risk score (HR 1.73, 95% CI 1.03 to 2.91, p=0.038). Conclusion: This analysis suggested that BG was associated with poorer AFS than EVT in patients with non-dialysis-dependent CKD and CLTI. Male sex, previous myocardial infarction, and the absence of runoff vessels were additionally identified as predictors of poorer outcomes.

Uveal melanoma size is a significant predictor of tumor metastasis. Although the relationship between antivascular endothelial growth factors (VEGF) and uveal melanoma growth has been studied, results are paradoxical, and the relationship remains controversial. We report the case of a 65-year-old man who presented with elevated intraocular pressure in his right eye, neovascularization of his iris, and significant corneal edema, which obscured the view of the angle. Given his history of proliferative diabetic retinopathy, he was diagnosed with neovascular glaucoma and subsequently received an intravitreal injection of bevacizumab and underwent Ahmed valve insertion. This was complicated by postoperative hyphema. Two and a half months postoperatively, a mass involving the inferior iris and ciliary body became visible, and fine-needle aspiration biopsy confirmed uveal melanoma. Seven weeks after diagnosis, the tumor’s largest basal diameter had increased from 2.51 mm to 18.0 mm, and apical height increased from 6.23 mm to 11.0 mm. His right eye was enucleated. Histopathological analysis showed discontinuous invasion next to the Ahmed valve. Tumor progression after injection raises the possibility that in some untreated uveal melanomas, accelerated growth may occur following exposure to anti-VEGF agents.

Objective Prostate cancer is the most common cancer in German men and associated with various physical and psychosocial problems. This study investigated the association between mental distress and the subjective need for psychosocial support comparing subgroups of patients with different treatments and disease stages. Method We performed an observational, cross-sectional study including patients with four medical conditions: Active Surveillance, radical prostatectomy, biochemical relapse, metastasized disease. Mental distress (NCCN Distress-Thermometer), symptoms of depression and anxiety (PHQ-9, GAD-7), psychosocial needs and coping resources (self-designed questionnaire) were assessed. Results N = 130 patients were included. 33.3% showed distress, 16.5% symptoms of moderate depression and 13% symptoms of moderate anxiety. We found no significant differences between the four groups. An association was present between distress and wish for psychosocial support ( χ2 = 4.3; p Conclusions Prostate cancer patients showed low levels of mental distress, depression and anxiety with no difference in terms of disease stage and treatment modality. Therefore, careful psychosocial screening of all patients is essential to identify those in need for support. Distressed patients express a need for psychosocial support more often. Interpersonal relationships, most often wives and children, represent important coping resources.

We report the final 2-year end-of-study results from the first clinical trial investigating combination treatment with ruxolitinib and low-dose pegylated interferon-alpha 2 (PEG-IFN alpha 2). The study included 32 patients with polycythemia vera and 18 with primary or secondary myelofibrosis; 46 patients were previously intolerant of or refractory to PEG-IFN alpha 2. The primary outcome was efficacy, based on hematologic parameters, quality of life measurements, and JAK2 V617F allele burden. We used the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria, including response in symptoms, splenomegaly, peripheral blood counts, and bone marrow. Of 32 patients with polycythemia vera, ten (31%) achieved a remission which was a complete remission in three (9%) cases. Of 18 patients with myelofibrosis, eight (44%) achieved a remission; five (28%) were complete remissions. The cumulative incidence of peripheral blood count remission was 0.85 and 0.75 for patients with polycythemia vera and myelofibrosis, respectively. The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score decreased from 22 [95% confidence interval (95% CI):, 16-29] at baseline to 15 (95% CI: 10-22) after 2 years. The median JAK2 V617F allele burden decreased from 47% (95% CI: 33-61%) to 12% (95% CI: 6-22%), and 41% of patients achieved a molecular response. The drop-out rate was 6% among patients with polycythemia vera and 32% among those with myelofibrosis. Of 36 patients previously intolerant of PEG-IFN alpha 2, 31 (86%) completed the study, and 24 (67%) of these received PEG-IFN alpha 2 throughout the study. In conclusion, combination treatment improved cell counts, reduced bone marrow cellularity and fibrosis, decreased JAK2 V617F burden, and reduced symptom burden with acceptable toxicity in several patients with polycythemia vera or myelofibrosis. #EudraCT2013-003295-12.

Background: We aimed to analyze preferred and perceived levels of patients’ involvement in treatment decision-making in a representative sample of cancer patients.Material and Methods: We conducted...

Significance Sepsis remains a leading cause of death. New insights into its pathophysiology are likely to be key to the development of effective therapeutic strategies against sepsis. Given the role of GDF15 in metabolism regulation and in cachexia during late stages of cancer, features that also occur in sepsis, elucidation of the possible mechanistic role of GDF15 in sepsis is of great importance. We find that septic patients have very high levels of GDF15 in the peripheral blood, which correlate with clinical outcomes. Using Gdf15-deficient mice, we show that GDF15 plays a causal role in sepsis by delaying the local control of infection. These findings suggest GDF15 as a potential therapeutic target in sepsis secondary to a bacterial infection., Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth and differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15, and that Gdf15-deficient mice are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum, leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.

Current diagnostic methods for the diagnosis of Cystic fibrosis (CF)-associated liver disease (CFLD) are non-specific and assessment of disease progression is difficult prior to the advent of advanced disease with portal hypertension. This study investigated the potential of Supersonic shear-wave elastography (SSWE) to non-invasively detect CFLD and assess hepatic fibrosis severity in children with CF.125 children were enrolled in this study including CFLD (n = 55), CF patients with no evidence of liver disease (CFnoLD = 41) and controls (n = 29). CFLD was diagnosed using clinical, biochemical and imaging best-practice guidelines. Advanced CFLD was established by the presence of portal hypertension and/or macronodular cirrhosis on ultrasound. Liver stiffness measurements (LSM) were acquired using SSWE and diagnostic performance for CFLD detection was evaluated alone or combined with aspartate aminotransferase-to-platelet ratio index (APRI).LSM was significantly higher in CFLD (8.1 kPa, IQR = 6.7-11.9) versus CFnoLD (6.2 kPa, IQR = 5.6-7.0; P 0.0001) and Controls (5.3 kPa, IQR = 4.9-5.8; P 0.0001). LSM was also increased in CFnoLD versus Controls (P = 0.0192). Receiver Operating Characteristic (ROC) curve analysis demonstrated good diagnostic accuracy for LSM in detecting CFLD using a cut-off = 6.85 kPa with an AUC = 0.79 (Sensitivity = 75%, Specificity = 71%, P 0.0001). APRI also discriminated CFLD (AUC = 0.74, P = 0.004). Classification and regression tree modelling combining LSM + APRI showed 14.8 times greater odds of accurately predicting CFLD (AUC = 0.84). The diagnostic accuracy of SSWE for discriminating advanced disease was excellent with a cut-off = 9.05 kPa (AUC = 0.95; P 0.0001).SSWE-determined LSM shows good diagnostic accuracy in detecting CFLD in children, which was improved when combined with APRI. SSWE alone discriminates advanced CFLD.

Objective The purpose of this study was to determine the point prevalence of low back pain (LBP), pelvic girdle pain (PGP), and/or combination pain (COMBO pain) and period prevalence (presence or absence of any of those pains), as well as to identify risk factors at 1, 3, and 6 months postpartum in a Canadian population. Methods Participants from a previous pregnancy study participated in a postpartum survey administered over the telephone at 1, 3, and 6 months following delivery. The survey included questions about LBP, PGP, or COMBO pain during the postpartum period, as well as questions related to risk factors (Canadian Task Force Classification II-3). Results At 1, 3, and 6 months postpartum, responses from 46, 58, and 64 participants, respectively, demonstrated that 15%–21% of women experienced LBP and up to 4% of women experienced COMBO pain (point prevalence). At no time point was PGP reported to occur alone. Period prevalence of back pain for the participants returned to pre-pregnancy levels at each time point. Back pain during pregnancy was the only risk factor identified for back pain at 3 and 6 months postpartum. Conclusion This study demonstrated that 76% to 80% of respondents were pain free at 1, 3, and 6 months postpartum. Pregnancy-related back pain was the only risk factor associated with postpartum-related pain at the 1 to 3 and 3 to 6 month time interval. Identification of site-specific postpartum-related back pain may assist in determination of management and treatment plans for this population.

The Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation for Men (LIFTMOR-M) trial examined efficacy and safety of two novel exercise programs in older men with low BMD. Men with low hip and/or LS BMD were randomized to high-intensity progressive resistance and impact training (HiRIT) or machine-based isometric axial compression (IAC) and compared to a nonrandomized matched control (CON). Outcomes included: hip and LS BMD; calcaneal ultrasound parameters; anthropometry; body composition; function (timed up-and-go [TUG], five-times sit-to-stand [FTSTS]); back extensor strength (BES); leg extensor strength (LES); compliance and adverse events. Ninety-three men (67.1 ± 7.5 years; 82.1 ± 11.6 kg; 175.2 ± 6.7 cm; FN T-score -1.6 ± 0.6) were randomized to HiRIT (n = 34) or IAC (n = 33), or allocated to CON (n = 26). HiRIT improved trochanteric BMD (2.8 ± 0.8%; -0.1 ± 0.9%, p = .024), LS BMD (4.1 ± 0.7%; 0.9 ± 0.8%, p = .003), BUA (2.2 ± 0.7%; -0.8 ± 0.9%, p = .009), stiffness index (1.6 ± 0.9%; -2.0 ± 1.1%, p = .011), lean mass (1.5 ± 0.8%; -2.4 ± 0.9%, p = .002), TUG, FTSTS, BES, and LES (p < .05) compared with CON. IAC improved lean mass (0.8 ± 0.8%; -2.4 ± 0.9%, p = .013) and FTSTS (-4.5 ± 1.6%; 7.5 ± 2.0%, p < .001) compared with CON. HiRIT improved LS BMD (4.1 ± 0.7%; 2.0 ± 0.7%, p = .039), stiffness index (1.6 ± 0.9%; -1.3 ± 0.9%, p = .025), and FTSTS (-10.7 ± 1.6%; -4.5 ± 1.7%, p = .010) compared with IAC. Exercise compliance was high (HiRIT 77.8 ± 16.6%; IAC 78.5 ± 14.8%, p = .872). There were five minor adverse events (HiRIT, 2; IAC, 3). HiRIT was well-tolerated and improved bone, function and fracture risk more than CON or IAC. © 2020 American Society for Bone and Mineral Research.

Elevated levels of serum ferritin (SF) are observed in several types of cancer; however, little is known on the association between ferritin and glioma, the most frequent type of human primary brain tumour. Here we report that GBM patients show significantly increased pre-surgical SF levels (i.e. ferritinaemia) within the SF reference range and a marked ferritin immunoreactivity of resected tumour tissue. Our findings account for an indirect association between ferritin synthesis in glioma-tissue and altered SF levels, which limits the clinical value of SF as a tumour marker in glioma. Importantly, we show for the first time that GBM-derived glioma cells release ferritin in vitro, which exerts an apoptosis-stimulating activity. Albeit the pathophysiologic context of apoptosis induction by a tumour-derived ferritin remains to be defined, our findings account for a distinct growth-regulatory role of these ferritin species in tumour biology.